A cautionary note about estimating effects of secondary exposures in cohort studies

K. A. Ahrens, S. R. Cole, D. Westreich, R. W. Platt, E. F. Schisterman

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Cohort studies are often enriched for a primary exposure of interest to improve cost-effectiveness, which presents analytical challenges not commonly discussed in epidemiology. In this paper, we use causal diagrams to represent exposure-enriched cohort studies, illustrate a scenario wherein the risk ratio for the effect of a secondary exposure on an outcome is biased, and propose an analytical method for correcting for such bias. In our motivating example, maternal smoking (Z) is a cause of fetal growth restriction (X), which subsequently affects preterm birth (Y) (i.e., Z → X → Y); strong positive associations exist between both Z, X and X, Y; and enrichment for X increases its prevalence from 10% to 50%. In the X-enriched cohort, unadjusted and X-adjusted analyses lead to bias in the risk ratio for the total effect of Z on Y. After application of inverse probability weights, the bias is corrected, with a small loss of efficiency in comparison with a same-sized study without X-enrichment. With increasing interest in conducting secondary analyses to reduce research costs, caution should be employed when analyzing studies that have already been enriched, intentionally or unintentionally, for a primary exposure of interest. Causal diagrams can help identify scenarios in which secondary analyses may be biased. Inverse probability weights can be used to remove the bias.

Original languageEnglish (US)
Pages (from-to)198-203
Number of pages6
JournalAmerican journal of epidemiology
Issue number3
StatePublished - Feb 1 2015
Externally publishedYes


  • Bias (epidemiology)
  • Cohort studies
  • Directed acyclic graph
  • Epidemiologic methods
  • Oversampling

ASJC Scopus subject areas

  • Epidemiology


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