Public Health Genomics Part I BACKGROUND Pre-marital Counseling, Chronic Diseases

1. Public Health GenomicsPart IBACKGROUNDPre-marital Counseling, Chronic Diseases Margaret Foster Riley, J.D. University of Virginia School of Law May 30, 2009

2. What is Public Health Genomics? • The application of genetics and molecular biotechnology to improve public health and prevent disease • The focus is on populations rather than the individual

3. Public Health Genomics--Prevention • Genotypic Prevention • The interruption of genetic trait transmission from one generation to another • Phenotypic Prevention • The prevention of disease and death among people with specific genotypes Source: Juengst (1995)

4. Public Health Genomics--Prevention • While public health agencies take an active (and likely growing) role in phenotypic prevention, genotypic prevention is far more problematic • the problem of eugenics • Genetic technologies may actually compromise overall population health if they lead to stigmatization and/or exclusion of certain groups

5. Public Health Genomics--Generally • In public health, the use of genomics must consider interventions based on behavioral and population-level factors in disease causation • In addition to general prevention issues, there is hope that genomics may be a way to deal with health disparities…but that is a two-edged sword

6. We’ve had a good idea of the public health plan for decades But we haven’t had the ability to fully implement it in any systematic fashion

7. 1975 “Genetic Screening: Programs, Principles and Research” • Committee for the Study of Inborn Errors of Metabolism; commissioned by NRC at National Academy of Sciences • Anticipated many of the ethical, legal, economic, social, medical issues that would be involved in systematic genetic screening.

8. 1975 “Genetic Screening: Programs, Principles and Research” • Warned against using a direct application of infectious disease model for genetic screening programs • Recommended that all screening programs should be voluntary rather than mandatory • Recommended the establishment of a federal agency (or connected state and local agencies) to oversee and standardize screening programs

9. 1975 “Genetic Screening: Programs, Principles and Research” • Evidence of substantial public benefit and acceptance • Feasibility has been studied and benefits outweigh costs • This includes evaluation of test methods and laboratory facilities, adequate resources for counseling and education and other potential consequences • Investigative “pretest” has been carried out demonstrating the above criteria • Means for Evaluation of program established

10. Since then, numerous commissions, largely consensus • Most still recommend voluntary screening and informed consent • Clear interventional pathways evident before testing • But let’s see how it works out in practice

11. CDC’s Strategic Plan (1997) • Surveillance • National Health and Nutrition Examination Survey III • Epidemiology • Human Genome Epidemiology Network (HuGE Net) • Evaluation of Genetic Testing • EGAPP • Development, Implementation and Evaluation of Population Interventions • Communication, Education and Information

12. Federal and State Government Entities • NIH—National Human Genome Research Institute (and other centers) • Bioterrorism—through NIAID (NIH) • National Office of Public Health Genomics (NOPHG)—CDC • Secretary’s Advisory Committee on Genomics, Health and Society • Genetics and Public Health Assessment Project--Council of State and Territorial Epidemiologists • State Initiatives (e.g. NY Genomics Institute)

13. Family History Project (2005) • Thanksgiving 2005 • Issues?

14. Principles of Population Screening as applied to Genetic Susceptibility to Disease (Khoury et. al. NEJM 2003) • Public Health Assessment • Important public health burden in terms of illness, disability and death • Prevalence of genetic trait and burden of disease attributable to it should be known • Natural history of the condition, from susceptibility to latent disease to overt disease, should be adequately understood

15. Principles of Population Screening as applied to Genetic Susceptibility to Disease (Khoury et. al. NEJM 2003) • Evaluation of tests and interventions • Data should be available on the positive and negative predictive values of the test with respect to the disease condition in the target population • Safety and efficacy of the test and accompanying interventions should be established

16. Principles of Population Screening as applied to Genetic Susceptibility to Disease (Khoury et. al. NEJM 2003) • Policy development and screening implementation • Consensus regarding the appropriateness of screening and interventions for people with positive results • Screening should be acceptable to target population • Facilities for adequate surveillance, prevention, treatment, education, counseling and social support

