Personal Genomes and Social/Ethical/Legal Issues

02-­‐223  Personalized  Medicine:  

Understanding  Your  Own  Genome  Fall  2014  

Declining Cost of Genome Sequencing

•  The  genome  sequencing  is  expected  to  happen  rouEnely  in  the  near  future    

The  era  of  big  data:  the  genome  data  are  already  being  collected  in  a  large  scale  and  being  mined  for  scien1fic  discovery  to  drive  more  accurate  descripEve  and  predicEve  models  that  inform  decision  making  for  the  best  diagnosis  and  treatment  choice  for  a  given  paEent.    

Schadt,  MSB,  2012  

Personal Genomes and Social/Ethical/Legal Issues

•  How  can  we  balance  the  need  for  scienEfic  research  and  the  need  to  protect  individuals?  

Privacy and Big Data Mining

•  A  Face  Is  Exposed  for  AOL  Searcher  No.  4417749  –  Search  keywords  lead  to  idenEficaEon  of  the  individual,  Thelma  

Arnold,  a  62-­‐year-­‐old  widow  who  lives  in  Lilburn,  Ga.  

•  Numb  fingers  •  60  single  men  

•  Dog  that  urinates  on  everything  •  homes  sold  in  shadow  lake  subdivision  gwinne[  county  georgia.  

h[p://www.nyEmes.com/2006/08/09/technology/09aol.html?_r=0  

Privacy and Big Data Mining

•  Credit  cards  and  privacy?  

•  Social  network  service  (and  other  internet  service)  and  privacy?  

•  Genomes  and  privacy?  

PERSONAL GENOMES AND PRIVACY

Would  you  post  your  genome  on  the  web?  

Privacy and Watson’s Genome

•  Watson’s  genome  available  except  for  ApoE  gene  status  –  ApoE  gene  sequence  is  a  strong  predictor  of  late  onset  Alzheimer’s  

disease  

–  Watson  did  not  want  to  know  the  sequence  ApoE  gene  

Genomes and Privacy

•  DNA  sequence  data  contain  informaEon  that  can  be  used  to  uniquely  idenEfy  an  individual  (i.e.,  genome  sequences  are  like  fingerprints)  

•  Balancing  the  need  for  scienEfic  study  and  privacy  

Genomes and Privacy

•  Privacy  concerns  –  Genome  sequence  data  and  other  related  types  of  data  (gene  

expressions,  clinical  records,  epigeneEc  data,  etc.)  are  collected  for  a  large  number  of  paEents  for  medical  research  

–  Most  types  of  data  are  freely  available  through  internet  except  for  genotype  data    

•  NCBI  GEO  database  for  gene  expression  data  –  Genotype  data  are  available  to  scienEsts  through  restricted  access  

(NIH  dbGAP)  

The Cancer Genome Atlas (TCGA) Data

Access Control for TCGA Data

•  Open  access  data  Eer  –  De-­‐idenEfied  clinical  and  demographic  data  –  Gene  expression  data  –  Copy-­‐number  alteraEons  in  regions  of  the  genome  –  EpigeneEc  data  –  Summaries  of  data,  such  as  genotype  frequencies,  compiled  across  

individuals  

•  Controlled-­‐access  data  Eer  –  Individual  germline  variant  data  –  DNA  sequence  data  –  One  should  apply  for  an  access  to  the  data  through  NIH  (database  of  

genotypes  and  phenotypes)  

Genomes and Privacy

•  How  much  should  we  be  concerned  about  the  privacy  issues  regarding  personal  genome  data?  

•  Non-­‐geneEc  data  can  be  used  to  predict  the  genotypes  of  individuals  (Bayesian  method  to  predict  individual  SNP  genotypes  from  gene  expression  data,  Schadt  et  al.  Nature  GeneEcs,  2012)  

–  Uses  gene  expressions  as  non-­‐geneEc  data  and  predicts  the  genotypes  based  on  the  gene  expressions  

Predicting Genotypes with Non-Genetic Data (Schadt et al., 2012)

•  Study  design  –  Learn  a  predicEve  model  for  predicEng  genotypes  given  gene  

expression  data  from  training  set  

–  Use  the  learned  predicEve  model  to  test  whether  genotype  can  be  predicted  correctly  given  gene  expression  from  test  set  

