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We’re working on 1M Covid-19 testing capacity per day

billiontoone.com

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Re: We’re working on 1M Covid-19 testing capacity per day

#71

Post by dvdt »

abhisuri97 wrote: post #53
dvdt wrote: post #2

I'm the co-founder and CTO at BillionToOne. I'm happy to answer any questions here. I've also posted a slightly more technical explanation of how the test works and why it can scale here: https://twitter.com/dtsao/status/1247642005510873088?s=21 Edit: Since our site seems to be overwhelmed at the moment, here's a recap: We’ve been working hard at BillionToOne on a new COVID-19 test that scales testing to everyone in…

Hey, lowly Bio undergrad here, but how are you able to skip the RNA extraction step? I read the paper and you use the viral transport medium, but wouldn't you have to also purify RNA from that (or is it just much easier to extract RNA from that medium)? I also dived into the paper behind the "skip the RNA extraction step" methodology and it basically seems to swap out one RNA extraction kit for another (Qiagen RNeasy…

Thanks for the question! The goal of skipping RNA extraction is to decrease the amount of labor necessary for processing samples and also to eliminate a dependency on RNA extraction reagents that have recently become difficult to find. The FDA is very strict about the specific brand and model of kit you use, so showing that you can swap out one RNA kit for another is actually very useful because you will have alleviated some of the supply chain strain (although I agree at high enough load both supply chains will then become limiting).

The way currently available COVID-19 testing works is by detection of viral RNA. Since the amount of viral RNA in a patient sample is too low to detect directly, we first need to amplify it by PCR. However, this viral RNA is packaged within all sorts of proteins and lipids that could make it inaccessible to amplification unless they are first purified away. Furthermore, the sample is shipped in "viral transport medium", which is essentially a cocktail of chemicals designed to preserve the virus. Unfortunately, these preservatives often have the side effect of interfering with PCR amplification, so these too need to be purified from the sample.

However, since RNA extraction is usually the most laborious part of the assay, there has been a lot of interest in optimizing the amplification so that it is resilient to all of these impurities. The preprint referenced in our manuscript (https://www.biorxiv.org/content/10.1101/2020.03.20.001008v1) gave us the initial idea that this could be possible, and much of it comes down to the choice of amplification method (e.g. choice of enzymes and buffers) that you choose.

However, even when you choose a "good" enzyme and buffer, you will still suffer an amplification penalty, and this will cause you to return a false-negative on some affected samples because there was so little virus in the sample to begin with. The innovation we have is to spike-in a correspondingly low level of DNA to the reaction mixture. That way, if you see the low level of DNA without seeing any viral signal, you can be assured that the amplification still worked and that there truly is no virus in the sample.

Re: We’re working on 1M Covid-19 testing capacity per day

#72

Post by billiontoone »

devy wrote: post #64
dvdt wrote: post #2

I'm the co-founder and CTO at BillionToOne. I'm happy to answer any questions here. I've also posted a slightly more technical explanation of how the test works and why it can scale here: https://twitter.com/dtsao/status/1247642005510873088?s=21 Edit: Since our site seems to be overwhelmed at the moment, here's a recap: We’ve been working hard at BillionToOne on a new COVID-19 test that scales testing to everyone in…

Hi David, what about Rosche Cobas 6600/8800 high-throughput diagnostics machines? Are they using the traditional RT-qPCR assay? How can they are able to test 400k samples per week? https://diagnostics.roche.com/us/en/news-listing/2020/roche-...

Roche 6600/8800 instruments are state-of-the-art automated RT-qPCR machines. We need them as well as other COVID-19 testing instruments.

That said, it is easier to ship the test kits than scale the instrumentation. Both Roche and Abbott still need to build hundreds of their instruments before the kits that they are shipping out this week can be used on the daily rate that they are trying to get to. I am not sure with Roche, but Abbott estimates the end of June to have enough machines shipped to achieve 50K per day capacity on their instruments.

Another potential problem with new instrumentation is that reimbursement for COVID-19 tests is very low ($30-$50), so it becomes financially difficult for hospitals and laboratories to buy very expensive instruments and also pay for test kits that cost $30-$50 per test, on par with reimbursement.

We try to avoid both issues by utilizing a currently unused Sanger install base and low-cost reagents.

Re: We’re working on 1M Covid-19 testing capacity per day

#73

Post by boyd »

devy wrote: post #64
dvdt wrote: post #2

I'm the co-founder and CTO at BillionToOne. I'm happy to answer any questions here. I've also posted a slightly more technical explanation of how the test works and why it can scale here: https://twitter.com/dtsao/status/1247642005510873088?s=21 Edit: Since our site seems to be overwhelmed at the moment, here's a recap: We’ve been working hard at BillionToOne on a new COVID-19 test that scales testing to everyone in…

Hi David, what about Rosche Cobas 6600/8800 high-throughput diagnostics machines? Are they using the traditional RT-qPCR assay? How can they are able to test 400k samples per week? https://diagnostics.roche.com/us/en/news-listing/2020/roche-...

