43
CSER: VENI, VIDI , AND A ROADMAP TO VICI Integrating Genomic Sequencing into Clinical Care: CSER and Beyond September 28, 2015
CSER VENI VIDI AND A ROADMAP TO VICI Integrating Genomic Sequencing into Clinical Care CSER and Beyond
September 28 2015
WHAT IS CSER
CSER Consortium Range of Issues bull Technology
Generate and interpret genomic sequence data in a variety of clinical contexts
bull Clinical Care Study the challenges of integrating comprehensive sequence data into patient care
bull Outcomes amp ELSI examine the implications of bringing genomic sequence data into the clinic
Consortium Organization
CSER Study Populations
377 Researchers21 Institutions1 Consortium
Amendola et13 al13 Per Med (2015) 12(3)283-shy‐29513
Study Diversity
Observational (Cases Only) vs Randomized Trial (Cases amp Controls) Adult vs Pediatric
ParticipantsPatients vs Clinicians Individuals vs FamiliesTrios
Germline Only vs Germline + Tumor Exome vs Genome
List-Guided (Candidate) Approach vs Unguided (Agnostic) Approach Genetics experts return results vs Non-experts return results
WHAT HAS CSER LEARNED SO FAR
Major Accomplishments
bull Generating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
2015 CSER Variant ldquobake-offrdquo Inter-shy‐laboratory13 Concordance13 of 98 variants13
Coun
t13
Range o Classifications13
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
WHAT IS CSER
CSER Consortium Range of Issues bull Technology
Generate and interpret genomic sequence data in a variety of clinical contexts
bull Clinical Care Study the challenges of integrating comprehensive sequence data into patient care
bull Outcomes amp ELSI examine the implications of bringing genomic sequence data into the clinic
Consortium Organization
CSER Study Populations
377 Researchers21 Institutions1 Consortium
Amendola et13 al13 Per Med (2015) 12(3)283-shy‐29513
Study Diversity
Observational (Cases Only) vs Randomized Trial (Cases amp Controls) Adult vs Pediatric
ParticipantsPatients vs Clinicians Individuals vs FamiliesTrios
Germline Only vs Germline + Tumor Exome vs Genome
List-Guided (Candidate) Approach vs Unguided (Agnostic) Approach Genetics experts return results vs Non-experts return results
WHAT HAS CSER LEARNED SO FAR
Major Accomplishments
bull Generating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
2015 CSER Variant ldquobake-offrdquo Inter-shy‐laboratory13 Concordance13 of 98 variants13
Coun
t13
Range o Classifications13
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
CSER Consortium Range of Issues bull Technology
Generate and interpret genomic sequence data in a variety of clinical contexts
bull Clinical Care Study the challenges of integrating comprehensive sequence data into patient care
bull Outcomes amp ELSI examine the implications of bringing genomic sequence data into the clinic
Consortium Organization
CSER Study Populations
377 Researchers21 Institutions1 Consortium
Amendola et13 al13 Per Med (2015) 12(3)283-shy‐29513
Study Diversity
Observational (Cases Only) vs Randomized Trial (Cases amp Controls) Adult vs Pediatric
ParticipantsPatients vs Clinicians Individuals vs FamiliesTrios
Germline Only vs Germline + Tumor Exome vs Genome
List-Guided (Candidate) Approach vs Unguided (Agnostic) Approach Genetics experts return results vs Non-experts return results
WHAT HAS CSER LEARNED SO FAR
Major Accomplishments
bull Generating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
2015 CSER Variant ldquobake-offrdquo Inter-shy‐laboratory13 Concordance13 of 98 variants13
Coun
t13
Range o Classifications13
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Consortium Organization
CSER Study Populations
377 Researchers21 Institutions1 Consortium
Amendola et13 al13 Per Med (2015) 12(3)283-shy‐29513
Study Diversity
Observational (Cases Only) vs Randomized Trial (Cases amp Controls) Adult vs Pediatric
ParticipantsPatients vs Clinicians Individuals vs FamiliesTrios
Germline Only vs Germline + Tumor Exome vs Genome
List-Guided (Candidate) Approach vs Unguided (Agnostic) Approach Genetics experts return results vs Non-experts return results