Predicting Genotypes with Non-Genetic Data (Schadt et al., 2012)

•  Two  datasets  from  non-­‐overlapping  groups  of  individuals  –  the  human  liver  cohort  (HLC):  liver  gene  expression  and  genotype  data  

for  378  European-­‐  American  individuals    

–  Roux-­‐en-­‐Y  gastric  bypass  cohort  (RYGB):  genotype  data  and  expression  data  for  liver  and  adipose  Essue  from  580  European-­‐American  subjects  undergoing  Roux-­‐en-­‐Y  gastric  bypass  (RYGB)  

•  Learn  model  from  HLC  data  (training  set)  and  predict  RYGB  genotypes  given  RYGB  expressions  (test  set)  

Predicting Genotypes from Gene Expressions

•  Leh  semicircle:  observed  genotypes  

•  Right  semicircle:  predicted  genotype  

•  Blue  line:  correctly  matched  individuals  

•  White  line:  incorrectly  matched  individuals  

Predicting Genotypes from Gene Expressions

•  Leh  semicircle:  observed  genotypes  

•  Right  semicircle:  predicted  genotype  

•  Blue  line:  correctly  matched  individuals  

•  White  line:  incorrectly  matched  individuals  

•  Overall,  we  can  resolve  99%      of  the  idenEEes  of  individuals  

Privacy and Watson’s Genome

•  Watson’s  genome  available  except  for  ApoE  gene  status  –  ApoE  gene  and  late  onset  Alzheimer’s  disease  

•  GeneEc  informaEon  is  hard  to  hide.  Why?  –  Linkage  disequilibrium!  

On  Jim  Watson's  APOE  status:  geneEc  informaEon  is  hard  to  hide  Eur  J  Hum  Genet.  Feb  2009;  17(2):  147–149  

Personal Genome Project (www.personalgenomes.org)

•  Volunteers  from  the  general  public  working  together  with  researchers  to  advance  personal  genomics  

•  Aims  to  sequence  genomes  of  100,000  individuals  from  the  general  public  

•  Volunteers  should  be  willing  to  make  their  geneEc  and  trait  informaEon  publicly  available    

PROTECTING RESEARCH PARTICIPANTS

Informed Consent for Scientific Research

•  Standard  pracEce  for  enrolling  human  subjects  in  a  research  study    –  fully  informing  potenEal  parEcipants  on  all  aspects  of  a  study  including  

the  aims  of  the  study,  risks,  benefits,  costs,  and  protecEon  of  personal  privacy  

–  The  origins  of  modern  day  informed  consent  for  medical  research  can  be  traced  to  the  Nuremberg  Code  in  1947  in  an  effort  to  protect  parEcipants  in  research  studies  (Homan,  1991).    

Nuremberg Code

•  Research  ethics  principles  for  human  experimentaEon    

•  Established  aher  the  Nuremberg  Trials  at  the  end  of  the  Second  World  War  

h[p://www.hhs.gov/ohrp/archive/nurcode.html  

Nuremberg Code •  On  August  19,  1947,  the  judges  of  the  American  military  tribunal  in  the  case  of  the  USA  

vs.  Karl  Brandt  et.  al.  delivered  their  verdict.  Before  announcing  the  guilt  or  innocence  of  each  defendant,  they  confronted  the  difficult  quesEon  of  medical  experimentaEon  on  human  beings.  Several  German  doctors  had  argued  in  their  own  defense  that  their  experiments  differed  li[le  from  previous  American  or  German  ones.  Furthermore,  they  showed  that  no  internaEonal  law  or  informal  statement  differenEated  between  legal  and  illegal  human  experimentaEon.    

•  On  April  17,  1947,  American  doctors  who  had  worked  with  the  prosecuEon  during  the  trial  submi[ed  a  memorandum  to  the  United  States  Counsel  for  War  Crimes  which  outlined  six  points  defining  legiEmate  research.    

•  The  verdict  of  August  19  reiterated  almost  all  of  these  points  in  a  secEon  enEtled  "Permissible  Medical  Experiments”,  which  became  known  as  the  "Nuremberg  Code."    

•  Although  the  code  addressed  the  defense  arguments  in  general,  remarkably  none  of  the  specific  findings  against  Brandt  and  his  codefendants  menEoned  the  code.  Thus  the  legal  force  of  the  document  was  not  well  established.    

