What does it mean to unlock the secrets of your DNA? Ethical, social and clinical Challenges of personalized genomics

1. What does it mean to unlock the secrets of your DNA?Ethical, social and clinical Challenges of personalized genomics Holly K. Tabor, Ph.D. Treuman Katz Center for Pediatric Bioethics Seattle Children’s Hospital Division of Bioethics, Department of Pediatrics University of Washington

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6. Where do we go from here? • What do genetic susceptibility results really mean? • Is there such a thing as personalized genomic medicine? • How will access to more genetic information affect the way people feel about genes, disease and identity? • How does this affect research?

7. Outline • There are substantial challenges to translating genetics results about disease susceptibility into practice. • example: Type II Diabetes • Studies on genetic susceptibility produce large volumes of data on a wide range of phenotypes: what are the potential risks? • example: Craig Venter • The impact of genetic data can extend beyond clinical utility. • example: presymptomatic ApoE4 testing • Where should we go from here?

8. Definitions Genetic Profiling • Using technology that interrogates the whole genome to develop a “profile” of a large set of genetic information that provides information about complex phenotypes Personalized Medicine • Using information to tailor health interventions specifically to individuals

9. Point 1:There are substantial challenges to translating results about disease susceptibility into practice. The example of Type 2 Diabetes.

10. What do we do when we identify genes for Mendelian disease? • Provide clinical testing in regulated approved labs • Identify therapies/interventions/drugs that may be more effective for subsets of disease • Create a different diagnostic, risk and treatment pathways for at-risk individuals

11. Huntington’s Disease “What does seem absolutely clear is that testing for Huntington’s is never innocuous, it is always a profoundly life-changing event, not only to the individual going through the testing, but to his or her family, and often to wider circles as well. Gene testing, in the case of Huntington’s disease, can never be taken lightly, it can never be routine.” -Alice Wexler, “Mapping Fate”

12. What do we do when we identify genes for complex disease? “Whole genome information, when combined with clinical and other phenotypic data, offers the potential for increased understanding of basic biological processes affecting human health, improvement in the prediction of disease and patient care, and ultimately the realization of the promise of personalized medicine.” -NIH Statement on GWAS But how well can we predict disease and improve patient care?

13. The Current Realities • Results from genome wide association studies are being published for complex traits • These results will be reported/interpreted as identifying genetic profiles for disease risk/susceptibility • Some results will be replicated, some not • Consumers will be able to get genetic profile data from: • Direct-to-Consumer Genetic Testing (e.g. 23andme) • Whole genome/targeted sequencing

14. Who will have this information? Near Future: • Participants in GWAS/Sequencing Studies • People who order Direct-to-Consumer products (23andme, DNA Direct, others) More Distant Future: • Patients with specific disorders may possibly obtain data through clinical tests Who will not have this information? • Low-income patients/patients without insurance • Individuals in the developing world

15. What could we do with results for Type 2 Diabetes? • Design a test: • conduct whole genome testing, or • create a panel testing just 8-500 SNPs. • Quantify the risk: • Assign risk of disease to each SNP/combination of SNPs/haplotypes. • Describe the scientific validity: • Replication results, populations studied, technologies used, how much risk is explained. • Describe the clinical validity: • what added information comes from this profile and how does this impact health care decisions?

16. Type 2 Diabetes Scott et al, Science, June 2007 • Population Attributable Risk of 5-27% at each locus • 95-63% of population risk of diabetes is NOT explained by each loci • All 8 loci combined contribute only 2.3% to the overall variance in diabetes risk Conclusion: • Most of diabetes risk in a subset of individuals is explained by other genetic and environmental factors It is difficult to translate even this kind of well-replicated data into a genetic profile with clinical validity.

