Test Quality: Physicians Stress Urgent Need for COVID-19 Antibody Reference Testing Standard

Widespread COVID-19 testing is essential to safely reopen the US. While test availability has been the main focus, test accuracy may prove to be the bigger issue. If a test erroneously delivers a negative result, an asymptomatic person may continue interacting with people believing they are not infectious. While debate has focused on the accuracy of antibody tests which identify prior infection, diagnostic testing identifying current infection has received less attention.

The Diagnostic Challenge

Diagnostic test inaccuracy can take the form of a false negative or a false positive result. A false positive erroneously identifying a person as infected has minor consequences including unnecessary quarantine and contact tracing. False negative results, however, are more consequential, because infected persons, including those who are asymptomatic, are not isolated or quarantined when they should be making them free to potentially infect others.

Inaccuracy is particularly dangerous for antibody tests relied on to determine whether persons are immune. In this case, false positives are the chief threat by emboldening people who are not actually immune to believe and act as if they were. Moreover, even antibody tests capably of accurately identifying previous infections remain an iffy proposition for reopening purposes to the extent that it remains unclear whether having SARS-CoV-2 antibodies confer immunity against reinfection. In fact, the World Health Organization (WHO) has argued that there is insufficient evidence to use positive test results to support the lifting of restrictions on individuals.

The Need for a Reference Standard

Given the need to know how well tests rule out infection, a group of Harvard and Yale physicians have called for urgent assessment of the sensitivity of coronavirus diagnostics in asymptomatic people to stop false negatives. In a paper published in the New England Journal of Medicine, the authors call for development of a reference standard for measuring the sensitivity of COVID-19 tests in asymptomatic people who may not be isolated and can potentially infect others. It is important to review assessment of test accuracy by the Food and Drug Administration (FDA) and clinical researchers, as well as interpretation of test results in a pandemic, the authors wrote.

The authors came to five conclusions:

1. Diagnostic testing will help in safely opening the country only if the tests are highly sensitive and validated under realistic conditions against a clinically meaningful reference standard.
2. The FDA should ensure that manufacturers provide details of tests’ clinical sensitivity and specificity at the time of market authorization; tests without such information will have less relevance to patient care.
3. Measuring test sensitivity in asymptomatic people is an urgent priority. It will also be important to develop methods, e.g., prediction rules, for estimating the pretest probability of infection (for asymptomatic and symptomatic people) to allow calculation of post-test probabilities after positive or negative results.
4. Negative results even on a highly sensitive test cannot rule out infection if the pretest probability is high, so clinicians should not trust unexpected negative results, i.e., assume that a negative result is a “false negative” in a person with typical symptoms and known exposure). It is possible that performing several simultaneous or repeated tests could overcome an individual test’s limited sensitivity; however, such strategies need validation.
5. Thresholds for ruling out infection need to be developed for a variety of clinical situations. Since defining these thresholds is a value judgement, public input will be crucial.

Takeaway

“Designing a reference standard for measuring the sensitivity of SARS-CoV-2 tests in asymptomatic people is an unsolved problem that needs urgent attention to increase confidence in test results for contact-tracing or screening purposes. Simply following people for the subsequent development of symptoms may be inadequate, since they may remain asymptomatic yet be infectious,” the authors wrote.  

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This article originally appeared in G2 Intelligence, Diagnostic Testing & Emerging Technologies, July 2020