A structured approach to hypotheses involving continuous exposures over the lifecourse

Background

Epidemiologists are often interested in examining different hypotheses for how exposures measured repeatedly over the lifecourse relate to later-life outcomes. A structured approach for selecting the hypotheses most supported by theory and observed data has been developed for binary exposures. The aim of this paper is to extend this to include continuous exposures and allow
for confounding and missing data.

Methods

We studied two examples: the association between (i) maternal weight during pregnancy and birthweight, and (ii) stressful family events throughout childhood and depression in adolescence. In each example we considered several plausible hypotheses including accumulation, critical periods, sensitive periods, change, and effect modification. We used least angle regression to select the hypothesis that explained most variation in the outcome, demonstrating appropriate methods for adjusting for confounders and dealing with missing data.

Results

The structured approach identified a combination of sensitive periods: pre-pregnancy weight, and gestational weight gain 0-20 weeks and 20-40 weeks, as the best explanation for variation in birthweight after adjusting for maternal height. A sensitive period hypothesis best explained variation in adolescent depression, with the association strengthening with the proximity of stressful family events. For each example, these models have theoretical support at least as strong as any competing hypothesis.

Conclusions

We have extended the structured approach to incorporate continuous exposures, confounding and missing data. This approach can be used in either an exploratory or confirmatory setting. The interpretation, plausibility, and consistence with causal assumptions, should all be considered when proposing and choosing lifecourse hypotheses.