Genetic Variation and Medical Research: A Comprehensive Approach

2. Non-profit research institute and world’s leading biobank

4. Copying Leads to “Spelling Mistakes” Some Diversity Enables Us To Resist Infectious Disease

6. 99.6% identical 0.4% unique Science magazine’s “Breakthrough of the Year” in 2007

7. Compare two chromosomes from any two people Only ~ 1 in 1000 bases differ Do these same sites show variation in other people? 90% chance that they do (freq. > 1%) Gabriel et al. Science, 2002 Most Genetic Variation is Shared Among Us All

8. Out of Africa

9. Measuring Genetic Variation is Now Possible, Comprehensive and Cost Effective

10. All known single Gene diseases ~2,000 Don’t we already know about many Human Disease Genes? Heart Disease, Diabetes Cancer, Obesity Impact on Public Health Multi-Gene Diseases

11. GWAS Studies Manolio et al. (2008) J. Cli. Inv. 118(5):1590

12. Maher, B. (2008) Nature 456

13. Many Differences in the Way Individuals Respond to Rx Drugs are Clear Already

14. Plavix Must Be Activated in the Liver CYP2C19 Plavix Plavix* liver Alternative Drug $8 Billion in Annual Sales Prasugrel Just Approved by FDA

15. Tamoxifen is a Pro-Drug 7-10% of Women do not activate Tamoxifen Alternative: aromatase inhibitors

16. Goal is to Determine Whether Using Personal Genome Information Will Be Useful In Medicine? Genome-informed medicine will not be widely Adopted until it is demonstrated to work in the clinic How data are provided to patient and doctor will Be critical determinants of successful adoption (i.e. what’s the right system?) Correlations in Observational Data

17. Observational Data Can Be Useful

18. Dr. Francis Collins “American Family Study” “We desperately need, in this country, a large-scale, prospective, population-based cohort study. And we need to enroll at a minimum half a million people. We would need to have their environmental exposures carefully monitored and recorded, their DNA information recorded, their electronic medical records included, and have them consented for all sorts of other follow-ups.” June 6, 2008 Interview with Science Magazine

19. Free Research study

20. The CPMC Uses Two “GeneChips” 2 million sites of variation 2,000 sites of known Relevance to drug action

22. D-MET Coverage

23. Coriell Genome Center CLIA!

24. Education of Medical Professionals “Don’t even tell me it’s a wart.” Input From Medical Professionals

25. Who can participate and how are they recruited? Eligibility: You must be at least 18 years old You must have an email address and access to the internet Recruitment Mechanisms: Community-based recruitment Cancer Clinic-based recruitment Primary Care-based recruitment Community and Chronic Disease Employer Cancer

26. The CPMC Web Portal cpmc.coriell.org

28. Jane Doe

29. Collection of Detailed Family, Medical History, Medication, Lifestyle and Demographic Info

30. What information do we collect? All cohorts: MFLQ Demographic Information Medical History Medications Family History Lifestyle Information Genetic Knowledge assessment Cancer Cohorts: Cancer Registry Data Cancer-related health records Prescribing Records Primary Care Cohorts: Electronic Health Records Prescribing Records

31. Who decides what genetic information is reported? Informed Cohort Oversight Board (ICOB), an external advisory board. Composed of scientists, medical professionals, ethicist, community members. Vote on whether conditions are potentially actionable. Meet at least twice a year. New results then reported to all participants. Actions completely transparent. RNR Foundation

32. CPMC Risk Reporting

33. CPMC Process Overview

34. Selection criteria for Genetic Variant: • Replicated associations • Adequately sized studies • On Affymetrix 6.0 GeneChip (currently) • Selection of Health Condition: • Health conditions only (no Traits) • Is disease potentially ‘actionable’? • Assess by review of medical society policies and recommendations Genetic Variant/Disease Selection Search Public Databases for published GWAS NHGRI GWAS catalogue; HuGENet™; PubMed Generate list of Health Condition/Genetic variant papers Final list of Health Condition/Genetic variants Prepare Document with Health Condition and a Genetic Variant Summaries for submission to ICOB

35. CPMC Risk Reporting

36. Risk Estimation Step 1: Study Selection • Evaluate Study Design and Size • Select study that will provide most representative and valid risk estimates • Assess Study Quality • Evaluate methods used for determining phenotype and genotype Step 2: Risk Determination • If study reports relative risk – report risks directly • If study reports odds ratios – estimate relative risk and report estimated risks

37. Study Selection Select studies from highest tier Hierarchy of Study Designs Meta-Analysis of Prospective Studies Individual Prospective Study Meta-Analysis of Case-Control Studies Individual Population-Based Case-Control Study Individual Case-Control Study (not population based) Perform Updated Search for ICOB approved SNPs PubMed & HuGENetTM • Study Quality • Disease Assessment • Carried out consistently? • Objective? • Clinically accepted definition? • Genotyping • Are methods valid? • Carried out consistently? • Population Stratification • Could risk estimates be biased? If more than one paper qualifies then select the largest study Select Paper

38. Example: CAD and SNP rs1333049 Hierarchy of Study Designs Meta-Analysis of Prospective Studies Individual Prospective Study Meta-Analysis of Case-Control Studies Individual Population-Based Case-Control Study Individual Case-Control Study (not population based) no no yes (Circulation 2008; 117:1675-1684) *reference group

39. How do participants learn about their results? EXAMPLE

41. Participant Risk Summaries include Non-genetic Risks

43. Potentially Actionable Conditions Complex Disease Drug Metabolism Obesity CYP2D6 Prostate cancer VKORC1 Colon cancer CYP2C9 Melanoma CYP2C19 Coronary artery disease Type 2 diabetes Type 1 diabetes Age-related macular degeneration As of 6-10-09 Hemochromatosis Inflammatory bowel disease Lupus Rheumatoid Arthritis

44. Pharmacogenomics Advisory Panel Dr. Issam Zineh FDA Office of Clinical Pharmacology CYP2D6-Tamoxifen

45. What Do My Results Mean? Genetic Counselors available at no cost In person or by phone

46. Nearly all states represented in the CPMC 10,000 Participants by 2010 Ultimate goal of 100,000

47. Minority Participation and Outreach U.S. Senator Robert Menendez

48. PRWT and Cherokee Pharmaceuticals Franklin Institute of Philadelphia Reverend Floyd White of Camden, NJ

49. What do participants do after viewing their results? • They can invite their physician or members of their family to register to view their personal risk information through the web portal • They may decide to make changes to their lifestyle to try to lower their risk of the health condition. • They may decide to talk to their physician about their risk of the health condition. • They can request genetic counseling at CPMC to discuss their risks, at no charge • CPMC will send them period emails asking them to log onto their web portal account and complete short questionnaires about what they did with their results

50. What research will be done with CPMC data? • CPMC scientists, health researchers and biostatisticians will determine whether giving people information about their genetic risk alters their health behavior or their health. • Outcome surveys, annual MFLQ, medical records • CPMC scientists will assess the genetic knowledge of CPMC participants during the course of their participation in the study. • Voluntary genetic knowledge survey • The broader scientific community will have access to genotypic and phenotypic data from those individuals who opt to release their de-identified data for biomedical research.