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

I&#x27;m the co-founder and CTO at BillionToOne. I&#x27;m happy to answer any questions here. I&#x27;ve also posted a slightly more technical explanation of how the test works and why it can scale here: <a href="https:&#x2F;&#x2F;twitter.com&#x2F;dtsao&#x2F;status&#x2F;1247642005510873088?s=21" rel="nofollow">https:&#x2F;&#x2F;twitter.com&#x2F;dtsao&#x2F;status&#x2F;1247642005510873088?s=21</a><p>Edit: Since our site seems to be overwhelmed at the moment, here&#x27;s a recap:<p>We’ve been working hard at BillionToOne on a new COVID-19 test that scales testing to everyone in the US. Our test (1) re-purposes existing infrastructure, (2) eliminates time-consuming RNA extraction, and (3) enables a distributed system for COVID-19 testing.<p>We need 1 million tests per day to end the stay-at-home orders. Schools are still open in Iceland because they test 15x more than the US does, per capita (<a href="https:&#x2F;&#x2F;www.washingtonpost.com&#x2F;world&#x2F;2020&#x2F;04&#x2F;02&#x2F;free-coronavirus-test-anyone-this-country-its-possible&#x2F;" rel="nofollow">https:&#x2F;&#x2F;www.washingtonpost.com&#x2F;world&#x2F;2020&#x2F;04&#x2F;02&#x2F;free-coronav...</a>).<p>The first thing we figured out is how to run COVID-19 tests on existing automated Sanger sequencers. One sequencer can process up to 3840 samples per day. There are hundreds of sequencers of excess capacity because they were built for the Human Genome Project over 20 years ago.<p>It would take only 2 sequencers to surpass the current test capacity for all of California. There are far more than 2 sequencers in California (some individual labs have 10 or more).<p>We tweaked the protocol so COVID-19 could be detected from sequencing data using linear regression. Basically, we add ~100 copies of a known DNA sequence to help us calculate how much virus nucleic acid is in the specimen. It works just as well as gold-standard RT-qPCR.<p>Lab workflow for COVID-19 testing is traditionally 1. Specimen accessioning, 2. RNA extraction, 3. RT-qPCR 4. Reporting. RNA extraction, in particular, has been a huge bottleneck in terms of reagent shortages and labor-intensiveness.<p>We showed that we can skip RNA extraction entirely without affecting test sensitivity and limit of detection.<p>By skipping RNA extraction and using automated Sanger sequencers, we think we can get to an additional 200,000 samples per day test capacity in existing clinical labs.<p>A distributed system is often the only way to operate at massive scale. A fully distributed system could have different sites and labs responsible for each process and dynamically re-allocate resources based on availability and capacity.<p>The Broad institute COVID-19 lab has already started doing this. They are asking for specimens to be submitted in a standardized tube format and pre-barcoded. They have essentially distributed the specimen accessioning work.<p>Because there is a highly developed service industry for Sanger sequencing with &lt;24 hour turnaround, there is an opportunity to further scale up testing by distributing the work to their (currently) idle sequencers.<p>Distributed testing could scale from 200k to &gt;1 million tests per day, but would require a change in regulations that currently prohibit it.<p>Thanks to the BillionToOne team for pulling this work together! Next step is to start manufacturing test kits and obtain Emergency Use Authorization from the FDA. We’re eager to work with clinical Lab Directors and contract kit manufacturers.<p>Edit 2: Link to scientific manuscript: <a href="https:&#x2F;&#x2F;www.dropbox.com&#x2F;s&#x2F;07esyehsvfpmllc&#x2F;A%20Highly%20Scalable%20and%20Rapidly%20Deployable%20RNA%20Extraction-Free%20COVID-19%20Assay%20by%20Quantitative%20Sanger%20Sequencing-final.pdf?dl=0" rel="nofollow">https:&#x2F;&#x2F;www.dropbox.com&#x2F;s&#x2F;07esyehsvfpmllc&#x2F;A%20Highly%20Scala...</a>

Thanks for your efforts! Inspiring to see our broader community spring into action.<p>I was part of a volunteer team that tested 3400 people on Friday&#x2F;Saturday in Santa Clara country for COVID-19 antibodies [1]. It took a team of 100+ volunteers 10 hours &#x2F; day just to collect samples.<p>Stanford, for example, has plenty of automated testing capacity, and even reagents. IMHO, the limiting factors are not that we need new tests, but rather we need (1) lighter regulations (2) funding to buy supplies and (3) massive manpower to scale-up drive through testing<p>[1] <a href="https:&#x2F;&#x2F;www.stanforddaily.com&#x2F;2020&#x2F;04&#x2F;04&#x2F;stanford-researchers-test-3200-people-for-covid-19-antibodies" rel="nofollow">https:&#x2F;&#x2F;www.stanforddaily.com&#x2F;2020&#x2F;04&#x2F;04&#x2F;stanford-researcher...</a>

I&#x27;m wondering, if the bottleneck in testing is number of tests per day available, could we use Bloom filter methodology for it? Like, for example, take samples of 1024 people, assign them 10-bit IDs randomly, mix samples of everyone with bit 1 in position 0 in one pool, with bit 1 in position 1 in 2nd pool and so on. Then do 10 tests, and whoever has negative result in any of set bits of his ID, does not have virus. If too many people of 1024 have virus, add another set of random IDs and do 10 more tests, etc. If there are no technical limitations, that would allow to get negative results to, let&#x27;s say, 900 people from 1024 with only 10-30 tests. Other 124 could be tested personally. That&#x27;s 85% reduction in number of tests needed.

