DISCLAIMER: Today’s episode is paid content from our feature sponsor, who helps Inside Reproductive Health to deliver information for free, to you! Here, the Advertiser has editorial control. Feature sponsorship is not an endorsement, and does not necessarily reflect the views of Inside Reproductive Health.
Dr. Klatsky’s opinions are his own. He receives an honorarium from CooperSurgical for his time and expertise.
“I always recommend parental DNA checking. Parental QC provides important protection for everyone, both patients and clinicians” – Dr. Peter Klatsky
Dr. Peter Klatsky, Co-Founder of Spring Fertility, provides harrowing examples of catastrophic close calls with gamete swaps, prevented only with the help of the latest advanced technology in PGT-A. Dr. Klatsky is joined by Chelsea Leonard, Clinical Science Specialist at CooperSurgical®, as she walks us through the current and future developments of PGT and its place in helping to maximize patient success while minimizing risk of irreversible harm.
Ms. Leonard and Dr. Klatsky dive into:
Developments in PGT-A testing that are critical to help avoid gamete swap
Real life examples of where and how PGT discovered DNA mismatches (Helping reduce legal and ethical liabilities)
The technology behind a new test called PGT-Complete (And its impact on the origin of aneuploidy)
AI’s place in PGT Testing (The new possibilities in scaling and learning)
Why tests like CooperSurgical’s PGT-Complete℠ Tests are necessary to help avoid gamete swapping catastrophes (And how they might protect those providing fertility treatment)
CooperSurgical
Dr. Peter Klatsky’s LinkedIn
Chelsea Leonard’s LinkedIn
Transcript
Dr. Peter Klatsky: [00:00:00]
100 percent of your patients, 100 percent of, I'll speak in the first person, 100 percent of my patients, whether they articulate it or not, have in the back of their head the day of their egg retrieval, don't mix up my eggs. I'm giving you my eggs, I'm giving you my sperm. How do I know that those are going to meet?
And it's a massive degree of trust that your patients send you and place in you.
Sponsor:
This episode was made possible by our feature sponsor, CooperSurgical®. Download CooperSurgical’s brand new PGT-A Clinician's Reference Tool, an indispensable guide for clinicians like you to unlock the full potential of genomic treatment, by clicking the button below.
Announcer:
Today's episode is paid content from our feature sponsor, who helps Inside Reproductive Health to deliver information for free to you. Here, the advertiser has editorial control. Feature sponsorship is not an endorsement and does not necessarily reflect the views of Inside Reproductive Health.
Dr. Klatsky 's opinions are his own. He receives an honorarium from CooperSurgical® for his time and expertise.
Griffin Jones:
You've got to hear this story because I think people are going to be talking about this at ASRM and other conferences. The whole time he's mentioning this example, I'm thinking it's a hypothetical. Come to find out, this was an incident that actually happened at gamete swap. But they caught it and that's at the root of my conversation today with Dr. Peter Klatsky, who, you know, as the co-founder of Spring Fertility, fast growing bi coastal group in New York and the Bay Area growing beyond. And Chelsea Leonard, she's a Clinical Science Specialist, a genetic counselor at CooperSurgical®, and she has some really keen insights. On the development of PGT-A developments that have implications that are critical for preventing some of the potential catastrophes like the one Dr. Klatsky talks about. We talk about because I was curious, why is PGT one of those things that you all really seem to care who you partner with for that other categories? You'll pick any random vendor, but it seems to be very important to you who you choose for PGT. So I want to know why that's the case.
Dr. Klatsky shares his view. We didn't cover an inflection point that happened around 2018 with PGT, particularly at Cooper. I asked Chelsea to reveal some of that. You can't get enough AI content, it seems, but we've never talked about how AI can be used for PGT, specifically PGT-A tests. Chelsea talks about the scale and the learning that the AI technology has that simply wasn't possible before.
And I asked her to let us under the hood a little bit about what's happening at Cooper. She talks about that technology and specifically the technology behind a test called PGT-Complete℠. That test, PGT-Complete℠, ends up becoming central in the conversation because we talk about how it impacts the origin of aneuploidy, how it changes the philosophy about discarding or keeping abnormally fertilized oocytes. [00:03:00]
And we talk about how this test raises the standard of care and has almost an incalculable benefit to the clinic and to the business because of its critical use for parental quality control. That has to do with the story that Dr. Klatsky tells. Have you ever heard of someone deliberately bringing someone else's sperm to the fertility clinic?
I hadn't I thought Peter was talking about something hypothetical. But keep on listening in the conversation and you'll find this was something that actually happened at Spring Fertility that would have been awful for them and awful for everybody involved, but they caught it. And they talk about how tests like PGT-Complete℠ are necessary for having that level of quality assurance, ensuring parental quality control, preventing gamete swap catastrophes.
And yes, they are catastrophes and how they critically raise the standard of care and protect you as someone who provides fertility treatments or who pays for those who provide fertility treatment. You can look for Dr. Klatsky and Chelsea and certainly the rest of the Cooper team at their booth at ASRM. [00:04:00]
Tell them they did a great job putting up with this host and they can tell you more about it and you can get more information by visiting Coopersurgical.com, by clicking on the page that's associated with this podcast episode that will take you right there. Enjoy this conversation with Dr. Peter Klatsky and Chelsea Leonard.
Ms. Leonard, Chelsea, welcome to the Inside Reproductive Health podcast. Dr. Klatsky, Peter, welcome back to the Inside Reproductive Health podcast.
Chelsea Leonard:
Hi there.
Dr. Peter Klatsky:
Thanks Griffin. It's a pleasure to be here.
Griffin Jones:
I'm in a fun spot where I get to talk to a scientist and geneticist and an REI physician about PGT and I want to talk about what Cooper's got going on. I have a premise to start with Peter, which is as I talk to docs, I'm just always curious about why do they buy things? Why do they choose certain things? Why do they hire people? Why do they partner with certain people? And there are certain categories of goods and services that they really care about who they partner with and then other categories that they don't.
