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Testing of symptomatic persons for infection with SARS-CoV-2 is occurringworldwide. We propose two types of case-control studies that can be carried outjointly in test-settings for symptomatic persons. The first, the test-negativecase-control design (TND) is the easiest to implement; it only demandscollecting information about potential risk factors for COVID-19 from thetested symptomatic persons. The second, standard case-control studies withpopulation controls, requires the collection of data on one or more populationcontrols for each person who is tested in the test facilities, so thattest-positives and test-negatives can each be compared with populationcontrols. The TND will detect differences in risk factors between symptomaticpersons who have COVID-19 (test-positives) and those who have other respiratoryinfections (test-negatives). However, risk factors with effect sizes of equalmagnitude for both COVID-19 and other respiratory infections will not beidentified by the TND. Therefore, we discuss how to add population controls tocompare with the test-positives and the test-negatives, yielding two additionalcase-control studies. We describe two options for population control groups:one composed of accompanying persons to the test facilities, the other drawnfrom existing country-wide health care databases. We also describe otherpossibilities for population controls. Combining the TND with populationcontrols yields a triangulation approach that distinguishes between exposuresthat are risk factors for both COVID-19 and other respiratory infections, andexposures that are risk factors for just COVID-19. This combined design can beapplied to future epidemics, but also to study causes of non-epidemic disease.

epidemiology

The test-negative design with additional population controls: a  practical approach to rapidly obtain information on the causes of the  SARS-CoV-2 epidemic