EuroBioForum2014_speaker_Manolio

Teri Manolio Director, Office for Population Genomics,

National Human Genome Institute (NHGRI),

USA

Perspective from a Global Leader

Applying Genomics to Clinical

Care: The Global Genomic

Medicine Collaborative (G2MC) National Human

Genome Research

Institute

National

Institutes of

Health

U.S. Department

of Health and

Human Services

U.S. Department of Health and Human Services

National Institutes of Health

National Human Genome Research Institute

Teri Manolio, M.D., Ph.D.

EuroBioForum Personalised Medicine 2014

September 22, 2014

Sunrise in Washington DC

http://iqdc.com/pics/sunrise.jpg

Discovery

Research

Clinical

Validation

Clinical

Implementation

Assess genotype-

phenotype associations

Assess outcomes after

using genetics to direct

therapy

Develop processes for

performing genetic testing

and using results in care

• Identify persons at

increased risk of disease

based on their genetic

variants

• Assess impact on health

outcomes and care

utilization of reporting

genomic findings

• Develop clinical

informatics systems for

reporting genomic results

and decision support

• Find all variants related

to given phenotype or

disease

• Identify causes of rare or

undiagnosed diseases

• Educate clinicians and

patients in clinical use of

genomic results

• Characterize variation in

genes known to be

related to disease or

treatment response

• Validate drug targets and

develop improved

therapeutic agents

• Define and disseminate

information on actionable

clinical variants and

relevant evidence base

Spectrum of Disease-Related Genomics Research

NHGRI Genomic Medicine Meetings

http://www.genome.gov/27549225 or google “NHGRI Genomic Medicine”

http://www.genome.gov/27549225

http://www.genome.gov/27549225

Genomic Medicine Colloquium, June 2011

GM II: Forming Collaborations, Dec 2011

GM III: Stakeholders, May 2012

GM IV: Physician Education, Jan 2013

GM V: Federal Strategies, May 2013

GM VI: Global Leaders, Jan 2014

GM VII: Genomic CDS, Oct 2-3, 2014

50 International Genomic Medicine Leaders

25 Countries

Courtesy,G Ginsburg, Duke U

Global Leaders International Attendees

• Canada (CIHR, GenomeCan)

• UK (MRC, WT, Genom Engl)

• Belgium (U Brux, U Leuven)

• Estonia (Eston Genom Ctr)

• France (INSERM)

• Greece (U Patras)

• Luxembourg (Ctr Syst Biomed)

• Sweden (Swed Res Council)

• European Commission

• Israel (Hadassah U, Clalit Med)

• Kuwait (Kuwait U)

• Saudi Arabia (Pr Salman Ctr)

• Tunisia (Tunis U)

• India (Min Sci Tech, Natl Inst

Biomed Genomics)

• Sri Lanka (U Colombo)

• China (Chinese Acad Med Sci)

• Japan (U Tokyo, Ctr Integ

Med, Min Science)

• Korea (NIH Kor, Seoul Natl U)

• Singapore (National U)

• Thailand (Mahidol U, Min Hlth)

• Australia (MRC)

• New Zealand (Natl Hlth Cmte)

Objectives of GMVI: Global Leaders in Genomic Medicine

• Identify areas of active translation and

implementation

• Prioritize common barriers to implementation

in healthcare

• Frame a policy agenda to advance the field

• Highlight nations with unique capabilities

• Discuss opportunities for international

collaborations

Plethora of Genomics Implementation Efforts

• UK: Genomics England to sequence 100K whole genomes and link to NHS medical record

• Japan: Implementation of Genomic Medicine Project including genomic prediction of drug response, efficacy and cost-effectiveness studies

• Estonia: proposed project for personal medicine

• Thailand: PGx card identifying risk for top ten SJS-TEN drugs, clinical exomes and genomes

