MethodsTest-Negative Designs Differences and Commonalities with Other Case–Control Studies with “Other Patient” ControlsVandenbroucke, Jan P.a,b,c; Pearce, NeildAuthor Information From the aDepartment of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands bDepartment of Clinical Epidemiology, Aarhus University Denmark cDepartment of Medical Statistics, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, United Kingdom dDepartment of Medical Statistics, London School of Hygiene and Tropical Medicine, United Kingdom. This work was supported by the European Research Council under the European Union’s Seventh Framework Programme [FP7/2007–2013 / ERC grant agreement number 668954]. The Centre for Global NCDs is supported by the Wellcome Trust Institutional Strategic Support Fund (097834/Z/11/B). The authors report no conflicts of interest. Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). Correspondence: Jan P. Vandenbroucke, Department of Clinical Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected]. Epidemiology: November 2019 - Volume 30 - Issue 6 - p 838-844 doi: 10.1097/EDE.0000000000001088 Buy SDC Metrics Abstract Test-negative studies recruit cases who attend a healthcare facility and test positive for a particular disease; controls are patients undergoing the same tests for the same reasons at the same healthcare facility and who test negative. The design is often used for vaccine efficacy studies, but not exclusively, and has been posited as a separate type of study design, different from case–control studies because the controls are not sampled from a wider source population. However, the design is a special case of a broader class of case–control designs that identify cases and sample “other patient” controls from the same healthcare facilities. Therefore, we consider that new insights into the test-negative design can be obtained by viewing them as case–control studies with “other patient” controls; in this context, we explore differences and commonalities, to better define the advantages and disadvantages of the test-negative design in various circumstances. The design has the advantage of similar participation rates, information quality and completeness, referral/catchment areas, initial presentation, diagnostic suspicion tendencies, and preferences by doctors. Under certain assumptions, valid population odds ratios can be estimated with the test-negative design, just as with case–control studies with “other patient” controls. Interestingly, directed acyclic graphs (DAGs) are not completely helpful in explaining why the design works. The use of test-negative designs may not completely resolve all potential biases, but they are a valid study design option, and will in some circumstances lead to less bias, as well as often the most practical one. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.