P3G: an international consortium in Human Genome Epidemiology Ultimate Goals: For the understanding of gene-environment causes of chronic diseases For better public health strategies

The Causal Complexity of Chronic Diseases Diabetes Asthma Heart Disease Schizophrenia Cancer Multiple Sclerosis Obesity Arthritis Genetics Environment Diet & Lifestyle Social Structure Most common disease in technologically advanced societies are multifactorial in origin. They are the product of interaction between our genetic endowment and the world around us acting over a human lifetime. “webs of causation”

Why Study Gene-Environment Interactions? Obtain a better estimate of the population attributable risk for genetic and environmental risk factors by accounting for their joint interactions Strengthen the associations between environmental factors and diseases by examining these in genetically susceptible individuals Help dissect disease mechanisms by focusing on biological pathways most relevant to that disease, and environmental factors most relevant to the pathway. Determine which specific compounds in a complex mixture of chemicals (from pollution, diet, etc.) cause disease. Use the information to design new preventative and therapeutic strategies Offer tailored preventive advice that is based on the knowledge of the genetic profile of an individual. Hunter, Nature Reviews/Genetics 2005

Resources needed for identifying genetic risk factors and gene-environment interactions affecting the predisposition to chronic diseases Comprehensive knowledge of genetic variation Genotyping Technologies Cohorts - Phenotypes - Exposures - Large Size Analytical Tools HapMap P3G

Example of Sample Size Issue for detecting ONE interaction for a dichotomous trait and a 10% exposure Hunter, Nature Reviews/Genetics 2005

What 10,000 incident cases in a gene-environment study can provide: (with power calculations that that take into account considerations of misclassification of exposure and outcome data, and realistic data collection scenarios) For genotypic and environmental prevalences of 10% and above, 10,000 cases will provide adequate power for interaction effects with an MDOR greater than 2. (MDORs; defined as the smallest odds ratio that can be detected at p=10-4 and power=80%). Paul Burton, UK BioBank Technical Report 2005

What 10,000 incident cases in a gene-environment study can provide: (with power calculations that that take into account considerations of misclassification of exposure and outcome data, and realistic data collection scenarios) 2. For a genotypic prevalence as low as 1% there will be adequate power to detect substantial (OR between 2 and 3) direct genetic effects. For this low genotype prevalence, gene-environment interactions will only be detectable for very large interaction effects (e.g. OR > 7). 3. 10,000 cases will provide a powerful platform for genome-wide indirect association studies (requiring rigorous definition of statistical significance of p<10-7). Paul Burton, UK BioBank Technical Report 2005

How long does it take to reach 10,000 cases in a cohort with 500,000 cases? Breast cancer (F) 17 yrs Colorectal cancer 22 yrs Prostate cancer (M) Lung cancer 34 yrs Stroke 18 yrs MI and coronary death 8 yrs Diabetes mellitus 6 yrs COPD 13 yrs Hip fracture 21 yrs Alzheimer’s disease Parkinson’s disease 23 yrs Paul Burton, UK BioBank Technical Report 2005

Public Population Project in Genomics A consortium dedicated to fostering international collaboration between researchers and projects in the field of population genomics

P3G: History and Launching Phase (2003-2005) International meetings leading to the creation of P3G: 2003: London, Montreal, Manchester 2004: Helsinki, Tallinn, Toronto Supported by: Wellcome Trust, European Union Genome Canada and Genome Quebec Non-for-profit organization incorporated in 2004 Secretariat and Observatory created February 2005 Seed money from Genome Quebec and Genome Canada for the launching phase Incorporated in 2004… but the project goes back to 2002 A small secretariat offers adminsitrative support and lead some of the work required to fulfill the need of P3G members. It also houses the P3G Observatory.

P3G mandate create a network in population genomics that will comprise over 3 million participants for epidemiological studies provide statistical power for analysing complex genetic and environmental determinants of health and disease leverage the combined expertise of hundreds of researchers around the world promote communication among national and international organizations increase the ability to share and generate new knowledge dedicated to improve public health and welfare.

