A Selective Review of Negative Control Methods in Epidemiology

Purpose of Review Negative controls are a powerful tool to detect and adjust for bias in epidemiological research. This paper introduces negative controls to a broader audience and provides guidance on principled design and causal analysis based on a formal negative control framework. Recent Findings We review and summarize causal and statistical assumptions, practical strategies, and validation criteria that can be combined with subject-matter knowledge to perform negative control analyses. We also review existing statistical methodologies for the detection, reduction, and correction of confounding bias, and briefly discuss recent advances towards nonparametric identification of causal effects in a double-negative control design. There is great potential for valid and accurate causal inference leveraging contemporary healthcare data in which negative controls are routinely available. Design and analysis of observational data leveraging negative controls is an area of growing interest in health and social sciences. Despite these developments, further effort is needed to disseminate these novel methods to ensure they are adopted by practicing epidemiologists.