Those systems process up to 384 or 1056 samples in ~8 hours. The proposed method should support a similar volume (even a bit higher) than the Roche 8800, but with a different large installed instrument base. So this should add a lot of capacity to that qPCR.

Re: We’re working on 1M Covid-19 testing capacity per day

#75

Post by dvdt »

sgw928 wrote: post #56
dvdt wrote: post #17

Earlier quoted context omitted.

Thank you for your efforts as well! Sample collection and accessioning (accessioning is unpacking test tubes one by one and aliquoting them into plates in the lab) is definitely going to require a lot of manpower. I'm hopeful that patients "self swabbing" can help alleviate some of the manpower needs. (Self-swabs are not allowed currently under FDA guidance).

A self-swab surveillance program has been launched in Seattle: https://publichealthinsider.com/2020/03/23/introducing-scan-... . Is self-swabbing allowed there because it's for research purpose, not clinical purpose? The program does tell users whether they test positive though.

My guess is that self-swabbing is allowed in the Seattle SCAN study because it is a research study. The SCAN study is super fascinating because it would be crazy unusual under normal times for a research study to return results back to patients; I'm very happy they are able to do that, and it speaks to the severity of this pandemic.

The FDA has recently made clear that no at-home self-collection tests are allowed (for now): https://www.fda.gov/medical-devices/emergency-situations-med...

Re: We’re working on 1M Covid-19 testing capacity per day

#76

Post by billiontoone »

12xo wrote: post #32

This is awesome. Thank you for all your work. One million a day seems like a lot until you realize it would take about a year to test everyone in the US... How can we increase this to 10m per day? Is that possible?

I think we can scale it to significantly more than 1M a day, but it would require the relaxation of certain regulations that currently prevent collaboration between clinical laboratories and other institutions that have Sanger instruments. FDA and CMS require that clinical laboratories process the sample end-to-end, so it prevents a distributed model of initial processing in the clinical laboratory followed up with send-out for Sanger sequencing.

California CLIA and FDA regulations for COVID-19 testing have been relaxed significantly over the last few weeks, so the above is perhaps not impossible.

Re: We’re working on 1M Covid-19 testing capacity per day

#78

Post by abhisuri97 »

dvdt wrote: post #71
abhisuri97 wrote: post #53

Earlier quoted context omitted.

Hey, lowly Bio undergrad here, but how are you able to skip the RNA extraction step? I read the paper and you use the viral transport medium, but wouldn't you have to also purify RNA from that (or is it just much easier to extract RNA from that medium)? I also dived into the paper behind the "skip the RNA extraction step" methodology and it basically seems to swap out one RNA extraction kit for another (Qiagen RNeasy…

Thanks for the question! The goal of skipping RNA extraction is to decrease the amount of labor necessary for processing samples and also to eliminate a dependency on RNA extraction reagents that have recently become difficult to find. The FDA is very strict about the specific brand and model of kit you use, so showing that you can swap out one RNA kit for another is actually very useful because you will have allevia…

Thank you so much for that explanation!

Re: We’re working on 1M Covid-19 testing capacity per day

#79

Post by pjschlic »

billiontoone wrote: post #50
aazaa wrote: post #29

Earlier quoted context omitted.

Your company has filed a US patent application (and it appears also a PCT) on the qSanger method, and this application is reference 8 in your document. What are your plans for licensing the technology?

If it is specific to COVID-19 testing, we will not seek anything, as long as the end-user is not financially benefiting from it or importantly, selling qSanger kits. If they need our bioinformatics automation & help with set-up, we would license the method for COVID-19 testing for $3-$5/sample as part of each sample that is being put through our pipeline. If they ask for 96-well plates with all reagents that are read…

When you say 'as long as the end user is not financially benefitting' - is the end user the lab conducting the test?

You said in an earlier comment that the reimbursement for testing is too low to justify buying expensive equipment. You are also proposing to charge half the reimbursed rate for it to run on someone else's equipment.

Are the current equipment owners expected to donate this crucial equipment, because if they are the bottleneck, shouldn't they be the ones compensated to encourage more equipment to be made available?

Re: We’re working on 1M Covid-19 testing capacity per day

#80

Post by billiontoone »

zrgiu wrote: post #63

Say I had a lab with the sequencers needed for this test. I can't claim to understand the work needed to onboard into this new process, but my question is: how long does the onboarding take before the lab can process these 3840/day ?

Thanks for the question. Last week, I sent half-a-page of instructions in a hastily written e-mail to a scientist working for the Switzerland government response team, and they told me that it worked beautifully in their first try this week.

With the details described in the manuscript, the onboarding can be only a few days (or even self-onboarding based on instructions). The only part that is somewhat tricky is the bioinformatics algorithm for positive vs. negative calls, which we can supply.

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