Belgian Medical Genomics Initiative A national plan for exomes

12

To create the best possible framework for exome sequencing in a clinical context

Courtesy M Abramowicz, Hôpital Erasme, Université Libre de Bruxelles

1st degree family history of breast cancer reported in Israeli National Mammo Program

11.4

17.2

9.6

14.2

4.8

8

3.2

6.8

0

2

4

6

8

10

12

14

16

18

%

Jews (n=812100) Christian Arabs (n=14363) Moslem Arabs (n=61068) Druze (n=7136)

Mammo no cancer (n=1,008,421)

Mammo with cancer (n=39,895)

OR=1.62

(1.57-1.67)

OR=1.55

(1.18-2.03)

OR=1.71

(1.38-2.11)

OR=2.22

(1.11-4.41)

Courtesy G Rennert, Clalit Health Services, Haifa

Courtesy R Balling, Luxembourg Centre for Systems Biomedicine.

The EuroPGx project

McLeod et al., in preparation, 2014; Dalabira et al., in preparation (2014)

European populations display significant differences in

>130 pharmacogenomic biomarkers each.

Replication of these findings in larger population

samples to establish common grounds for

pharmacogenomic testing in developing countries.

Courtesy G Patrinos, U Patras.

www.hgucolombo.org

Only Medical Genetics Center in Sri Lanka Provide Clinical /Diagnostic Genetic Services, Provide Undergraduate and Postgraduate Training,

and Conduct Research by it self and in collaboration with academic and the private sector both nationally and internationally

Serving a Population of 20.1 Million People

Courtesy V Dissanyake,

U Colombo

Bench to Bedside in a Developing Country: Sri Lanka

Singapore: Stromal Corneal Dystrophies

and TGFBI Testing

• Inherited disorders leading to loss of corneal transparency.

• TGFBI mutations underlie the majority of stromal corneal dystrophies.

Screening of family

members

Disease Diagnosis

Treatment Selection for

Patients TGFBI Testing

Clinical Utility

Courtesy P Tan, Duke-Natl U Singapore

Approved at the Estonian Government Research and Development Council on 17.12.2013.

- Health care

- Educating health care professionals

- Educating the patients

- Further development of eHealth including decision support systems

- Research and Development

- Sequencing 5,000 individuals, Estonian Chip and analysis software

- International collaboration

- Commercialization

- Business agreements

- IPR

Proposed Estonian Program for Personal Medicine

Courtesy A Metspalu, U Tartu

Estonian Program: Research and Development


PILOT PROJECT

- Sequence 5,000 – assay SNV up to 0.1%

- Estonian chip – ca 0.7 – 1.0 million SNVs

- Pilot with 50,000 gene donors from the Estonian Biobank during one year using PCP, eHealth database, and decision support software

MAIN PROJECT

- Offer to everyone 35-65 years old as a disease risk and drug response prediction test (75-80% will accept)

- Estimate ca 500,000 people in the database with EMR, genotypes, samples and longitudinal prescription data

This system could be used as a additional “instrument” for physicians in diagnosing, treating and preventing disease, but also for research.

Virtuous Cycle of

Clinical Decision Support

Measure

Guideline

CDS

Practice

Registry

http://www2.eerp.usp.br/Nepien/DisponibilizarArquivos/tomada_de_decis%C3%A3o.pdf




Evidence Generating Medicine

• The next step beyond evidence-based

medicine

• The systematic incorporation of research

and quality improvement considerations into

the organization and practice of healthcare

• To advance biomedical science and thereby

improve the health of individuals and

populations.


Partly supported by

Genomic Medicine in Thailand

Courtesy W Chantratita, Ramathibodi Hospital

High Incidence of SJS/TEN in Thailand


Carbamazepine: SJS/TEN

B*1502 Carbamazepine and SJS/TEN: Allele

Frequency of HLA-B*15:02


Name & Family

Name

Outcome of the PGX

assay

PGx Interpretation

8 Jan 2014

High Risk of SJS/TEN from

Carbamazepine, according

to update information

Suggestion: According to

update information, this person

has HLA-B*1502 which has a

high risk to develop a severe

skin disorder (SJS/TEN), if he

takes carbamazepine or drug

structurally similar.