Your site seems to be getting hugged to death. Can you answer a few questions here:<p>- Is this test to see if someone currently has it, or if they have the anti-bodies and are (presumably) immune?<p>- What are the false-positive&#x2F;false-negative rates? How does this compare to current leading tests?<p>- What&#x27;s the cost per test? How does this compare to current leading tests?

This would be HUGE. Not only has the testing capacity in America been maxed out, but the % of positive results has been more than 20% and trending upward. In order to quarantine effectively (read: end the shut down) we need to test the family, coworkers, and contacts of every positive result.

Germany decided to mix 10 specimens and run a test, only then - if positive - test individual samples. They increased their testing capacity 10x (roughly) overnight. <a href="https:&#x2F;&#x2F;edition.cnn.com&#x2F;world&#x2F;live-news&#x2F;coronavirus-pandemic-03-31-20&#x2F;h_c9b8259b105b4f26a4ade9fb61b954ce" rel="nofollow">https:&#x2F;&#x2F;edition.cnn.com&#x2F;world&#x2F;live-news&#x2F;coronavirus-pandemic...</a>

This is awesome. Thank you for all your work.<p>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?

Can someone here explain in a couple of points what the idea is? While the site is overwhelmed?<p>Edit, is the idea (for the non-expert):<p>1) Repurposing idle gene sequencing equipment left over from Human Genome project<p>2) Reducing &#x2F; removing the step of having to extract the RNA of the virus as the marker<p>3) Making these tests &#x2F; machines available widely across the country so that the delay to getting a result is minimized ?

Since the site response has been intermittent, here&#x27;s Internet Archive&#x27;s copy from earlier today.<p><a href="https:&#x2F;&#x2F;web.archive.org&#x2F;web&#x2F;20200407224229&#x2F;https:&#x2F;&#x2F;www.billiontoone.com&#x2F;covid-19" rel="nofollow">https:&#x2F;&#x2F;web.archive.org&#x2F;web&#x2F;20200407224229&#x2F;https:&#x2F;&#x2F;www.billi...</a>

Cool technique that uses existing Sanger sequencing equipment that has been optimized for decades. So you are sanger sequencing the loci + a synthetic frame-shifted oligo that you spike in. Then you essentially &quot;demultiplex&quot; the chromatogram knowing the two molecules are frame-shifted and compare the peaks to get a relative measure.<p>I guess the trick is to find a loci that is specific enough to covid-19, but can still produce a good frame-shifted oligo that allows you to maximize the resulting chromatogram signal.<p>I am surprised that the detection limit of a no-extraction PCR can be this sensitive. But it looks like the data checks out. Does this work for every type of sample? I would assume differing buffers, collection methods will influence the PCR?

Is the 1M&#x2F;day figure for individual tests? When the expected number of positives is low, can&#x27;t you run group tests? Mix the first samples from 16 patients together and test them as a batch. If the result is negative, all 16 are negative. Otherwise re-run the second samples. Depending on how many samples you take from each patient, you can binary search, or just run 16 individual tests on the second samples. By doing this, you can get something upwards of 10x increase in people tested per day.

What is the expected false positive rate&#x2F;range? A number or range will be helpful (rather that extremely rare, which is what I get when I ask about rt-pcr test)

On a separate note - DVDT and billiontoone (David and Bobby) - you guys have been impressive on how you have handled the conversation in this thread. You are polite, informative and a template for me to follow. In addition to what you guys are doing, kudos on your PR skills.

Your site states you use a “proprietary machine learning algorithm”. As someone who has seen a gamut of companies use the machine learning phrase to justify almost any conceivable product, could you share any non-confidential information about what you achieve using ML?

