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Science and Society: Genomics Amy L. McGuire, JD, PhD Center for Medical Ethics and Health Policy Baylor College of Medicine Amy L. McGuire, JD, PhD Center.

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Presentation on theme: "Science and Society: Genomics Amy L. McGuire, JD, PhD Center for Medical Ethics and Health Policy Baylor College of Medicine Amy L. McGuire, JD, PhD Center."— Presentation transcript:

1 Science and Society: Genomics Amy L. McGuire, JD, PhD Center for Medical Ethics and Health Policy Baylor College of Medicine Amy L. McGuire, JD, PhD Center for Medical Ethics and Health Policy Baylor College of Medicine

2 How Many of You Are involved in research? Collect samples for research purposes? Collect samples for or conduct genetic/genomic research?

3 Informed Consent Process Sample Collection Sample Storage Research Use DNA Data Analysis, Storage, Sharing and Use Biobanking and Genomic Research Pipeline

4 Evolution of Genetic Testing

5 Whole Genome Sequencing: Evolution of the Technology Jim Watson 2007 $1M Complete Genomics 2009 $4,400 HGP 2001 (13 years) $2.7B Ion Torrent 2012 $1,000 (1 day) Nanopore 2012 USB Sequencer

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7 Estimated Number of Genomes (To Be) Sequenced 2007: : : 30-75k 2014: up to 1M Wade N. The New York Times August 11, 2009; Collins FS. Brigham and Women's Hospital Medical Grand Rounds. Boston, MA2011.

8 Paths for Obtaining Personal Genome Information

9 The Responsible Conduct of Genomic Research Concerns about genomic research deeply rooted in historical misuse of genetics to advance social and political agenda of eugenics movement

10 Genetics Then Doctrine of eugenics combined social Darwinism with Mendelian theory of heredity Advocates saw eugenics as a way to perfect the human gene pool by influencing the reproductive process & some scientists advocated keeping the “Anglo-American race” pure From 1907 onward, at least 60,000 Americans were sterilized against their will under legal basis of eugenics laws

11 Buck v. Bell (U.S. 1927): affirmed the constitutionality of Virginia’s sterilization law – “It is better for all the world, if instead of waiting to execute degenerate offspring for crime, or to let them starve for their imbecility, society can prevent those who are manifestly unfit from continuing their kind…Three generations of imbeciles are enough.” (Supreme Court Justice Oliver Wendell Holmes)

12 Eugenic ideology was deeply embedded in U.S. pop culture in 1920s – 1930s Kansas State Fair 1920s Fitter Family Exihibit Better Baby Contest

13 Hitler closely followed U.S. eugenic legislation: – “I have studied with great interest the laws of several American states concerning prevention of reproduction by people whose progeny would, in all probability, be of no value or be injurious to the racial stock.” – This philosophy was the foundation and justification for acts of murder and torture in the name of medical science.

14 The voluntary consent of the human subject is absolutely essential!

15 Importance of Transparency and Informed Consent for Public Trust Carletta Tilousi, Havasupi State to destroy 4 million newborn blood samples Published 06:30 a.m., Tuesday, December 22, 2009

16 Complexity of Consent in Biobanking and Genomic Research Treatment and/or sample collection (e.g., resection, biopsy, blood draw) Retention and Storage of Biological Specimen Genetic Analysis + Risks and Benefits Data Sharing Return of Results Unspecified Future Use Permission to Recontact

17 NHGRI Consent Form Examples and Model Consent Langauge Texas Cancer Research Biobank

18 Informed Consent

19 Data Sharing Policies and Genomic Privacy

20 Developed in the context of large-scale sequencing studies (HGP, HapMap) – Primary purpose: create a reference dataset – Cost efficient – Promotes scientific utility

21 Must balance scientific and clinical utility with privacy protection Traditional means of protecting privacy: de- identification Problem: DNA is a unique identifier Data Sharing and Privacy

22 2004: “Specifying DNA sequence at only 30 to 80 statistically independent SNP positions will uniquely identify a single person.” 2008: Can uniquely identify an individual from pooled or aggregate DNA data.

23 “Surnames can be recovered from personal genomes by profiling short tandem repeats on the Y chromosome (Y-STRs) and querying recreational genetic geneology databases.”

