Revolutionizing Molecular Pathology: The Evolution of Next-Generation Sequencing Proficiency Testing

Learn more about the CAP's proficiency testing program.

Listen to other episodes in the 75 Years of Proficiency Testing Series:

• Enhancing Public Health Readiness: Laboratory Preparedness Exercise
• Infectious Disease Program: Continuously Evolving to Bolster Public Health
• Pioneering Precision: The Evolution and Future of Accuracy-Based Proficiency Testing

Becca Battisfore:

Welcome to the latest edition of the College of American Pathologists' CAPcast. I'm Becca Battisfore, content strategist with the CAP. In this episode, we'll be discussing molecular proficiency testing programs with a focus on next generation sequencing. This episode is part of a series celebrating the 75th anniversary of the CAP's proficiency testing program. So please check out the previous episodes on the topic. I'm delighted to have Dr. Joel Moncur with me today to lead the conversation. He and our three guests have all played a role in the development of the next generation sequencing program. Without further ado, Dr. Moncur, I'll let you take it from here.

Dr. Joel Moncur:

Thank you, Becca. This podcast is intended to share information about the CAP next-generation sequencing and proficiency testing programs, how they were developed, what role they play in high quality healthcare, and where both the technology and the PT programs are heading into the future. So the CAP for your awareness has leading PT programs for next generation sequencing that support laboratories in achieving their goals of high quality testing. And they also help laboratories meet and exceed regulatory requirements they provide in valuable data about laboratory performance. And those data are not only very useful for laboratories, but also for patients, for treating providers, for payers, regulators, and any number of other stakeholders.

So my name is Joel Moncur. I am a molecular and genetic pathologist, and I'm the Chief Medical Officer and Deputy Director of the Joint Pathology Center in Silver Spring, Maryland. I'm a member of the CAP Council on Scientific Affairs and House of Delegates, and I'm the prior chair of the CAP Molecular Oncology Committee that oversees next gen sequencing, PT for testing and cancer. So I'm joined today by three very distinguished guests, Dr. Wayne Grody, Dr. Karl Voelkerding, and Dr. Jason Merker. Thank you all for participating in this conversation. So Dr. Grody, I'd like to begin with you. You were the chair of what was once called the CAP Molecular Pathology Resource Committee. I'm wondering if you could please introduce yourself and then share some of the history of the molecular PT and how it helped form a foundation for next-gen sequencing PT programs that we have today.

Dr. Wayne Grody:

Great. Thank you Joel, and we're glad to be here for this very important anniversary recognition. I'm Wayne Grody. I'm a professor at UCLA in the Departments of Pathology, Pediatrics and Human Genetics. I'm the founding director of our Molecular Pathology Lab and Clinical Genomic Center. I'll reflect on that in a minute or two. And yes, as you mentioned, Joel, I was actually not the very first chair of what was then called the CAP Molecular Pathology Resource Committee. That was Bob Nakamura, a very beloved senior pathologist based at Scripps Clinic. He was involved in, I think, being of Japanese descent, the Atomic Bomb Commission studies of the effects of people exposed in Hiroshima and Nagasaki. And so he was interested in radiation damage to DNA and I think that was kind of what led to his being the first chair. And then I took over shortly after that.

The committee was started in around 1988 or 89, and the listeners have to realize this was really the dark ages, the infancy of molecular diagnostic. In fact, not even infancy, I would say probably in utero. It was truly the wild West. There were no practice guidelines, no accreditation, no certification, no board exams. Karl and I were very involved in getting that board started in molecular genetic pathology. It coincided with starting our own lab here at UCLA, which was also very crude tiny. After years of pleading with the hospital leadership, they gave us a room literally the size of a walk-in closet, half a technician borrowed from a research lab, not a CLS. We had one test that we were doing really limping along. And so the early meetings of this resource committee were very gratifying to me, not only the great scientific discussions we had, but just the comradery here.

