Welcome to Natera's 2020 fourth quarter and full year 2020 financial results conference call. At this time, all participants are on a listen-only mode. Following management's prepared remarks, we will hold a Q&A session. To ask a question at that time, please press star followed by one on your touch-tone phone. If anyone has difficulty hearing the conference, please press star zero for operator assistance. As a reminder, this conference call is being recorded today, February 25th, 2021. I would now like to turn the conference call over to Michael Brophy, Chief Financial Officer. Please go ahead. Thanks, operator. Good afternoon. Thank you for joining our conference call to discuss the results of our fourth quarter and full year results for 2020. On the line is Steve Chapman, our CEO, Robert Schueren, Chief Operating Officer, Solomon Moshkevich, General Manager of Oncology, and Paul Billings, Chief Medical Officer. Today, we also have our Co-Founder and Chairman, Matthew Rabinowitz, on to review the results of the SMART trial. Today's conference call is being broadcast live via webcast. We will be referring to a slide presentation that has been posted to investor.natera.com. A replay of the call will also be available at investor.natera.com. During the course of this conference call, we will make forward-looking statements regarding future events and our anticipated future performance, such as our operational and financial outlook, our assumptions for that outlook, the impact of the COVID-19 pandemic on our business and operations, market sizes, partnerships, clinical studies, opportunities and strategies, and expectations for various current and future products, including product capabilities, expected release dates, reimbursement coverage, and related effects on our financial and operating results. We caution you that such statements reflect our best judgment based on factors currently known to us, and that actual events or results could differ materially. Please refer to the documents we file from time to time with the SEC, including our most recent 10-K or 10-Q, and the Form 8-K filed with today's press release. Those documents identify important risks and other factors that may cause our actual results to differ materially from those contained in or suggested by the forward-looking statements. Forward-looking statements made during the call are being made as of today. If this call is replayed or reviewed after today, the information presented during the call may not contain current or accurate information. Natera disclaims any obligation to update or revise any forward-looking statements. We will provide guidance on today's call, but will not provide any further guidance or updates on our performance during the quarter unless we do so in a public forum. We will quote a number of numeric or growth changes as we discuss our financial performance, and unless otherwise noted, each such reference represents a year-on-year comparison. Now I'd like to turn the call over to Steve. Thanks, Mike. Good afternoon, everyone, and thanks for joining us. Let's get into the highlights. Q4 2020 was the best quarter we've ever had at Natera. We processed 295,000 tests, up 13% sequentially versus a very strong Q3 2020, and up 41% over Q4 2019. Revenues were $112 million, our first quarter above $100 million, and product revenues were up 43% versus Q4 of last year. This represents the fastest quarterly net unit growth in company history. I'll get into more details on what's driving our performance in a moment. On top of 2020 being a great year for Natera, we enter 2021 with significant momentum across all of our businesses. In women's health, we've seen an acceleration in commercial payer coverage in average-risk NIPT even since we last spoke in November. As of January, all of the major national plans are covering NIPT for all women, and we've seen significant adoption among state Medicaid plans. We also released the results of the SMART trial at the SMFM conference in late January, and we announced the validation of our new Panorama artificial intelligence platform. The final results from this trial were even stronger than expected and put us in an excellent position to achieve reimbursement for our microdeletions test and further drive market share gains within the NIPT space. Our growth is being further amplified by the progress we are making in the transplant business. We've collaborated with top KOLs to present data at each of the major academic conferences this winter. We've continued to produce data on Prospera's unique differentiators, including the ability to detect background cell-free DNA simultaneously from the same workflow with no extra turnaround time or added cost. We believe this differentiator will be valuable for physicians. For example, the high level of background cell-free DNA we are seeing in patients affected by COVID-19 can mask rejection, and we've completed a study highlighting our ability to assess when this might be occurring. All of these data sets are being submitted for publication, and I will spend more time on that when it comes out later this year. Overall, we continue to hit our internal volume growth targets for Prospera, and we're very pleased with how the transplant business is developing. In oncology, on the pharma side of the business, we announced in January that deals signed in 2020 exceeded $65 million, up from $9 million two years ago. That business got a boost in December when Genentech's IMvigor study was presented. This was the first time an MRD assay has been evaluated in a phase III clinical trial, and the results for Signatera were compelling. On the clinical side of the business, our colorectal cancer launch is underway, and we've now completed the build-out of our commercial team. This investment gives us a great jumpstart as we seek to capitalize on our first-mover advantage. Now that the commercial team is in place, we can start executing on our plan to expand the Signatera indications and add other new products to their bag. I'm excited today to announce two oncology launches, Signatera IO monitoring and Altera tissue-based comprehensive genomic profiling, which allows physicians to select targeted therapies for cancer patients. Altera can be ordered from the same tissue sample used to power Signatera, but will also be available as a standalone offering. There are significant synergies between the two tests, particularly in advanced stage indications, where the use of a therapy selection panel is commonplace and reimbursed, and the need for improved monitoring of patients' response to immunotherapy is clear. Altera fits right into the bag of the clinical field force we have in place for Signatera. We think this combined offering will be compelling for oncologists. Solomon will get into more detail on that later in the call. Michael's going to get into details on the revised guide at the end of the call. There are two major headlines. The first is that we're guiding total revenues at $500 million-$525 million. Second, we expect the