24 What MIT Group Did 1000 Genomes Project database Includes participants’ age and region where they live (all Americans are from CEPH population in Utah) Pulled out short tandem repeats on Y chromosome and matched to genetic geneology database to get surname Did a google search to find obituary and was able to identify entire family tree Identified nearly 50 people this way – published method, not names of people identified 1000 Genomes Project database Includes participants’ age and region where they live (all Americans are from CEPH population in Utah) Pulled out short tandem repeats on Y chromosome and matched to genetic geneology database to get surname Did a google search to find obituary and was able to identify entire family tree Identified nearly 50 people this way – published method, not names of people identified

25 Policy Response: Shift to Restricted Databases NIH Data Sharing Policy for GWAS (dbGap) NIH expects specific language about sharing genotype and phenotype data through dbGaP in the informed consent document For retrospective studies: Submitting institution decides if submission is appropriate based on language in consent document

26 Examples of Open Access Databases Human Genome Project HapMap 1000 Genomes Personal Genomes – PGP, Venter, Watson Human Microbiome Project

27 “we recommend a stratified consent process in which all subjects who participate in future genomic sequencing studies are fully informed about how their DNA data may be broadcast and have the authority to decide with whom they want their data shared.”

28 Randomized Consent Study: R01 HG ( ) Participants from 6 GWAS at BCM Randomized Traditional Consent Binary Consent Tiered Consent Follow-up Interview Subjects debriefed, shown all three consents, and given the opportunity to change their consent form or data sharing option.

29 Sample Size Randomization: 335 decisions made by 323 individual subjects Survey: 285 eligible individuals (debriefed in person) – 229 participants ( Response rate = 84.4%) Randomization: 335 decisions made by 323 individual subjects Survey: 285 eligible individuals (debriefed in person) – 229 participants ( Response rate = 84.4%)

30 Data Release Selections After Debriefing After Debriefing Public Release Restricte d Release No Release All Participants Consent Type Traditional Binary Tiered

31 Participants’ Reported Understanding Reported Understanding Agree or Strongly Agree % (n = 229) I felt sure about what to choose with regard to sharing my genetic information 85.1% The decision to share my genetic information was easy for me to make 86.9% I feel I have made an informed decision with regard to sharing my genetic information 91.2%

32 Participants’ Actual Understanding Actual Understanding “No” % (n = 224) “I don’t know” % (n = 224) Do you know if you are participating in a research study?* 40.2%NA Have you ever heard of genetic studies?28.1%NA Have you already given DNA to your doctor? 16.1%36.6% Do you know if your DNA has been stored as part of any study? 25.9%35.7% Do you remember signing a consent form to participate in a genetic study? * 25.9%NA No significant difference based on consent type *Participants from brain and epilepsy studies significantly more likely to know they are participating in research study and to remember signing consent form

33 General Understanding of Research Participation Daugherty et al, J Clin Onc (1995) – 27 patients enrolled in a phase I clinical trial: Only 33% were able to state the purpose of the trial in which they were participating Joffe et al, Lancet (2001) – Most participants considered themselves to be well informed, but many did not understand that they may receive non-standard treatment (74%), the potential for incremental risk from participation (63%), the unproven nature of the treatment (70%), the uncertainty of benefits to self (29%), or that trials are done mainly to benefit future patients (25%) Sanchini et al, J Med Ethics (2013) – 77 patients enrolled in randomized phase II or phase III clinical trial: 38% did not understand the purpose and nature of the trial they were participating in; 56% did not understand the study procedures, and only 40% correctly listed at least one of the major risks or complications related to their participation in the trial Flory and Emanuel, JAMA (2004); Tamariz et al, JGIM (2012) – Efforts to improve understanding have had only limited success – Most effective intervention: one-on-one education

34 Possible Explanations A. McGuire (PI), 1 R01 HG Recall issue (time lapse between consent and survey) Time lapse was only shown to be associated with “Do you remember signing a consent form to participate in a genetic study” Communicability issue ICD was complex (>8 th grade reading level) Variation in consent process

