5 ms·

Stanford Medicine COVID-19 test now in use

128 points by divbzero 7y ago

WrtCdEvrydy 7y ago
Hug of death.
woliveirajr 7y ago
> As with all currently available tests, it’s not yet clear how long a person needs to be infected before testing positive, or whether they could be identified by the test before displaying symptoms. Kind of made me sad. We're celebrating that we are able to test something, in very... precarious? .... results. Of course it's amazing that we're able to known the genetic sequence in so few days. But as travels are much faster around the globe, it takes so few days to spread. Everything being so fast isn't exactly helpful to settle emotions.
- deleted 7y ago
  [deleted]
daemonk 7y ago
Looks like it's a RT-PCR. How different are their primers compared to the IDT sets (https://www.idtdna.com/pages/landing/coronavirus-research-reagents https://www.idtdna.com/pages/landing/coronavirus-research-re...)? There are also a couple of papers on biorxiv with primers for RT-LAMP tests, which should be much faster, easier to perform than RT-PCR. And it requires non-sophisticated equipment. It all comes down to the false negative rates though.
anaphor 7y ago
Do we have any idea of what the false-positive rate of these types of tests generally are? It sounds pretty thorough but some actual data on that would be nice. Also, given that the prevalence of the virus is still very low, I am assuming (and the article seems to support this) that the test would only be used on people that have some pre-existing risk factor, like exposure to a known infected person, or travel to/from one of the high risk locations. Otherwise (let's assume a FP rate of 1%) you would still be getting a large number of false positives. Even with the assumption that there are a large number of very mild undiagnosed cases. The reason I bring this up is because I have seen many people calling for mass testing of everyone in the United States, regardless of symptoms or risk factors. I think doing that would be a very big mistake because then you end up with a few possible scenarios: 1. You tell everyone who tested positive without any symptoms/high risk factors that they probably don't have it actually. 2. You end up treating massive amounts of people with potentially risky treatments, or quarantine people for no reason. 3. You have to do lengthy/expensive follow up tests of millions of people and waste valuable time and resources. I guess 1 isn't a big deal, but then how do you prioritize who to treat given the symptoms alone don't provide a very useful criteria for judging who has it? Obviously the doctors and scientists working on this know all of this already, but the general public and politicians seem to be demanding mass testing of the entire population, which worries me.
- ISL 7y ago
  False negatives may actually pose a greater public-health problem. A suspected case, assayed as a false negative can be released back into the community without quarantine.
  - anaphor 7y ago
    That's very true. From what I can tell they are focusing on making the false negatives very unlikely for that reason. Do we know how easily it spreads without any symptoms? If someone is exhibiting flu-like symptoms then I'd expect/hope they self isolate and take precautions regardless of whether they test positive or not.
  - lacker 7y ago
    Right now we are releasing everyone who has non-extreme flu symptoms without testing whether it’s flu or covid-19, so even a small false negative rate would be a great improvement.
- code4tee 7y ago
  It’s generally hard to have a “false positive” in a PCR based test unless the sample was contaminated with the material trying to be detected. False negatives would be much more common.
  - arkades 7y ago
    My understanding - from the context of criminal forensics - is that false positives from RTPCR are quite problematic, actually, due to the tendency to pick up non-target DNA that comes close enough to catch the primer. It's an issue in DNA-rich environments (e.g., nasal swabs swarming with local flora). I'm open to learning to the contrary if anyone has a decent citation on the topic.
    - tlb 7y ago
      Human DNA is extremely similar to any other human, but coronavirus is not very similar to other contaminants. So you need fewer samples of DNA to determine a match. Also, even a few percent chance of error in forensic DNA matching is a huge problem. If a virus test is wrong a few percent of the time it's still useful.
ck2 7y ago
I hope the publish their own (anonymized) stats and don't let the whitehouse tamper with hiding numbers like they did with the CDC. NY State has their own test too right? Are they going to publish stats?
sebastianconcpt 7y ago
How test works The Stanford test uses a technique called reverse-transcriptase polymerase chain reaction, or RT-PCR, to rapidly identify the presence of viral RNA in swabs from the noses of potentially infected people. RT-PCR uses short stretches of DNA called primers that bind tightly and specifically only to matching sequences in SARS-CoV-2 RNA. An enzyme called reverse transcriptase then converts the viral RNA into complementary DNA, and as the reaction continues, an enzyme called polymerase is used to generate billions of DNA copies that can be detected by fluorescently tagged molecules called probes.
