  Testing of symptomatic persons for infection with SARS-CoV-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 demands
collecting information about potential risk factors for 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 health care 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 non-epidemic disease.