reproductive health business to get to a sustainable cash flow breakeven during 2021. Having our core women's health franchise cash flow breakeven allows us to continue making substantial investments to maintain our leadership position in oncology for the long term. This guide presumes we keep the volume growth going across all three areas of the business. That's exactly what we've seen so far this year in 2021. Going above the $500 million mark in revenues and getting to cash flow breakeven in women's health are two major milestones that have been years in the making. We're excited now to have these goals in sight. Okay. With that, let's get into some of the business trends. The next slide is our volume progression over time. Q4 represents a big step up even compared to our very strong Q3 performance. This breaks from historical trends where both Q3 and Q4 have traditionally been more muted, providing a nice momentum into 2021. The volume growth we experienced in the second half of the year was driven by strong account retention and new business wins during the height of COVID-19 last spring and early summer. The mix in our women's health business between average-risk and high risk hasn't changed that much. We believe two potential future drivers of growth, average-risk and NIPT market penetration, and a bump from the SMART trial are likely still in front of us. The next slide demonstrates that revenue growth is tracking nicely with volume growth, once again, accelerating meaningfully over what we've seen in the past. If you just zero in on product revenues on the right-hand side, you'll see revenue growth rates of 43%. This removes development revenue from partners, which was larger in 2019 than it is now. We saw recurring ASP step up again in Q4 versus prior periods, and blended COGS remained in the low $200 range. The combination of consistent gross profit per test and volume growth that we talked about in the past is working as expected, allowing us to get the women's health business to cash flow breakeven, supporting even bigger investments in the oncology business. The payer response to the ACOG Practice Bulletin has been stronger and faster than we anticipated last fall. We were really pleased to see all the major payers start covering NIPT in all women and continue to see excellent progress among state Medicaid plans. This is positive not only for coverage, but also for market penetration. As health plans expand coverage, many providers are changing their protocols from serum to NIPT. Given those trends, the timing of our SMART trial data readout is very timely. We are very pleased to be joined on the call today by Matt Rabinowitz, our Board Chairman and Natera's co-founder, who helped initiate and steer this trial for several years. Matt? Thank you, Steve. Good afternoon, everyone. I decided to join the call today to highlight the significance of the team's achievement on the SMART trial, which was over five years in the making. The trial was designed to affirm the performance of our NIPT technology in the general population and in the detection of microdeletions. We have made some big predictions at Natera. These include that NIPT would be adopted and reimbursed in all risk categories, and that our personalized oncology assay, Signatera, would achieve differentiated performance and reimbursement across multiple cancer indications. These have now occurred as we predicted because solid science usually prevails. Based on the exceptional performance of our technology in the SMART trial and the prevalence of microdeletions in the study, we now believe that professional guidelines can change and that microdeletions testing in NIPT will be more broadly reimbursed. SMART was an over 20,000-patient prospective clinical trial with 21 global centers. We collected pregnancy clinical outcomes as well as genetic truth samples from the fetus or the born children for 18,497 cases. This unprecedented data was used to showcase unique capabilities of Panorama, including Panorama AI. The AI or artificial intelligence component uses deep learning neural networks to model the sequencing data better than could be achieved by our team of classical statisticians. This amazing science was enabled by more than 1.6 million samples that we could use for training the deep learning network, and the performance can continue to evolve with more samples. This is like a modern biotech equivalent of the competition between Kasparov and the supercomputer over the game of chess, which the supercomputer ultimately had to win. Panorama AI extends our leadership in women's health. Two major presentations came out of the trial, and each are now being submitted for publication. First, SMART serves as the largest ever prospective aneuploidy NIPT trial and the only study of this scale to collect genetic outcomes at birth, setting a new bar in quality and size. The majority of the patients in the study were average-risk, and we demonstrated best-in-class performance with 99% sensitivity and 99.97% specificity in trisomy 21, with a positive predictive value in the general population of 95.1%. As a large number of newly adopting providers start using NIPT, we think this study confers a significant advantage and further separates us from NIPTs that have limited or no peer-reviewed data. Panorama AI lowered the no-call rate to roughly 1.5% while maintaining best-in-class accuracy. This category of cases that have very low fetal fraction were also clinically significant, as these cases were at substantially increased risk for other conditions, including preterm birth and preeclampsia. These add to the list of unique clinical differentiators, which have made Panorama the leading test. Second, SMART serves as a major advancement for microdeletion testing, rigorously validating Panorama's best-in-class performance and advancing clinical knowledge of the most common microdeletion, 22q11.2 microdeletion syndrome. We showed excellent performance in detecting 22q11.2 microdeletion syndrome as we expected, detecting 100% of cases of the most common microdeletion, 2.6 megabases or greater. Using Panorama AI, we were able to also detect the smaller microdeletions below 2.6 megabases, down to 0.7 megabases, which amounted to 41% of the disease load, significantly more than previously believed. Including microdeletions of all sizes in the 22q11.2 region, we demonstrated a sensitivity of 83% and a positive predictive value of 53%. This performance is unique in the industry. Today, none of the massively parallel shotgun sequencing labs are testing for the smaller microdeletions, which is a critical issue given how common they are. This could prove to be a major competitive advantage for Natera. Clinically, 22q11.2 microdeletions prove to be much more common than previously believed, but consistent with our estimates based on commercial experience. At an incidence of one in 1,525, this disorder is more common than cystic fibrosis at one in 4,000 or spinal muscular atrophy at one in 10,000, each of which are in the guidelines for screening