- LatteLazy 7y ago
  Thanks!
- semi-extrinsic 7y ago
  What I don't get from this description is hos they get the virus to release the RNA? I thought virii only release their RNA after entering a cell? Is there some sort of artifical cell wall involved?
  - hobofan 7y ago
    You can just destroy the virus, e.g. by grinding it down or via a certain chemical and then you have a resulting crude mixture of RNA + other virus parts. In the past you had to separate the RNA first, but with newer methods you can do the PCR directly on the crude mixture.
voidmain 7y ago
Why can't RT-PCR tests be used to detect virus in a sample mixed from a large number of individual samples? This would enable cheap and accurate mass testing, since you can find P positives from S samples with O(P*log(S/P)) tests. What's the catch?
- tlb 7y ago
  The main cost isn't per sample, it's the amount of time the machine takes to sequence enough fragments of RNA to achieve statistical significance. If you combine samples and want to not miss anything, you need to run it for longer.
  - voidmain 7y ago
    Realtime PCR isn't sequencing. It increases the concentration of the targeted sequence exponentially, so it "should" take only logarithmically more temperature cycles to handle a smaller concentration of virus . If that is actually a big contributor to the testing cost, it would make the log in my analysis into a log^2.
- yunesj 7y ago
  There's no catch. It's called "pooling" and is used, e.g., to keep costs down for early detection of primary HIV infection.
- mxwsn 7y ago
  Just curious, can you expand a bit on the analysis? I see that by binary search you get O(log(S)) to identify a single positive, and naively rerunning search from the beginning P times yields O(P*log(S)). One can certainly do better by avoiding redundant tests but at some point one needs to start reasoning about the distribution of the positives in the samples and I'm not sure how to do that.
  - daef 7y ago
    See https://youtu.be/GqAdVQeIXA0 https://youtu.be/GqAdVQeIXA0 for an explanation: starting at around 30% probability pooling stops making sense.
leemailll 7y ago
Isn’t China using rtpcr for the test from the beginning?
DataDrivenMD 7y ago
To everyone questioning the false positive and false negative rates: your point is well-taken, and it is the reason why it was necessary to push the FDA to allow non-CDC labs to perform COVID-19 testing based on a fast-tracked version of the clinical validation process. To those that point out that there are newer/faster/better ways to actually achieve the same results: you're right but that doesn't mean that the machines, reagents, collection media, etc. are ready for prime time in this type of setting. Remember: the entire process needs to be clinically validated in order to earn the trust of doctors and public health officials who are literally making life vs. death decisions. TL;DR - Your points are valid, and there are real challenges that make certain solutions impractical at this point in time. Consider this a call to action to entrepreneurs who are serious about helping patients at home and around the world.
devy 7y ago
RT-PCR is the typical way to test viral infection. Anyone knows if Stanford Clinical Virology Laboratory has invented anything new or just a press release to note that they are prepared to do SARS-CoV-2 viral testing since CDC has finally authorized all private and university labs can perform tests just recently?
- deleted 7y ago
  [deleted]
- pkaye 7y ago
  The last two paragraphs mention that they look for two gene while the CDC test looks for a different gene. So I don't think anything fundamentally new but having multiple tests let them crosscheck each other.
alyx 7y ago
Is nobody else bothered by the logic in the 3rd paragraph? > As with all currently available tests, it’s not yet clear how long a person needs to be infected before testing positive, or whether someone who's infected could be identified by the test before displaying symptoms.
- osrec 7y ago
  I suppose they haven't yet had a chance to test it fully in the field, so they don't know the error rates. Doesn't necessarily mean the test is useless.
- sliken 7y ago
  A recently saw a paper calling that COVID-19 was easy to detect early in the course with an oral swap. But later in the disease course it was easier to detect with a fecal test. Turns out a lung scan was more accurate than either.
- eric-hu 7y ago
  It bothers me too reading about the testing methodology on various countries. In China anal swabs tested positive in released infected patients, while they were repeatedly testing negative with oral swabs. This has come up in their "reinfection" investigations, which may have really been partial recoveries appearing as full recoveries according to oral swab tests.
- usrusr 7y ago
  What exactly is it that bothers you? Were you hoping for a test that could flag a person as soon as the first body cell was invaded by a copy of the virus?

