Outcomes Rocket Podcast_Natera_Dr_Jelsema: this mp3 audio file was automatically transcribed by Sonix with the best speech-to-text algorithms. This transcript may contain errors.
Saul Marquez:
Hey, Outcomes Rocket Nation, Saul Marquez here. I want to talk to you about Natera, a leader in personalized genetic testing and diagnostics that is transforming how we make critical healthcare decisions. Natera is revolutionizing the standard of medical care with next-generation, cell-free DNA testing, its non-invasive blood tests provide critical health insights to improve outcomes and enable earlier and more targeted interventions that lead to longer, healthier lives. Be sure to check out Natera.com to learn more. That’s Natera, N A T E R A.com to learn more.
Saul Marquez:
Hey, everybody, welcome back to the Outcomes Rocket, such a pleasure to have you here again. I’m super excited today as we continue the series that we’ve done with Natera. Today’s episode is going to be fascinating. It’s going to be on non-invasive prenatal testing, and today we have the outstanding Dr. Russ Jelsema with us. He’s currently the senior medical director of women’s health at Natera, he has 25 years of experience in maternal-fetal medicine, practicing in urban and regional settings, his work, it’s focused on prenatal diagnosis, including ultrasound, chronic villa sampling, and genetic amniocentesis. Dr. Jelsema is particularly interested in ensuring that families receive the most accurate and scientifically-based information regarding the health of their children. He received his medical degree from Wayne State Medical School in Detroit, completed his residency in obstetrics and gynecology from Butterworth Hospital in Grand Rapids, Michigan, and a fellowship in maternal-fetal medicine at Wayne State University. Dr. Jelsema is board certified in both obstetrics and gynecology, and maternal-fetal medicine, and what I love most about him is that he loves to just keep it so common sense and helps all of us understand the basics, which is what we all need, with this type of testing. So Dr. Jelsema was such a pleasure to have you here on the podcast!
Russ Jelsema:
Thank you, sir.
Saul Marquez:
Yeah. So really, you know, the thing that we’re going to dig into today is, NIPT, non-invasive prenatal testing, really just to level-set here, it’s just a method used to determine the risk factors for fetuses born with certain conditions, and we’re going to learn a lot today. And so what exactly is NIPT testing and who should get it?
Russ Jelsema:
Well, as you said, NIPT testing is testing to determine which mothers are at risk for having a baby with certain genetic birth defects. As doctors understand it, we talk about non-invasive prenatal testing, NIPT, it refers specifically to the use of cell-free DNA. Now, all of us have cell-free DNA to determine the risk specifically, so all of us have cell-free DNA in our bloodstreams, we’re living cells, they die through natural process called apoptosis or through disease process, inflammation or infection, resulting in the spillage of that cell free DNA into the bloodstream. So all of us have cell-free DNA. In pregnancy, there’s cell-free DNA from the pregnancy as well in the mom’s bloodstream, and the proportion of that cell-free DNA we call fetal fraction. Unfortunately, that’s a misnomer and has led to misunderstandings because the perception is it’s directly from the fetus. It’s really from the placenta, we should call it placental fraction. So the placental cell-free DNA spills into the mother’s bloodstream and cells die under the natural process, and that is the cell-free DNA that we’re evaluating when we look with NIPT, long answer to your first question.
Saul Marquez:
Fascinating.
Russ Jelsema:
The second part is that I think everybody should get it, just like obstetrical ultrasound to screen for birth defects, everybody should have NIPT.
Saul Marquez:
Got it. No, fascinating. So, you know, you mentioned, Dr. Jelsema, the history and I think history kind of lays out some interesting insights, no matter how we look at it and NIPT, there’s history. So talk to us about that in prenatal screening and just the different things that we can learn about.
