Vision for Accelerating the Development and Dissemination of the Knowledge Base on Human Genetic Variation and Health Muin J. Khoury

Outline The Public Health Genomics Enterprise Evolution of Networks Added Value of HuGENet Vision for an Online Encyclopedic Distributed Knowledge Base

The “Public Health Genomics” Enterprise –Developing and applying Genome-based knowledge for the benefit of population health –The central role of knowledge integration

Communication and Stakeholder Engagement Improvement in Population Health Informing Public Policy Developing and Evaluating Health Services Society Research Education and Training Genome- based Science and Technology Knowledge Integration Within And Across Disciplines Population Sciences Humanities and Social Sciences From the Bellagio Group

Risk Factors Demographics Diet Occupation Smoking Alcohol Environment Adverse Health Outcomes The End of Black Box Epidemiology

proteases Preterm Delivery Uterine Contractions Cervical change Infection: - Chorion-Decidual - Systemic Decidual Hemorrhage Abruption CRH E1-E3 Prothrombin G20210A Factor V Leiden Protein C, Protein S Type 1 Plasminogen MTHFR Pathological Uterine Distention Multifetal Pregnancy Polyhydramnios Uterine abnormalities Inflammation Maternal-Fetal Stress Premature Onset of Physiologic Initiators Activation of Maternal/Fetal HPA Axis CRH + + Chorion Decidua uterotonins Mechanical stretch Gap jct IL-8 PGE2 Oxytocin recep PROM Interleukin s TNF-α Fas L Adapted from: C. J. Lockwood, Paediatr Perinat Epidemiol 15, 78 (2001) & X. Wangl. Paediatr Perinat Epidemiol 15, 63 (2001) MMPs Susceptibility to environmental toxins CYP1A1 GSTT1 Courtesy S. Dolan MD

Data/Sample Collection Platforms Reports & Publications Network Evolution of Networks and Consortia

Data/Sample Collection Platforms Reports & Publications Systematic Reviews Updated Summary Knowledge base Network Evaluation of Genetic Tests in Practice & Prevention Identify Gaps For Research Evolution of Networks and Consortia

Data/Sample Collection Platforms Database(s) Reports & Publications Database(s) Systematic Reviews Database (s) Updated Summary Knowledge base(s) Portal Network of Networks Communicate, Assist, Harmonize Evaluation of Genetic Tests in Practice & Prevention Identify Gaps For Research Evolution of Networks and Consortia: Network of Networks

Data/Sample Collection Platforms Database(s) Reports & Publications Database(s) Systematic Reviews Databases Updated Summary Knowledge base(s) Network of Networks Communicate, Assist, Harmonize + HuGENet Evaluation of Genetic Tests in Practice & Prevention Identify Gaps For Research STROBE Statement Develop Methods Foster Research Conduct Workshops HuGE Journal/Portal Evolution of Networks and Consortia HuGENet Contribution

Data/Sample Collection Platforms Database(s) Reports & Publications Database(s) Systematic Reviews Databases Updated Summary Knowledge base(s) Network of Networks Communicate, Assist, Harmonize + HuGENet Evaluation of Genetic Tests in Practice & Prevention Identify Gaps For Research STROBE Statement Develop Methods Foster Research Conduct Workshops HuGE Journal/Portal HuGENet Manual HuGENet Software Develop Methods FosterResearch Conduct Workshops Evolution of Networks and Consortia HuGENet Contribution

Data/Sample Collection Platforms Database(s) Reports & Publications Database(s) Systematic Reviews Databases Network of Networks Communicate, Assist, Harmonize + HuGENet Evaluation of Genetic Tests in Practice & Prevention Identify Gaps For Research STROBE Statement Develop Methods Foster Research Conduct Workshops HuGE Journal/Portal HuGENet Manual HuGENet Software Develop Methods FosterResearch Conduct Workshops Dissemination Methods for Grading evidence & Synthesis Develop methods Evolution of Networks and Consortia HuGENet Contribution Online Encyclopedia

Proposed Online Encyclopedia of Human Genetic Variation and Health Succinct summary of gene-disease associations Online and widely disseminated Updated regularly Peer reviewed Distributed knowledge base Evidence based synthesis Grading of evidence

Clinical Evidence “Summarises the current state of knowledge and uncertainty about the prevention and treatment of clinical conditions, based on thorough searches and appraisal of the literature. It is neither a textbook of medicine nor a set of guidelines. It describes the best available evidence from systematic reviews, RCTs and observational studies where appropriate, and if there is no good evidence it says so.”

Diseases are Associated with Multiple Genes and Vice Versa Diseases A B C D E F G Genes/Variants

What could an Encyclopedia Entry Look Like? Health Outcome Gene (s) Association for each gene with outcome (RR, AF, including gene-gene and gene-environment interactions) –Systematic reviews –Scattered studies Methodologic comments: Grading of evidence Clinical and public health implication References and link to other internet sites/databases

Grading of Evidence? Size of effect –ASmall effect (RR <1.5) –BModerate effect (RR 1.5-4) –C Large effect (RR>4) Replication –ASingle or scattered studies –BMeta analysis of group data –CMeta analysis of individual data Modified from Ioannidis, Int J Epi 2005

Grading of Evidence? Methodology –AClear presence of bias –BUncertain of presence of bias –CClear protection from bias Biology –ANo or negative biologic data –BLimited or inconsistent functional data –CBiologic data supportive or consistent Modified from Ioannidis, Int J Epi 2005

GRADING OF EVIDENCE? Effect Size Replica- tion Metho- dology Biology A B C NO EVIDENCE WEAK TO MODERATE EVIDENCE ----STRONG EVIDENCE---- Criterion &Grade

Data/Sample Collection Platforms Database(s) Reports & Publications Database(s) Systematic Reviews Database (s) Online Encycopledia Network of Networks Communicate, Assist, Harmonize Evaluation of Genetic Tests in Practice & Prevention Identify Gaps For Research Evolution of Networks and Consortia: Network of Networks