Science and Society: Genomics

Amy L. McGuire, JD, PhDCenter for Medical Ethics and Health

PolicyBaylor College of Medicine

How Many of You

Are involved in research?

Collect samples for research purposes?

Collect samples for or conduct genetic/genomic research?

Informed Consent Process

Sample Collection

Sample Storage

Research Use DNA Data Analysis, Storage, Sharing and Use

Biobanking and Genomic Research Pipeline

Evolution of Genetic Testing

Whole Genome Sequencing: Evolution of the Technology

Jim Watson 2007$1M

Complete Genomics 2009

$4,400

HGP2001

(13 years)$2.7B

Ion Torrent2012

$1,000 (1 day)Nanopore

2012USB Sequencer

Estimated Number of Genomes (To Be) Sequenced

2007: 22009: 72012: 30-75k2014: up to

1M

Wade N. The New York Times. 2009 August 11, 2009; Collins FS. Brigham and Women's Hospital Medical Grand Rounds. Boston, MA2011.

Paths for Obtaining Personal Genome Information

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

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

• 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)

Eugenic ideology was deeply embedded in U.S. pop culture in 1920s – 1930s

Kansas State Fair 1920s

Fitter Family Exihibit

Better Baby Contest

• 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.

The voluntary consent of the human subject is

absolutely essential!

Importance of Transparency and Informed Consent for Public Trust

Carletta Tilousi, Havasupi

State to destroy 4 million newborn blood samplesPublished 06:30 a.m., Tuesday, December 22, 2009

Informed Consent

Data Sharing Policies and Genomic PrivacyData Sharing Policies and Genomic Privacy

• Developed in the context of large-scale sequencing studies (HGP, HapMap)– Primary purpose: create a reference

dataset– Cost efficient– Promotes scientific utility

• 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

2004: “Specifying DNA sequence at only 30 to 80 statistically independent SNP positions will uniquely identify a single person.”

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.

2008: Can uniquely identify an individual from pooled or aggregate DNA data.

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

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

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

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

Examples of Open Access Databases

• Human Genome Project• HapMap• 1000 Genomes• Personal Genomes

– PGP, Venter, Watson

• Human Microbiome Project

“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.”

“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.”

Randomized Consent Study: R01 HG004333 (2007-2011)

Participants from 6 GWAS at BCM Randomized

Traditional Consent

Traditional Consent

Binary ConsentBinary

ConsentTiered

ConsentTiered

Consent

Follow-up Interview

Subjects debriefed, shown all three consents, and given the opportunity to change their consent form or data sharing

option.

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%)

Data Release Selections After Debriefing

After Debriefing

Public Release

Restricted Release

No Release

All Participants 53.1 33.1 13.7

Consent Type

Traditional 62.1 31.9 6.0

Binary 50.9 30.2 18.9

Tiered 46.0 37.2 16.8

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%

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

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

Possible Explanations

A. McGuire (PI), 1 R01 HG004333

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 (>8th grade reading level)

Variation in consent process

Privacy-Utility Trade-Off

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

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)

Consensus… And Controversy

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.

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.

Objective: To describe the practices and beliefs of GWAS investigators regarding the return of individual genetic research results to study participants.

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

Incidental Findings in Clinical Practice

Unexpected Findings

Informed Consent

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

HG004333– 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