I was working alone in this tiny lab. No one else at UCLA could help me or knew what I was doing. And then I suddenly met all these brilliant people from around the country at other leading institutions, pretty much in the same boat as me with the same struggles. So I often likened this resource committee to kind of meetings of Alcoholics Anonymous where we could kind of share the empathy and what we were going through. So our committee was charged right from the beginning with two products we had to come up with. One, as you mentioned, was proficiency testing in the various areas of molecular pathology, which includes microbiology, genetics, tumor testing, and so on. And then two, develop an inspection checklist in molecular pathology so that labs could become accredited by the CAP. This was especially important because CLIA says nothing about molecular testing or genetics.

The only thing close in there is cytogenetics. And even that it's just karyotype, not even FISH. CLIA was always considered to be inadequate for showing that a lab was competent, and I credit the leadership of CAP at the time, none of whom were doing molecular testing for their vision, knowing this was going to be so important and putting CAP in a leadership position right from the start. So we developed these proficiency tests and guidelines, none of which existed. As I said, you've got to have pre and post PCR rooms and so on. The first proficiency tests, which I believe were immunoglobulin and T cell receptor clonal gene rearrangements. And from that, it just grew exponentially over the years to the point where that one committee had to give birth to others devoted only to oncology, only to forensic DNA testing. And then most recently, the one we're talking about today on next generation sequencing.

Dr. Joel Moncur:

It's amazing history. Thank you, Dr. Grody. Dr. Voelkerding, I'd like to move on to you, please. You were previously the chair of the CAP Genomic Medicine Committee. You led the creation of the first next-gen sequencing proficiency testing programs. Could you please introduce yourself and share how you did that and what was involved?

Dr. Karl Voelkerding:

Yes. Thank you, Dr. Moncur. Hi everyone. I'm Karl Voelkerding. I am also a molecular genetic pathologist. I am now retired from my former day job as a professor of pathology at the University of Utah, and I was previously the chair of the CAP Genomic Medicine Committee. And my current activities with CAP is that I'm a member of the CAP Checklists Committee. First, in terms of the history, I just want to say that I had the great privilege to work with an amazing group of laboratory directors and CAP staff during the development and launch of the first next-generation sequencing PT program. Approximately 10 years ago, we began our work as what was initially called the CAP NGS Project Team, which was the precursor to the Genomic Medicine Committee. And our first NGS PT program was designed for laboratories analyzing for germline sequence variants. And at that point in time, a decade ago, NGS for germline variants was being adopted by a growing number of laboratories.

We chose to develop a methods based PT approach to assess the overall analytical process from sample preparation through sequencing, bioinformatics and germline variant identification. And a methods based PT approach allowed assessment of a diversity of individual lab workflows whose analytical targets ranged from multi-gene panels to exomes. And the PT sample provided to labs was genomic DNA that we had within CAP highly characterized for its sequence variant content using both exome and genome sequencing. Labs received a list of 200 chromosomal positions or intervals in genes associated with a range of inherited disorders. For example, cardiomyopathies congenital hearing loss, germline cancer predisposition syndromes. And if a laboratory tested for sequence variants in any of the genes and their associated chromosomal positions, they were asked to respond if a sequence variant was present or not. So the first PT program was really an analytical assessment of germline variant identification. And we rolled this out first as an educational PT program in 2015 and converted it to a graded program in 2016.

Dr. Joel Moncur:

That's again, an amazing history. I wanted to ask you a follow-up question, which is that I know you led the initial design also of what was called wet and dry or what's also called in silico next-gen sequencing PT programs. Could you talk about both those types of programs and why both are important?

Dr. Karl Voelkerding:

Yes. The importance of the way we designed the first methods based PT program where laboratories received a genomic DNA sample was truly a way to assess their ability to go from genomic DNA through the process of preparing a NGS library and then sequencing all the way to a variant identification. So that assessed their kind of wet bench into their bioinformatics. Now, the challenge with that is that the samples that we use, the genomic DNA samples we used, they contained a limited number of sequence variants in any given gene. And also those variants were predominantly classified as benign single nucleotide variants. And whereas laboratories that were assessing samples for germline variants were really looking for likely pathogenic or pathogenic variants. So there were inherent limitations to using a single genomic DNA sample and to address this type of limitation. And we wanted to expand PT program testing in the realm of NGS.

