Negative controls: a tool for detecting confounding and bias in observational studies

Abstract

Noncausal associations between exposures and outcomes are a threat to validity of causal inference in observational studies. Many techniques have been developed for study design and analysis to identify and eliminate such errors. Such problems are not expected to compromise experimental studies, where careful standardization of conditions (for laboratory work) and randomization (for population studies) should, if applied properly, eliminate most such noncausal associations. We argue, however, that a routine precaution taken in the design of biologic laboratory experiments--the use of "negative controls"--is designed to detect both suspected and unsuspected sources of spurious causal inference. In epidemiology, analogous negative controls help to identify and resolve confounding as well as other sources of error, including recall bias or analytic flaws. We distinguish 2 types of negative controls (exposure controls and outcome controls), describe examples of each type from the epidemiologic literature, and identify the conditions for the use of such negative controls to detect confounding. We conclude that negative controls should be more commonly employed in observational studies, and that additional work is needed to specify the conditions under which negative controls will be sensitive detectors of other sources of error in observational studies.

FIG 1

Causal diagram for the effect of an exposure of interest (A) on an outcome of interest (Y), with confounders L (assumed measured) and U (assumed uncontrolled) that cause both A and Y. The dashed line between L and U indicates that either may cause the other, and they may share common causes.

FIG 2

Causal diagram showing an ideal negative control outcome N for use in evaluating studies of the causal relationship between exposure A and outcome Y. N should ideally have the same incoming arrows as Y, except that A does not cause N; to the extent this criterion is met, N is called U-comparable to Y.

FIG 3

Causal diagram showing an ideal negative control exposure B for use in evaluating studies of the causal relationship between exposure A and outcome Y. B should ideally have the same incoming arrows as A; to the extent this criterion is met, B is called U-comparable to A. Z is an instrumental variable of the A-Y relationship and is depicted to illustrate the difference between an instrumental variable and a negative control variable.