Sometimes it's like, that's just a commodity. We can use any vendor for that and then there are things that they really care about who they partner with and PGT-A is almost always one of those things that they really care about who they partner with for PGT-A.
So the first question is, Is that correct? Is PGT-A in that camp of who they really care they partner with?
And if it is correct, why is that the case?
Dr. Peter Klatsky:
Absolutely. It is one of the most important decisions we make in a lab, that also where we get media and what reagents we use. We, patients trust in us and we take that trust and that confidence very seriously. If we are going to send four cells, a sample of four cells, five cells out for analysis, that's on us later on.
If we are trying, if we get inaccurate results, if we get a high no call rate or if we are potentially throwing and discarding good embryos, potentially viable embryos, all of that will hit our patients, lower their success rates, and in turn, lower their confidence in us. So similarly, the ability to accurately call diagnosed embryos will make us appear better to our patients and ultimately deliver better results. So once we send that sample out, we are really relying on our partners to deliver accurate and complete results.
Griffin Jones:
What makes a good partner then? Like, why does it matter who you choose? I get the gravity of PGT-A, but what's the difference in the type of people that could provide what makes someone really good at that. You feel trusting them with that.
Dr. Peter Klatsky:
Well, I, first of all, I love that you said partner, right? Because whoever you're working with, with PGT, they have to be a trusted partner. It's not a vendor relationship because it's not a commodity. So a good partner is somebody who's going to, with regard to PGT, is get us the most accurate results first. [00:07:00]
And that means the lowest false positive rate. A low no call rate, but who's going to have a really high level of professional confidence and professional professionalism and accuracy and who's going to be your partner if something happens and I don't know any PGT companies that haven't experienced a case or cases where there's a high no call rate.
Or something happens in the amplification and we expect our partners to continue to be our partners and not try to throw the clinic under the bus. Oh, something happened in the lab versus something happened in the center. We want to investigate it. We want to explore it together and when you have a high priority situation like that, you really want their attention.
And occasionally there's cases where you need a result quicker or there's some specific peculiarities about it and you want a partner who's going to listen to your clinic's needs. And who's going to be responsive to those, both on individual case and as you grow together, I would also say that the field is so rapidly advancing.
The technology that we're using today for PGT-A is not the same technology. It's not the same platform that we were using four years ago. And frankly, I would bet that within 12 to 18 months, the entire field is using a different platform, a whole different template procedure to analyze embryos. So, also in choosing that partner, you want to choose a long term partner who's going to have the resources to be at the bleeding edge of the field, but not advance that technology, not advance that science until it's been adequately tested, validated, so that your patients are getting accurate results.
Griffin Jones:
I want to talk about that progress that's happened in the last four years. So it's not even the same platform that was used four or five years ago. Chelsea, our audience probably has a general idea of the history of PGT, you know, at a high level, but to what Peter's talking about.
The dramatic changes that have happened in the last four or five years. What are those and what's been happening at Cooper during that time?
Chelsea Leonard:
Yeah, so I think it's always really incredible when we reflect on that history. Like you said, Griffin, even in the last couple of years, Cooper came out with what we call PGTai®.
AI standing for, of course, artificial intelligence and its first iteration in 2018, where we moved away from what we would consider totally subjective interpretation, where you have a human technician looking at a next generation sequencing profile, all of the blips along every chromosome, making decisions.
[00:10:00] Is this noise? Is this aneuploidy? Somewhere in between mosaicism, what am I looking at? So removing that potential for error with that subjective component and really making calls based on big data with all of the embryos, thousands at this point where we have made a classification, seen an outcome and fed that back into the algorithm.
And as Dr. Klatsky said, really important that we have confidence in our calls and we're doing that based on big data.
Griffin Jones: Tell us more about how the AI works. There's been a lot of hot topics on our show in the field recently. The episode that I did with Dr. Gada and Manish Chadwa about chat GPT was like a really popular episode.
And we talked about the different applications that AI might have a virtual Dr. Klatsky in a couple of years that people are seeing on there, but we didn't really talk about how AI specifically applied to PGT. So tell us about how AI is specifically being applied to PGT. [00:11:00]
Chelsea Leonard:
Yeah, so I know that AI is a really hot topic and not all forms of AI, even in the context of PGT, are equal, right?
But I like to think about it when I'm explaining PGTai on an individual basis with clinicians is that human technician that would be making a call on an NGS profile, may have years of experience, be highly qualified and trained, but that person doesn't ever get to know the outcome of an embryo they classified, right?
They don't know what happened. Did that embryo implant then miscarry? Did it result in a healthy live birth? The difference with AI is we have a classification, an outcome, and all of that data can then be fed back into how we decide on and classify embryos with with future patients. It's not continuous learning, so we don't let it run wild, but it's important that that data is being fed back into how we make those future decisions and how the platform continues to improve.[00:12:00]
Griffin Jones:
This might be elementary for a lot of the audience, but then how are human clinicians getting, how are they advancing their knowledge of what worked? Are they basically having to look at retrospective data in cohorts afterwards? And how does this compare to what the AI is doing?
Chelsea Leonard:
Yeah. Are you talking about the subjective interpretation approach?
Griffin Jones:
So if the human clinician doesn't actually get to know, like, the, what happened afterwards, then how are they learning about what's working? Are they just looking at retrospective data in cohorts after where the machine is learning about specific cases and what happened in specific cases?
Chelsea Leonard:
Yeah. So I, of course, Cooper doesn't use that approach at this point, but I would imagine to your, to your point, you know, there, I'm sure there are training sets and comparison between technicians to make sure they would make the same call on the same sample, but that's not big data, right. And we can't learn from nearly as many embryos nearly as quickly when we compare against AI. [00:13:00]
Griffin Jones:
So you've got big data happening for, at a scale that isn't been the case for when we were calling it PGD and PGS years ago. How did this start to unfold in 2018, 2019? What did that timeline look like at your company?