We also developed an in silico approach. So operationally labs would sequence the genomic DNA that was provided to them by CAP, that was our original approach. And then they would return their base sequencing data files back to CAP. And then within CAP, we introduced into the labs sequencing files a variety of sequence variants into target genes using a software algorithm capable of in silico mutagenesis. Then the mutagen eyes files were returned back to the labs where the labs would analyze them using their bioinformatics pipeline and labs would report back to cap the variance that they had identified. So the importance of this in silico program allowed CAP to assess the lab's ability to identify a greater diversity of variants of different pathological characteristics. And also importantly, we were able to expand the assessment of how a lab could identify an insertion or deletion because we could mutagenize the files for insertions and deletions, which were limiting in terms of their numbers in the wet bench samples or the genomic DNA samples we provided to labs.

And also, and this will lead into other discussions later, is that we were able to introduce variants at different allele fractions within the sequencing data files. So this modeled essentially for laboratories somatic variant detection, and this was very important to compliment and augment the molecular oncology PT programs. And the last point I'd want to make is that if a laboratory only performed bioinformatics in a distributive testing model, if we could provide to them sequencing data files that they could be introduced into their bioinformatics pipeline, we were also able to start to begin to assess and provide PT for those laboratories in that distributive testing model.

Dr. Joel Moncur:

Thank you, Dr. Voelkerding. I have one other follow up question for you, which is that I understand that patient privacy was a big consideration when next-gen sequencing PT was originally being developed. Could you tell us a little bit about that please?

Dr. Karl Voelkerding:

Yeah, so the origin of the DNA used for the first NGS PT program for the germline variant identification was obtained through an initiative called the Personal Genome Project, which was based in Boston, started at Harvard University. And this personal genome project was comprised of individuals who donated their blood to this project and it would be allowed, their blood could be used for essentially multiple purposes, including establishment of cell lines, extraction and sequencing of genomic DNA and commercial uses. And they had a very extensive informed consent process, and that donors consented to the possibility that their identity might be revealed through sequencing studies. So this is how we address the issue of potential identification of an individual by use of exome or whole genome sequencing and hence the privacy issue.

Dr. Joel Moncur:

That's fascinating. Alright, well thank you. I'd like to move on to Dr. Jason Merker. Jason, you helped lead the iterative process of creating standardized proficiency testing samples that mimicked real world samples, especially for molecular oncology. Could you please introduce yourself and share what it took to create standardized samples that performed well for all laboratories that participate in next-gen sequencing pt?

Dr. Jason Merker:

Of course. My name is Jason Merker. I'm an associate professor in the departments of Pathology and Laboratory medicine as well as genetics at the University of North Carolina. There I'm an attending molecular pathologist and clinical cytogeneticist and I focus on molecular oncology. I was vice chair and then chair of the Molecular Oncology Committee from 2011 to 2018, and also a member of the CAP NGS project team. During that time within the molecular oncology committee, we were involved in the development of samples to support NGS based PT surveys for solid tumors and hematologic malignancies. And this occurred in parallel with broader efforts within molecular oncology to transition from largely patient derived samples to other alternatives. And there are many, many advantages to patient derived samples, but there were key limitations that just we couldn't overcome. One was that when you think about the large specimens that are required to support a PT program, there's quite a bit of variability, notably in nucleic acid quality as well as the variant allele levels that occur throughout the sample and addition, it was becoming increasingly difficult to source those materials, particularly when we wanted to include certain variant types as well as certain variant levels.

So we started by developing specification for what we wanted the materials to do. First off, we wanted to rigorously evaluate laboratory performance with a particular focus on actionable biomarkers. To the extent possible, we wanted to mimic clinical specimens without heterogeneity. So the sample we sent to the first laboratory would be identical to the sample we sent to the hundredth or 200th laboratory. It needed to be used across broad methods. It needed to support both current as well as future PT offerings. This is a rapidly evolving field and it's important that PT efforts can keep up with that. And finally, it had to fit in with the operational requirements of a CAP PT program. So subsequent to the defining the specifications, we evaluated a number of different engineering approaches that were available at the time. We tested the most promising techniques. We identified an initial approach.