P3G Consortium Model An international resource for the coordination and exchange of ideas and data that will be generated by the various population biobanks Kora-Gen LifeGene (Sweden) (Germany) Generations NHLBI (Scotland) (USA) (Europe) (Canada) Genoma Espana NIGM (Mexico) (Spain) Danubian Biobank Foundation CIGMR WAGHP (Australia) (UK) (Europe) LifeLines ALSPAC (Netherlands) (UK)

P3G Membership 3 3 Regular Member Associate Member Individual Member

NEED FOR HARMONIZATION Analogie: Bill Ollier

HARMONIZATION IS NOT REGIMENTATION

P3G Operational Chart Funders Auditors P3G General Assembly P3G Board of Directors P3G Secretariat P3G Steering Committee IWG 1 (Social/Clinical/ Environmental) IWG 2 Informatics IWG 3 Ethics and Governance IWG 4 Epidemiology/ Biostatistics Core Core Core Core Here is the operational chart of P3G’s P3G is a membership –based organization It should be noted that population biobanks who become regular members keep their own governance structure and their administrative and scientific independence. However, they join a network where they will find and develop common scientific and ethics research resources, with an aim to foster harmonization. Each biobank is free to include these tools in their strategy. Core Core Core Core Core Core Core Core P3G OBSERVATORY

International Working Groups (IWGs), leaders and early outcomes Social, Environmental and Biochemical Investigations Leader: H. Erich Wichmann (KORA-Gen, Germany) -Common Core Variables for Population Based Studies -Common DNA Quality and Quantity Control -Conceptual model for harmonization of physiologic and biochemical measures Knowledge Curation And Information Technology Jan-Eric Litton (LifeGene, Sweden) -Nomenclature Working Group -Protocols for Data Sharing -Biobank lexicon Ethics, Governance and Public Engagement Alastair Kent (Genetic Interest Group, UK) -Intellectual Property Policy -Consent form Inter-operability Epidemiology and Biostatistics Muin Khoury and Julian Little (CDC) -Leader was just appointed: first meeting in September IWG are composed of 1 expert from of each of our regular members (i.e. population based biobanks) and P3G members who are experts in the field There are four IWG covering 4 key topics EACH IWG is t

P3G Cores Principal work units of P3G, Self-funded, Focused on specific issues related to biobanks, Cores activities are reported to IWG regularly 2006 goals to create cores in areas such as: Questionnaires and Clinical Measures Population Genetics And Policymaking DNA/SNPs and Genotyping Nomenclature Laboratory Phenotypes Impact of Commercialization Environmental Assessment Federated Databases Statistics and Epidemiology Participation: Gender Age, Ethnic Differences

McGill University and Genome Quebec, The P3G Observatory: a web-site describing Biobanks and Population Genetic Studies Isabel Fortier, Ph.D. Vincent Ferretti, Ph.D. Denis Legault, MPA McGill University and Genome Quebec, Innovation Center 740 Dr. Penfield Avenue Montreal (Qc) H3A 1A4

The P3G Observatory The Observatory contains: a description of studies (57 as of May 29, 2006) a catalog of questionnaires, consent forms, etc. a search tool using key words for common variables used in genetic epidemiology a companion tool for questionnaire development and harmonization between studies www.p3gobservatory.org

57 large population-based studies Catalogue of Studies A standard way to describe population studies in genomics General Information Background Objectives Methods Status Ethics and Governance Available Documents Publications 57 large population-based studies (P3G members and non-members) 22 studies with complete information 35 studies with summary information

General Tools in Development DESIGN OF STUDIES BioBank lexicon Ethics and governance “good practices” guidance documents ETHICS AND GOVERNANCE General reference procedures for: Questionnaires development/collection; Physiological measures collection; Samples collection, manipulation, storage or analysis INFORMATION COLLECTION/ TREATMENT INFORMATION TECHNOLOGY Open source information management system for Biobanks Reference tools for statistical analysis and power calculation DATA ANALYSIS

How do we get from here to there? Meta-studies enabled by P3G From Biobanks to improving health and preventing disease: How do we get from here to there? Meta-studies enabled by P3G

P3G Future Research

P3G 2020 With the synergy of P3G: The scientific community will benefit from having a powerful international resource for gene-environment studies of complex diseases Return of investment will be quicker, more efficient and of higher quality through international harmonization Health Care Systems will benefit from accurate information for designing and implementing population health strategies

MERCI Bartha Knoppers, Leena Peltonen, Andres Metspalu, Bill Ollier, Eric Wichmann, Jan-Eric Litton, Julian Little, Muin Khoury, Alistair Kent, Lyle Palmer, Thomas Hudson, Paul Burton, Claude Laberge, Isabel Fortier and Mylene Deschenes,