Chelsea Leonard:
Yeah, so I think one of the things that many of the listeners may recall if, if they were in the field in the last five, six years is Cooper Genomics formed from several legacy genomics companies and at that time, when all of those laboratories were coming together and standardizing protocols amongst themselves, it was realized that technicians at each laboratory, whether within a single location or across, were sometimes making different calls on, on the same or similar samples, right, using different approaches and so it was realized at that stage, as the labs were coming together, that this subjective interpretation component was really a problem because again, we want to have confidence in the call we're making for embryos. [00:14:00]
So at that point, Cooper decided to invest in this AI approach that we've continued to iterate on and lots more to share about that in the coming discussion.
Griffin Jones:
And Peter, can you tell us about like what's happening with case studies during this time that you talked about the emphasis of you have to be able to innovate but only after there's a substantial amount of evidence to support it.
Can you tell us about the case studies of what's gone on in the last few years?
Dr. Peter Klatsky:
Yeah, or not case studies, but clinical trials really, where they compare the outcomes and the calls and how often are they different and how would they be different? And you know, so anytime you're applying AI, I think best practice is to do so with clinical oversight, human oversight, for a long time, and I believe Cooper did that for several thousand cases prior to writing it. [00:15:00]
So what if, you know, I, I'm a quote, believer slash somebody who fears the implications of AI long term. So there are benefits, there are social challenges with it that are going to be dramatic, but I think whenever you're introducing new technology, you need to validate it, and you need to validate it.
Not, you know, in a small case series with a hundred people, but rather, you know, series of thousands and thousands of hundreds.
Chelsea Leonard:
And Dr. Klatsky, I think that's such an important point because the validation as, as we've talked about so far, this is based on actual. embryos, embryos that have resulted in an outcome that's been tracked rather than cell lines, for example, which might not be the best representation of, of what we're doing with PGT.[00:16:00]
So real embryos, real outcomes.
Griffin Jones:
Peter, can you give me an idea of like what the significance of the scale is introducing this new technology, because it seemed to me like PGT has always been a powerful tool. I'm a complete lay person, not a clinician. I'm not a scientist. And it seems like whenever you have a powerful tool, it's going to be more important in certain cases than in others.
And the more data you have, the more scale you have, the better you're going to have for fine tuning exactly which implications and which uses maximize them. So, can you give me an idea of, of how much of scale is a game changer with having the technology of AI behind it?
Dr. Peter Klatsky:
I'm not the best person to speak to that.
I think somebody at Cooper or one of the other genetics companies are, cause they know how much time it takes for somebody to look at the data point, the key point for the audience to recognize is when you're currently testing an embryo, you're getting read lengths of one of those chromosomes that you're testing that are only about 70 base pairs long and, you know, 75 to 150 base pairs.[00:17:00]
That's the current generation of, if you're, if you're doing it through sequencing, if you are, you know, and then you get a area that may be five to 10, 000 base pairs with no reads. And, and now you've got a chromosome that's a hundred million bases long, right? So you can get enough, and I always talk about it as Shazam for embryos, like you get enough, you know, snips of that song, you know, okay, that song is present, and here's the number of times that's present.
And so when people are looking at it, they're looking at how many hits are in chromosome seven, how many hits are in chromosome eight, how many hits are in chromosome nine. And they're using that to judge how many copies of that DNA, and if there's twice as many hits on chromosome seven as there are on chromosome eight.
And then chromosome seven and chromosome eight have the same length. Then someone's going to interpret, well, chromosome seven, there must be twice as many copies of that chromosome than there are of chromosome eight. And that's how this is done. And sometimes when you look at the reports and you know, in those heat maps, it's super clear and a monkey could do this.[00:18:00]
And then sometimes, it’s ambiguous, so the AI probably gives that human interpreter more confidence, um, potentially, you know, does it help in the workflow? Um, as increasing numbers of people are using AI should, and you know, and where I think it probably helps is on those edge cases where, where they're developing confidence intervals and where they are constantly learning.
But as far as like, does it improve flow? Does it improve ability to scale? That's a question I'd leave to the Cooper, Natera, genomics, you know, all the other, you know, to the companies that are delivering this service.
Griffin Jones:
Chelsea, can you expand on that a little bit?
Chelsea Leonard:
Yeah, I think a little just to say it, it does, right, but I think At least in my clinical conversations with providers, we really focus on not so much how it improves the workflow in a practical sense on our side, but what it means in terms of confidence for those cases that Dr.
Klatsky mentioned, right? If, if we have a noisy sample that we're not over calling that as aneuploidy, if we're seeing blips across multiple chromosomes, but that sample may in fact be noisy and is either euploider or no result as an example. So in those cases, it's critical for us. [00:19:00]
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Griffin Jones:
Tell us about how this impacts parental quality controls from the business development seat that I sit in the public relations seat that I sit in whenever I see a case of someone got the wrong embryo or or something happened, not having necessarily to do with genetics testing, but just any case like that, I, you know, anything happening with down the road in chain of custody, I think, wow, that's, that's a big area for concern. [00:22:00]
So are there implications here for improving parental QC?
Chelsea Leonard:
Yeah, so from our end, one of the things that we've been excited about what we've sort of built on in the last year or so is our newer test PGT-Complete℠ that is built off of PGTai. So our, our standard PGT-A test, but with the addition of parental buccal swabs. And in those buccal or cheek swabs, we're looking at SNPs, single nucleotide polymorphisms and comparing those genetic markers from the egg and sperm provider to what we're seeing in the embryo and with that, we're able to do a couple things. One of those is parental QC. Helps us confirm that we have a match between the egg and sperm provider and the embryo sample that was submitted to us.[00:23:00]
The other components that I'll share very briefly that I'm sure we'll get into later are what we call genetic PN check where we can confirm at a genetic level that normal fertilization has happened. That we have not only two copies of every chromosome, a euploid sample, but that one copy came from each side, the egg and sperm, and also origin of aneuploidy.
We know that that information is important to patients and to providers as they make future treatment decisions.
Griffin Jones:
Peter, how important is that as a clinician to and how different is that from what previous technology it offered?