We broadly evaluated this by having multiple committee members and other CAP members test different methods. And then we repeated this over a course of a couple of years until we found a method that we thought was appropriate. And I will say this work ultimately spanned four different chairs. So the work started with Dr. Larry Jennings, moved on to myself, to Dr. Moncur, and then currently to Dr. Neal Lindeman. There were many committee members that were involved in both the discussions as well as the testing and materials. And last but certainly not least, Patty Vasalos was the staff member for molecular oncology. She was the one who sourced the specimens, took care of logistics, and ultimately was the one who got it done. So thank you.

Dr. Joel Moncur:

Thank you, Jason. I really appreciate you mentioning many of the other chairs that worked on that and individuals, and also Patty, because I think that all of us, I think I could say without taking any risks, that all of us collectively just think that Patty Vasalos is an absolutely remarkable individual who's had an enormous impact on advancing the field of molecular oncology and molecular testing in general. So anyhow, thank you very much for those comments. So another component of next-gen sequencing PT was how it was rated. And this is something that I was heavily involved with, so I'll share a little bit about that and what it took to be able to successfully grade these PT programs. So historically, molecular PT has been graded one gene at a time, but with next-generation sequencing laboratories assess hundreds of genes in one test and it was no longer feasible to grade gene by gene.

So we redesigned next-gen sequencing proficiency testing to reflect how testing is done today. We implemented a plan for grading that focused on each lab's ability to detect a variety of common and uncommon mutations at a range of mutation frequencies or fractions. And so this grading scheme allowed us to calculate an overall sensitivity and specificity score for each of the participating laboratories for molecular oncology specifically. And since we introduced this grading schema, it's been accepted by the Laboratory Accreditation Program, which is great news because it means not only is it graded, but it's monitored, which gives labs the best opportunity for ensuring that they're providing high quality testing. So overall, this scheme is given laboratory is really very manageable and an excellent way to assure the quality of their testing. And those are my comments about how we'd go about grading. I think I would just lastly say that CAP was very thoughtful in how they implemented this and involved multiple councils and committees and had the input of a lot of wonderful, again, very thoughtful people, and we just wanted to express gratitude to all of them for doing that. So with that, I have now a series of questions really for the whole group, and I'm hoping that those who have something to share would be willing to pass that along. So first question is about questionnaires. So questionnaires have really played an important role in the success of CAP's next-gen sequencing PT programs. And could all of you, if you have something to share, talk about how questionnaires that are included in CAP PT program mailings were used for next-generation sequencing PT?

Dr. Wayne Grody:

Yeah, so I'll start. This is a very crucial part of the PT programs. All of us who've served on these committees know that the committee members spend at least as much time crafting and fine tuning the questionnaires as we do developing the actual challenge samples that are going to be distributed. And it's not so easy. There's a lot of subtleties and nuance, but it's worth the effort because this is very valuable. As I mentioned in molecular pathology, this started when the field was very young and the CAP surveys were the only source at that time and still perhaps the best source of giving a national snapshot of what molecular testing labs are doing, what tests they offer, what their volume is, what platforms they choose to use. We ask a lot about technique and platform. And so the PT results give us a good handle on which platforms are performing better than others, and the community can run with that and think about it the next time they order an instrument. We also compare commercial kits, which in the beginning there were none, but now they've become more plentiful with in-House Lab developed tests, the LDTs. And that's especially crucial now that we're all aware that the FDA is proposing to assume a lot more oversight of LDT tests based on the theory that maybe they're not so good since they haven't been reviewed. And it's wonderful that we can point to the excellent performance in the CAP programs to say that that is not the case. These are very robust.

Dr. Joel Moncur:

Great comments. Thank you. Dr. Voelkerding, did you have something to share?