17. Principles of Population Screening as applied to Genetic Susceptibility to Disease (Khoury et. al. NEJM 2003) • Policy development and screening implementation (Cont’d) • Screening should be a continual process, including evaluation of laboratory quality and health services and effect of screening • Cost effectiveness should be established • Screening and interventions should be accessible to the target population • Safeguards for informed consent, privacy, coercion and manipulation—and protections against stigmatization and discrimination

18. Ethical, Legal and Social Issues (Generally) • Testing children for adult-onset disorders • Unanticipated information • Discrimination

19. Premarital Screening • In its successful use, more “community health” than “public health” • Not widespread and of limited applicability in modern American culture • Most useful in culturally genetically isolated groups that adhere to strict cultural rules and practice endogamy • E.g. Old Order Amish, Finnish, Hutterite, Sardinian and some Jewish populations

20. Premarital Screening—DorYeshorim • Tay-Sachs serum enzyme test developed in 1970 • Early 1980s rabbi Josef Ekstein established a non-profit community screening program to serve the Orthodox community in Brooklyn, New York • Most marriages arranged

21. Premarital Screening—DorYeshorim • Young adults could have their blood tested for Tay-Sachs as well as a series of other genetic mutations common among Ashkenazy Jews • Every participant is given an identification number and his or her test is stored in a secure database

22. Premarital Screening—DorYeshorim • Results are accessed only when marriage is contemplated • If both are proclaimed to be carriers of the same disease or diseases they are declared “genetically incompatible” but are not told which specific mutations they have • Mass screenings sponsored by some Jewish high schools

23. Premarital Screening—DorYeshorim • Generally well-received and accepted in the community • Identification of 800+ genetically incompatible couples

24. Premarital Screening—Other Programs • Central Conference of American Rabbis • Madison Community Tay-Sachs Screening program (1975-1999) • Mental Health Issues among the Amish • A different experience with sickle cell

25. Sickle Cell • Sickle cell disproportionately affects African Americans • Early 1970s 10 states enacted mandatory screening programs in response to suggestions of lack of public health resources • A lesson in inappropriate legislation

26. Premarital Screening • Limitations of Ethnically-based Screening • Pre-marital Screening in a 21st century culture

27. Carrier Screening • Pre-conceptual and Pre-natal testing for recessive diseases • Typically not done as medical treatment—not public health…but should it be? • Mostly only patients whose insurance cover reproductive genetic testing or • Patients who know of a family history • No obvious point for government involvement • Community Genetics

28. Carrier Screening—Couple Based • Couple-based screening involves collection and testing of specimens from both partners, with each informed of the results after both have been tested • Sequential screening: one member of the couple (usually the woman) is tested first, and if a positive result is obtained, then the partner is tested, with full disclosure of the test results to both individuals • Alternative where only given results when both are positive

29. Screening in Infectious Disease • May have some important public health benefits (i.e. appropriate direction of resources and care) • Significant potential for stigmatization

30. Chronic Disease Screening—A Holy Grail? • Most adult-onset diseases are polygenic and multifactorial • It may therefore be possible to screen for specific mutations, but the implications of the findings are far from clear— • Typical odds ratios found in GWAS studies are less than 1.5 • Gene-Environment Interactions • What does this mean for public health?

31. Chronic Disease Screening • Once risk estimates are more stable, the usefulness of genetic screening will need to be considered for each disease, and recommendations about potential interventions for people whose predicted risk exceeds a specified threshold • Some of those may be likely public health candidates

32. Chronic Disease Screening • Alzheimer’s Disease • Cardiovascular Disease • Cancer • Potential for Misunderstanding and Discrimination • But early public focus groups indicate lower public interest in diseases that are not viewed as “emergent.” • Low long term behavioral changes weak—e.g. lung cancer susceptibility and smoking

33. Screening and Pharmacogenomics? • The central question is this better managed as a public health issue or a medical issue (or even that?) • Not yet clear how genetics should affect patient dosing or outcomes • Examples • SSRI and CYP450 genotyping • Warfarin—3-10% users experience a serious bleeding event--testing for CYP2C9 and VKORC1 (But even CMS has restrictive coverage) • Tamoxifen—CYP2D6 may have less effectiveness and there are alternatives

34. Generally, public health genomics is still in early stages But what about newborn screening?