WHAT HAS CSER LEARNED SO FAR
Major Accomplishments
bull Generating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
2015 CSER Variant ldquobake-offrdquo Inter-shy‐laboratory13 Concordance13 of 98 variants13
Coun
t13
Range o Classifications13
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
CSER Study Populations
377 Researchers21 Institutions1 Consortium
Amendola et13 al13 Per Med (2015) 12(3)283-shy‐29513
Study Diversity
Observational (Cases Only) vs Randomized Trial (Cases amp Controls) Adult vs Pediatric
ParticipantsPatients vs Clinicians Individuals vs FamiliesTrios
Germline Only vs Germline + Tumor Exome vs Genome
List-Guided (Candidate) Approach vs Unguided (Agnostic) Approach Genetics experts return results vs Non-experts return results
WHAT HAS CSER LEARNED SO FAR
Major Accomplishments
bull Generating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
2015 CSER Variant ldquobake-offrdquo Inter-shy‐laboratory13 Concordance13 of 98 variants13
Coun
t13
Range o Classifications13
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Study Diversity
Observational (Cases Only) vs Randomized Trial (Cases amp Controls) Adult vs Pediatric
ParticipantsPatients vs Clinicians Individuals vs FamiliesTrios
Germline Only vs Germline + Tumor Exome vs Genome
List-Guided (Candidate) Approach vs Unguided (Agnostic) Approach Genetics experts return results vs Non-experts return results
WHAT HAS CSER LEARNED SO FAR
Major Accomplishments
bull Generating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
2015 CSER Variant ldquobake-offrdquo Inter-shy‐laboratory13 Concordance13 of 98 variants13
Coun
t13
Range o Classifications13
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
WHAT HAS CSER LEARNED SO FAR
Major Accomplishments
bull Generating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
2015 CSER Variant ldquobake-offrdquo Inter-shy‐laboratory13 Concordance13 of 98 variants13
Coun
t13
Range o Classifications13
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Major Accomplishments
bull Generating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
2015 CSER Variant ldquobake-offrdquo Inter-shy‐laboratory13 Concordance13 of 98 variants13
Coun
t13
Range o Classifications13
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
bull Contributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
2015 CSER Variant ldquobake-offrdquo Inter-shy‐laboratory13 Concordance13 of 98 variants13
Coun
t13
Range o Classifications13
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
2015 CSER Variant ldquobake-offrdquo Inter-shy‐laboratory13 Concordance13 of 98 variants13
Coun
t13
Range o Classifications13
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
2015 CSER Variant ldquobake-offrdquo Variant with major disagreement Why
SPG7c1529CgtT (pAla510Val)bull Present in 04 (26766688) of European
chromosomes (ExAC)13 bull Associated with late-shy‐onset +-shy‐ reducedACMG13
Classification13 penetrance spastic paraplegia
Laboratory13 ACMG Rules PP3 PS313 PM3 PP1 PS113 PS413 PP5 PM2 BS1 PP2 PP4Pathogenic PathogenicPathogenic PathogenicPathogenic PathogenicPathogenic Pathogenic
X X X X XX X X X X XX X X X X X
X XLikely Path Likely Path X X X X X X
X X XVUS13 Likely Path Likely Path
PathogenicLikely Benign13 VUS13
X X X XLaboratoryX X X XClassification13 VUS13 VUS13 X X X
Jarvik et al ASHG13 201513 Poster13 1896F
Actionability amp Return of ResultsWG
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Cross-platform comparison
Sequencing Standards WG
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Yield (Germline) of subjects with ge 1 finding
(median of variants reported) Clinical Characteristics
Sample Size P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1) DDID Syndromic IDAutism 392 18 (1) 12 (1) 05 (15) 13 (2)
Other 45 16 (1) 18 (1) 67 (2) 0 Cardiovascular
Cardiomyopathy 103 26 (1) 27 (1) 0 10 (1) Other 55 18 (1) 53 (2) 0 18 (1)
Ophthalmology 73 42 (1) 18 (1) 82 (1) 0 All Other 254 16 (1) 23 (1) 11 (1) 28 (1) Characteristics
Single13 recessive13 means the individual has one copy of a recessive mutation in a gene related to the phenotype