17. Point 2:Whole Genome Sequencing What if you could “unlock the secrets of your DNA?” What does that mean?

18. HuRef: September 2007

19. What is the difference?

20. Associated Common Traits • Blue eye/fair skin color • Evening preference • Novelty seeking • Alcohol • Tobacco Addiction • Confidence of Genotype

21. HuRef Variants and Phenotypes • Cardiovascular Disease • family history • several genotypes associated with CVD, but conflict in direction of risk/protection • Cancer • heterozygous for GSTM1 • unclear “if this variant contributes to the reported health status events experienced by the donor, such as skin cancer.” • Unknown data: • novel deletion causing protein truncation for an enzyme associated with lipid metabolism • Inconsistencies: • Genotype should confer adult lactose tolerance, but does not match with self-reported phenotype

22. Tracking/understanding potential “adverse events” • Paternity/genealogy • Issues of identity/profiling • “Right not to know” genetic information • Communicating genetic information to minors/relatives • Lack of insurability (health or life) • Employment discrimination • Forensic uses/abuses • “Claim relatedness of the volunteer to infamous villains” • Perceived stigma • Therapeutic misconception: “suggestion for diagnostic tests” • Reproductive decision-making

23. Example 3:How do patients use genetic information about susceptibility? The example of ApoE4 testing.

24. ApoE4 Testing: Study Design • Gooding et al, Patient Education and Counseling, 2006 • 60 adult children of individuals with AD • Tested for ApoE4, interviewed about the testing process • ApoE4 neither necessary nor sufficient for development of AD • No therapeutic or preventive course of action • ACMG recommends against ApoE4 testing…but you can order it online!

25. ApoE4 Testing: Results “Even though the development of Alzheimer’s disease was seen as uncontrollable by most individuals, for some the act of acquiring genetic information was seen as a way to confront their risk and therefore exert control.” “Even without prevention or treatment options, genetic testing may be a useful coping strategy for some at risk individuals.” “The ApoE genotype is more memorable than a numeric risk estimate for Alzheimer’s disease. Health professionals testing for complex disorders like Alzheimer’s disease must find an appropriate balance between communicating risk in an understandable format and addressing the probabilistic nature of the information.”

26. Implications for Genomic Profiling and Personalized Medicine • There may emotional, rather than practical benefits and risks of genetic risk information. • The emotional meaning may be more relevant for very large amounts of genetic information and information on susceptibility and risk, rather than prediction/diagnosis. • People may react very differently to this kind of data, based on personality/coping strategy and the context of the information. • Patients should be encouraged to consider the range of results, how they might cope, and the range of possible actions/reactions before testing.

27. Where should we go from here? • As genetic studies on susceptibility to disease proliferate, we need to demand replication and understanding of population attributable risks of significant findings. • As patients/consumers seek out genetic profiling, physicians need to understand the clinical validity and limitations of the data for making health-related decisions. • We need well-designed studies about how patients/consumers are affected by genetic data, especially large amounts of data, in order to understand the risk and benefits.

28. There Is Nothing New Under the Sun “Personalized medicine has always been a component of good medical practice. Genetic tests may provide new tools, but they do not change the fundamental goals of clinicians to adapt available medical tests and technologies to the individual circumstances of their patients. . . When genetic testing is used, the personalized nature of the care will extend well beyond the patient’s base pair sequence.” -Wylie Burke and Bruce Pstay JAMA, October 10, 2007

29. There is Nothing Good or Bad But Thinking Makes it So “My guest Craig Venter has successfully decoded his own genome, which has been hailed as a breakthrough in the field of medicine . . . for Craig Venter.” Stephen Colbert The Colbert Report, October 30, 2007

30. Benjamin Wilfond Mildred Cho David Magnus Sandra Lee Jennifer McCormick Martine Lappé Funding from NHGRI 1 K99 HG004316-01 5 P50 HG003389-04 Acknowledgements

31. My Research • Ethical and Social Issues in the Study of Genetics of Complex Traits • Focus groups • Goal: explore the attitudes of adolescents towards genetic research on complex traits and the risks and benefits of participation • Examine perspectives on risk of genetics for complex behavioral traits, like smoking, and perspectives on consent/assent in participation in large genomic and health databases

32. My Research • Other Research Settings • Disease Context: Studies of autism • Health Care Setting Context: Genome Wide Association Studies at Group Health Cooperative • Prospective Cohort Study Context: The National Children’s Study