Dr. Karl Voelkerding:

Maybe one additional aspect I would add is that the field of next-generation sequencing really disseminated quite rapidly over a very short period of time in terms of clinical testing. And we found that the surveys were critical in order to provide feedback to us about how rapidly that dissemination was occurring and into what areas were laboratories developing testing. And that was incredibly important in terms of sort of thinking ahead in terms of, okay, we've started this NGS PT initiative, but it is diversifying and almost we could see laboratories moving ahead in a way that was faster in some ways than we could keep up with in terms of developing new areas of PT testing because it takes several years from concept to launch of a given PT program. I think maybe I would just also share that with the audience. It's a very, very thoughtful process that goes into creating a PT project. Laboratories were essentially racing ahead adopting NGS sequencing, and we were trying to say, okay, we have to meet needs now, but what are the needs going to be five years from now? So there was a lot of looking into the crystal ball to create PT programs, and the surveys were critical in guiding us in that regard.

Dr. Joel Moncur:

Those are great comments, and I totally agree. I think those questionnaires were invaluable in allowing the CAP to remain nimble, to create PT that matched the rapidly evolving pace of clinical practice. Dr. Merker, did you have anything?

Dr. Jason Merker:

I agree with everything that's been said. I was thinking back to whenever we first were designing the solid tumor and hematologic malignancy surveys and we sent out questionnaires and people were very generous with their time, and that was central to guiding these products. And this has been already noted, it was very important to guide the evolution of these products. So a big thank you to the participants for spending the time to do that. That information is used in extremely valuable

Dr. Joel Moncur:

Thank you. And I think I would only add that I applaud CAP with this approach of transparently sharing that questionnaire information so that labs can use it to both improve their performance and also to adapt and monitor what is happening, the advancements in the field, and adapt accordingly. So that's been a very useful thing, a very useful approach by the CAP. Next question is that PT programs is a little bit related. CAT PT programs are just an incredible source of data about laboratory performance, and I'd like to hear each of your thoughts about CAT PT performance data and the role it plays in quality and advancing medicine. And again, this question's for everyone. Dr. ine, would you like to go first perhaps?

Dr. Karl Voelkerding:

Well, I'd like to maybe I'm going to give an overarching statement that, and others can give some of their own personal experiences with this, but I guess the overarching statement is that within CAP, one of the key things is that all the PT data and the surveys are monitored longitudinally. And this is occurring not only in the area of the molecular scientific committees, but essentially within proficiency testing at large clinical chemistry immunology. And so this longitudinal analysis is inherent in the process of how CAP operates. So in addition to providing critical information for both monitoring how laboratories are performing, it also provides information for continuous improvement of CAP PT programs. And also these types of longitudinal analysis have often been summarized and then published in peer reviewed manuscripts and peer reviewed journals. And so in the realm of molecular testing, including NGS based testing, these publications have time and again, demonstrated that laboratories are performing very solidly to excellently in terms of performance on proficiency testing. And again, these types of results allow us to then say, are there any areas where we would like to see laboratory performance improve and how can we modify a given PT testing or initiate a new program to sort of assess those areas.

Dr. Joel Moncur:

Really helpful comments. I completely agree about the ability to track and trend over time. That's really very useful. Dr. Merker, do you have anything, any thoughts on this topic?

Dr. Jason Merker:

Maybe to add, I think in addition to shaping the PT programs, it has also shaped other educational and advocacy efforts within CAP that I think have been very important to improving laboratory performance. I will say as a laboratory director, this information was really critical, I think for me to benchmark what we were doing and very helpful in guiding next steps. So I remember one case where a particular library preparation method we used was being discontinued, and I was able to look at the survey and see this is what's being used in the community and go there first. So I think it's a very rich source of quality information.

