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

Epidemiology. 2020 Nov;31(6):836-843. doi: 10.1097/EDE.0000000000001251.

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.

MeSH terms

  • Betacoronavirus
  • COVID-19
  • COVID-19 Testing
  • Case-Control Studies*
  • Causality
  • Clinical Laboratory Techniques
  • Control Groups*
  • Coronavirus Infections / diagnosis
  • Coronavirus Infections / epidemiology*
  • Epidemiologic Research Design*
  • Humans
  • Pandemics
  • Pneumonia, Viral / diagnosis
  • Pneumonia, Viral / epidemiology*
  • Respiratory Tract Infections / epidemiology
  • Risk Factors
  • SARS-CoV-2