•  The  uncertain  use  of  the  code  conEnued  in  the  half  century  following  the  trial  when  it  informed  numerous  internaEonal  ethics  statements  but  failed  to  find  a  place  in  either  the  American  or  German  naEonal  law  codes.    

•  Nevertheless,  it  remains  a  landmark  document  on  medical  ethics  and  one  of  the  most  lasEng  products  of  the  "Doctors  Trial."  

h[p://www.ushmm.org/informaEon/exhibiEons/online-­‐features/special-­‐focus/doctors-­‐trial/nuremberg-­‐code  

Nuremberg Code

•  Nuremberg  Code  says  –  The  consent  of  individual  is  required  –  The  experiment  should  be  based  on  the  results  of  animal  experiment  –  Should  not  result  in  injury  or  suffering  of  the  parEcipants  

Institutional Review Board (IRB)

•  A  commi[ee  that  has  been  formally  designated  to  approve,  monitor,  and  review  biomedical  and  behavioral  research  involving  humans  

•  Title  45  Code  of  Federal  RegulaEons  Part  46  –  h[p://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html  

•  Requires  consent  of  research  parEcipants/subjects  

Current Generation Informed Consents

•  Single  study  focused  •  Top-­‐down  unidirecEonal  researcher-­‐parEcipant  (research  

subject)  relaEonship.  

•  Data  ownership  and  terms  of  use  driven  by  the  invesEgator  and/or  hosEng  insEtuEon  

Current Generation Informed Consents

•  ProtecEng  the  parEcipant  is  considered  among  the  chief  aims  

•  Study  parEcipants  are  counseled  to  ensure  they  understand  all  aspects  of  the  study,  although  no  evidence  of  understanding  is  sought  or  required  

•  In  most  cases,  anonymity,  privacy,  and  confidenEality  are  guaranteed  as  a  key  condiEon  for  a  parEcipant’s  consent  

•  Big  data,  more  open  data  sharing  mentality  demand  a  new  genera1on  of  informed  consents  

The Evolving Informed Consent for Scientific Research I

•  Open  consents  for  public  resources  -­‐  the  Personal  Genome  Project  (PGP)  Consent  (Church,  2005;  Lunshof  et  al,  2008)  

•  Differs  from  classic  informed  consent  in  the  following  ways  –  Data  ownership  and  terms  of  use  of  data  no  longer  driven  by  study    

invesEgator  

–  Single-­‐study  focused,  but  has  broad  and  open-­‐ended  scope  (data  sharing  as  an  aim)  

–  Data  are  published  to  the  web  and  made  available  without  restricEon  

The Evolving Informed Consent for Scientific Research I

•  Differs  from  classic  informed  consent  in  the  following  ways  –  ParEcipants  agree  to  reciprocal  interacEon  with  researchers  –  ParEcipants  must  pass  an  exam  to  ensure    

•  they  possess  basic  geneEc  literacy  •  They  are  informed  about  the  public  nature  of  the  study  

•  They  understand  the  possibility  of  re-­‐idenEficaEon  •  some  risks  are  unknown  and  unpredictable.  

The Evolving Informed Consent for Scientific Research II

•  Interoperable  and  Open  Consents  -­‐  The  Portable  Legal  Consent  (PLC)  (h[p://weconsent.us/)  

•  Based  upon  the  PGP  consent,  but  altered  in  the  following  important  ways  –  The  PLC  can  be  used  across  any  number  of  studies  –  If  variaEons  of  the  same  PLC  form  guarantee  the  same  freedoms  and    

creates  no  more  than  the  same  obligaEons,  then  it  can  be  cerEfied  as  interoperable  across  the  PLC  network  

–  Fully  digital,  requires  no  input  from  a  physician  or  other  health/  research  professional  

–  Requires  users  sign  terms  of  a  contract  to  ensure  compliance  with  data  use  terms  

–  Intended  for  data  already  generated  to  enable  open  access  of  data  across  many  studies  

SHARING INFORMATION WITH PATIENTS

Whole Exome Sequencing Test (at Baylor College of Medicine)