and broadly reimbursed. In women under the age of 35, the incidence of this disorder nears that of trisomy 21. Crucially, none of these 22q11.2 microdeletion syndrome cases were detected at the first trimester ultrasound, and only roughly half were detected by any other means throughout the pregnancy. We can't be prescriptive yet on timing, but we think that this study should be sufficient to drive changes to society guidelines. We received a dedicated reimbursement code for microdeletions testing, which is priced by CMS at $759, and we already run more than 400,000 of these tests annually, which grew 37% year-on-year from 2019- 2020. The next step is to get these data sets accepted for publication in high-impact journals. Back to you, Steve. Thanks, Matt. Panorama is the market-leading NIPT. We've performed over two million tests to date. We're uniquely leveraging the power of SNPs to deliver best-in-class performance and differentiated clinical value. The SMART trial further amplifies those differences. We've studied more than 1.3 million patients in 23 peer-reviewed publications. With the completion of the SMART trial, we now have the largest, most rigorous, and the highest quality validation data for both aneuploidy and microdeletion testing. Combine that with our seasoned clinical and commercial teams. We're very well-positioned for the increase in NIPT adoption over the next several years. We believe the average-risk NIPT market could get close to 75%-90% penetration over the next three to five years, which bodes well for our business, especially with the high and consistent attachment rates of both carrier screening and microdeletion testing to NIPT, which further amplify the benefit of the expanding NIPT market penetration. Now, I'd like to hand the call over to Solomon Moshkevich to cover some of the recent highlights in oncology. Solomon? Thanks, Steve. The first slide here is on addressable markets in liquid biopsy that we've shown before. Natera is the leader in MRD and monitoring, and we're aggressively investing to maximize our first-mover advantage. We have hired up the commercial oncology team, and we're well underway with our launch in colorectal cancer, which is going very well. As Steve announced earlier, we're now launching Signatera for immunotherapy monitoring as well, on the strength of both our peer-reviewed data in Nature Cancer, published last year, and our draft coverage decision from Medicare, which we expect to be finalized later in this year. We're now also leveraging our leadership position in monitoring and MRD to expand into adjacent markets. We're excited today to announce the launch of Altera, tissue-based comprehensive genomic profiling, or CGP, for therapy selection. Therapy selection, we believe, is a $6 billion market opportunity with established reimbursement, which makes a lot of sense for Natera given the growing strength of our customer relationships in oncology. Altera also pairs nicely with our launch of Signatera in immunotherapy monitoring, which we'll go into more in a moment. Let's first dive into how Altera works. Altera reports genomic alterations found in the cancer across the full exome, with extra boosted coverage in over 400 clinically relevant oncogenes. Altera is at the cutting edge of therapy selection tests, with its exome-wide coverage of nearly 20,000 genes, its full transcriptome-based RNA-Seq analysis for optimal detection of structural rearrangements, its matched normal DNA analysis to filter out germline mutations that can sometimes cause false positives in other tests, and its ability to identify MSI status and gold standard TMB status based on the exome. Altera will be offered as a standalone test and also in conjunction with Signatera for those who want to combine therapy selection with personalized monitoring. A big advantage here is that Signatera is a tumor-informed test, where whole exome sequencing is already performed on the tissue and normal DNA specimens from all Signatera patients to inform the personalized assay design. We can deliver the Altera CGP results seamlessly from the same specimens. This is a key advantage for advanced stage patients, where both CGP and treatment monitoring are both clinically indicated and where tissue can often be scarce. Let me share a typical patient journey that includes both Altera and Signatera for a patient receiving immunotherapy. As we've discussed before, over 200,000 patients per year are treated with immunotherapy, but an even higher number of patients are screened annually for immunotherapy eligibility. This eligibility assessment often depends on biomarker status, including what alterations are found in the patient's tumor. For example, the FDA has approved a pan-cancer indication for the immunotherapy drug pembrolizumab in patients with MSI-high tumors or tumors with high tumor mutational burden, or TMB. We think that using our Altera test would be an efficient way for a treating physician to assess immunotherapy eligibility or eligibility for other targeted therapies, and then use the pretreatment blood sample as the baseline for future treatment response monitoring with Signatera, with no additional tissue specimen required. Both Altera and Signatera would be covered by Medicare in this scenario. In our clinical business, we're now full steam ahead with early-stage colorectal cancer, where we are enrolling nicely into the Bespoke CRC registry trial as commercial adoption of Signatera gains broader momentum. Now we're launching IO monitoring and Altera. We look forward to releasing more updates on the clinical market as time goes on. Now shifting gears to the pharma business, you see the rapid progression we've had these last two years since launch. This business has continued to mature as we have predicted, and we're now seeing significant interest in larger phase III studies, which, if successful, can lead to having Signatera included in the drug's label as a companion diagnostic. Pharma is now using Signatera in studies of more than 12 different cancer types. A key driver of this business is the compelling data that we've been able to generate from some of the clinical trials. The muscle-invasive bladder cancer data presented just a couple of months ago by Genentech at ESMO IO is an excellent case study. This was the IMvigor010 trial, which was a global phase III randomized and controlled trial of atezolizumab that took more than five years to run at great expense. Unfortunately, the trial itself failed to meet its primary endpoint in all comers after cystectomy. Atezolizumab improved overall survival by 41% for the Signatera-positive patients, which was 37% of the population. With 581 patients analyzed, IMvigor010 is by far the largest study evaluating any MRD assay, and it's the first ever randomized controlled phase III trial presenting results stratified by MRD status. Critically, the study shows how Signatera can take a trial that did not work in all comers and make the results positive by getting the drug to the right patients who are MRD