Harmonisation between cohorts:Holy Grail or Fool’s errand

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!

Bigger studies (combining cohorts)

versus

Better measurement

Combination likely to inflate misclassification

• Genetic

• Outcome

• Exposure

…..therefore, do the gains in sample size compensate for these effects?

Increased power for improved allele classification is not great for relatively common alleles

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

What about sub-phenotypes?

Comparison of sRaw in children with no history of wheeze, and unconfirmed and confirmed wheeze.

OUTCOMES – INTERMEDIATE

• Pulmonary function measurements– Equipment, protocols, standards

• Assessment of allergy– SPT v Specific IgE

• Bronchial hyperresponsiveness– Method, data censoring, repeatability

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.

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?

• 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

The fool doth think he is wise, but the wise man knows himself to be a fool.