The Human Genome Epidemiology Network (HuGENet)

1. The Human Genome Epidemiology Network (HuGENet) Muin J. Khoury

2. Outline • The epidemiologic approach to genomics • The challenge of integrating data: HuGENet • HuGENet Products and Processes

3. Gene-Based Medicine in 2010?“Hypothetical Genetic Test Report” • Condition Genes RR Lifetime • Prostate Ca HPC1, 2, 3 0.4 7% • Alzheimer’s APOE,FAD3,XAD 0.3 10% • Heart disease APOB,CETP 2.5 70% • Colon Cancer FCC4,APC 4.0 23% • Lung Cancer NAT2 6.0 40% Collins FC, New Engl J Med 1999;341:28-37.

4. Prediction of Risk of Myocardial Infarction from Polymorphisms in Candidate GenesYamada et al. NEJM 2002;347:1916-1923. • Case-Control Study (5061 MI and 2242 Controls) • Analysis of 71 candidate genes with 112 polymorphisms • A few associations were found…small odds ratios… • Accompanying editorial • “Findings should be used to initiate further research • Recommendations for primary prevention cannot be based on these findings.”

5. “Systematic application of epidemiologic method and approaches to assess the impact of human genetic variation on health and disease” Khoury, Little and Burke, HuGE 2004

6. “Systematic application of epidemiologic methods and approaches to assess the impact of human genetic variation on health and disease” Khoury, Little and Burke, HuGE 2004 • Genotype prevalence • Gene - disease association • Gene - gene interactions • Gene - environment interactions • Assessment of Genetic tests

7. “Systematic application of epidemiologic methods and approaches to assess the impact of human genetic variation on health and disease” Khoury, Little and Burke, HuGE 2004 • Genotype prevalence • Gene - disease association • Gene - gene interactions • Gene - environment interactions • Assessment of Genetic tests HuGE problem: 25,000 genes, their combinations and interactions with risk factors

8. “Systematic application of epidemiologic methods and approaches to assess the impact of human genetic variation on health and disease” • Khoury, Little and Burke, HuGE 2004 • HuGE involves a continuum from gene discovery to applications in health care and disease prevention • “Genetic Epidemiology with a capital E”. D Thomas. Genet Epidemiol 2000;19:289

9. Human Genome Epidemiology Network (HuGENet) Knowledge Integration on Genetic Variation and Health • Global collaboration of individuals and organizations to assess population impact of genomics on population health • Information Exchange • Training and Technical Assistance • Knowledge Base Development • Information Dissemination

10. HuGENet • Executive Committee • 4 Coordinating Centers (Atlanta, Cambridge, Ioannina, Ottawa) • 8 Collaborating Journals • > 700 “Members” from > 40 Countries

12. Human Genome Epidemiology Network: From Primary Research to Knowledge Integration Epidemiologic Studies/Platforms Guide Research Agenda HuGENet Knowledge Base “Genomics and Population Health” Analyses and Publications Guide Health Services & Inform Public Policy Systematic Reviews

13. Epidemiologic Studies/Platforms • Individual Studies • Cross sectional studies • Case-control studies • Cohort studies/biobanks • Consortia/Networks • P3G • “Network of Networks”

18. Human Genome Epidemiology Network: From Primary Research to Knowledge Integration Epidemiologic Studies/Platforms Guide Research Agenda HuGENet Knowledge Base “Genomics and Population Health” Analyses and Publications Guide Health Services & Inform Public Policy Systematic Reviews

21. Number of Published HuGE Papers* 2001-2004 • Year Prevalence Associations Interactions • 2001 308 2141 436 • 2002 349 2799 569 • 2003 323 3010 598 • 2004 368 3486 604 • MOST ASSOCIATION STUDIES ARE CASE-CONTROL STUDIES

23. Bogardus et al. JAMA 1999;281:1919-26. Aim: To examine clinical epi quality of recent papers in molecular genetic analysis 40 inferential articles in 4 clinical journals (1995) 38% articles passed 4 or less methodologic standards Methodologic % Standard Reproducibility 38% Objectivity 33% Case Group 78% Case Spectrum 88% Comparison Group 70% Comparison Spectrum 88% Quantitative Summary 90% Epidemiological Quality in Molecular GeneticResearch: Need for Methodological Standards

25. What is STROBE ? • STROBE: international collaborative initiative for STrengthening the Reporting of OBservational studies in Epidemiology

27. Human Genome Epidemiology Network: From Primary Research to Knowledge Integration Epidemiologic Studies/Platforms Guide Research Agenda HuGENet Knowledge Base “Genomics and Population Health” Analyses and Publications Guide Health Services & Inform Public Policy Systematic Reviews

28. The Need for Systematic Reviews:on Genetic Variation and Health • Unmanageable amounts of data • Small sample size of individual studies • Small effect size of gene-disease associations • Replication of associations • Publication bias • Heterogeneity • Generate and test hypotheses

35. Human Genome Epidemiology Network: From Primary Research to Knowledge Integration Epidemiologic Studies/Platforms Guide Research Agenda HuGENet Knowledge Base “Genomics and Population Health” Analyses and Publications Guide Health Services & Inform Public Policy Systematic Reviews

36. HuGENet Products (as of September 1, 2005) • HuGE Reviews 40 • Meta/Pooled Analyses 269 • Fact sheets 13 • E-journal clubs 66 • Case studies 5 • Genotype Prevalence Database 13 • Published Literature Database 17,467 • # Genes 2003 • # Risk Factors 656 • # Outcomes 2068

41. Human Genome Epidemiology Network: From Primary Research to Knowledge Integration Epidemiologic Studies/Platforms Guide Research Agenda HuGENet Knowledge Base “Genomics and Population Health” Analyses and Publications Guide Health Services & Inform Public Policy Systematic Reviews