Dr. Peter Klatsky:
Anytime you can make a technology safer, I think we should. Anytime you can provide reassurance to a patient, I think we should. And, you know, in parental QC or parental DNA matching and confirmation PGT a hundred percent of your patients, a hundred percent, I'll speak in the first person, a hundred percent of my patients, whether they articulated or not, have in the back of their head the day of their egg retrieval, don't mix up my eggs. I'm giving you my eggs, I'm giving you my sperm, how do I know that those are going to meet?[00:24:00]
And it's a massive degree of trust. That your patient sends you and, and placing you and, and as the provider, I am not present when the sperm and egg are being fertilized and we are not present at every step in this, in this equation. We make sure at Spring, we 100 percent of the time, we have two people signing off on every transition of every gamete.
[00:25:00] That's what I tell everybody. And, and we never sacrifice on that and no matter what somebody is doing, you have to stop, get a second eyeball. Right? And without that, you can't be sure. Your patient has to trust you on that, and they do, and, you know, having that other layer of backup of saying, hey, by the way, we took a cheek swab before this, we, we have a copy of your DNA, and, and just when we ran that, that, that embryo result, oh, we have a little check mark, yep, it was your DNA.
That reassurance to your patient. It is well worth the extra time in this whole process where we're making people go through multiple blood tests, right, to see how your estradiol is changing, how, you know, is your progesterone fluctuating, go through multiple ultrasound things to get that, you know, reassurance on egg quality.
Why wouldn't we just make sure that that embryo corresponds to the embryo that was tested?
Griffin Jones:
I had heard of a gamete swap case recently. I wasn't familiar with that case study. Are you familiar with that, Peter? [00:26:00]
Dr. Peter Klatsky:
No, I'm not. Well, no, I, so one, you know, there are these crazy stories that you hear about on the Today Show, Good Morning America, that are devastating for families and then, you know, you hear about cases in the back, you know, round of people who, at age three, their child, they're devastated by the fact that their child develops leukemia. And they're trying to see if they can give a bone marrow transplant to their kids. In this one case, you know, high profile lawsuit where the parents then found out while their child's going through chemotherapy that not only was the, the father not an HLA match, but, but it wasn't his sperm.
I can't even fathom what that must be like for that family and for that clinic. And, you know, fortunately, every case I've ever heard of that happening, there were not two people witnessing every transfer of every gamete. So I want to, so I always want to reassure patients that to date, at least to my knowledge, there's never been a gamete mix up with double identification at each step.[00:27:00]
Every single one of those cases that I'm aware of, one embryologist working that day. You know, and, and, and didn't have double sign offs. So, to my colleagues and peers out there, like just let's make sure we all take that really seriously to sign offs, two names, two eyeballs every time and not signing it, but really looking at it.
Our lab director enforces that in our lab takes that very seriously. The other part about this is one that one has trouble contemplating when you have high profile cases like that. That are going on Good Morning America, Today Show, and there's lawsuits that one can't even begin to contemplate what the settlement amount is.
[00:28:00] One could also contemplate that somebody, a bad actor or somebody for other reasons, might decide to misrepresent fraudulently a relationship and have somebody else provide sperm in place of their, their partner. So, so the way this could work out is that if I were a three parties, right. And, and there's my intimate partner who I want to have a child with, but maybe for other reasons, I married somebody else, whether they have to do with whatever reason, right. And so you have a legal arrangement with a marriage with one person. And, and maybe the, the intimacy has changed. And there's a third party who's really the, the, the long term life partner for, for that patient. Um, now that person could go into a fertility clinic, um, take Shady Grove, right?
They're a very big clinic with deep pockets and, and, and they could. present themselves as two people, man and a woman, who want to have a baby together and they end up doing IVF and they want to do PGT and they go through the process and the day of the egg retrieval, the husband brings in the other intimate, the true intimate partner's sperm source, right? [00:29:00]
And, you know, sperm production remains a private act without two people identifying the actual sperm production. And it's not that hard to, you know, bring in a cup with somebody else's sperm. And then that sperm is handed off to the embryologist who confirms the identity of the person who came out of the sperm production room, but it may not be his sperm.
And if you do at home sperm production, then it's just, you're trusting the husband is handing off his sperm. And you would never know about that, right? The only way you can know about that before transferring embryos, so let's play this out, if you didn't do parental source DNA, you'd then transfer an embryo, lose somebody else's DNA, and then that family, six months later, says we have a baby and we did a 23andMe cheek swab, and it says my husband is not the genetic parent of this baby, but we went to your fertility clinic. [00:30:00]
Jaw drop, right? You're in a really a world of hurt. And if you don't genetically type everybody and make sure that that embryo's coming from the sperm and, and egg. And in that case, that fertility clinic might have done everything right.
And…You know, yet, what would be your, your next steps, right? I, I would want to QA everything, make sure that everybody signed off, that we, and you'd look at chain of custody with a sperm and you'd see there were no errors on your side. And yet you're looking at a baby and his ostensible two parents and there's not a genetic ID.
So, so just, there's like a pause thing. Okay, now what's your next step? Right? And, and, and your next step is, well, how, if this baby's not using this husband's sperm, who gave us the sperm, where could an error have gone off? And so, in that moment [00:31:00]
Griffin Jones:
Okay, Peter, now that you've scared the crap out of everybody, I actually, I actually do think this is worth digging into, because these are, these incidents do happen from time to time and they can be career ending. They can be reputation tarnishing. They can be, they're beyond traumatic for the families that are involved. So I do think that this is a point that is worth digging into more. And I also think that things that start off as new features or new tools, sometimes quickly become the standard they're established.
I feel like it could be something like five or 10 years from now, we're saying like, oh, remember back when Cooper started doing this? Remember back when they were calling it PGT-Complete and now it's like, and, and so it's like, it, it's something thar you know, is, is starting now. That might become the standard of care in short order. [00:32:00]
Chelsea, can you talk a bit more about how it works at, at a technical level to prevent the types of situations that Peter's talking about?
Chelsea Leonard:
Yeah, absolutely. I think. Really, really what we're talking about here is with those parental buccal or cheek swabs that are collected before or at the time of the egg retrieval, you know, when we can and get patient and partner to provide an easy sample, we are using the SNP or single nucleotide polymorphism data from.