Dr. Joel Moncur:

I would add that I think that proficiency testing or external quality assessments have to be among the very best, if not the very best data available on laboratory performance. It's not a single vendor performing their test. It's not a couple of academic medical centers that are performing their tests. These are mostly accredited laboratories internationally, both domestic and non-US that are performing clinically validated tests. In that way, I think that there's no better reflection of actual performance than the performance we see on proficiency testing, particularly given how thoughtfully and well those PT samples have been designed and provided. I'd like to go on the next to question, which is that next-gen sequencing has come such a long way. I'm wondering if you could please share your thoughts about the future of next-gen sequencing pt, particularly given how the clinical use of next-gen sequencing continues to grow.

Dr. Jason Merker:

I think certainly there's a need to keep up with new applications, and that's something that the committees have been very good at doing. I've also been very encouraged with efforts to more closely mimic clinical specimens as well as clinical workflows. And I think that's something that we'll continue to see. Our ability to engineer without artifacts of engineering has gotten much better. I think we've been able to be much more precise in the variant allele fractions, which I think is very helpful. My hope is that we can move toward workflows that more closely resemble what we do in clinical practice. And when you look at other surveys in clinical chemistry and hematology laboratories receive a specimen, they generate a report just like they would, and that report is graded, and I think there's significant opportunity there to do similar work. And I know some of that's ongoing. And then I think there are open questions that I don't have the answer to, and particularly in the oncology space, we're seeing increased customization of these assays. And the question is, how do you provide PT for these while still maintaining the concept of working with a peer group?

Dr. Wayne Grody:

I second what Jason said, that this is a bit of an open question. NGS, it's been absolutely revolutionary. It's led us from molecular medicine to genomic medicine. The future, I don't think any of us can even begin to guess the future applications even five years from now, which in turn will require CAP input. If you had told me in those early days of molecular pathology when we could barely detect a single mutation, that someday we'd be sequencing the whole genome of patients and turning it around in a few days and that it would even have a clinical utility, I would've just laughed at that. I'll give one future prediction just based on my own experience with CAP. So just as all of us on this call have graduated to other committees and activities with CAP since our original ones, I'm now on a fairly new and novel committee, a work group I guess you would call it on gene editing.

And this is incredibly forward looking by CAP because there are no clinical applications yet, or gene editing. There've been great successes, but they've only been in the context of clinical trials. But the idea is we want to be ready when this does translate. And so we'll obviously have to use NGS in many ways first to find what gene and what mutation we're trying to edit after the edit to make sure it was done correctly, that there were no off target effects to develop positive mutation controls PT programs. So it's another example of CAP variant being very proactive and one aspect that I can predict for the future. Obviously pathologists will not be the ones administering gene therapy and gene editing, but we will be the ones testing and monitoring it.

Dr. Joel Moncur:

That's really great points, Dr. Grody. Thank you. Dr. Voelkerding?

Dr. Karl Voelkerding:

Yeah, I would say that when you look across the landscape of how NGS is being used, part of follow up to Dr. Grody is that we've seen an increasingly broad adoption of whole genome sequencing, especially in the realm of undiagnosed disorders. And that is now becoming sort of, if you will, standard diagnostics in the setting of academic children's hospitals throughout the US and internationally. And of course, those are large data files. Those are complex cases. In order to be able to specifically assess the proficiency of those laboratories, they're increasingly using very sophisticated software algorithms in terms of genotype phenotype analysis in order to identify diagnoses as all part of the overall laboratory process. And to essentially understand how laboratories are doing in those realms is incredibly important. The other shift that we will see to some degree over time is NGS to date has been predominantly short read sequencing that has come forth through several sequencing platforms.

But we do have platforms that now do long read sequencing, and that has opened up the ability to identify more complex, larger sequence variants. And those are going to need to be assessed from a proficiency standpoint. And some laboratories in the realm of doing undiagnosed disorder testing are also looking at RNA expression in terms of the impact of variance on splicing and regulation of gene expression. And all of those are areas that will be critical over time to fully assess laboratories that are involved in that type of testing. And this will require initiatives both at the physical sample level or the wet bench sample level, and probably also develop a more complex and silico proficiency testing.

