Background: The process of creating a cohort or cohort substudy may induce misleading exposure–health effect associations through collider stratification bias (i.e., selection bias) or bias due to conditioning on an intermediate. Studies of environmental risk factors may be at particular risk.

Objectives: We aimed to demonstrate how such biases of the exposure–health effect association arise and how one may mitigate them.

Methods: We used directed acyclic graphs and the example of bone lead and mortality (all-cause, cardiovascular, and ischemic heart disease) among 835 white men in the Normative Aging Study (NAS) to illustrate potential bias related to recruitment into the NAS and the bone lead substudy. We then applied methods (adjustment, restriction, and inverse probability of attrition weighting) to mitigate these biases in analyses using Cox proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Analyses adjusted for age at bone lead measurement, smoking, and education among all men found HRs (95% CI) for the highest versus lowest tertile of patella lead of 1.34 (0.90, 2.00), 1.46 (0.86, 2.48), and 2.01 (0.86, 4.68) for all-cause, cardiovascular, and ischemic heart disease mortality, respectively. After applying methods to mitigate the biases, the HR (95% CI) among the 637 men analyzed were 1.86 (1.12, 3.09), 2.47 (1.23, 4.96), and 5.20 (1.61, 16.8), respectively.

Conclusions: Careful attention to the underlying structure of the observed data is critical to identifying potential biases and methods to mitigate them. Understanding factors that influence initial study participation and study loss to follow-up is critical. Recruitment of population-based samples and enrolling participants at a younger age, before the potential onset of exposure-related health effects, can help reduce these potential pitfalls.

Citation: Weisskopf MG, Sparrow D, Hu H, Power MC. 2015. Biased exposure–health effect estimates from selection in cohort studies: are environmental studies at particular risk? Environ Health Perspect 123:1113–1122;  http://dx.doi.org/10.1289/ehp.1408888

Address correspondence to M.G. Weisskopf, Harvard T.H. Chan School of Public Health, EOME, Landmark Center, 3rd Floor East, P.O. BOX 15677, Boston, MA 02215 USA. Telephone: (617) 384-8872. E-mail: mweissko@hsph.harvard.edu

We acknowledge R.M. Seals for his comments on an earlier version of this paper.

This work was supported by grants R01-ES05257and ES-00002 from the National Institutes of Health (NIH). D.S. is supported by a VA Research Career Scientist award, and M.C.P. is supported by NIH grant T32 AG027668. The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts.

The authors declare they have no actual or potential competing financial interests.

Received: 27 June 2014 Accepted: 6 May 2015 Advance Publication: 8 May 2015 Final Publication: 1 November 2015

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