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

Testing of symptomatic persons for infection with SARS-CoV-2 is increasingly used in different countries. To collect information to understand the causes of the COVID-19 pandemic, 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 demands collecting information about potential risk factors for COVID-19 from the tested symptomatic persons. The second, standard case-control studies (CC) 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. We first summarize the TND and explain how to add it to large-scale testing of symptomatic persons. 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. Second, we discuss how to add population controls to compare with the test-positives and the test-negatives separately, yielding two additional case-control studies. We describe two different types of population control groups: one composed of accompanying persons to the test facilities, the other drawn from existing country-wide health care databases. We also describe other types of population controls that may be most suitable in other situations. Combining the test-negative design 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.