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A Tale of (More Than ?) Two Cohorts – from Canada By Dr. John Frank, Scientific Director, CIHR-Institute of Population & Public Health Professor, Dept.

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Presentation on theme: "A Tale of (More Than ?) Two Cohorts – from Canada By Dr. John Frank, Scientific Director, CIHR-Institute of Population & Public Health Professor, Dept."— Presentation transcript:

1 A Tale of (More Than ?) Two Cohorts – from Canada By Dr. John Frank, Scientific Director, CIHR-Institute of Population & Public Health Professor, Dept. of Public Health Sciences, University of Toronto Senior Scientist, Institute for Work and Health, Toronto November 16 -19, 2005

2 Why study gene-environment interactions?  Most disease burden is jointly determined by interaction of individual genetic endowments and complex sequence of environmental factors  These gene-environment interactions require decades to fully manifest over the life course  Diseases and conditions of later life occur in some and not others because of intense interactions between particular genetic constitutions and particular sequence of social and physical environments

3 Why study gene-environment interactions? cont’d  BUT…little is known about underlying causes of these conditions and why they are now increasing in frequency – for e.g. asthma  Requires study of these sequential events in large numbers of people over time, on whom baseline genetic and repeated environmental exposures are taken, to:  understand the causal pathways; and,  develop disease prevention strategies

4 Canadian “Contenders” in the Great Cohort Competition  Canadian Longitudinal Study of Aging [CLSA] – let by the CIHR – Institute of Aging  Canadian National (Multi-Generational) Birth Cohort [CN/MBC] – led by the CIHR Institutes of Human Development, Child and Youth Health; Population and Public Health; and Genetics  Both of the above are also called the Canadian Lifelong health Initiative [CLHI]  A “Canadian” Cancer / Chronic-Disease Cohort?

5 Canada’s scientific capacity for a Birth Cohort Study  Disciplinary perspectives required in design and execution of a cutting-edge birth cohort – for example: reproductive and developmental biology, neurosciences, genetics, epidemiology and biostatistics  Small size of scientific communities – help facilitate formation of required trans-disciplinary teams  Determinants of health conceptual framework – provides scientific context  Single payer health system  Capacity to link administrative datasets with interview and examination data  Unique ‘environmental exposures’ in the Canadian context

6  CLSA first “out of the gates”  Protocol with 3 PIs, 200 Canadian collaborators  International peer-review of protocol  50,000 “tracking cohort” and 30,000 “intensive cohort”, age 40 +  CNBC focused on quantitative traits (height, weight, adiposity, BP, lipids, [IgE]/FEV 1, attentiveness) for sample size reasons (n = 30 to 50,000) given costs per subject  Linking CLSA and CNBC into a multi-generational cohort suggested at CNBC meeting  Excited Canadian geneticists and international experts Linking Adult and Child Cohorts

7 A Multigenerational Birth Cohort Study International Workshop on a Birth Cohort, Toronto, Feb. 2003

8 Linking Adult and Child Cohorts  Advantages  Easier to “market”  Children can be link to recruiting grandparents  Exposures and DNA over 3 generations  Ascertain intermediate phenotypes on parents  Can supplement with sample of older adults without grandchildren  Disadvantages  Excludes elderly parents and therefore children of recent adult immigrants  Excludes children of grandparents who died prematurely if CLSA is sampling from CNBC  Timing / financing challenges

9 Cancer/Chronic Disease Cohort  Cancer community convinced of necessity  Emphasis on modifiable environmental and life-style risk factors  Difficult/impossible to measure retrospectively (case-control)  EPIC, Biobank very expensive, payoff questionable?  Other Institutes/communities “not satisfied with” chronic disease aspects of CLSA  Cardiovascular disease  Neurological disease  Arthritis and other musculoskeletal disease  Canada could participate in international cancer cohort study (John Potter’s “Last Cohort”; n = 10 6 )