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Cancer Yield (Germline) of subjects with ge 1 finding
(median of variants reported)
Cancer Ascertainment SampleSize P or LP VUS Single
Recessive Other
Cancer (all) 1111 61(1) 35 (1) 23 (1) 05 (1)
Pediatric CNS Solid Tumor 106 66 (1) 71 (3) 94 (1) 0
Non-CNS Solid Tumor 201 11(1) 72 (3) 50 (1) 0
Leukemia 29 34 (1) 41 (1) 0 0
Cancer Lung 122 16 (1) 33 (1) 0 0
Breast 69 87 (1) 45 (1) 14 (1) 0
Colorectal 97 10 (1) 93 (1) 0 0
Other 229 66 (1) 35 (1) 13 (1) 0
Hereditary Cancer CRCP-Related Risk 133 45 (1) 16 (2) 08 (1) 0
BreastOvarian 82 24 (1) 1 (1) 0 61 (1)
Other 43 12 (1) 93 (1) 0 0
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Other Findings (Germline)
Data as of August 15 201513
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Benefits of Sequencing in Childhood Cancer (Tumor + Germline)
102 refractory relapsed or high risk pediatric or young adult cases
(solid tumors brain tumors hematology malignancies)
89 had adequate tissue
46 had potentially actionable findings
In 25 treatment team changed management
10 achieved partialcompleteremission gt6 mo
10 family screening
Mody et al JAMA 2015314(9)913-shy‐925
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Approaches to ROR
Genet Med (2015)PMID13 26270767
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Case studies
Amendola et13 al13 Per Med (2015)12(3)283-shy‐295
Genetic Counseling13 WG
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Case Study Example bull 36 yo diagnosed at 6
with ldquohereditary spastic paraplegiardquo bull Confined to crutches
and wheelchair for decades
bull Painful episodes ofspasticity on daily basis 5 surgeries
bull GCH1 [pArg216]diagnosis of dopa-responsive dystonia
bull Dramatic response bull Walking without
crutches free ofpainful daily symptoms Photos courtesy of Jim Evans and permission of patient
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Cost analyses utilization studies
Vassy et al Impact of genome sequencing on the medical care ofhealthy adults ASHG13 201513 Platform 256F
Dukhovny et al Short-shy‐term costs of integrating genome sequencinginto clinical care ASHG13 201513 Platform 257F
Himes et al Economic impact of genome sequencing for13 preconception carrier13 screening ASHG13 201513 Platform 130Th
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Psychosocial amp Behavioral Outcomes
Outcomes ampMeasuresWGGray et alGenet Med 2014 16(10)727-shy‐ 73513
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Normative amp Legal Analyses
Pediatrics WG amp U amp R Award sites
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Major Accomplishments
uumlGenerating new evidence for the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines
bull Development of infrastructure methods resources amp tools
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Professional Guidelines Genet Med 2013 15(7)565-shy‐574AcknowledgementsMargaret Adam Jeffrey BotkinWendyChung David Dimmock Christine Eng MadhuriHegde Gail Jarvik Stephen Kingsmore Michael MurrayKatherine Nathanson Sharon Plon Reed Pyeritz CherylReidV Reid Sutton and BenjaminWilfond
Genet Med 201513 17(5)405-shy‐424
Genet Med 201313 15(9)733-shy‐747
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Responses to the ACMG guidelineshellip
Genet Med 2013
rdquoThe recommendations represent an initial attempt to set aprofessional13 standard13 for13 best laboratory13 practiceshelliprdquo
Science 2013 340(6136)1049-shy‐50Science 201313 340(6136)1047-shy‐4813
rdquoAutonomy protects the patientrsquos right to make a decisiondifferent from what the clinician might chooserdquo
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Major Accomplishments
uumlContributions to the Evidence Base bull Analytic validity bull Clinical validity bull Clinical utility bull Ethical legal regulatory amp social issues
uumlContributions to Professional Guidelines uumlDevelopment of infrastructure methods resources amp
tools
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Major Accomplishments