And it becomes very apparent when you're looking at all of those genetic markers for those three parties, if there is a match or a non match. I think it's also important for listeners to understand that a non match could occur for a variety of reasons. For example, contamination, maternal cell contamination is another thing that we think about in these examples where we're seeing only SNP representation from the maternal side.[00:33:00]
In the sample, and that's another situation where we could end up with a false result for an embryo, even if we've done everything right in the laboratory, because we'd be picking up euploid or normal female just from the maternal cells and underneath the surface, that embryo could be male, could be abnormal.
We could have any number of scenarios. And if we didn't have those parental swabs, then we may not know that until after a transfer. So lots of different things that we can detect in addition to gamete switches.
Griffin Jones:
I want to talk a bit about aneuploidy as well. It's something that I have very little understanding of. It's something that I hear you all talking about all the time. And it's. And so I hear about it being associated with maternal factors, but I also hear that that's not always the case. It sounds like this test is able to determine where aneuploidies come from. Can you each talk more about that? [00:34:00]
Chelsea Leonard:
Yeah, I think I can jump in and just start that conversation by saying, you know, we, we often think of aneuploidy primarily in that maternal context.
Right. We know that aneuploidy rates increased with maternal age and that most of the aneuploidy and most cycles is maternally derived. Right. So for an example, if there's an extra copy of a chromosome in an embryo, most of the time that may have come from the maternal side, but not 100 percent of the time.
[00:35:00] We know that about 90 percent of whole chromosome aneuploidy is maternally derived. On average, but about 70 percent of segmental aneuploidy, where just a part of a chromosome is impacted is paternally derived based on recent studies. So we've all had those cases where we get a PGT report back for a patient and there's aneuploidy across embryos and it's unexpected based on maternal age. Something's not really making sense. I think we're realizing more and more that at least in some of those cases, it's the sperm that's creating that result.
Dr. Peter Klatsky:
And if it's the sperm, is it accurate?
Griffin Jones:
Tell me about that, Peter.
Dr. Peter Klatsky:
Chelsea made a really good point. When you look at the studies on just mono, uh, monochromosome aneuploidy, so single whole chromosome aneuploidy, you will see most studies looking at that. We'll find rates that I think Chelsea now correct me if I'm wrong, but around seven to 8 percent paternal whole chromosome derived aneuploidies, uh, and maybe depending on the platform, it may be higher, but, but, but I've seen data as much as 6 percent whole chromosome.[00:36:00]
So then just talk about your, your, the test PGT. It's not perfect. It may, it has false positives. Does not matter whose platform you're using. Every patient should recognize that there is, there are mitotic errors and mitotic errors are going to happen and that's going to lead to the ability to sample an embryo and and have discordant trophectoderm and inner cell mass.
So, so if you recognize that this is a good test but a good test means there's a four to five percent false positive ratio. Every single one of my patients getting this test knows that. Every single one of my patients says no matter what platform I'm using we are going to throw away We are going to discard some potentially good embryos.
[00:37:00] And that's a cost of the test. It's a cost of the improved accuracy, the lower number of embryos to transfer. And that's a limitation. It's not a platform limitation. It's a biologic limitation. Unless you believe there's no mitotic errors, which I don't think anybody believes. And so a mitotic error, Griffin, is as the embryo is growing, cells divide and have errors.
Right. And so you can be sampling up so that, so then the embryo is a true mosaic and the area outside is going to become the placenta may have errors. You biopsy that, that embryo is called abnormal. And then the inner cell mass, if you were to re biopsy, destroy the embryo, you'd find more normal. And in the studies looking at that range from about 3.5 to 5%, and that's what I, what I tell patients. Now, there's a really nice non selection study where they transferred 104 abnormal embryos and not one live birth. So that's reassuring. But if they'd transferred a thousand embryos, I would bet you'd find about 20 live births. So about 2%. That's my guess based on my understanding of the false positive rate.
So now say you're 44 and you've been at IVF for six attempts and you've been fortunate enough since you were 43 and 44 and been able to make a lot of embryos. And in one of those embryos, you find out that the only chromosomal abnormality was parental, paternal DNA. Is it possible that that's your false positive? [00:38:00]
Well, if you look at sperm DNA studies... Right. Looking at individual sperm from sperm donors, what they find is about 98, 99 percent of individual sperm are, are you not, you put it, but haploid and have one copy of each chromosome present. So they have 23 chromosomes, each one copy of each chromosome in 98 to 99 percent of sperm.
And there's a nice study out of China looking over 20, I think it was like over 20,000 sperm samples and so that's a pretty low error rate, one to 2%. And now if you're looking at clinical studies saying, Hey, we're seeing 6% whole chromosome abnormalities that only come from the sperm, but we know that most sperm, maybe it's 2%. [00:39:00]
And if you were to find that difference, what, 4% is the difference? Isn't that the false positive rate in the test itself? So, so could we take a patient well counseled, maybe under a research protocol to say, if you have a whole chromosome abnormality, nobody's doing this yet, by the way, this is like, like just forward looking for that rare patient who, who's so hard and only has one, and it's one of like 20 chromosomes.
And if you don't think this exists, like it's personal to me because like I know a patient's name who's like this and we got tons of embryos and we couldn't get a euploid embryo. There's one aneuploid embryo that only had parental, paternal only error and I'm looking at the studies showing that, well, paternal only aneuploidy of embryos about 6% sperm DNA about one to 2%. And then most of those other studies are showing that four to 5% false positive rate.
[00:40:00] So does that mean that for that embryo, there's a two-thirds chance that, that that was actually one of the false positives. And if it was a two-thirds chance, we're looking, you know, so there's a 66% chance that this is actually a euploid embryo and that's a mitotic error.
And if you were to sample the inner cell mass, and, and if you knew that, then you could transfer that embryo. You wouldn't give her a 65% live birth rate, but you might give her a 35% live birth rate. with their own DNA. So I'm getting a little bit into the weeds here, but like these are ways in the future with further studies.