10 Studying Genetic and Environmental Contributions to Disease Causation: An Uneven Playing Field Measurement Attribute Genetic Exposure Measures Environmental Exposure Measures Time-varying? No – one sample per lifetime is enough (unless gene expression arrays are used) Yes – new samples needed whenever exposure changes Data Collection CostsCheap (on a sample)Expensive (real-time assays) Sample Storage (for later analysis) Easy (buccal swab, buffy coat) Difficult (e.g. air/water/diet samples) Data Analysis CostsGetting cheaper by the day Getting Costlier (as awareness of chemical/physical/biological complexity increases) Overall Ease & Cost of Accurate Ascertainment Easy / CheapDifficult / Costly

11 Comparison of “Huge, Data-Thin” Cohorts (e.g. U.K. BioBank) And “Small, Data-Thick” Cohorts (e.g. Southampton) Cohort Attribute Huge – ThinSmall – Thick Cost Per Subject due to: Low (e.g. < $500. / data-wave) High (if > $1,000. / data-wave) Sample Size due to choice of: 500,000 + < 30,000 Exposures Cheap-to-collect/store measures – e.g. genetic Expensive, balanced mix of environmental and genetic measures Outcomes Cheap-to-collect administrative data – e.g. hospitalizations for diagnoses/deaths (dichotomous)   SS. Expensive, directly measured bi- chemical physiologic, imaging, functional outcomes (often continuous)   SS. Leading “Exposure- Measure Bias” Large environmental exposure error >> genetic factor errors “Better balanced errors” for environmental versus genetic factors Leading to: Biased main effects and interaction results Less biased results

12 How Many Cohorts?  Can Canada fund more than one large national cohort study?  Sample size dictated by rarest outcomes  100,000-300,000 too small even for common cancers in adults  30,000-50,000 sufficient for healthy aging and most chronic diseases in adults, and for detecting gene-environment interactions influencing quantitative traits in both adults and children  Exposures often outcome-specific for children  Pre- and peri-conceptional exposures and pregnancy outcome  Indoor air exposures and asthma  Maternal-child interaction and ADHD or conduct disorder (CD)

13 Canadian Pregnancy/Birth Cohort: Remaining Questions 1) Is a cohort study of primarily quantitative traits of major scientific value, or must dichotomous diseases be the primary outcomes? 2) Can a single, omnibus cohort study address the exposures and outcomes most important for Canadian mothers and children? 3) Are we better off with several very small purpose-built cohort studies of specific outcomes and exposures important to child health (like IHDCYH’s recently-launched RFA on asthma)? 4) Should we become the “Canadarm” of the U.S.’s NCS? At what level of investment / sample size (10% = 10,000)? 5) What is the precise scientific value of a multi-generational study? 6) Should the CLSA wait until the CNBC “catches up”? What are the resultant risks and costs?

14 Funding Issues  Can Canadian contribution to international cancer cohort be funded from existing sources? (n = 50,000? 100,000?)  CLSA requires substantial resources outside of IA’s (and CIHR’s) current budget – what to do?  Purpose-built pregnancy/birth cohort studies for powerful gene-environmental interaction modeling (n = 30,000 +) cannot be modeled on IHDCYH’s asthma RFA  Partners like Allergen, NRC, and CHMC not readily available for pre-conception exposures and ADHD/CD  Cannot realistically be funded from any individual Institute’s $8 m annual budget (or CIHR’s current budget of $700 m, annually) given other pressures on them.

15 Next Steps  Meeting in Toronto on December 8-9  Distinguished international advisory panel  Canadian experts in reproductive/child health, genetics, aging, and cancer  Potential federal partners (StatsCan, Public Health Agency of Canada, Social Science and Health Research Council, Health Canada)  Discuss Canada’s scientific “cohort niche”  Panel to advise CIHR on best strategy(ies) to pursue  Decision by CIHR President, VPs, and SDs  Decision by CIHR Governing Council  Joint (with partners) “ask” for additional funding to ? Federal Cabinet – new “Big Science Review” Process

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