•  The  test  is  ordered  based  on  a  paEent’s  medical  history  and  physical  exam  findings  for  diagnosis,  ohen  aher  a  set  of  geneEc  tests  on  a  small  number  of  genes  

•  100-­‐120x  coverage,  95%  of  the  exome  is  covered  at  >20x  coverage,  13Gb  sequence  data  per  paEent  

•  15  day  turn  around  Eme  to  receive  results  and  report    

Note:  James  Watson  got  his  genome  sequence  in  a  hard  drive  

Whole Exome Sequencing Test (at Baylor College of Medicine)

•  Results  on  genes  that  are  not  directly  relevant  to  the  given  clinical  phenotype  may  or  may  not  be  reported  

•  Results  on  some  condiEons  are  not  reported  –  NOT  report  findings  in  genes  causing  adult  onset  demenEa  syndromes  

such  as  early  onset  Alzheimer,  for  which  there  is  no  treatment.  T    

•  Other  related  test  –  Blue  print  WES  for  a  panel  of  customized  genes  (up  to  100)  based  on  

paEent  clinical  symptoms    

–  Cancer  exome  sequencing  test  

Whole Genome Sequencing Test vs Traditional Genetic Test

•  TradiEonal  GeneEc  Test  –  Tests  one  or  a  few  genes  –  Physicians  should  understand  the  test,  knows  how  to  interpret  the  test  

•  Whole  Genome  Sequencing  Test  –  Thousands  of  “test  results”  per  paEent  –  Only  a  few  of  the  test  results  can  be  readily  interpreted  or  clinically  

useful  

–  OpportuniEes  for  clinical  research  

Sharing Information with Patients

•  How  much  informa1on  should  be  shared  with  pa1ents?  –  Sequence:  by  itself,  meaningless  

–  AnnotaEon  •  what  type  of  annotaEons  should  be  shared?  •  Sharing  research  results  that  have  not  been  thoroughly  validated?  

ClinSeq

ClinSeq

•  To  explain  how  geneEc  changes  relate  to  health  –  IniEally  focus  on  a  form  of  heart  disease  

•  To  learn  the  best  ways  to  share  the  results  of  geneEc  tests  with  people  –  Return  informaEon  on  disease-­‐causing  mutaEons  but  not  the  full  

sequencing  data  

–  Report  high-­‐penetrance,  Mendelian  variants,  but  what  about  lower-­‐penetrance  variants?      

–  Too  much  informaEon  to  paEents  is  counter-­‐producEve  

Sharing Information with Genetic Relatives

•  An  individual’s  genome  can  reveal  the  genome  informaEon  of  relaEves  –  Informed  consent  for  research  parEcipants,  but  how  about  the  

relaEves?  

–  If  you  publish  your  genome  informaEon  to  the  public,  how  can  we  protect  the  privacy  of  your  relaEves?  

Other Social/Ethical Issues in Personal Genomes

•  A  greater  parEcipaEon  of  informed  paEents  

•  ProtecEng  individuals  from  discriminaEon  –  GeneEc  InformaEon  NondiscriminaEon  Act  (2008)  

•  Law  protecEng  individuals  from  discriminaEon  based  on  their  geneEc  informaEon  for  health  insurance  and  employment  

•  Consumer  genomics  services  –  23andme,  deCODE  geneEcs,  Navigenics  –  Personal  genomic  services  are  offered  in  the  private  sectors  more  widely  

than  by  clinicians  –  Commercial  genomic  services  may  displace  clinicians  as  the  primary  

provider  of  health-­‐related  geneEc  informaEon    –  Individuals  may  assume  more  responsibility  for  health-­‐promoEng  behavior  

Other Social/Ethical Issues in Personal Genomes

•  P4  medicine  (h[p://p4mi.org)  –  PredicEve,  prevenEve,  personalized,  and  parEcipatory  medicine  

–  Apply  systems  biology  to  personalized  disease  prevenEon  and  maintenance  of  health  

Summary

•  Ethical/Social/Legal  issues  in  personal  genomes  –  ProtecEng  privacy  in  terms  of  geneEc  informaEon  while  enabling  

scienEfic  research  

–  ProtecEng  individuals  as  research  parEcipants  –  Keeping  individuals  informed  

–  Empowering  individuals  by  keeping  them  informed  of  the  various  issues  involved  in  personal  genomes