I've always wanted to do that study looking at well counseled patients with a paternal only whole chromosome aneuploidy. Obviously not chromosome 13, not chromosome 18, 21, but something that's not compatible with life and transfer them. And, and you might find similar to the segmental aneuploid studies.
[00:41:00] Julia Kim did a great study during her fellowship looking at segmental aneuploidies and not finding a difference in, in outcome when you transfer those. So, you know, as we refine our thinking about how to use this technology, you know, we talk a lot about the platform, but I'd almost argue that as important as choosing a platform is understanding the underlying science and the limitations across all platforms.
Griffin Jones:
Are these the same as AFOs, Peter, because I hear, I hear abnormally fertilized oocytes, but is this the same thing that you're talking about?
Dr. Peter Klatsky:
It is a bit different. So this is more of, as an embryo is dividing, say it's going from four to eight cells, does one of those four cells have an error in that mitotic error?
And then is there, you know, and so now you've got two out of six cells that are abnormal, but they keep dividing and and some people would argue that well those abnormal cells won't divide as well And so it's lower chances But we know that there is not a hundred percent concordance between the trophectoderm which we biopsy and the inner cell mass Anybody who says differently has not read a scientific paper on this, right?And so it doesn't mean you throw the baby out with the bathwater, right? [00:42:00]
Like, it doesn't mean you say, you say, okay, the test is no good, right? There, you know, the folks who are anti PGT, it's inaccurate, it's got false positives. I say, yeah, you're right. And I still do it over 95 percent of my cases. I counsel the patient, here's the limitation, but the ultimate benefits of the test, lower miscarriage rate, higher single embryo transfer, you know, we do a hundred percent single embryo transfers when you have a euploid embryo, but I don't kid myself that there's not an error rate.
So, so I talk too much. Sorry, Griffin. Back to your question of like, how does identifying the parental source of the aneuploidy make a difference. One, it provides a reassurance to the patient that their DNA were used, in fact. Two, it addresses the issue that Chelsea mentioned that maybe it didn't fertilize and maybe you've got two copies of maternal only DNA that you wouldn't otherwise know and then, or maternal cell contamination. [00:43:00]
And then three, if there's a really smart fellow with a great REI division director and program that wants to do this study and, and, and we'll collaborate with you at Spring Fertility because, because, you know, we all want to participate in those studies too.
I would love to understand when you have paternal only errors. If there's viability to those embryos, if that's a marker of a possible false positive and mitotic error. And if that were true, then you, that could be a way to pick up about half of those mitotic errors.
Griffin Jones:
So AFO is being something different than it's a, it's a different category.
Chelsea, can you talk a bit about, have you seen changes in philosophy in terms of whether you discard those evos, whether you keep them, what's, what's happening in that landscape?
Chelsea Leonard:
Yeah, I would love to, before I just have one additional thought to, to tack on to what Dr. Klotsky was describing with origin of aneuploidy.[00:44:00]
Which is when I go into clinics and talk with providers about that feature of the testing, you know, oftentimes the provider will share. There's that case that they recall where a patient had persistently high aneuploidy in their embryos across cycles, and that patient was transitioned over to egg donor.
And in that cycle, after utilizing an egg donor, there was still unfortunately a high rate of aneuploidy. And at that point, the provider considered maybe it was. the sperm that was contributing in that particular case. And typically providers can think of a case, maybe a handful of cases where that was the situation where we realized after shifting to egg donor that it may have been the sperm that was contributing.
[00:45:00] And so I think for that reason also origin of aneuploidy information, especially before we consider transitioning a patient over to a gamete donor, making sure that we're going in the right direction. And sometimes it could be the sperm. But the area of, of AFOs or abnormally fertilized oocytes, I think is really exciting and love chatting with colleagues in the laboratory about this because there's that step that occurs after the egg and sperm meet.
I love that phrase that Dr. Klatsky used where we want to make sure that fertilization has occurred, right? So the embryologist is looking under the microscope for, uh, the pronuclei in the Petri dish to make sure that we are seeing what would represent a copy of chromosomes from both sides, the egg and the sperm fertilization has taken place and we have an embryo starting to develop.
[00:46:00] We know though that that's not a perfect science and there are laboratories that may look under the microscope at a single time point to try to visualize those pronuclei. Maybe they're faint, they're stacked, it's hard to see quite what we're looking at. And that call that the embryology just makes, for example, this embryo has one pronucleus or has two pronuclei.
Oftentimes that's then a decision made on whether to discard that sample or attempt to keep growing it out to the blasts stage. What we have found is that there are laboratories that are shifting their protocols on that slightly, where they will hold on to what we would call those abnormally fertilized oocytes, try to continue to grow them out to that blastocyst stage and biopsy them for testing.
And from the studies that have come out to date, there are what I would consider a meaningful, significant amount of those AFOs that continue to develop. And when we biopsy them, They turn out to be euploid and not just euploid, meaning two copies of every chromosome, but with proper representation from both sides, egg and sperm.
[00:47:00] The implication of that is that this is an embryo that may have been discarded based on that visual check that can now be considered for transfer. And that's so important for patients, especially those that have few options in the process.
Griffin Jones:
Peter, in your view, is this going to become part of the standard of care?
Because I just go back to the what used to be nice to haves become must haves, what used to be a feature or tool or, or then becomes part of, you couldn't imagine practicing medicine without it. And I think I'm paraphrasing one of David Sable's quotes, but he says that today's ceiling has to be tomorrow's floor.
In other words, if, as we expand access to care, we can't lower the quality as the quality raises, that needs to become the, the minimum in order to provide the scale, we have to be able to, to have more control over outcomes. And so these technologies are part of it. So is, is, is this task something that you see going to become a part of the standard of care? [00:48:00]
Dr. Peter Klatsky:
Yeah, I mean, first of all, I love everything David Sable says. So, today's ceiling, tomorrow's floor, like... I like that. Yeah, you know, for me, you know, in our lab, we don't tend to discard, you know, if there's a 1PN for exactly the reason that Chelsea mentioned.