Need more information: please

contact our PGx laboratory.

Tel 02-200-4330-3… Signature of molecular

clinical pharmacist. Courtesy W Chantratita

Cost Effectiveness Analysis

• Incremental cost-effectiveness ratio of universal HLA-B*15:02 screening estimated at 222,000 THB ($6,660)/ QALY gained for epilepsy pts; 130,000 THB/QALY for neuropathic pain pts

• Test 343 patients to prevent one case of SJS/TEN

Courtesy S Mahasirimongkol, Ministry of Public Health

National Academy of Sciences Bldg

2101 Constitution Avenue, NW

Washington, DC

Opportunities for International Collaboration

• Bioinformatics/Health IT

• Education

• Evidence Generation

• Pharmacogenomics

• Policy

G2MC

Goals of the Global Genomic Medicine Collaborative (G2MC)

An international genomic medicine community hosted by the Institute of Medicine and formed to:

• Serve as nexus, clearinghouse, and knowledge base for GM activities globally

• Develop opportunities for global GM demonstration projects (implementation and outcomes research)

• Capture and disseminate best practices for GM (IT, education, evidence, Pgx, policy) across the global GM community

• Develop a financial model for sustained efforts

G2MC Steering Committee Geoff Ginsburg (US), Robyn Ward (Australia)

Marc Abramowicz Belgium

Fahd Al-Mulla Kuwait

Adam Berger US

Steve Bleyl US

Wasun Chantratita Thailand

Vajira Dissanayake Sri Lanka

Thierry Frebourg France

Anne Kolbe New Zealand

John Wong Singapore

Bruce Korf US

Michiaki Kubo Japan

Erkki Leego Estonia

Teri Manolio US

Gert Matthijs Belgium

Yaakov Naparstek Israel

Irene Norstedt Belgium

George P. Patrinos Greece

Gad Rennert Israel

G2MC Bioinformatics/Health IT Working Group Steve Bleyl (US), Erkki Leego (Estonia)

Goal

Adopt (or develop) and implement standards for storing individual, discrete, coded genomic features as transmitted from labs for databases or EHRs

Use Case

Copy number variant transmitted from lab and stored as discrete features in EHR, containing all pertinent data (patient identifiers, test indication, chromosomal anomalies, actionability, array used)

Collaboration with GA4GH

Define requirements for a global database of clinically actionable variants

G2MC Pharmacogenetics Working Group Wasun Chantratita (Thailand), George Patrinos (Greece)

Goal: implement broad program internationally to eradicate preventable SJS/TEN using PGx assays

• Biorepository for identifying additional markers, modifiers, recurrence risk, non-genetic factors

• Pharmacy practice guidelines for preventing recurrence

• Health economic and cost-effectiveness analyses

• In vitro diagnostic tests for causative drugs

• Clinical trials of treatment

G2MC Policy Working Group Anne Kolbe (New Zealand), Yaakov Naparstek (Israel)

Goal: assess and address needs of health technology assessors, regulators, industry, policy writers, funders and decision makers including governments

• Identify major issues facing health and social services sectors in next 5, 10 and 15 years, based on global burden of disease

• Determine genomic/epigenetic applications currently available and those in R&D pipeline (gap analysis)

• Bring fit-for-purpose genomic technologies into routine adoption quickly and efficiently

• Map research and R&D activities and investments, gaps

• Work with industry and regulators to bring technologies into effective use

What are the next big questions in genomic medicine implementation?