positive. As you can imagine, we've fielded a lot of interest after the results of this study. Going forward, we expect most adjuvant trials to include some level of MRD-related stratification. In addition, we also are seeing the impact of this predictive data on how physicians in the clinical market are perceiving the utility of Signatera, even in early-stage colorectal cancer and in other indications. To summarize, in oncology, we have a lot of activity underway to drive the business. Clinical launch of Signatera in CRC and now in IO monitoring, launch of Altera CGP to drive additional insights for our ordering physicians, and continuing to ramp in our pharma business. Beyond that, this slide gives a good snapshot of the data that we've already published to date and our pipeline that we'll be reporting out over time. As you can see, we have a significant head start in published data across a range of cancer types. That leadership creates its own momentum and network effect. The leading biopharma companies, academic medical centers, and community oncologists all have a strong incentive to use the most thoroughly validated technology for their patients and in their clinical trials, which could in turn enable us to accelerate our lead in generating more data, which eventually leads to more coverage and adoption in new clinical indications. It's a virtuous cycle. As Mike will cover in a second, this demands a significant investment on our part. The rationale for our patients and our business is very clear. Let me hand the call over to Mike to cover the financials. Mike? Thanks, Solomon. The slide here is just a summary set of results for the quarter. Steve covered the major trends on volumes and revenues at the top of the call. You can see on the first two rows of the chart that the revenue growth was driven by robust product revenue growth and accounting-driven revenue recognition around signing the BGI and Foundation Medicine deals in 2019, was actually a headwind for the year-on-year revenue growth comparison. That's a very healthy dynamic and exactly what we had hoped to see. Within the reproductive health business, we continued to see a stable mix between Panorama and Horizon carrier screening, and microdeletions testing was ordered as part of the Panorama NIPT about 75% of the time, which is consistent with what we've seen for the last five years or more. COGS per unit in the women's health business continued to improve. We are now below $200 per unit in that category. We saw improving trends in the NIPT average selling price. On NIPT ASP, we started to benefit from average risk NIPT coverage policies, the full benefit, I think, will gradually translate to revenue over several quarters as we get more history with changing payer coverage policies. To be clear, we start getting paid right away when coverage changes, the visible impact of the P&L is really driven by the history required for accounting accruals on our revenue. The unit economics for our reproductive health tests continue to improve. Overall gross margins were slightly softer owing to driving some volumes in our new businesses prior to getting fully reimbursed. That's also a fairly transient impact, as I'll discuss on the guide. On the expenses side, we were able to significantly accelerate our build of the infrastructure for commercialization and oncology. Accelerating this build-out is crucial to making sure we can win on every dimension, not just technology and published data leadership, but also in the experience we provide for the physician and the patient. It's much the same story in R&D. There's really two categories of R&D efforts we have going. One is a very targeted effort on true research. These teams are doing things like leveraging the data we are collecting from early-stage cancer exomes to develop new tests that can expand our addressable market. We've always committed a minority of our R&D team to this kind of work. The results include the technology behind Panorama AI and the Signatera and Prospera franchises. The second, much larger effort is focused on development work that requires time and effort from a lot of really high-quality people, but the technical risk is relatively low and the returns are very clear. If you could sit in our reviews of these projects, you would want us to fund all of them. One of the large projects in this category is our aggressive effort, partnering with academia to generate validation data in a growing set of oncology indications. These types of projects have obviously paid off for us in the past, and we are happy to have more sample banks and studies to run in this area. We built a strong cash position last year, and we've been able to use it to our competitive advantage. For example, in return for more favorable terms for partners and vendors in long-term deals, we made prepayments of roughly $15 million in Q4. Other than those prepayments, our cash burn last year actually came in below our previous guide. Okay, let's get to the next slide and the guidance for the year 2021. Steve gave you the headline at the top of the call. We expect revenues to be $500 million-$525 million, gross margins in the 47%-52% range, and we are expecting our cash burn to be $230 million-$250 million this year, distributed across SG&A and R&D, as you can see on the page. Let's walk through each of the key assumptions for each of these lines. First, the revenue line presumes that we will continue to see strong volume growth across all three business areas. In reproductive health, we've historically focused on the absolute unit volume growth per sales rep, given that team is more mature. The guide presumes we can produce a similar unit growth pace as last year, which of course will require very good execution given the year we just had. The guide does not presume we get a huge windfall of units in a short period of time from the average-risk NIPT market opening up, since the specific timing and speed of broader NIPT adoption are not under our direct control. We've tried to take a balanced approach in modeling the volume trajectory in transplant and oncology, recognizing that we now have big teams in large markets for these areas, but these are also basically new categories, and we have less forecasting history with them. We've taken a conservative tack on average selling price assumptions for the year's guide. That's mainly a philosophical point in that we just don't think it's wise for diagnostics businesses to just assume ASPs are going to improve, because the factors that can move against you are also largely behind your control. If the very recent trends we've seen so far in Q1 hold up, our blended ASP assumption could end up being slightly conservative for the year. The gross margin assumptions have several crosscurrents running this year. We feel great about the reproductive health gross margin trajectory both because of the improving NIPT coverage, but also because cost of goods sold per unit continues to decline. For example, we've got a better Illumina supply agreement, and the