PDevelopment of infrastructure methods resources amp tools
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent forms bull Clinical reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
SharingResources amp Knowledge
bull Publications bull Presentations bull Consultations bull Federal
Databases bull Online
postings
Impact onClinical Services
bull Internal Sites bull External Sites bull Other
Research Studies
bull Commercial Labs
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Slide courtesy of Dan Robinson
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Genet Med 201315(11) 860-shy‐867
Actionability amp Return of ResultsWG
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Dominant ACTA2a
ACTC1 ACVRL1
APC BMPR1A BRCA1 BRCA2
CACNA1C CACNA1S CACNB2 CDC73 CDH1 CNBP
COL3A1 DMPK DSC2 DSG2 DSP ENG
EPCAM FBN1
FH FLCN GCH1 GPD1L HCN4 HMBS KCNE1 KCNE2
KCNE3 KCNH2 KCNJ2 KCNQ1
KIT LDLR LMNA MAX MEN1 MET
MLH1 MLH3 MSH2 MSH6
MUTYH MYBPC3 MYH11 MYH7 MYL2 MYL3 MYLK NF2
PDGFRA PKP2 PLN
PMS2 PRKAG2
PRKAR1A PROC PROS1 PTCH1
PTEN RBM20
RET RYR1 RYR2
SCN1B SCN3B SCN5A
SDHAF2 SDHB SDHC SDHD
SERPINC1 SGCD
SMAD3 SMAD4
SMARCB1 STK11 TGFB2 TGFB3
TGFBR1 TGFBR2
TMEM127 TMEM43
TNNI3 TNNT2 TP53 TPM1 TSC1 TSC2 VHL
X-Linked DMD EMD GLA OTC
Recessive ATP7B BCHE BLM
CASQ2 COQ2 COQ9 CPT2 F5b
GAA HAMP HFEb
HFE2 IDUA
LDLRAP1 PAH
PCBD1 PTS
QDPR SERPINA1 SLC25A13 SLC37A4 SLC7A9
wwwgenomegov27560596
=112 Total Genes
Amendola et al 201513 Genome13 Res 25(3)305-shy‐1513
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Consent13 Forms
J Law Med Ethics 2014 42(3)344-shy‐55
201513 17(8)644-shy‐50
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
Informed Consent13 amp Governance WG
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Examples
Vassy et al Public HealthGenomics13 201513 18(2)123-shy‐9
McLaughlin et al BMCMedGenet 2014 15134
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
cser-shy‐consortiumorgcser-shy‐research-shy‐materials
ReportTemplates
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Examples
JAMIA 201513 PMID13 26142422
Genet Med 201313 1513 (10)824-shy‐ 832
Electronic13 Health RecordsWG
Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
CSER has13 1149 dbGaP submissionsCSER is one of the top submitters to ClinVar
Submitter Total Submissions with Assertions
OMIM 25994 GeneDx 19618 Emory Genetics Lab 15983 ISCA (all sites) 14438 Lab for Molecular Medicine 12207 Ambry Genetics 9995 Genetic Services Lab U Chicago 7147 Invitae 1949 GeneReviews 3928 CSER (all sites) 2617
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Examples Development
bull Analytic pipelines
bull Return of results committees
bull Gene Lists bull Consent
forms bull Clinical
reports bull EHR
integration bull dbGaP amp
ClinVar deposits
bull Tools
iexcl MEG (MEdicineGeneAnnotation)13 the official13 CSERvariant database httpsredcapithsorg
iexcl TARGET (TumorAlterations Relevant for GEnomic-shy‐driveTherapy)13 database13 of13 genes that13 when somaticallyaltered in cancer are directly linked to a clinical actionhttpwwwbroadinstituteorgcancercgatarget
iexcl PHIAL13 (Precisio Heuristics13 for13 Interpreting13 the13 Alteration Landscape)13 heuristic algorithm for13 clinicalinterpretation of cancer13 genome sequencing datahttpwwwbroadinstituteorgcancercgaphial
iexcl Cassandra combines annovar13 output with other13 publicdata sources to output annotated vcf fileshttpswwwhgscbcmedusoftwarecassandra
iexcl Atlas13 2 Suite of variant analysis toolshttpswwwhgscbcmedusoftwareatlas-shy‐2
iexcl Proband app for13 taking family history pedigreeshttpprobandappcom
iexcl Interactive13 Graphic13 Sequencin i Clinical Practice aNEJM interactive graphic on clinical genome and exomesequencing13 httpwwwnejmorgactionshowMediaPlayer doi=101056NEJMra1312543ampaid
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Impact These sites endorse the following statement
ldquoThe knowledge shared from the CSER consortium has influenced andaccelerated our plans and implementation of clinical sequencingrdquo
bull Other Research Studies bull Internal Organizations bull BabySeq (NSIGHT) bull OHSU Molecular Genetic Diagnostic Lab
