May 24, 2024

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WHO: labs should be wary of false positives from cycle thresholds

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The World Health Organization (WHO) last week joined others in sounding an alarm about false positives being reported due to cycle thresholds being set too high on COVID-tests.

The most common test for COVID-19 is the Polymerase Chain Reaction (PCR) test in which genetic material is copied until a detectable virus is found.

However, the more the material is copied or “cycled,” the less likely it is that the person being tested had the virus or has transmissible amounts of the virus in their body.

According to the Director of the National Institute of Allergy and Infectious Diseases, Dr. Anthony Fauci, the “cycle threshold” should be 34 or below.

“If you get a cycle threshold of 35 or more, the chances of it being replication-competent are minuscule,” Fauci said at roughly the four-minute mark of this video. ‘Replication competent’ means particles capable of infecting cells and replicating to produce additional infectious particles.”

The Kansas Department of Health and Environment says the cycle threshold on its most commonly used test is 42 and many private labs have thresholds set far above 35 — including Quest Diagnostics at 40 and LabCorp at 38.

WHO statement on false positives

On Dec. 14, 2020, the WHO issued a statement noting the dangers of false positives.

“The design principle of RT-PCR means that for patients with high levels of circulating virus (viral load), relatively few cycles will be needed to detect virus and so the Ct (cycle threshold) value will be low,” the directive states. “Conversely, when specimens return a high Ct value, it means that many cycles were required to detect virus. In some circumstances, the distinction between background noise and actual presence of the target virus is difficult to ascertain. (emphasis added)”

WHO goes on to suggest that labs make sure to read the instructions carefully to make sure they are not reporting positive cases that are negative.

Kansas testing

Meanwhile, in Kansas, it is impossible to ascertain how many reported COVID-19 cases may be false positives because neither KDHE nor counties such as Wyandotte seem inclined to request the information from labs or to reveal the Ct their labs are using.

In early November, Kansas Policy Institute (parent company of the Sentinel) CEO Dave Trabert sent a Kansas Open Records Act request to KDHE asking for Ct data from the state labs.

“The KDHE KORA officer responded to our request for cycle threshold data, saying the labs do not provide that information to the state,” Trabert wrote in an email to KDHE Secretary Dr. Lee Norman on Nov. 2, 2020. “So we’re writing to ask if you will obtain the data from them and share it with the public.

“It is critical to know how many of the reported positive results may not be contagious or ‘replication-competent’ but contributing to the extraordinary emotional and economic consequences, including suicides and attempted suicides, related to COVID-induced isolation and economic consequences.”

KDHE has still not responded to that request.

One of the principal labs in Wyandotte County — Clinical Reference Laboratory, of Lenexa — through spokeswoman Mary Berlin, has refused even to explain what cycle threshold they are using.

By contrast, the State of Florida has begun requiring labs to release Ct data.

On Dec. 3, the Florida Department of Health issued a memorandum requiring all Florida laboratories doing COVID testing to “begin reporting this information to FDOH within seven days of the date of this memorandum,” and if the “laboratory is unable to report CT values and their reference ranges, please fill out the brief questionnaire attached to this memorandum.”

Additionally, Florida is requiring “all positive, negative and indeterminate COVID-19 laboratory results must be reported to FDOH via electronic laboratory reporting or by fax immediately. This includes all COVID-19 test types—polymerase chain reaction (PCR), other RNA, antigen and antibody results.”

Cycle threshold data critical

Dr. Michael Mina, an assistant professor of epidemiology at both Harvard Medical School and the Harvard T.H. Chan School of Public Health, told Harvard Magazine that reporting people positive on tests with a high cycle threshold are “false positives.”

“Tests with thresholds so high may detect not just live virus but also genetic fragments, leftovers from infection that pose no particular risk,” Mina said. “Akin to finding a hair in a room long after a person has left.”

One maker of the COVID PCR test, Bioningentech, offers guidance quite similar to those in a New York Times article, which points to oversensitive tests nationwide.  Cycle thresholds between 12 and 36 are considered positive; results between 36 and 40 cycles are considered marginally positive, and anything over 40 cycles is considered negative.

“Any test with a cycle threshold above 35 is too sensitive, agreed Juliet Morrison, a virologist at the University of California, Riverside. “I’m shocked that people would think that 40 could represent a positive,” she said.

“A more reasonable cutoff would be 30 to 35, she added.

Dr. Mina said he would set the figure at 30, or even less.

“Those changes would mean the amount of genetic material in a patient’s sample would have to be 100-fold to 1,000-fold that of the current standard for the test to return a positive result — at least, one worth acting on.”

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