Panorama AI platform is cutting down on our redraw rates once again. We are also pleased with the cost per unit trends we are seeing in oncology and transplant, which should be no surprise since both franchises are based on our core technology. The pressure on gross margins is much more transient and linked to volume growth, as I mentioned. For example, we are excited about launching in the IO monitoring indication and hope to grow units quickly, but don't expect a final reimbursement decision from CMS until the second half of the year. I covered the major drivers of SG&A and R&D increases in my review of the Q4 results. I expect those lines to grow in Q1 and Q2 and basically stay flat in the second half of the year based on the objectives we have mapped out for 2021 at this point. I do think there's one more variable that gets obscured on the page. We have found that investing in SG&A and R&D is much more effective and capital efficient than doing lots of acquisitions. Many of the players in our space paid full price for targets to stay relevant. What we've done instead is we've built our team. We'll try to be opportunistic on the M&A front. I think you'll see us selectively picking up technologies for relatively small dollars, and that's because the organic growth engine here is really strong. We've talked in the past about the gross profit per test and the unit volume metrics we would need to get to cash flow breakeven in the reproductive health business. Even with some additional investment targeting new product features and commercial activities to support the growth we've seen, we feel confident we can cross over the cash flow breakeven line in reproductive health this year, as Steve mentioned at the top of the call. That's a huge milestone for us and should give some confidence that the investments we are making are primarily focused on these large markets in transplant and especially in oncology. To summarize, we are very excited about 2021. We are off to a great start so far in Q1, we think we've got a bunch of interesting catalysts to unlock as the year progresses. With that, let me hand it back to the operator for questions. Operator? Ladies and gentlemen. If you have a question or a comment at this time, please press the star, then the one key on your touch-tone telephone. If your question has been answered, you wish to move yourself from the queue, please press the pound key. Our first question comes from Tejas Savant with Morgan Stanley. Hey, guys. Thanks for the time here. Congrats on the strong quarter. I just wanted to ask an overarching question on the guide here. I know, Mike, you mentioned that you've been relatively conservative in your assumptions for Signatera and Prospera. I'm assuming Altera is probably not in there at this stage at all. Can you sort of put a finer point on it in terms of giving us some color around volume trends, particularly in the back half for each of those tests? Hey, thanks for the question. Mike, do you want to take that? Yeah. Hey, yeah. Thanks for the question. I think you hit on something there in your question, which was just the weighting for the year. I would expect the year to be somewhat back-end weighted as we kind of grow into these launches. In terms of specifics, Tejas, I think in the future, we will start to give you more color on volume trends broadly in those new areas. Not yet. We're basically starting from launches in Signatera, effectively in Q4, and then middle of the year last year is when we got going in transplant. We started to see some green shoots there and some contribution to revenue in Q4, and we're just going to expect that to grow consistent with our comps so far this year. Got it. Fair enough. Matt, it's good to hear from you again. Following the SMART study readout and the validation of the algorithm here, can you just share some color on early feedback you've had since the SMART study? I know it's very recent. I'm especially interested in the ability to detect patients at increased risk of preterm birth and preeclampsia. Are those sort of standalone indications something that you could look to essentially add to the reproductive portfolio here? On microdeletions, over what timeframe do you think you start generating meaningful payer traction following the readout? This is Steve. Thanks, Tejas. I'll take those. On the payer side, we think the most important thing is society guidelines. We're in a position now generating this really gold standard evidence, frankly the largest NIPT prospective trial that's ever been done, but now doing that for microdeletions to have the type of data that societies will react favorably to. Once the paper's published this summer, we expect to hear from the societies. If you look at some of the press releases where the PIs on the study have been quoted, they've spoken very favorably about the opportunity here to change society guidelines. If that occurs, the payers will absolutely change their guidelines. We look forward to the paper coming out, followed by updated society guidelines, and then payer policy following suit. As we mentioned in the prepared remarks, last year, we did 400,000 microdeletion tests, and that was at a growth rate of 37% year-over-year versus 2019. This is really a rocket ship that's growing. We're running the test. If we can get reimbursement, we're going to be off to the races. When you look at the first question, preeclampsia, preterm birth, we made a decision a long time ago to not report out results at extremely low fetal fraction because we thought that there's something biologically going on there that is important for the physicians to not get tricked by and to not just get a negative NIPT result when there might be something more going on there. It turns out that not only is fetal fraction important as a quality control metric in getting an accurate aneuploidy or microdeletion result, patients that have low fetal fraction actually are at risk for preterm birth, fetal demise, preeclampsia at very significant levels. We look forward to seeing, again, how physicians in the KOL community want to digest this information. With the Panorama AI algorithm, we were seeing risk percentages of 15%, 16%, 17% risk to the pregnancy, that's very significant compared to other biomarkers that are out there. It's unlikely that will be a standalone test, it's important when you're getting a no callback that you can get this extra information that no other laboratory can provide. Got it. That's super helpful, Steve. One final one on Prospera for me. I feel like that's a part of the pipeline that sometimes doesn't get as much attention as oncology. The market is sort of still relatively at low levels of penetration. Over what time frame do you think you have a shot at sort of pulling even with your competition there, and have you thought about sort of creating an ecosystem of service offerings around Prospera? Your competitors launched a referral service and a wait list management service and a software like EMR platform, et cetera. Is that something that's