A Test-Negative Design with Additional Population Controls Can Be Used to Rapidly Study Causes of the SARS-CoV-2 Epidemic

Epidemiology, vol. 31, pp. 836–843

Abstract

Testing of symptomatic persons for infection with severe acute respiratory syndrome coronavirus-2 is occurring worldwide. We propose two types of case-control studies that can be carried out jointly in test settings for symptomatic persons. The first, the test-negative case-control design (TND) is the easiest to implement; it only requires collecting information about potential risk factors for Coronavirus Disease 2019 (COVID-19) from the tested symptomatic persons. The second, standard case-control studies with population controls, requires the collection of data on one or more population controls for each person who is tested in the test facilities, so that test-positives and test-negatives can each be compared with population controls. The TND will detect differences in risk factors between symptomatic persons who have COVID-19 (test-positives) and those who have other respiratory infections (test-negatives). However, risk factors with effect sizes of equal magnitude for both COVID-19 and other respiratory infections will not be identified by the TND. Therefore, we discuss how to add population controls to compare with the test-positives and the test-negatives, yielding two additional case-control studies. We describe two options for population control groups: one composed of accompanying persons to the test facilities, the other drawn from existing country-wide healthcare databases. We also describe other possibilities for population controls. Combining the TND with population controls yields a triangulation approach that distinguishes between exposures that are risk factors for both COVID-19 and other respiratory infections, and exposures that are risk factors for just COVID-19. This combined design can be applied to future epidemics, but also to study causes of nonepidemic disease.

Authors 4

1. Jan Paul Vandenbroucke corresponding Aachen Department of Clinical Epidemiology

   Aarhus University · Leiden University Medical Center · London School of Hygiene & Tropical Medicine

   Affiliation as printed

   Department of Clinical Epidemiology, Aarhus University, Denmark

   Department of Clinical Epidemiology, Leiden University Medical Center, The Netherlands

   Departments of Medical Statistics, Non-communicable Disease Epidemiology and Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom

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2. Elizabeth Bailey Brickley

   London School of Hygiene & Tropical Medicine

   Affiliation as printed

   Departments of Medical Statistics, Non-communicable Disease Epidemiology and Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom

   Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com)

3. Christina M. J. E. Vandenbroucke‐Grauls

   Amsterdam University Medical Centers

   Affiliation as printed

   Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, The Netherlands

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4. Neil Pearce

   London School of Hygiene & Tropical Medicine

   Affiliation as printed

   Departments of Medical Statistics, Non-communicable Disease Epidemiology and Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom

   Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com)