• Can it be done: accuracy, turnaround (warfarin genotyping) burden

• Is it interpretable:

• Can experts interpret it: VUS, penetrance

• Can clinicians interpret it: education and CDS

• Is it actionable: treatment, family at risk

• Does it cause harm: anxiety, unnecessary procedures, diversion of resources

• Can we learn from it: learning healthcare systems

• Does it work (help patients), does it reduce cost

50 International Genomic Medicine Leaders

40 US Genomic Leaders and NHGRI Staff

Larson, G. The Complete Far Side. 2003.

“The prospect of

using the genome as a

universal diagnostic is

upon us today.”

Richard Resnick

Genetically Inherited Diseases

NGS Cancer Panels; Targeted

PGD/PGS

Prenatal Dx based on NGS

Newborn Screening based on NGS

MGC: 5Year

project plan for

2013-2017

Viral Deep Sequencing to Detect Emerging Drug Resistance (HIV, HBV, HCV)

Unknown Pathogen, Emerging and Re emerging infectious

Noninvasive Prenatal Diagnosis Using NGS

Courtesy R Balling, Luxembourg Centre for Systems Biomedicine.

Incidence of SJS/TEN in Thailand,

1984-2013

0

200

400

600

800

1000

1200

1400

1600 1984-1

993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

ไมร่ะบเุพศ M F Unknown


• Current capacity for genomic medicine is small for a country the size of Thailand, need training and capacity building

• Thailand is moderate in size with unique genetic diversity and Universal Health Coverage (UHC)

• Any technology proven to be cost effective can be considered in the UHC package

• SJS/TEN PGx study is unique in having direct access to Thai FDA and being incorporated in the pharmacovigilance program

Unique Aspects of Thai Genomic Medicine


Top Ideas in Five Key Areas

• IT/bioinformatics

• Define key elements to be stored in EMR

• Identify most robust and generalizable solutions for potential wider adoption

• Global resource for actionable variants

• Education:

• Define workforce needs

• Develop existing/new educational tools that can be widely shared

• Develop region-specific teaching materials, perhaps common templates

Five Break-out Groups’ Top Ideas

• Evidence Generation

• Catalog evidence-generating projects

• Identify poolable/extendable projects

• Develop systems to capture evidence; federated network, standardized APIs (e-tools)

• Pharmacogenomics

• Global eradication of SJS/TEN

• PGx card

• Policy

• Share efforts in consent, results reporting

• Study economics, cost-effectiveness

Economic Evaluation • Cost-effectiveness and cost-utility analyses of various

genetic-based medical treatments by reducing the

incidence of adverse drug reactions, and reciprocally

healthcare expenditure at the national level.

Current projects focus on anticoagulation treatment of

warfarin (Croatia), acenocoumarol (Serbia, Greece) and

clopidogrel (Serbia) and nicotine addiction treatment

(Greece).

• Endorsement of the production of the textbook “Economic

Evaluation in Genomic Medicine” by Elsevier/Academic

Press in early 2015.

Courtesy G Patrinos, U Patras.

• Stevens-Johnson syndrome (SJS) is a rare in

other countries, but not in Thailand.

• In Thailand, we interviewed many who survived

SJS/TEN

– They felt that their bodies were burning and

that someone had poured acid into their eyes

– The pain was so extreme that they wish to

die, but they could not

• Eradication of SJS/TEN in Thailand is a priority

for our Thai medical genomics team

A Fate Worse than Death



Stevens-Johnson Syndrome, HLA-B*15:02, and Carbamazepine

Chung et al., Nature 2004;428:486.

N Engl J Med. 2011;364:1134-43.

Clin Pharm Therap 2012;92:757-65. “Clinicians must determine if a patient has ancestry

across broad areas of Asia. This requires clinicians

to know what ‘Asian ancestry’ means and use a

consistent, reliable method to figure out which

patients have this ancestry.”

CAUTION: This patient carries the HLA-

B*15:02 allele, a known risk factor for

carbamazepine-induced SJS in persons

of Asian ancestry…

Date post:	22-May-2015
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EuroBioForum2014_speaker_Manolio

Health & Medicine