Negative controls: Concepts and caveats

Unmeasured confounding is a well-known obstacle in causal inference. In recent years, negative controls have received increasing attention as a important tool to address concerns about the problem. The literature on the topic has expanded rapidly and several authors have advocated the more routine use of negative controls in epidemiological practice. In this article, we review concepts and methodologies based on negative controls for detection and correction of unmeasured confounding bias. We argue that negative controls may lack both specificity and sensitivity to detect unmeasured confounding and that proving the null hypothesis of a null negative control association is impossible. We focus our discussion on the control outcome calibration approach, the difference-in-difference approach, and the double-negative control approach as methods for confounding correction. For each of these methods, we highlight their assumptions and illustrate the potential impact of violations thereof. Given the potentially large impact of assumption violations, it may sometimes be desirable to replace strong conditions for exact identification with weaker, easily verifiable conditions, even when these imply at most partial identification of unmeasured confounding. Future research in this area may broaden the applicability of negative controls and in turn make them better suited for routine use in epidemiological practice. At present, however, the applicability of negative controls should be carefully judged on a case-by-case basis.