Increase accuracy, reduce false positives of COVID-19 PCR tests

December 12, 2022

Strong points:

  • PCR tests are the gold standard for diagnosing COVID-19, but they’re not always accurate.

  • Both false positives and false negatives have negative repercussions and risks for patients.

  • New research suggests that adding a test of the genetic response of the infected individual (the host) could improve accuracy.

  • The researchers derived and tested a classifier, based on 2 host genes, which could easily be added to existing PCR tests.

Washington, DC – December 12, 2022 – PCR swab tests that look for viral RNA have become the gold standard for identifying infection with the SARS-CoV-2 virus, but their results are not 100% accurate. This week inmSystems,researchers report that testing the levels of certain immune system-related genes in an infected individual, in addition to looking for the genetic material of the virus itself, could increase diagnostic accuracy.

The researchers compared gene expression data from people diagnosed with COVID-19 to those from people diagnosed with other viral respiratory illnesses and people with non-viral illnesses. The analysis revealed that the expression of a combination of 2 host genes is strongly associated with SARS-CoV-2 infection. Furthermore, a test for this genetic response could be easily integrated into existing PCR tests and retain its accuracy for existing and future variants of the virus.

“We envision this as a complement to a PCR test which always looks for direct evidence of the virus and uses the host genes as a fallback to ensure we catch situations where there could be false positive or false results. viral PCR negative. said computational biologist Eran Mick, Ph.D., of the University of California, San Francisco.

Mick was one of the 3 main authors of the article. The other 2 were UCSF microbiologist Estella Sanchez-Guerrero, Ph.D., and Stanford University undergraduate Jack Albright, who began working on the project as a high school intern at Chan Zuckerberg (CZ) Biohub. Infectious disease researcher Charles Langelier, MD, Ph.D., also at UCSF and CZ Biohub, was the study’s lead author.

The U.S. Food and Drug Administration approved the first PCR test for COVID-19 in the spring of 2020. However, in widespread use, the test is vulnerable to false negatives — especially as the virus progresses to new variants that could escape detection – and false positives such as contamination from other samples in a testing laboratory. A person who has received a false negative result can become ill without treatment and continue to spread the virus. A false positive result could cause a person to endure unnecessary isolation or have scheduled medical procedures cancelled.

“There are a lot of repercussions,” Langelier said.

In November 2020, Mick and Langelier conducted a study which demonstrated that COVID-19 causes a unique gene expression pattern in infected individuals. The observation prompted them to investigate whether these genes might have diagnostic utility. In previously published work, the team used RNA sequencing data from nasopharyngeal swabs to identify combinations of several genes that could serve as diagnostic classifiers for COVID-19.

However, according to Langelier, testing the response of large numbers of genes is not routinely feasible and is incompatible with existing clinical PCR tests. For the new work, the researchers tested a range of 2-gene combinations to find a pair that could accurately diagnose COVID-19. They found that the optimal signature included IFI6, a gene stimulated by interferon and strongly induced in COVID-19 compared to non-viral conditions, and GBP5, which is strongly induced in other viral infections.

“It’s really a combination of a gene that does a good job of separating those who don’t have a viral infection from those who have. [an infection]and another gene that separates COVID-19 cases from other respiratory viral infections,” Albright said.

“So many different biological processes change as part of an infection,” Langelier said. “It was surprising that all of this complex biology could be distilled down to these 2 genes with predictive value.”

Once they identified the gene pair, the team showed that the classifier could be included in a PCR test, is unaffected by cross-contamination (because it measures host response), and works for all common virus variants.

“Breaking it down to such a small number of genes is a game-changer,” Mick said.

Mick noted that this 2-gene host signature is designed to be used in combination with a viral PCR test to diagnose COVID-19 because there is still significant overlap between the response to SARS-CoV-2 and the response to other viral infections. However, a purely host-based classifier could be used as a wide-range surveillance tool to identify people infected with any respiratory virus. Even before the pandemic, Mick noted that viral infections were a major public health concern and many went undetected. A diagnostic tool that flags viral infections could be useful for screening vulnerable populations in nursing homes or hospitals.

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The American Society for Microbiology is one of the largest life science societies, made up of more than 30,000 scientists and health professionals. ASM’s mission is to promote and advance microbial science.

ASM advances microbial science through conferences, publications, certifications, educational opportunities, and advocacy efforts. It enhances the capacity of laboratories around the world through training and resources. It provides a network for scientists in academia, industry and clinical settings. Additionally, ASM promotes a deeper understanding of microbial science among diverse audiences.

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