So, so that part may add value and it may add value again to the fact that, you know, to avoid, um, you know, uniparental and so to me that, yeah, I don't know whether the PN check is the way really solves for that, but it, but it certainly would solve for the rare cases of uniparental disomy. And again, once you get it into your clinical flow, it doesn't slow things down much, and it just adds more reassurance.
[00:49:00] And so finding ways to do this in a way that is not necessarily increasing cost to the patient, but providing that reassurance and safety, like I said before, I think it should become the standard of care. I think it protects. Patience is, it protects, it protects the clinic, and it just, you know, the safer we can make our technology, the better it is for everybody involved. Physicians, embryologists, and above all patients.
Griffin Jones:
Let's talk a little bit about that in terms of the benefit to the clinic as a business. That is, after all, why the heck people listen to this show or pay any attention to whatever content I put out.
They're not coming to me for the latest scientific developments. The reason why this platform reaches a few thousand of you.
Dr. Peter Klatsky:
You have some good stuff, man. You have some good stuff.
Griffin Jones:
Peter, I'm not saying this to be modest every time I say it on the show I was a D student in high school. I barely got through high school biology.
[00:50:00] What I understand is what's, what's important to end users. What I understand is how markets function and how things that that maybe were once novel become part of the standard of care. That's part of how innovation happens. I also understand how competitive forces come together. And I try to bring all these perspectives together so that people can listen to them.
And they listen because there's so many people that are either, maybe they're young docs and they are starting a trajectory of where they're going to be a senior partner at a big group. Maybe they're going to come join you. Maybe they're going to go start their own group. We have more embryologists and lab directors, lab directors starting to take business interest.
[00:51:00] We've got a lot of CEOs that listen to this show and CFOs and COOs who are parts of these big MSOs and it used to be just us people that are listening and now it's people from India, it's people from China, people from Australia, it's, it all of these business folks that are listening. And so I, I look at a test like this and I, and I see like, okay, I can, I can see that this clinical benefit and I can see at a public relations marketing level, how necessary these controls are to have in terms of the scale and opportunity. I see how important the AI implications are. I'd like to hear from you. What are the business benefits that you see from a test like this?
Dr. Peter Klatsky:
Anything that makes, first of all, you've got a great audience of amazing people listening and biologists, clinicians, any of them who want to have the most rewarding career possible, who are interested in going to the Bay Area or New York please reach out to Spring Fertility.
[00:52:00] So I, I, sorry, Griffin, I can't help, but for our, our actual practice, anything that makes this process safer, anything that makes this process one where I can have more confidence that when I transfer an embryo, I am going to, you know, have the highest success rates possible and avoid a catastrophic event.
In our field, we've seen catastrophic events. We've seen, you know, child fertility in Los Angeles does not exist anymore. We've seen cryo tank failures. Those are catastrophic events that I cannot fathom. And my heart goes out to the patients. My heart also goes out to the doctors who are in that situation, who probably didn't have anything to do with it.
But we'll be held to account. So what, what I know is that this, you know, this is a tool that can make a double check and everybody who's been in an IVF lab who knows the, the, the behind the scenes knows that there's redundancy and there's not redundancy twofold there's usually in triplicate.
[00:53:00] So our nitrogen gas, right? We have three tanks and two rows. So when this tank ends, we go to the second row and in fact, in most of our gas tanks, we have three rows of multiple tanks so that we will never run out of gas. We will never run out of CO2 and duplicate isn't enough. Almost every IVF center in the world has three levels of redundancy.
So this is just another level of redundancy to reassure your patient and so if you want to be totally business, attempt about it. We've never had an embryo mix up at Spring, but we did once have somebody take somebody else's sperm, and we only caught that because we were checking parental source and to this day, I don't think that they were bad actors.
[00:54:00] I think there may have been other cultural factors, other, other issues going on, but I couldn't figure out, you know, at first it sounds funny, right? When somebody, when you hear about, like, essentially a married couple that separated, yeah and they're no longer living together. And the husband brings in the new partner's sperm.
And for the first four minutes, when you discover that people are like wow, relationships are complicated and interesting. Right. But then when you say, well, why? And you think, hearken back to that Good Morning America episode with it, with the, with the gamete mix up and you think about the liability there that shook me and everybody who had visibility into that because you couldn't help but wonder, are we being set up?
So yes, if you're, if you're managing a practice that in you are the CEO and you are the Director of Operations. I can't fathom why you wouldn't want to have that double check. Because that is so easy to do.
Griffin Jones:
I think of, of, if you're the CFO of a group or the CEO or whatever, and that catastrophic event does happen. It's one thing if the technology doesn't exist. You can say, well, these are the measures that were currently in place. But if you didn't have it and like two or three other networks do and use it and, and people can point it, courts can point to that. Patients can point to that. The media can point to that.
To me, that seems like doomsday. I want, I want to focus more on the positive of the, the, of the test, but part of what the positive is, is avoiding that potential absolute negative cat. [00:55:00]
Dr. Peter Klatsky:
That's right. And I want to be fair, you know, Cooper is not the only company that offers that and and so but but I would make sure whatever whoever your PGT partner is that they are providing that.
Griffin Jones:
I want to talk to you about your selection process for a partner because I know how, oh, what's the polite word of saying idiosyncratic you and Nam Tran are with you QA at, at Spring and like, it's so embedded into how you, you've built your, your practice group. You have QA measures that I hadn't even heard about before. We talked about that in the first episode that you came on and I know everyone listening is, is really important. QA is really important to them. I just feel like you take it to another level.[00:56:00]
And so it's like one of those scenarios where it's like, what if they're good enough for him. That means, that means there's something there. What was it about, and I, and I also presume that you have worked with other partners in the past. What was it about Cooper that made you say this is the partner for me?
Dr. Peter Klatsky:
I want to be cautious because there are a lot of great colleagues in this space and there are a lot of great PGT labs. And so I want to speak more in general, generalities because you know, one, you want to have like we started off at the beginning, you want to have a, I want to have that one, a high degree of confidence in the accuracy of the calls.[00:57:00]
Two, I want to have a low, no call rate. My current no call rate is under 1% in New York with Cooper. I have worked with other companies. I know I had a positive experience with Natera as well and so I want to know the professionalism of the people. I want to believe in their accuracy. And then I want to know my limitations in Griffin.
