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Harmonisation between cohorts:Holy Grail or Fool’s errand
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Some of the problems:
• Lots of genes with modest effects
• Ergo, lots of genes modifying environmental effects
• Ill-defined outcomes
• Reliance on proximal phenotypes
• (Usually) imprecise exposure measurement
• Size versus detail; Cost!
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Bigger studies (combining cohorts)
versus
Better measurement
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Combination likely to inflate misclassification
• Genetic
• Outcome
• Exposure
…..therefore, do the gains in sample size compensate for these effects?
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Increased power for improved allele classification is not great for relatively common alleles
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OUTCOMES - ASTHMA
• Physician diagnosed – direct observation
• Physician diagnosed – parent reported
• Parent-reported symptoms– Many studies have ISAAC or equivalent– GA2LEN survey suggests many studies use
idiosyncratic definitions of eczema & hay fever
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What about sub-phenotypes?
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Comparison of sRaw in children with no history of wheeze, and unconfirmed and confirmed wheeze.
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OUTCOMES – INTERMEDIATE
• Pulmonary function measurements– Equipment, protocols, standards
• Assessment of allergy– SPT v Specific IgE
• Bronchial hyperresponsiveness– Method, data censoring, repeatability
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Maternal anxiety score 32 weeks GA
ORadj Asthma ORadj Asthma + BHR
1st quartile 1 (reference) 1 (reference)
2nd quartile 1.36 (1.09-1.71) 1.35 (0.79-2.30)
3rd quartile 1.42 (1.14-1.77) 1.55 (0.93-2.58)
4th quartile 1.65 (1.30-2.08) 2.09 (1.24-3.53)
Stratification of asthma by objective measures, e.g.
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EXPOSURES
• Mostly proxy measures (questionnaires, derived variables, modelled)
• Where directly assessed, often focus of one study (diet, pollution, allergen, endotoxin)
• Repeat measures likely to reduce misclassification
• Can we compare different methods?
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• Outcome and exposure misclassification have major effect on power to detect interactions
• Some outcomes sufficiently similar between cohorts to allow combined analyses
• Even with ‘objective’ outcomes there are potential problems
• Repeat assessment of exposures can reduce effect of misclassification
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The fool doth think he is wise, but the wise man knows himself to be a fool.