Dr. Joel Moncur:

Thank you, Dr. Voelkerding. What I'd like to do is just ask if any of you have any other final thoughts before we wrap up.

Dr. Wayne Grody:

So I'll start, and I want to really give credit to CAP on this anniversary of the PT program. Again, as all of us have mentioned for being visionary, what that has done is put CAP and the discipline in a leadership role in the area of the new age of molecular medicine and now genomic medicine. It's become really the go-to agency for lab accreditation and more important prestige and evidence of expertise by other organizations and specialties that otherwise might not have been so inclined to work with us such as genetics, oncology and so on. In fact, the opposite has been true that CAP has been very inclusive in the committees that develop these programs. After the Molecular Pathology Committee, I went on to chair an offshoot committee called Molecular Genetics, and that was comprised of equal members from CAP and from the equivalent organization in medical genetics, the A CMG, the American College of Medical Genetics. So there was always great mutual respect there. And lastly, I want to reiterate what others have said and give credit to CAP staff. They're so knowledgeable. They're the best I've ever worked with, and I mean many other medical and scientific organizations, they're responsive to anything we need. And keep in mind in these new areas, we're making requests that they've never heard before and nobody has ever heard before, and yet they're very creative in meeting it, and they become great colleagues and indeed lifelong friends.

Dr. Joel Moncur:

Thanks, Dr. Grody. Dr. Voelkerding.

Dr. Karl Voelkerding:

Yeah. I would add that when we look at the current diversity of current NGS PT programs, it really is a reflection of a multitude of CAP members who have volunteered many hours over the past decade in conjunction as to reiterate Dr. Grody's comment, an amazing group of CAP staff who needed to be flexible, creative, and to accommodate some of the, shall I say, that this field took off so quickly that they needed really push the boundaries within CAP to allow us to keep pace with the field. And I would just like to say to the audience listening today, CAP always needs new individuals to come forth with, in this case, molecular expertise to volunteer to spend time on these committees. It is an amazing way to develop a network of individuals that you'll maintain for decades to come. And that's been one of the greatest privileges that I've had in my professional career, has been working for CAP.

Dr. Joel Moncur:

Well said. Dr. Voelkerding. Thank you. Dr. Merker, what are your thoughts as we wrap up?

Dr. Jason Merker:

A central focus of laboratory medicine is continual process improvement. And since leaving the committee five years ago, it's been really enjoyable to see the PT programs continue to expand and innovate in new ways. I just heard today that over 190 clinically actionable variants in 60 genes have been evaluated as part of the solid tumor in hematologic malignancy surveys. And I think that represents a really tremendous accomplishment for CAP. I'll say that while we've been focused on PT, I think there have been significant parallel works involving the checklist, education and advocacy that are equally important and deserve a voice. And then finally, I'll end as others have, I really want to thank the participants for the effort they put into this, the CAP staff and leadership, the committee membership, as well as the committee leadership that made this possible. It was an outstanding group to work with, and I look forward to see where it goes in the future.

Dr. Joel Moncur:

Thank you, Dr. Merker. So I'll just add that I think that I'll circle back to the question about the future of NGS PT, just to say that I think that the future is bright. The CAP has really made such an investment that over time has grown into an incredible library of samples, as you mentioned, Jason, that really is just a very comprehensive look at lab's ability to detect both common and uncommon variance at a whole range of varying fractions or mutation frequencies or fractions. And it's a remarkable accomplishment and has just been designed to scale and to grow as the field grows. And so I think that's, again, the future is bright with regards to our ability to support laboratories and our ability to understand overall performance and support labs as they continue to seek the best performance.

Becca Battisfore:

Thank you to Dr. Moncur for moderating this fantastic conversation about the past, present, and future of next generation sequencing. I want to echo Dr. Moncur's closing remarks and acknowledge the incredible contributions of our guests and everyone else involved in developing the program over the years. And I want to thank you all for listening to this CAPcast. You can find links to the rest of the episodes in this series and the CAP's proficiency testing and external quality assessment program in the show notes. For more information about the CAP, visit cap.org.

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