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:
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
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
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
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?
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
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
A Multigenerational Birth Cohort Study International Workshop on a Birth Cohort, Toronto, Feb. 2003
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
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 )
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
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
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)
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?
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.
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