very much on your radar as well as you think about ramping up Prospera volumes here? We didn't spend a lot of time today talking about organ health, but that's an area where we continue to invest, and we're actually doing really well in 2020. I think we mentioned at the JP Morgan conference that we actually beat our pre-COVID estimates for Prospera. We're pleased with the performance of the test. We're pleased with the interactions we've had with Key Opinion Leaders. Certainly, we keep our eyes on some of these ancillary opportunities. You have to sort of decipher whether it fits in with the broader strategy at Natera. These ancillary services, whether they fit in with the broader strategy at Natera and whether they fit in with the strategy of interacting with patients and physicians. If it does, we're certainly going to take a look. We're keeping our finger on the pulse, and it's an area that we think has an enormous opportunity to grow in the future. Got it. Thanks so much, and congrats again. Thanks. Our next question comes from Tycho Peterson with JP Morgan. Hey, thanks. A couple on Signatera-IO and Altera. Given the timeline for the final LCD that you laid out, I guess, is the initial use case for Signatera-IO for RUO for pharma until you have the final LCD? Then, pricing, you previously talked about $1,800-$3,500. I'm just curious if there's any updated thoughts. Then how are you thinking about pricing for Altera? Yeah. On the Signatera-IO side, the test is CLIA validated. We have a peer-reviewed publication that came out in Nature Genetics last summer that serves as the validation study. It's on the market now through our sales force in a CLIA environment clinical offering. It's available to pharma as well as a CLIA test. It is being sold through the commercial clinical sales force at this point. We're getting out there pre-reimbursement, and we expect reimbursement to come in at some point this summer. As you build the ramp when you initially launch something, in the earlier days, the volume coming in and the ramp is less significant. We think we'll be hitting our stride right around the time that that reimbursement comes in. The great thing about the Altera launch is that it's the same tissue sample, and it's going to be very convenient for physicians to be able to order Altera, get the information back on therapy selection, tumor mutational burden, MSI status, and then do ongoing monitoring and surveillance with personalized Signatera. Now, the reimbursement for Altera is already established, so we can piggyback on the broad reimbursement that's already in place there. That's one of the reasons why we thought it made sense to launch this and to add it to the bag. How often do you expect Signatera-IO and Altera to be used together? Do you think that becomes the norm? If you look at the opportunity and the percentage of patients that are eligible for IO monitoring and then how that decision is made on who's eligible for IO treatment, it does seem like the vast majority of the time, someone setting up for potential Signatera, that they're going to want Altera. Okay. As we think about your work with Foundation Medicine on developing liquid exome, how do we think about that in the context of these launches? Is that something that potentially could replace Altera over time, or no? We think about the Foundation partnership as separate. Foundation Medicine is really the leader in tissue-based comprehensive genomic profiling. The product that we're working on with them is going to be a therapy monitoring product that is based on their FoundationOne CDx product, which is a targeted panel of comprehensive genomic profiles. They have a large team in place. They have a big customer base. Whenever somebody orders that FoundationOne CDx, they'll be eligible to design personalized primers. We think about our exome-based Altera and Signatera as an independent offering. Together we're going to approach this market. Okay, a follow-up on the microdel commentary. I just want to be sure I heard that right. You think the guidelines could actually change as soon as this summer? I mean, we're all a little bit jaded from the average-risk ACOG situation. Why do you think you're more bullish on microdels than some of your peers who have talked it down? Yeah. Look, the societies respond to peer-reviewed data, this is the study that is going to change, move the needle. If you look at the studies that moved the needle for non-invasive prenatal testing in high risk or even in average-risk, they were significantly smaller than this and less rigorous than this study. A study of this magnitude with this level of clinical outcome has never been done before. If you were to go back and design the perfect study that the societies would respond positively to, this is it. At the outset, when we met with the key opinion leaders and society members and we said, "What do you need to see in order to change society guidelines?" They said two things. A disease incidence that is in line with expectations, and at that time it was thought that 22q11.2 microdeletion syndrome had a prevalence of about one in 2,000. In the study, we showed that it was about one in 1,500, so it's actually more common than what was thought. The second thing was we have to show a high sensitivity and a high positive predictive value, and we've done both of those. The sensitivity in the microdeletions of above 2.6 megabases was 100%. For all microdeletions, all 22q11.2 microdeletions, it was 83%, and the positive predictive value was 53%. If you think about aneuploidy screening overall, serum screening has a positive predictive value of 5%. NIPT and aneuploidy has a higher PPV, 80%-90% for trisomy 21 and lower for the other aneuploidies, trisomy 18 and 13. This performance is right in there now with the top common aneuploidies. We feel very positive about it. It's a severe genetic disorder that has a significant outcome on live births. There's a screening test that works very well. The gold standard study has been done, and the results came out very positively. It's exactly what you would need in order to change guidelines. Now, of course, we can't promise anything, but this is exactly what you would want. It's the perfect setup for a guideline change, and if guidelines do change, the payers certainly will change. We're looking forward to the publication coming out at some point this summer. Okay, that's helpful. Just last one quickly on guidance. On the guidance slide for R&D, you highlighted expansion into new oncology indications. Is that anything you can kind of shed some more color on? Is that other indications beyond CRC? Is it pan-cancer MRD? Is it liquid exome? What's the priority list? We're looking at multiple different things. That includes rapidly expanding Signatera indications. While we work on commercializing colorectal and IO monitoring, we're looking at a long list of additional indications. We think eventually Signatera will be a pan-cancer assay, and we're working on generating the data in multiple different indications