I am not the smartest person at Spring Fertility. I want so I, when I need that scientific, we're going to go to Nam Tran. Who is our Chief Medical and Scientific Officer working with our, our head of all of our IVF labs, Sergio, and, and get insight from them. But it's also important that your physicians who work in your practice have autonomy and, and physicians may have preferences as well. [00:58:00]
So when physicians are working at Spring, we, we put it up to our whole group. We look at the data. We have every group come in and, and give a presentation. After that presentation, we talk about it. We, we try to limit. The number of PGT partners to two per each lab, just because it makes it easier for your lab.
It's hard if you're going to have 10 different providers using 10 different labs. That's hard. So, so you want positions to have autonomy and to be respected and have their reasons, but you want to have an open dialogue. And I'm lucky enough to have, you know, people smarter than myself guiding me and then we constantly review the literature.
We constantly review the outcomes. And so when we choose a partner, we want to make sure that there's a quick turnaround time that they are responsive to the clinic, that if we need something in a hurry for a particular case or particular reason that they're able to do that, if we need, uh, an exceptional case that we need to do that, but as a general rule, I don't want to work also with a PGT provider who can't source the DNA, can't provide parental source DNA.[00:59:00]
And, and, um, my experience with Cooper working in New York has been wonderful. I don't want to be, you know, a commercial and I have a lot of wonderful colleagues who work for other organizations, you know, outside of Cooper. And so I don't, but, but I think you want to have an honest conversation. You want to know that you're in this together.
And if something happens, you know, that you're going to get a phone call and you're going to be able to work through it quickly and come to a resolution about things. Because there will always be cases, no matter who your provider is, where you'll have like suddenly a high no call rate. For one case, right?
And, and you want to be able to delve into that and in a non confrontational, but, but information finding way solution.
Griffin Jones:
I want to conclude with a couple of different ways. First, what are the takeaways that, that people should walk away with about this test specifically thinking of PGT-Complete℠, knowing that we have the scientists listening. [01:00:00]
We get the lab and embryology folks. We've got the docs listening. We have the business folks. that are like me that don't have clinical backgrounds. Chelsea, maybe you start. What should they walk away with?
Chelsea Leonard:
Yeah, I think from my perspective, a buccal cheek swab takes 20-30 seconds. It can be done from home or from the office at the center itself and really enables us to produce the most informed and confident results, right?
[01:01:00] When we get that PGT report back for the embryo reassurance protection and the potential to, in some cases, rescue embryos that may have been discarded or make the correct treatment decision going forward. For example, choosing, choosing the appropriate gamete toner. So, it's an easy thing, a cheek swab, and it leads to our ability to offer improved outcomes to patients, and, and we all know that there are cases where this could have been useful if, if it had been around at the time, and now it is, and it's available.
Griffin Jones:
Peter?
Dr. Peter Klatsky:
Yeah, I think that's, I think you said it well. I've given a variety of reasons. I think that one case in particular probably is going to stand out for a lot of people in this audience. And, you know, again, there, you also want to track your outcomes, right? So you also want to track what is my, uh, single euploid embryo by birth rate.
[01:02:00]And, you know, if there's deviations in that, if you feel like you're not getting the outcome that you should be, that's, that's what I do. But, but, but, Griffin, I think the ceiling should be the floor and when you have something that makes a technology safer and provides reassurance for patients, again, 100 percent of your patients are afraid of this, whether they tell you or not 100 percent of your patients.
Griffin Jones:
So let's use the things that give them less to worry about. I want to as you about where people can learn more about PGT-Complete℠. We're going to link to information about PGT-Complete℠. It will go out in the email that delivers this podcast. For those that subscribe, it will also be on the podcast page. We'll also include it in the show notes. Tell us, where can people learn more about PGT-Complete℠?
Chelsea Leonard:
Yeah, of course, there's lots of great information about PGT-Complete℠ on our website, so CooperSurgical’s website, including white paper, you know, further description of the features, some case examples. We'll be chatting about it extensively, I'm sure, at ASRM, as well as hopefully some upcoming discussions about real case studies with what we've observed with Complete in the last year or so, since it came out.
Griffin Jones:
So that’s the timing. Some people are going to listen to this episode, maybe three or six months after it comes out, but a lot of people are going to be listening to this episode right as it comes out, which is right about ASRM time. Some of you are probably on the plane right now, headed to New Orleans, listening to this episode.[01:03:00]
And if that's the case, Cooper's I imagine is going to have a big booth and big presence as always. And you're going to have a lot of your scientific people there. A lot of your sales people there. I invite you to go to their booth, talk to them about it. Tell them about this conversation. Peter, will you be at ASRM?
Dr. Peter Klatsky:
I will be, and anybody who's interested in having an amazing career in New York or Bay Area, we're hiring there. We're interviewing people. We're a great group of folks. We deliver the best science and look forward to meeting my peers there too.
Griffin Jones:
When you bump into Dr. Klatsky or Chelsea, tell them that you heard them on the show and tell them thanks for putting up with the host. [01:04:00]
Dr. Peter Klatsky:
Are you going to be there Griffin? Are you going this year?
Griffin Jones:
I wouldn't miss it. Yeah, I will be there.
Dr. Peter Klatsky:
Will you bring your baby?
Griffin Jones:
I will go sans baby. But, uh, I've thought about future appearances with the baby in some matching suit that I wear that fits my Conor McGregor suit MO. So not 2023, but, uh, we might see it in 2024 that all right, Cooper Marketing team, there's, there's something that we could do for our 2024 initiatives, but brand, brand new baby.
Two, two months old. Yeah, it'll be two months old by the time this episode airs.
Dr. Peter Klatsky:
Awesome. Congratulations.
Griffin Jones:
Well, thank, thank, thank you. And thank you both so much for coming on and advancing the conversation.
Chelsea Leonard:
Thanks so much.
Dr. Peter Klatsky:
Thank you.
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