As states are beginning to phase out total lockdown in the US, there is much discussion about how best to do it, minimizing the chance of causing a resurgence in COVID-19 cases. Just about every expert questioned about this topic focuses on testing – we have to do lots of testing in order to track people who have the disease, trace their contacts, and isolate them. At its core the idea is simple – instead of isolated everyone, we isolate those who have the virus, but in order to do that we have to know who has it and who doesn’t. Symptoms are one guide, but you can have the virus and pass it on without displaying symptoms. Therefore testing is critical. Some experts estimate we will need to do millions of tests per day to safely open up.
What is the state of our testing technology, and how reliable is it? There is a lot of work in this area, so this is a rapidly moving target, but some recent reviews help put things into perspective. First some background on technology. Often the media talks about how “accurate” the tests are, but this is not a technical way to evaluate testing. For that we need to understand sensitivity and specificity.
Sensitivity, specificity, and predictive value
Sensitivity is the percentage of individuals with the condition being tested for who test positive, the so-called true-positive rate. So if a test in 90% sensitive (usually written as 0.90), it will come back positive in 90% of people who have the condition. Specificity is the percentage of people who don’t have the condition who test negative, the true-negative rate. A test that is 90% specific will be negative 90% of the time in people who do not have the condition, and will have a 10% false positive rate.
Sensitivity and specificity, however, only get you halfway to where you need to go. What you really want to know is the predictive value of a test – if a test is positive what is the chance you have the disease, or if negative that you don’t have it? In order to know this you not only need to know the sensitivity and specificity, you need to know the base rate of the disease in the population being tested. The more people who have the disease the more false negatives you are going to get compared to true negatives, and the fewer people with the condition the more false positives compared to true positives. This matters when we consider testing only people who are symptomatic, vs testing the general population.
By the way, I often use this as an analogy for science-based medicine itself. In order to interpret a p-value of a study you need to know the prior probability of the hypothesis. Even with a low p-value, if the hypothesis being tested is highly unlikely (like homeopathy) it is still far more likely the study is a false positive.
DNA/RNA tests for active infections
The most widely used current test for active infection with the SARS-CoV2 virus that causes COVID-19 is a PCR test for viral RNA. PCR is polymerase chain reaction, a method of amplifying a tiny bit of RNA or DNA into a large amount that can then be detected. A test will key in on a segment of RNA that is specific to SARS-CoV2. A false positive can occur if the subject has other viruses with overlap in the RNA sequence that triggers a positive test. Also, the PCR is so powerful it can amplify a tiny bit of viral RNA that is a contaminant at any point in the process, and not from the subject being tested.
At first it was thought that if you have viral RNA in your body, you are infected with the virus, and this is still largely true. However some patients who were cleared of the virus tested positive with a PCR RNA test. This caused some concern that they may have been re-infected. However, it seems that these subjects tested positive because they still had bits of dead virus in them from the prior infection.
How good are the currently available PCR tests for active virus? A recent review concludes that the quality of the various tests is highly variable, and that protocols and testing quality need to improve and be standardized. There are too many different tests to review here so I will just mention some of the more common ones.
Perhaps the most common PCR test being used in retrospect has been found to have a sensitivity of 0.777 and a specificity of 0.988. That is great specificity, which means if you test positive you likely have the virus – but again, depending on the prior probability. If you are symptomatic during a pandemic, or were exposed to someone, then yeah, you probably have it. The sensitivity is a concern, however – about 23% of those with the virus will be missed by the test.
This is still a very useful test, however. One of the reasons for a false negative might be that it was done too early, and the virus was below detectable levels. You can improve the predictive value of the test by repeating it, therefore.
One of the emerging tests that promises to perhaps be even better than PCR is a CRISPR-based test. They claim a 100% specificity, but also a 97% sensitivity. We’ll have to see if these numbers hold up in independent testing.
There are other important features of a screening test if it is going to be used in millions of subjects – cost, time, and resources needed. Current testing can take days if it has to be sent to a lab, and requires testing equipment and trained professionals to administer. CRISPR and other testing being developed promised to be quicker, available in minutes, and easier to administer, possibly even self-administered. Again, we’ll see, but it does sound promising.
Antibody tests for past infections
An entirely different type of testing is serological testing that looks not for the presence of the virus but for the presence of antibodies to the virus. This would indicate not necessarily active infection, but past infection (at least long enough to have formed antibodies, and for as long as the antibodies persist). These tests would be used not to screen people to see if they have COVID-19 and need to be isolated, but to see if they had COVID-19 (even asymptomatically) in the past and now have antibodies to the virus.
This is useful mostly if those antibodies confer resistance, even immunity, to reinfection. Right now this is somewhat of an open question. If antibodies prove protective, then antibody testing could be used to provide “antibody passports” – an indication of immunity that will free people from lockdown.
There are two manifestations of immunity that need to be studied. The first is whether or not the presence of antibodies protects the individual from getting infected by keeping the virus from establishing a foothold. The second is whether or not the antibodies will protect someone from getting sick, even if they get the virus. And the third consideration is whether the antibodies will reduce the virus enough that it will not be passed on to others. All three are important and will affect recommendations in terms of the “passport” approach.
Here is a good review of currently available antibody testing. The bottom line is that there is a lot of variability, and we need more data. We specifically need more data on how protective the antibodies being tested for are.
Conclusion: SARS-CoV-2 tests are a moving target
Given all the uncertainty, the currently available tests for SARS-CoV-2 are useful, if not perfect, and are getting better. Tests are being rapidly developed and tested in the middle of the pandemic, and we don’t know as much as we would like, but the situation is steadily improving. Even the currently available imperfect tests are incredibly useful in guiding treatment and behavior to limit the spread of the virus.