Hello to the list. Thought I would share with the list an essay on COVID and bias I co-authored with my colleague Paritosh Prasad MD. All stay healthy!
Art Papier MD
Associate Professor of Dermatology and Medical Informatics
University of Rochester College of Medicine
Yes coagulopathy is common. In this case the patient was COVID negative. But your point speaks to the complexity of the current situation!
Sequential testing is not going to be the solution to improving testing for COVID-19. I was thinking of this earlier in the week when the White House came out with a couple powerpoints on national COVID-19 testing, and one of the powerpoints had a figure suggesting that sequential antibody testing could improve predictive values. I was cringing as I read it.
In lab testing in general, most of the limitations of sensitivity and specificity aren't due to random error, but rather to inherent chemical and biological properties of the patient and test. With the COVID-19 PCR test, most of the sensitivity issues appear to be that swabs just don't pick up all that much virus from the surface of the nasopharynx. RT-PCR is great at amplifying RNA, but it has to have something to start with. If the PCR test is, say, 80% sensitive in symptomatic patients, running two different PCR tests at the same time on that same patient (regardless of whether it's the same sample) is unlikely to improve sensitivity more than running a single one. You don't magically pick up 80% of the initially missed 20% (i.e. you don't bring sensitivity up to 96%) just because you do a second test. The only time repeating *might* be helpful would be if the patient's viral load (again, the load on the surface of the nasopharynx) happens to be right at the limit of detection, where random effects could make a difference in the result.
Same story with serology testing. The main cause of false negatives is going to be sampling too soon after infection, and repeating the test with a different manufacturer's kit isn't going to do anything useful.
False-positives aren't as much of a problem for either PCR or serology (unless you're talking about the rapid lateral flow devices which are mostly crap), but again, sequential testing isn't going to be particularly useful here.
When does sequential testing make sense? Mainly when there's a fast and inexpensive test that you want to use most of the time, and thereby only have to rely on the expensive/slow (but more accurate) confirmatory test later. Sequential testing does *not* make sense unless the confirmatory test is more accurate, and even then there has to be a practical reason why you don't just start with the more accurate test to begin with.
I didn't address the last part of the original question. If you're looking at a short-cycle PCR test (with presumed inferior sensitivity) followed by a second long-cycle PCR, then the main issue you're addressing is indeed sensitivity. The second test is essentially replacing the first test in an effort to try to catch the low-positives. So the effective sensitivity of the 2-test algorithm essentially equals the sensitivity of the second test.
It's harder to comment on specificity, but that really is less of a problem if both tests are well-designed and well quality-controlled. The RT-PCR assay we're running on the Hologic platform (and I think the Roche is the same) detects two different sequences that are believed to be quite specific to this virus. If it's a poorly-designed test or a poorly-managed lab, then you could potentially get contamination issues (ref: Dartmouth pertussis pseudo-epidemic from 20 years ago) but that's different from a random effect.