128 points by divbzero 7y ago

Hug of death.

> As with all currently available tests, it’s not yet clear how long a person needs to be infected before testing positive, or whether they could be identified by the test before displaying symptoms. Kind of made me sad. We're celebrating that we are able to test something, in very... precarious? .... results. Of course it's amazing that we're able to known the genetic sequence in so few days. But as travels are much faster around the globe, it takes so few days to spread. Everything being so fast isn't exactly helpful to settle emotions.

deleted 7y ago
[deleted]

daemonk 7y ago

Looks like it's a RT-PCR. How different are their primers compared to the IDT sets (https://www.idtdna.com/pages/landing/coronavirus-research-reagents https://www.idtdna.com/pages/landing/coronavirus-research-re...)? There are also a couple of papers on biorxiv with primers for RT-LAMP tests, which should be much faster, easier to perform than RT-PCR. And it requires non-sophisticated equipment. It all comes down to the false negative rates though.

anaphor 7y ago

Do we have any idea of what the false-positive rate of these types of tests generally are? It sounds pretty thorough but some actual data on that would be nice. Also, given that the prevalence of the virus is still very low, I am assuming (and the article seems to support this) that the test would only be used on people that have some pre-existing risk factor, like exposure to a known infected person, or travel to/from one of the high risk locations. Otherwise (let's assume a FP rate of 1%) you would still be getting a large number of false positives. Even with the assumption that there are a large number of very mild undiagnosed cases. The reason I bring this up is because I have seen many people calling for mass testing of everyone in the United States, regardless of symptoms or risk factors. I think doing that would be a very big mistake because then you end up with a few possible scenarios: 1. You tell everyone who tested positive without any symptoms/high risk factors that they probably don't have it actually. 2. You end up treating massive amounts of people with potentially risky treatments, or quarantine people for no reason. 3. You have to do lengthy/expensive follow up tests of millions of people and waste valuable time and resources. I guess 1 isn't a big deal, but then how do you prioritize who to treat given the symptoms alone don't provide a very useful criteria for judging who has it? Obviously the doctors and scientists working on this know all of this already, but the general public and politicians seem to be demanding mass testing of the entire population, which worries me.

ISL 7y ago
False negatives may actually pose a greater public-health problem. A suspected case, assayed as a false negative can be released back into the community without quarantine.
- anaphor 7y ago
  That's very true. From what I can tell they are focusing on making the false negatives very unlikely for that reason. Do we know how easily it spreads without any symptoms? If someone is exhibiting flu-like symptoms then I'd expect/hope they self isolate and take precautions regardless of whether they test positive or not.
- lacker 7y ago
  Right now we are releasing everyone who has non-extreme flu symptoms without testing whether it’s flu or covid-19, so even a small false negative rate would be a great improvement.
code4tee 7y ago
It’s generally hard to have a “false positive” in a PCR based test unless the sample was contaminated with the material trying to be detected. False negatives would be much more common.
- arkades 7y ago
  My understanding - from the context of criminal forensics - is that false positives from RTPCR are quite problematic, actually, due to the tendency to pick up non-target DNA that comes close enough to catch the primer. It's an issue in DNA-rich environments (e.g., nasal swabs swarming with local flora). I'm open to learning to the contrary if anyone has a decent citation on the topic.
  - tlb 7y ago
    Human DNA is extremely similar to any other human, but coronavirus is not very similar to other contaminants. So you need fewer samples of DNA to determine a match. Also, even a few percent chance of error in forensic DNA matching is a huge problem. If a virus test is wrong a few percent of the time it's still useful.

ck2 7y ago

I hope the publish their own (anonymized) stats and don't let the whitehouse tamper with hiding numbers like they did with the CDC. NY State has their own test too right? Are they going to publish stats?

sebastianconcpt 7y ago

How test works The Stanford test uses a technique called reverse-transcriptase polymerase chain reaction, or RT-PCR, to rapidly identify the presence of viral RNA in swabs from the noses of potentially infected people. RT-PCR uses short stretches of DNA called primers that bind tightly and specifically only to matching sequences in SARS-CoV-2 RNA. An enzyme called reverse transcriptase then converts the viral RNA into complementary DNA, and as the reaction continues, an enzyme called polymerase is used to generate billions of DNA copies that can be detected by fluorescently tagged molecules called probes.

