The test-negative design can be used to rapidly study the causes of COVID-19

Prof Elizabeth Brickley

There is still much to learn about SARS-Cov-2, the virus responsible for the COVID-19 outbreak. For example, we are still relatively in the dark about why some people get infected and others don’t.

Testing for SARS-Cov-2, both in symptomatic people and in the general population, is a crucial part of understanding the infection, how it spreads, and how we can best prevent it. And we believe that a little-used study design, known as the test-negative design, can be adapted to study these causes of the infection.

There are many basic things that we don’t know about how infections spread – for example, we know that social distancing can reduce the risk of infection, but which activities carry the greatest risks? We know that health care workers are at higher risk, but what about other workers who have contact with the public, or travelling to work on public transport, or going to the supermarket, or exercising? And what about risk factors such as overcrowding when being ‘locked-down’?

We believe that the test-negative design, an approach which has mainly been used to study vaccine effectiveness, can be used to answer these types of questions. 

When the test-negative design is applied to COVID-19, people who come to be tested can be given a short questionnaire on risk factors, and we then compare those who test positive with those who test negative. Since people are mostly being tested because they have symptoms, those who test negative likely have a different respiratory infection. 

Thus, when we compare these two groups we can learn about risk factors that are specific for SARS-Cov-2 (rather than respiratory infections in general). We can learn even more by giving the same questionnaire to an accompanying person (e.g. the person who brought them for testing), or another control (e.g. from the same GP practice). 

By comparing the test-positives with their controls, we can learn about risk factors for SARS-Cov-2, and by comparing the test-negatives with their controls, we can learn about risk factors for other respiratory infections. By putting the three sets of analyses together – using triangulation – we can learn a great deal. 

This can rapidly provide information which will be useful in deciding which aspects of social distancing can be relaxed, and which will remain important, even after strict lock-down finishes.


Jan P Vandenbroucke, Elizabeth B Brickley, Christina M J E Vandenbroucke-Grauls & Neil PearceAnalysis proposals for test-negative design and matched case-control studies during widespread testing of symptomatic persons of SARS-Cov-2. Available on (arXiv:2004.06033v1)

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