Selecting on treatment: a pervasive form of bias in instrumental variable analyses

Am J Epidemiol. 2015 Feb 1;181(3):191-7. doi: 10.1093/aje/kwu284. Epub 2015 Jan 21.


Instrumental variable (IV) methods are increasingly being used in comparative effectiveness research. Studies using these methods often compare 2 particular treatments, and the researchers perform their IV analyses conditional on patients' receiving this subset of treatments (while ignoring the third option of "neither treatment"). The ensuing selection bias that occurs due to this restriction has gone relatively unnoticed in interpretations and discussions of these studies' results. In this paper we describe the structure of this selection bias with examples drawn from commonly proposed instruments such as calendar time and preference, illustrate the bias with causal diagrams, and estimate the magnitude and direction of possible bias using simulations. A noncausal association between the proposed instrument and the outcome can occur in analyses restricted to patients receiving a subset of the possible treatments. This results in bias in the numerator for the standard IV estimator; the bias is amplified in the treatment effect estimate. The direction and magnitude of the bias in the treatment effect estimate are functions of the distribution of and relationships between the proposed instrument, treatment values, unmeasured confounders, and outcome. IV methods used to compare a subset of treatment options are prone to substantial biases, even when the proposed instrument appears relatively strong.

Keywords: collider stratification bias; epidemiologic methods; instrumental variable; selection bias.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Comparative Effectiveness Research / standards*
  • Diabetes Mellitus / chemically induced
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Male
  • Middle Aged
  • Observational Studies as Topic
  • Selection Bias


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors