1. Challenges and Opportunities of Incorporating Genetics into MCH Studies Session: Genetics, Genomics, Epidemiology, and MCH 12th Annual Maternal and Child Health Epidemiology Conference, Atlanta, GA Sonja A Rasmussen, MD, MS National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention

2. National Birth Defects Prevention Study (NBDPS) Case-control study of major birth defects Evaluate genetic and environmental risk factors Enrollment began with births on or after 10/1/97 CA UT TX AR GA NC NY MA IA

3. Components of NBDPS Case ascertainment and review Maternal interview DNA collection on infant, mother, father Yoon et al., Public Health Rep 116:32-40, 2001 Rasmussen et al., Teratology 66(4):177-84, 2002 Rasmussen et al., Birth Defects Res Part A Clin Mol Teratol 67:193-201, 2003

4. Why Study Genetic Factors and Gene-Environment Interaction? Results in improved understanding of etiology Allows identification of: – –populations at high risk (susceptible genotype) – –modifiable risk factors (environmental exposures) Increases opportunities for prevention

5. Important Considerations in the Incorporation of Genetics into MCH Studies Selecting source of specimens Maximizing participation rates Human subjects-related issues – –Informed consent for studies of genes not yet identified – –Disclosure of individual results Choosing genes for analysis and analytic approach to be used

6. Selecting Source of Specimens Venous blood Buccal cells (collected by swab, cytobrush, FTA ® cards, mouthwash, saliva) Newborn blood spots (previously collected)

7. Issues to Consider when Selecting Source of Specimens Amount of DNA Quality of DNA Other possible uses of sample source Cost/ease of collection Age of participants Impact on participation rates

8. NBDPS Source of Specimens Buccal cells collected by cytobrush

9. Participation Rates for Interview and Buccal Cell Collection, NBDPS (Atlanta) 1999-2002 Crider et al., Am J Epidemiol 164:805-12, 2006

10. Factors Associated with Higher Participation in Buccal Cell Collection Non-Hispanic white race/ethnicity English-language (vs. Spanish) interview Receipt of a redesigned mailing packet and additional $20 incentive Consumption of folic acid Crider et al., Am J Epidemiol 164:805-12, 2006

11. Informed Consent for Studies of Genes Not Yet Identified “Blanket” consent Periodic re-consent Burke and Diekema, J Pediatr 149:S34-38, 2006

12. Informed Consent for NBDPS Genetic Studies Study started in 1997 - biologics specimens to be used for decades Plan to study hundreds of genetic factors – some not yet discovered, methods of study likely to change Informed consent states that samples will be used to study genes that may play a role in birth defects causation

13. NBDPS “Gene One-Pager” For each genetic factor to be studied, investigator will submit gene one-pager to CDC IRB as protocol amendment for expedited review

14. Components of “Gene One-Pager” Proposed genetic research and justification of why testing is important Is this test of clinical significance? If yes, what additional efforts that concern human subjects protection will be made by the investigators? Any other information related to this research that may be important to IRB

15. Approaches to Disclosure of Individual Genetics Results Research-focused approach – results should generally not be offered because goal of research is to provide generalizable (not individual) knowledge Autonomy-focused approach – all results should be offered because individuals have a right to information about themselves Ravitsky and Wilfond, Am J Bioeth 6:8-17, 2006

16. Reporting Genetic Results in Research Studies: Recommendations Key criteria –Risk for disease should be significant –Disease should have important health implications (i.e., mortality, morbidity, significant reproductive implications) –Proven therapeutic or preventive interventions should be available Final decision should be made with IRB approval after careful consideration of risks and benefits NHLBI Working Group on Reporting Genetic Results in Research Studies Bookman et al., Am J Med Genet A 140:1033-40, 2006

17. Reporting Genetic Results in Research Studies: Recommendations (continued) Genetic test results should not be reported to study participants and their health care providers unless test was performed in a CLIA-certified laboratory Counselor/consultant should be provided to explain nature of study, implications of participation, potential relevance of genetic results Information on what to do with results should be summarized, preferably on a single page NHLBI Working Group on Reporting Genetic Results in Research Studies Bookman et al., Am J Med Genet A 140:1033-40, 2006

18. NBDPS Plans for Genetic Factors of Clinical Significance Testing must be done in a CLIA-certified laboratory so results can be provided to study participants if desired Study participants notified of summarized results of genetic factors with clinical significance by NBDPS newsletter Participants can request results if desired Informed consent form reflects this approach

19. Reporting Results to Study Participants: Additional Issues Unintended information may be revealed by genetic studies –Information on other family members –Non-paternity Reporting individual results on children 1, 22, 3 1, 1

20. Choosing Genes for Analysis Candidate genes Genome-wide studies

21. Candidate Gene Studies Candidate gene – a gene for which there is evidence of its possible role in the trait or disease that is under study – –Based on previously reported associations in epidemiologic or family studies, biologic plausibility, expression or linkage studies, and other factors Green and Moore, Birth Defects Res Part A Clin Mol Teratol 76:798–810, 2006

22. Genome-Wide Studies Linkage mapping Genome-wide association studies Hirschhorn and Daly, Nat Rev Genet 6:95-108, 2005

23. Conclusions Incorporating genetics into MCH studies holds promise for better understanding of disease etiology and possibly improved primary prevention Several considerations need to be taken into account when designing a study that incorporates genetics

24. Acknowledgments Margaret Honein Mary Jenkins Cynthia Moore CDC and other participating IRBs NBDPS Investigators in AR, CA, CDC, IA, MA, NC, NJ, NY, TX, UT