as we've shown in the slide deck. We're also looking at other ways that we can penetrate into the $50 billion liquid biopsy market. We talked today about tissue-based therapy selection, but we think that there's a lot more that Natera can do to leverage the strength of our technology across the entire $50 billion TAM, and you can certainly believe we have irons in the fire in each of those circles that we've shown in the slide deck. Okay. Thank you. The next question comes from Doug Schenkel with Cowen. Hey, good afternoon, guys. Thank you for taking my questions. First, I guess just a trend and kind of math question. Doing this on the fly, it looks like you guys were doing about 22,000 tests per week in the fourth quarter. I'm just wondering how that trended over the course of the quarter from beginning to end. Keeping in mind you were doing, using the same logic, 17,000- 19,000 tests per week over the first three quarters of the year. How much of the lift relative to the beginning of the year versus what we saw in Q4 was a function of average-risk or new products versus seasonality? I guess the final component of this, presumably you're expecting to trend up from here as we look ahead to Q1 and beyond. Yeah. Thanks, Doug. I apologize. Actually, my phone broke up for the first half of the question. I got it. Maybe, Mike, do you want to take that? Yeah. I think the core of the question is how much of the uplift in Q4 is due to average-risk versus just the business humming along and our typical kind of seasonality here. Look, if you look back over the year, what we saw was that in retrospect, from the spring and the summer, what really drove the volume outperformance for the year was just organic kind of new account wins paired with even better than normal account retention. The mix between average-risk and high risk in NIPT didn't really change all that much through the course of the year. I think historically that makes for 60% average-risk and 40% high risk, that's ticked up. Maybe that's 63/37 something in that (ZIP code), Doug. That's not just positive, but that's sort of a rough and ready metric to tell you that it's not like, I don't think that a lot of the average-risk penetration is what's really driving us yet. I think that's largely in the future for us. What led to Q4? I think typically there's some step-up Q4 versus Q3, but not like what we've seen here. I think the second or third chart in the deck just shows you visually the size of the step-up in this Q4 versus the typical step-up that we've seen in years past. I think that is a lot of good account wins and just organic growth. We'll be able to tell with the benefit of hindsight to what extent it was some more kind of average-risk penetration. Anecdotally, it seems like that average-risk penetration is still ahead of us. In terms of the volume for next year, it's kind of encapsulated in the revenue guide. It does presume a strong volume growth next year tempered with the other areas of conservatism that we talked about in the prepared remarks. Okay. Just a couple of clarifications, Mike, and thank you for all that. There's nothing in there. I think Signatera would be in that number in terms of kind of Q3 to Q4, where you had another quarter of marketing, you started to get paid. Yeah. That wasn't a big mover to the sequential improvement. Yeah. That is a contributor, Because it didn't exist really as much in Q3, it's because it's our growth. I think that is a contributor. Really, if you look at the sequential growth in the women's health business or really across the product lines, it's not a huge disparity where the new products are growing and the existing products are flat, the women's health products are flat. On the contrary, we saw very strong uplift across the business. Okay. Super helpful. Steve, I'm going to ask a similar question to what I've asked other companies in this sub-segment over the course of earnings. Sorry for folks listening, but we're going to go there again. You and your peers seem to be skating in the same place when it comes to cancer menu, which is something we've envisioned for a while. It just seems to be happening at a quicker pace than maybe we thought was going to happen. With you guys, your movement to MRD monitoring was a pretty natural and smart extension, given your leadership in high sensitivity cell-free DNA assay development. That said, you're now moving into tissue where you don't have a ton of experience, at least in terms of using tissue for actual diagnostic purposes. You would seem to need assays in screening and blood-based therapy selection to kind of round things out. With that in mind, my questions are, one, how did you build out the tissue capabilities? Two, how are you expanding your commercial infrastructure pursuant to the full menu build-out, and is that the right way to think about it? Third, how do you think about building out the menu? Mike, at the end of his prepared remarks, talked about increased investment in R&D and SG&A. When I think of some of these things, particularly screening, that's an example of where you might be better served going inorganic. I just want to get your thoughts on that. Thank you. Yeah. Thanks, Doug. First, I think we've been doing a lot of hiring in R&D, and I think that's reflected in the numbers that we put out. We have a really solid team in place. We've been working on different things. I think we're excited about the Altera launch. We think this is the first step into the $6 billion therapy selection opportunity. We do think that looking at liquid therapy selection and asymptomatic screening makes sense, but I think we're going to make smart decisions and be very targeted with our efforts. We do have some unique advantages. For example, we're doing a lot of early-stage exomes at this stage, and that gives us information that others don't have access to that we can leverage to design assays that can perform well in an asymptomatic environment. We're doing things in a very targeted manner on asymptomatic screening, but it is something that we're looking at, and I think as that program develops, we'll release more information. On the tissue side and on the liquid therapy selection side, these techniques are the same techniques that we use for other assays, and we have very skilled team members, and I think we're in a great position to put good tests out on the market, and we'll be very competitive. What we're trying to do is leverage the commercial footprint that we've put in place and offer a full menu back to physicians. The oncology team that we built is top quality, high-quality medical staff, sales staff, MSL staff. When they're meeting with a physician, especially where there's significant amount of synergies like there are with IO monitoring and Altera, it makes a lot of sense to capitalize on these different opportunities. Thank you. Steve, can I add a comment there? Yep. Sure, Solomon. Yeah. There's obviously a lot of opportunity here, Doug, you pointed out. From my perspective, our first priority is to maintain