LatteLazy 7y ago
Thanks!
semi-extrinsic 7y ago
What I don't get from this description is hos they get the virus to release the RNA? I thought virii only release their RNA after entering a cell? Is there some sort of artifical cell wall involved?
- hobofan 7y ago
  You can just destroy the virus, e.g. by grinding it down or via a certain chemical and then you have a resulting crude mixture of RNA + other virus parts. In the past you had to separate the RNA first, but with newer methods you can do the PCR directly on the crude mixture.

voidmain 7y ago

Why can't RT-PCR tests be used to detect virus in a sample mixed from a large number of individual samples? This would enable cheap and accurate mass testing, since you can find P positives from S samples with O(P*log(S/P)) tests. What's the catch?

tlb 7y ago
The main cost isn't per sample, it's the amount of time the machine takes to sequence enough fragments of RNA to achieve statistical significance. If you combine samples and want to not miss anything, you need to run it for longer.
- voidmain 7y ago
  Realtime PCR isn't sequencing. It increases the concentration of the targeted sequence exponentially, so it "should" take only logarithmically more temperature cycles to handle a smaller concentration of virus . If that is actually a big contributor to the testing cost, it would make the log in my analysis into a log^2.
yunesj 7y ago
There's no catch. It's called "pooling" and is used, e.g., to keep costs down for early detection of primary HIV infection.
mxwsn 7y ago
Just curious, can you expand a bit on the analysis? I see that by binary search you get O(log(S)) to identify a single positive, and naively rerunning search from the beginning P times yields O(P*log(S)). One can certainly do better by avoiding redundant tests but at some point one needs to start reasoning about the distribution of the positives in the samples and I'm not sure how to do that.
- daef 7y ago
  See https://youtu.be/GqAdVQeIXA0 https://youtu.be/GqAdVQeIXA0 for an explanation: starting at around 30% probability pooling stops making sense.

leemailll 7y ago

Isn’t China using rtpcr for the test from the beginning?

DataDrivenMD 7y ago

To everyone questioning the false positive and false negative rates: your point is well-taken, and it is the reason why it was necessary to push the FDA to allow non-CDC labs to perform COVID-19 testing based on a fast-tracked version of the clinical validation process. To those that point out that there are newer/faster/better ways to actually achieve the same results: you're right but that doesn't mean that the machines, reagents, collection media, etc. are ready for prime time in this type of setting. Remember: the entire process needs to be clinically validated in order to earn the trust of doctors and public health officials who are literally making life vs. death decisions. TL;DR - Your points are valid, and there are real challenges that make certain solutions impractical at this point in time. Consider this a call to action to entrepreneurs who are serious about helping patients at home and around the world.

devy 7y ago

RT-PCR is the typical way to test viral infection. Anyone knows if Stanford Clinical Virology Laboratory has invented anything new or just a press release to note that they are prepared to do SARS-CoV-2 viral testing since CDC has finally authorized all private and university labs can perform tests just recently?

deleted 7y ago
[deleted]
pkaye 7y ago
The last two paragraphs mention that they look for two gene while the CDC test looks for a different gene. So I don't think anything fundamentally new but having multiple tests let them crosscheck each other.

alyx 7y ago

Is nobody else bothered by the logic in the 3rd paragraph? > As with all currently available tests, it’s not yet clear how long a person needs to be infected before testing positive, or whether someone who's infected could be identified by the test before displaying symptoms.

osrec 7y ago
I suppose they haven't yet had a chance to test it fully in the field, so they don't know the error rates. Doesn't necessarily mean the test is useless.
sliken 7y ago
A recently saw a paper calling that COVID-19 was easy to detect early in the course with an oral swap. But later in the disease course it was easier to detect with a fecal test. Turns out a lung scan was more accurate than either.
eric-hu 7y ago
It bothers me too reading about the testing methodology on various countries. In China anal swabs tested positive in released infected patients, while they were repeatedly testing negative with oral swabs. This has come up in their "reinfection" investigations, which may have really been partial recoveries appearing as full recoveries according to oral swab tests.
usrusr 7y ago
What exactly is it that bothers you? Were you hoping for a test that could flag a person as soon as the first body cell was invaded by a copy of the virus?