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

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

3. Gene-Based Medicine in 2010? “Hypothetical Genetic Test Report” Condition Genes RR Lifetime Condition Genes RR Lifetime Prostate Ca HPC1, 2, 3 0.4 7% Prostate Ca HPC1, 2, 3 0.4 7% Alzheimer’s APOE,FAD3,XAD 0.3 10% Alzheimer’s APOE,FAD3,XAD 0.3 10% Heart disease APOB,CETP 2.5 70% Heart disease APOB,CETP 2.5 70% Colon Cancer FCC4,APC 4.0 23% Colon Cancer FCC4,APC 4.0 23% Lung Cancer NAT2 6.0 40% 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 Genes Yamada et al. NEJM 2002;347:1916-1923. Case-Control Study (5061 MI and 2242 Controls) Case-Control Study (5061 MI and 2242 Controls) Analysis of 71 candidate genes with 112 polymorphisms Analysis of 71 candidate genes with 112 polymorphisms A few associations were found…small odds ratios… A few associations were found…small odds ratios… Accompanying editorial Accompanying editorial “Findings should be used to initiate further research “Findings should be used to initiate further research Recommendations for primary prevention cannot be based on these findings.” 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. Genotype prevalence Gene - disease association Gene - gene interactions Gene - environment interactions Assessment of Genetic tests “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

7. Genotype prevalence Gene - disease association Gene - gene interactions Gene - environment interactions Assessment of Genetic tests “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 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 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 “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 Global collaboration of individuals and organizations to assess population impact of genomics on population health Information Exchange Information Exchange Training and Technical Assistance Training and Technical Assistance Knowledge Base Development Knowledge Base Development Information Dissemination Information Dissemination

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

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

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

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

21. Number of Published HuGE Papers* 2001- 2004 YearPrevalenceAssociations Interactions YearPrevalenceAssociations Interactions 20013082141 436 20013082141 436 20023492799 569 20023492799 569 20033233010 598 20033233010 598 20043683486 604 20043683486 604 MOST ASSOCIATION STUDIES ARE CASE-CONTROL STUDIESMOST ASSOCIATION STUDIES ARE CASE-CONTROL STUDIES

22. RankGene Symbol Gene name# of Papers 01-03 1 APOEapolipoprotein E481 2 ACEangiotensin I converting enzyme (peptidyl- dipeptidase A) 1 398 3 MTHFR 5,10-methylenetetrahydrofolate reductase (NADPH) 377 4 HLA- DRB1 major histocompatibility complex, class II, DR beta 1 376 5 TNFtumor necrosis factor (TNF superfamily, member 2) 346 6 GSTM1glutathione S-transferase M1253 7 HLA- DQB1 major histocompatibility complex, class II, DQ beta 1 248 8 F5coagulation factor V (proaccelerin, labile factor)213 9 GSTT1glutathione S-transferase theta 1204 10 IL10interleukin 10177

23. Epidemiological Quality in Molecular Genetic Research: Need for Methodological Standards 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%

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

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

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

36. HuGENet Products (as of September 1, 2005) HuGE Reviews 40 HuGE Reviews 40 Meta/Pooled Analyses 269 Meta/Pooled Analyses 269 Fact sheets13 Fact sheets13 E-journal clubs66 E-journal clubs66 Case studies 5 Case studies 5 Genotype Prevalence Database13 Genotype Prevalence Database13 Published Literature Database 17,467 Published Literature Database 17,467 # Genes 2003 # Genes 2003 # Risk Factors 656 # Risk Factors 656 # Outcomes 2068 # Outcomes 2068

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