and extend our leadership position in MRD, which has opened up so much opportunity to improve patients' lives, a huge amount of demand, just inbound coming in from the data and utility we've been able to generate. If you think about it, there's some serious platform opportunity when you think about two things. First, to run a Signatera test, you automatically get the tissue sample, a normal DNA sample, and plasma samples. All right? There's just so much you can do with those specimens. The second thing is, once you've generated a personalized assay for a patient and you're running monitoring for a long period of time, that's our patient for a long time. That's a very special type of long-term relationship that's less common, historically, in this industry. We intend to make the most out of that, to deliver the most services and insights we can for those patients. Those two things together is also going to help us generate our clinical genomic data strategy as well. Generating an enormous amount of genomic information that's never before been available from exomes in early and late-stage patients with long-term follow-up. It's going to create a whole new opportunity we're investing in significantly that will further extend our leadership position. I think there's a lot of opportunity on the table, and we're well-positioned. Thank you. Our next question comes from Catherine Schulte with Baird. Hey, guys. Thanks for the questions. Just one on guidance and then I have a couple on Signatera. Mike, how should we think about revenue pacing throughout this year, kind of weighting in the first half versus the back half? I'd imagine transplant and oncology, as well as some of that average-risk ASP lift, are likely more back-end loaded. Yeah, that's exactly right, and thanks for that question. It is significantly back-end loaded, and part of that is just the natural tempo of the business and the fact that you've got volumes growing through the course of the year since the business is growing so quickly. Part of that is related to reimbursement, where you'll have broader reimbursement for things like IO monitoring, which will be contributing volumes in the first half and can start to contribute actual revenues in the second half, so long as we can get the CMS reimbursement in place. Drivers like that do tend to put you more back-end weighted this year. Okay. On Signatera RUO, you had $55 million as total contracted value at the end of 2019, added another $65 million to that last year. Can you just talk to how much that contributed to revenue in 2020, and when can we expect to see that ramp up more materially? Yeah. Just to refresh everyone, the typical waterfall is you sign a contract to do a pharma deal. It takes about a year from signing for the patients to start actually sending samples, you book whatever revenue you sign from that contract in years two and three post-signing, if that makes sense. You can kind of see on that chart, you started in the $9 million-ish range grew from there. That waterfall is actually pretty high fidelity indication of where we landed for pharma revenues this year, high single, low double-digit millions in revenue is the sense of that. That's just going to continue to ramp, much more so as you hit into these bigger studies. That's why results like this in bigger trial are so important to us. Okay. Then on the breast cancer recurrence, a phase II trial initiated by Massachusetts General Hospital last year, are you still expecting a data readout sometime this year? Is it your thought that that would be enough to take to Medicare, or do you think you would have to wait for the phase III data? Yeah, I'll make a comment on that and then maybe Solomon, you can come in. We actually announced two trials, one with Pfizer and the other with Novartis, that we're looking at breast cancer treatment on molecular recurrence. Both phase II trials, and I think we're excited about that because that's an enormous opportunity. The breast recurrence market is maybe five, six times bigger than the colorectal market. That's an area where there are phase III trials that we've competed for and we're feeling very good about. I do think that in order for physicians and pharma companies to be enabled to actually make that change, you'll need to see the phase III data. Certainly, I think these phase II trials will be good initial readouts. There are phase III trials underway, and we look forward to making announcements in the near future. Solomon, would you like to make additional comments there? Sure. Yeah. Just echoing, breast cancer is a hugely important area with a lot of unmet need. There are other studies that are underway that have not been announced yet. I agree with Steve that in terms of base case assumption, you need some strong Level 1 data, like phase III data, to really enable that. There is upside potential. We've seen before, the breast cancer patient population is very active, very forward-thinking. A lot of patients who take matters into their own hands and push policy forward more than you see in some of the other cancer types. Between that and a lot of the data we'll be reading out earlier, I think there's some upside potential. In general, I agree with Steve. Okay. Oh, go ahead. Yeah, just going to say, Catherine, as a reminder too, we just published some great data in neratinib breast. As you saw on the slide deck, we've had another peer-reviewed paper in breast cancer that's been accepted that we can't talk about now, but just adding to the massive amount of data that we have out there. One of the main things that separates Signatera from some of the other groups that are coming into MRD is the amount of data that we have. We now have eight accepted and published peer-review papers in over 2,000 patients that have been studied. When you look at some of the competitors that are now coming in that really don't have any peer-reviewed data, I think it's a very significant differentiator. Okay, got it. Just sneaking one in, you've talked a lot about early detection today. What's the general timeline we should think about for hearing more about your early detection plans, and is your general thought to take a multi-cancer or single cancer approach there? Yeah. I think at this point, we haven't really released any of the details of our plans, and we're going to update everyone on that in the future when we're ready. What we're saying at this point is that we have irons in the fire. We have some unique capabilities based on all the early-stage exome data that we have, and we have a very targeted way from an investment standpoint to go after this market. We look forward to giving some future updates when those are ready. As you can see, we didn't include it in any of the prepared remarks. We will do that in the future when we're ready. We're not ready to do that today. All right, great. Thank you. Well, ladies and gentlemen, this is all the time we have for questions today, and this also does conclude today's presentation. You may now disconnect, and have a wonderful day.