What the 90% non-infectious PCR positive test rate means
Recent data show that up to 90% of positive PCR tests in the U.S. aren’t infectious or harmful to individuals, leading to a proportionate inflation of the Covid-19 death rate
The New York Times dropped a quiet bombshell at the end of August with a story titled “Your coronavirus test is positive. Maybe it shouldn’t be.” It quotes a number of academics and researchers who express strong concerns about how the “gold standard” PCR tests for the coronavirus are being applied.
In short, the tests are being applied in a way that amplifies their sensitivity far beyond what is warranted for tracking current cases of Covid-19 — which is the ostensible purpose of the PCR test.
Here’s the money quote from the article:
In three sets of testing data that include cycle thresholds, compiled by officials in Massachusetts, New York and Nevada, up to 90 percent of people testing positive carried barely any virus, a review by The Times found.
On Thursday, the United States recorded 45,604 new coronavirus cases, according to a database maintained by The Times. If the rates of contagiousness in Massachusetts and New York were to apply nationwide, then perhaps only 4,500 of those people may actually need to isolate and submit to contact tracing.
The article never uses the term “false positive” but the primary researchers who track this issue do use this term. Jefferson et al. 2020 “Viral cultures for COVID-19 infectivity assessment — a systematic review (Update 3)”, the third update issued by Jefferson’s team calibrating the accuracy of PCR tests (by using viral cultures) through comprehensive tracking of published test results around the world, concludes (emphasis added):
Prospective routine testing of reference and culture specimens are necessary for each country involved in the pandemic to establish the usefulness and reliability of PCR for Covid-19 and its relation to patients’ factors. Infectivity is related to the date of onset of symptoms and cycle threshold level. A binary Yes/No approach to the interpretation RT-PCR unvalidated against viral culture will result in false positives with segregation of large numbers of people who are no longer infectious and hence not a threat to public health.
In layman’s terms, the PCR tests are being used overly aggressively to amplify a very small signal, which is probably in most cases dead viral fragments, through an excessive number of cycles. By going beyond the now-established cycle threshold (CT), for detecting live infections, of 25-30 cycles the PCR tests are creating an artificial positive test result through excessive amplification.
Another quote from the NY Times article:
“I’m really shocked that it could be that high — the proportion of people with high C.T. value results,” said Dr. Ashish Jha, director of the Harvard Global Health Institute. “Boy, does it really change the way we need to be thinking about testing.”
The NY Times article adds, quoting another virologist:
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.
Dr. Mina is Harvard Medical School epidemiologist Michael Mina, an assistant professor at the Center for Communicable Diseases. He also told the NY Times:
In Massachusetts, from 85 to 90 percent of people who tested positive in July with a cycle threshold of 40 would have been deemed negative if the threshold were 30 cycles, Dr. Mina said. “I would say that none of those people should be contact-traced, not one,” he said.
I reached out to various scientists to follow up on this issue because, well, if the gold standard PCR test is being applied throughout the U.S. and other countries in a way that is finding up to 90% effective false positives, that’s a rather important evolution of our understanding that people should know about.
I reached out to Michael Mina first and he let me know that he doesn’t like the term “effective false positive.” He said “They should definitely be labeled as positive” and he prefers “non-infectious late positive.”
Mina, due to the CT issue, advocates switching primarily to antigen tests, a newer and less accurate virus test that has a major advantage in terms of getting results back in 15–30 minutes rather than waiting days or weeks. My next essay will look in detail at the accuracy of antigen tests.
Calling the 90% or so positive PCR tests that are no longer infectious “non-infectious late positives,” as Mina suggests, doesn’t seem to me to convey quite the degree to which this new data about CT numbers seriously changes the shape of the pandemic and how we respond to it.
To be specific, CDC and many others have suggested that the current infection rate in the U.S. may be more than ten times the positive test rate at any given moment in time. But if the positive PCR tests are returning 90% non-infectious late positives then the current societal infection rate begins to map fairly closely to the PCR positive test rates — an order of magnitude lower than what CDC and others have suggested. (Nerdy sidepoint: with this change in understanding of the PCR test function it seems that the PCR test is functioning more like the antibody tests, which are designed to track past infections rather than current infections).
And if 90% of these positive PCR test results are non-infectious then this is a massive difference in terms of contact tracing, isolation, school reopenings, travel policies, hospital isolation policies, and countless other impacts.
Mina thinks this 90% difference doesn’t change the overall shape of the pandemic that much, but it’s hard to see how a 90% change in contract tracing, isolations, infectiousness, etc. isn’t a massive change to the contours of the pandemic.
Perhaps the most significant impact of this misapplication of the PCR test relates directly to how the U.S. and many other countries define a Covid-19 related death: any death resulting after a positive PCR test, regardless of the actual cause of death or the time elapsed between the positive tests and the death (the U.S. is actually far more inclusive than this in defining Covid-related deaths, but the majority of deaths are tallied based on a positive PCR test).
If 90% of positive PCR tests are detecting past non-infectious cases, then a large majority of Covid-19 related deaths shouldn’t be included in this category. If we adjust the U.S. Covid-19 death count based on this figure alone we find that a small fraction (around 10%) of the overall U.S. Covid-19 deaths were actually from the virus. This logic follows from the fact that the large majority of positive tests are recovered patients with tiny amounts of the virus.
I also reached out to professor Jo Vandesompele in Belgium, a recognized world expert on PCR testing to ask him about the false positives issue. He also did not like that term, despite its use by the Jefferson team, and insisted that the problem is not with the test itself but the policies followed in relation to the test results. He told me that “lowering the [cycle] threshold (from e.g. 40 to 30) will result in fewer true positive cases, but will at the same time inflate the number of analytical false negatives (samples you call negative but do in fact contain virus, so are true (but low) positives).”
He also told me, after I asked him about efforts by WHO and other international agencies to standardize and calibrate PCR and other virus tests that “there is very little effort done or ongoing to standardize.” WHO is, however, working on this issue currently, with no definite timeline for completion.
In other words, there is no global standard for how PCR tests should be conducted in terms of cycle thresholds, for interpreting high CT tests results, or translating those results into policy.
There is, however, a U.S. standard set by the CDC in early February with its instructions for the Covid-19 PCR test kit that CDC itself developed. That document, first issued on February 4, recommends a 40 CT — way higher than the science since then would recommend because almost no live infections will require higher than 25–30 CT.
In sum, these revelations about overly high cycle thresholds in applying the highly sensitive PCR tests should be considered a bombshell, regardless of what terminology we use about “false positives” or “non-infectious late positives.” When the effect of these test data is to inflate the case count, hospitalizations, and death count from the new coronavirus by up to 90% we should all be discussing these results and definitional issues.