Services bull ClinGen bull Broad Institute CLIA Sequencing Lab bull eMERGE sites (BrighamMGHChildrenrsquos bull Laboratory for Molecular Medicine Clinical Hospital)
Services bull eMERGE site (CHOP)
bull Individualized Medical Genetics Center bull NC NEXUS (NSIGHT) (CHOP) bull Prostate Cancer FoundationStand Up 2 bull Clinical Genetics Think Tank (International
Cancer International Dream Team Collaboration) bull NCIChildrenrsquos Oncology Group Trial bull External Organizations bull pedsNet (PCORI) bull One-on-one consultations with major
pediatric oncology institutions bull Cerner EPIC IOM Roundtable bull Vidant Cardiology
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
LOOKING AHEAD ONGOING WORK IN THE CSER CONSORTIUM UNTIL JUNE 2017
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
CSER Consortium-wide Efforts Topic Lea Site(s)
Clinician bake-shy‐off13
Combined outcomes13
Compare approaches tocarrier13 results reporting
Impact of13 changing13 the13 interpretation of findings
Secondary findings acrossthe consortium
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
CSER Site-specific Questions
- How effective are the genomic educational programs - How should ROR visits be structured - What are patient preferences and expectations - How well were preferences and expectations met
- What are the downstream healthcare costs
- What are the long-term psychosocial impacts - Are patients satisfied with result delivery - Do patients understand results and genetic concepts
- What is the impact of providing clinical decision support - What is the impact on care delivery - How are results used by patientsclinicians
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Summary
bull Yield differs by clinical indicationbull Incidental finding rate is lowbull Need better13 ways to consistently classify variantsbull Providing an evidence base amp resolving obstaclest genomic13 medicine
bull Whenbull Best practicesbull What do all those variants mean
bull Integration with ELSI work amp regulatory analysesbull How best to approach informed consentbull Managing pediatric resultsbull Impact of results disclosure
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
LOOKING TO THE FUTURE WHAT QUESTIONS WILL REMAIN
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Future Directions Todayrsquos Agenda Topic CSER Consortium
Recommended Priority Areas Interpreting VariantsActionability
Assessing Clinical Utility
Patient-Centered Research
Increasing Diversity
Healthcare utilization economics amp value
Other
bull Clinical diagnosis of unsolved cases bull Determination of appropriate use of
genome amp exome sequencing bull Conduct biopsychosocial research bull Continue ELSI investigations bull Investigate the use of clinical sequencing
in larger more diverse populations bull Evaluation of downstream health and
economic outcomes bull Optimization of the delivery system bull Iterative phenotyping
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
Acknowledgements Baylor College of Sharon Plon amp13
Will Parsons13 Boston Childrenrsquos Ingrid Holm13 Medicine13Robert Green HospitaBrigham ampWomenrsquos
Hospital Columbia University Paul Appelbaum13
NHGRI ClinSeq Study Leslie Biesecker13 13Wendy Chung
Childrenrsquos Mercy Jeremy GarreDIan Krantz amp13
13 Childrenrsquos Hospital ofPhiladelphia
HospitaNancy Spinner13 Johns Hopkins Michelle Lewis13
University13 Mayo Clinic Rich Sharp13
Dana-shy‐Farber Cancer Levi Garraway amp13 13Pasi JanneInsEtute
HudsonAlpha InsEtuteKaiser Permanente
University of MichiganUniversity13 of North13 CarolinaUniversity13 of Washington13
CoordinaEng13 Center13 (UW)
Richard Myers13
Katrina Goddard amp Ben Wilfond13
Arul Chinnaiyan13
Jim Evans13
Gail Jarvik13
13 Gail Jarvik13
SeaGle ChildrenrsquosHospitalUCSF Mayo Collegeof Medicine ampUniversity13 ofMinnesota
Vanderbilt ampMcGill University
Holly Tabor13
Barbara Koenig 13 Gloria Petersen amp Susan Wolf13
Ellen Clayton amp13 Bartha Knoppers13
13Wylie BurkeDebbie Nickerson13
13Peter Tarczy-shy‐HornochNCI NHGRI
