A research team at Beth Israel Deaconess Medical Center has developed a mathematical model to estimate the false negative rate for COVID-19 tests.
According to a study published earlier this month in Clinical Infectious Diseases, the assay limit of detection (or the smallest amount of viral DNA detectable that a test will catch 95% or more of the time) meaningfully affects clinical performance of COVID-19 tests.
The highest LoDs on the market will miss a majority of infected patients, the researchers found.
“For getting back to business as usual, we all agree we’ve got to massively ramp up testing to figure out who’s negative and who’s infectious – but that’s only going to work optimally if you can catch all the positive cases,” said corresponding coauthor Dr. James E. Kirby, director of the Clinical Microbiology Laboratories at BIDMC, in a press release announcing the findings.
“We found that clinical sensitivities vary widely, which has clear implications for patient care, epidemiology and the social and economic management of the ongoing pandemic,” Kirby continued.
WHY IT MATTERS
The team used data from 27,098 tests performed at Beth Israel Lahey Health hospital sites between March 26 and May 2 of this past year. They noted that viral loads from patients can vary, and suggested that the lower the viral load, the greater the likelihood the infection will be missed.
“Concerningly, some of these missed patients are, have been, or will become infectious, and such misses will undermine public health efforts and put patients and their contacts at risk,” wrote the researchers in the study.
The team analyzed repeat test results for the nearly 5,000 patients who tested positive and determined that the in-house test provided a false negative in about 10 percent of cases.
According to the study, the team then developed a sliding scale relationship to predict the clinical sensitivities of assays based on their limits of detection.
“We confirmed the validity of our mathematical model by comparison with a calibration curve established through testing of serial dilutions of an inactivated SARS-CoV-2 virus reference material,” wrote the researchers.
They found that each 10-fold increase in LoD is expected to lower assay sensitivity by 13%.
“These misses will undermine public health efforts and put patients and their contacts at risk,” said corresponding coauthor Dr. Ramy Arnaout, associate director of the Clinical Microbiology Laboratories at BIDMC. (The release notes that Arnaout is principal investigator on an unrelated study sponsored by Abbott Molecular.)
“This must give us pause, and we really need to benchmark each new test even in our rush to increase testing capacity to understand how well they support our testing goals.”
THE LARGER TREND
Many policy leaders – including President Joe Biden – have pointed to increased testing as an integral part of continued COVID-19 response strategy over the coming year. The U.S. Food and Drug Administration has also approved a slew of COVID-19 tests over the past year, many aimed at allowing individuals to test themselves in their own home.
Other health systems have turned to alternate methods, such as an artificial intelligence test developed by the University of Oxford that correctly predicted the COVID-19 status of 92.3% of patients coming to emergency departments at two English hospitals over a two-week period.
But the study results suggest – as other experts have – that testing alone will not be enough to stop the continued spread of COVID-19.
ON THE RECORD
“These results are especially important as we transition from testing mostly symptomatic individuals to more regular screening across the community,” said Arnaout.
“How many people will be missed – the false negative rate – depends on which test is used. With our model, we are better informed to ask how likely these people are to be infectious,” Arnaout continued.