Negative Controls: A Tool to Detect Confounding and other Sources of Bias in Epidemiologic Studies
Noncausal associations between exposures and outcomes threaten the validity of causal inference in observational studies. Many techniques have been developed for study design and analysis to identify and eliminate such errors. Many scientists imagine that such problems are minor or nonexistent in experimental studies, where careful standardization of conditions (for laboratory work) and randomization (for population studies) should eliminate most such noncausal associations.
We argue, however, that a routine precaution taken in the design of biological 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
Marc Lipsitch is Professor of Epidemiology and Director of the Center for Communicable Disease Dynamics at the Harvard School of Public Health.
He is an author of more than 140 peer-reviewed publications on antimicrobial resistance, mathematical modeling of infectious disease transmission, bacterial and human population genetics, methods for analysis of infectious disease data, and immunity to Streptococcus pneumoniae.
Current work is focused on estimating incidence and targeting interventions for infections when data are limited, understanding the seasonality of influenza, understanding the innate and acquired immune responses to Streptococcus pneumoniae and their impact on bacterial population structure, and the biological factors maintaining long-term coexistence of strains in bacterial pathogens.
Dr. Lipsitch has received several outstanding young investigator awards and is a current or recent member of the editorial advisory boards/associate editor of PLoS Medicine, the Journal of Infectious Diseases, American Journal of Epidemiology, Epidemiology, and Epidemics. He served on the President’s Council of Advisors on Science and Technology Working Group on H1N1 Influenza and on CDC’s Team B for the 2009 H1N1 pandemic.
He has provided advice on antimicrobial resistance, SARS and influenza to local, state, and national governments and to the WHO. Dr. Lipsitch received his BA in philosophy from Yale University, completed his doctoral work in zoology at Oxford University as a Rhodes Scholar and did postdoctoral work at Emory University and at the CDC from 1995-1999. He joined the faculty of Harvard School of Public Health in 1999.