I really think this explanation of how the number of people in the population who have the disease affects the chances of a positive test being incorrect, it is very unintuitive but look at the video as it explains that even very Sensitive and Specific tests can be problematic to see who in the population has a disease: <a href="https:&#x2F;&#x2F;www.instagram.com&#x2F;tv&#x2F;B-qZLJoAf3V&#x2F;" rel="nofollow">https:&#x2F;&#x2F;www.instagram.com&#x2F;tv&#x2F;B-qZLJoAf3V&#x2F;</a><p>Spreadsheet to play with is here: <a href="https:&#x2F;&#x2F;docs.google.com&#x2F;spreadsheets&#x2F;d&#x2F;1IPcX2JYt9mXdaTvj-3mhXQY22m4wrs4Kd6nxPhDWM-M&#x2F;edit?usp=sharing" rel="nofollow">https:&#x2F;&#x2F;docs.google.com&#x2F;spreadsheets&#x2F;d&#x2F;1IPcX2JYt9mXdaTvj-3mh...</a>

You can test all you want, with a spread like in the USA, there will be trouble to have proper treatment for all the cases. If such testing had begun earlier, then maybe lock down or near lock down scenarios could have been avoided. I see little chance, even with such 1 mio tests, to get it back under control without some kind of lock down or similar restriction to slow the spread. Where do you put all the infected people without locking down? If everyone infected is just told to stay at home, even if everyone complies, it is like a self quaranteen, like a lock down for those people.

Is it possible to create an at home cov2 test with a $25 homemade PCR<p><a href="https:&#x2F;&#x2F;hackaday.io&#x2F;project&#x2F;27623-coffee-cup-polymerase-chain-reaction-machine" rel="nofollow">https:&#x2F;&#x2F;hackaday.io&#x2F;project&#x2F;27623-coffee-cup-polymerase-chai...</a><p>and some synthetic DNA derived from cov2 (seems to cost about $0.09 per base pair)?<p><a href="https:&#x2F;&#x2F;www.twistbioscience.com&#x2F;products&#x2F;genes" rel="nofollow">https:&#x2F;&#x2F;www.twistbioscience.com&#x2F;products&#x2F;genes</a>

Hi and thank you for the efforts of your team. What can I do to have my country becoming ready for your solution when and if this will be available?

Great work, a friend of mine is molecular biologist and she is furious about how in germany they don&#x27;t use alternative methods for RNA Extraction like Phenol&#x2F;Chloroform (labor intensive but no shortage of material) &#x2F; SPRI (with magnetic beads) or skipping it altogether.

How will the process for the &quot;last mile&quot; be implemented?<p>There still needs to be tests taken from individuals and conveyed to the labs? many of these tests will be repeats from individuals who might have taken it earlier? etc

Thank you! Please also ensure all the countries on the planet have access to this tech.

am i reading correctly that you packaged synthetic viral RNA into viral particles and then suspended in transport medium? do you plan on studying actual patient samples and comparing to gold standard tests?

How quickly can this method be retooled for other pandemics, if there are 1000s of potential corvid-19s out there how quickly can it be adapted for the next one?

Can we fund this directly? Meaning can we donate to your effort directly? I believe it&#x27;s one of the most important things to return society to normalcy!

Are you reaching out to governments of other countries ?. How does this process work ? and is the canadian government aware of this work ?.

Why advertise before you&#x27;ve got FDA approval?

Amazing work!!! Thank you for working on this

all of the underlined &quot;filling out this form&quot; links are bad

How does this help with RNA decay?

I’d like to point out that schools are not open in the normal sense in Iceland. All the older kids school is stopped and Universities are shut. Our youngest is three and is in her leikskoli on alternate days so they can maintain small group sizes with no contact between them. Our eldest is six and only in school for a few hours in the morning, skips a bunch of more risky activities and is again segregated from other classes. As many businesses are working from home or shut completely a lot of parents have also opted to have their kids at home.<p>We’re currently in a better situation than a lot of places but it’s by no means without significant changes to daily life. It’s also a lot to do with the early response.

Say I had a lab with the sequencers needed for this test. I can&#x27;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&#x2F;day ?

We are seeing example after example of the power of entrepreneurship and private enterprise. I hope we remember this going forward and weave it into our national culture deeper and wider than it already is.

LMK if you need help making your site work.

Hmm... website seems overloaded atm.

&#x27;Machine learning algorithms&#x27;<p>Nothing to see here, just trying to make a quick buck using the pandemic

Isn’t this a log-scale problem? (binary tree)

The machine learning bit is the buzzword that makes it trendy.

Please take 10 minutes to get your site on the free cloudflare cache.<p>It&#x27;s not a good first impression (especially promising scale) not be to able to see it.

So, I can&#x27;t get to your site, but this seems a little disingenuous as a title. You&#x27;re not seemingly &quot;unlocking&quot; anything more than a protocol for Sanger sequencing that, if it eventually was approved and actually tested against real samples and people elsewhere adapted the protocols to use for testing, you would then... at that point... unlock a thing.

Scaling a static website involves far less technical knowledge than scaling a high politics &#x2F; moderate complexity scientific process.<p>The website looks terribly designed from a scaling standpoint. Have you run even a basic google pagespeed on it? Why no cache TTL on the custom TrueType font? Why no CDN backing?<p>This is a bit random, but if you have a &quot;proud&quot; web developer who &quot;knows best&quot; find someone with no pride who can get this sort of thing done.<p>We believe google can scale in part because they seem to be able return web search &#x2F; autocomplate &#x2F; google assistant responses pretty quickly.