35 Privacy-Utility Trade-Off

36 Desire for Involvement The majority (86.4%) of participants reported it is important to extremely important for them to be involved in the decision about whether to share their genetic information. – How: ask me – Why: RESPECT The majority (86.4%) of participants reported it is important to extremely important for them to be involved in the decision about whether to share their genetic information. – How: ask me – Why: RESPECT A. McGuire (PI), 1 R01 HG004333

37 Returning Research Results Participants report they would like to receive results Existing Guidelines (NBAC, NHLBI, NIH GWAS): Investigators should offer to return valid results that have (immediate) clinical significance (and proven therapeutic or preventive interventions are available)

38 Consensus… And Controversy

39 What would you do? A couple is approached about enrolling their 7 year old daughter who has severe undiagnosed cognitive delay into a genomic research study. They have had clinical genetic testing (including CMA), with no significant findings. The study will do WES on the daughter, as well as the mother, father, and 14 year old (healthy) brother. The parents consent and the 14 year old brother assents to participate in the study. They are told that medically significant results discovered during the course of the research may be returned. Mom is pregnant and has had standard prenatal genetic testing on the fetus, with no significant findings. The WES provides a definitive diagnosis for the daughter. It also, however, indicates that the brother has Von-Hippel-Lindau syndrome (VHL), which is autosomal dominant and characterized by multi-system tumors and cysts, including renal cell carcinoma. Testing indicates that neither mom nor dad has VHL and non-paternity is confirmed. The research informed consent form said that incidental findings of non-paternity would not be disclosed. A couple is approached about enrolling their 7 year old daughter who has severe undiagnosed cognitive delay into a genomic research study. They have had clinical genetic testing (including CMA), with no significant findings. The study will do WES on the daughter, as well as the mother, father, and 14 year old (healthy) brother. The parents consent and the 14 year old brother assents to participate in the study. They are told that medically significant results discovered during the course of the research may be returned. Mom is pregnant and has had standard prenatal genetic testing on the fetus, with no significant findings. The WES provides a definitive diagnosis for the daughter. It also, however, indicates that the brother has Von-Hippel-Lindau syndrome (VHL), which is autosomal dominant and characterized by multi-system tumors and cysts, including renal cell carcinoma. Testing indicates that neither mom nor dad has VHL and non-paternity is confirmed. The research informed consent form said that incidental findings of non-paternity would not be disclosed.

40 Survey Study Obtained list of published GWAS using NIH Catalog of Genome-Wide Association Studies (N=517) Identify all unique corresponding authors (N=365) N=200 (56% RR) Objective: To describe the practices and beliefs of GWAS investigators regarding the return of individual genetic research results to study participants.

41 Practices and Perspectives Only 6% had returned individual results from the GWAS – 2% had plans to return – No secondary users 63% thought individual genetic results should be returned in some, most, or all circumstances Only 6% had returned individual results from the GWAS – 2% had plans to return – No secondary users 63% thought individual genetic results should be returned in some, most, or all circumstances

42 Incidental Findings in Clinical Practice

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44 Unexpected Findings

45 Informed Consent

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47 Acknowledgements Amy McGuire (PI) Co-Investigators – Consent Grant: Sue Hilsenbeck, Richard Gibbs, Adam Kelley – RoR Grant: Steve Joffe, Rachel Ramoni, Sharon Plon Project Coordinators/Research Assistants – Christina Diaz, Jeanne Higgs, Jennifer Fackler, Melody Slashinski, Jill Oliver, Ayesha Chawdhary, Stacey Pereira GWAS PIs – Ching Lau – William Fisher – John Goss – Jeff Noebels and Alica Goldman – Diane Treadwell-Deering GWAS Research Coordinators – Suzanne Hegmeier, Melissa Pagaoa, Sally Hodges, Tiffany Zgabay, Melissa Lambeth, Morgan Lasala Expert Panel Members – Aravinda Chakravarti, Gail Geller, Laura Beskow, Louise Strong, Mildred Cho, Rebecca Fisher, Laura Rodriguez, Wylie Burke Funding Sources – NHGRI-ELSI Grant # 1 R01 HG – Greenwall Foundation Faculty Scholars Program in Bioethics – Gillson-Longenbaugh Foundation – ARCO Foundation, Young Teacher-Investigator Award – BCM Clinical Translational Research Grant A. McGuire (PI), 1 R01 HG004333


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