Russ Jelsema:
Well, I’d actually like to go back to the, almost the beginning of time, but not quite, the beginning of obstetrical screening. So back in the 1980s, early 1980s, when I was a medical student, when we talked about screening for risk for Trisomy 21, we knew that as mothers age, their risk increased. And so we offered screening to women who are 35 and older. But the vast majority of women 35 or older didn’t have babies the Trisomy 21, so it wasn’t a very good screening test, best we had. Then we introduced looking at markers in the maternal mother’s blood, not cell-free DNA, but things like AFP and HCG, depending on the level of those markers, determine the risk of aneuploidy, chromosome problem for trisomy 21 specifically, and we called that maternal serum screen. We had an ultrasound and even with ultrasound looking at the baby’s neck and serum markers, the likelihood if you had a positive test, the positive predictive value was only three or four percent. So it wasn’t a great test, but it was better than what we had with age. Then we looked at babies with Ultron at 20 weeks, didn’t help a whole lot because half the babies with Down Syndrome looked perfectly normal ….. That led us to cell-free DNA in 2011.
Saul Marquez:
Wow. OK, so 2011 is when it started.
Russ Jelsema:
Yes.
Saul Marquez:
OK, so you know, you mentioned all of these iterations as we move to cell-free DNA, he accuracy goes up, and so let’s talk about accuracy when we look at cell-free DNA testing with NIPT.
Russ Jelsema:
Sure. So exactly, and this is the part is that when we talk about accuracy by itself, parents sometimes perceive, they think of accuracy as a diagnostic test. So when we talk about mammograms, for example, the most common screening test that OB-GYNs offer, order, they understand it’s a screening test requires a biopsy to confirm. So we talk about accuracy of mammograms and biopsies, but physicians usually focus on the biopsy accuracy versus the screening test, parents focus on the accuracy of the screening test compared to what we have been doing is very accurate. So if your test comes back positive, unlike the serum screening, which was a three to four out of one hundred positives would actually have a baby with Down syndrome, here it’s 90 percent of those who have positive tests, so the accuracy from a screening test is much better. You still need, key point here, a diagnostic test of some kind, whether it’s Koranic sampling, as you mentioned earlier, or amniocentesis to confirm the abnormality.
Saul Marquez:
Got it! Ok. This is the first step, and then you need the diagnostic test to do the rest.
Russ Jelsema:
Yes, typically you’d need a diagnostic test. Let’s say you had an NIPT and it came back higher risk for trisomy 21, patient comes to see a high-risk pregnancy specialist as myself, not all will have genetic counselors available, so I pitch, for a pitch for genetic counseling, but that’s not available for all maternal-fetal medicine specialists. But we start with ultrasound, and if we look with ultrasound and we see that the baby has a lot of fluid around it, for example, or there’s a major birth defect of the heart, that now raises the likelihood of trisomy 21 much greater. However, as I said, half of babies will look perfectly normal. So a normal ultrasound after an abnormal NIPT doesn’t eliminate the risk of trisomy 21.
Saul Marquez:
Got it! Now, good to know, and by the way, folks, if you didn’t get a chance to listen to the episode on counseling, genetic screening counseling, definitely check that out. We’ll leave a link in the show notes for this episode as well. Just the phenomenal talk track with some of the stuff that Natera is doing in that space, too. This stuff is not easy, and a lot of assumptions are made, and it’s better to just be super clear about everything. So glad you brought that up. So really, if you get a positive result, what happens?
Russ Jelsema:
Well, I think the key part here is before we even get the positive result is that the counseling by whoever orders the test, the physician, the midwife, whoever it is that orders the test explains that this is a screening test and uses if they need to use an analogy or metaphor like mammogram or pap smear so that the patient realizes when she gets that phone call, hopefully, she doesn’t get an email, but hopefully she finds her by phone call from the nurse or the NMA or the physician that your test is positive, it does not mean your baby has the condition we’ve screened for. That’s a key, and that’s where you mentioned the podcast you did with Sheetal Parmar, my colleague, we have a great terror of the opportunity for patients to call ahead of time even and ask, hey, what’s this test? How accurate is it, to answer your question. But once you get the positive result, I think it’s important again to couch it in the language that this is a screening test. It doesn’t mean your baby has Down syndrome because when I’ve called parents, the first thing they hear when I say your test is positive, my baby has Down syndrome. That’s not true. It’s me to make sure that then have them come in, if the genetic counseling is available, provide it either by the genetic counselor or by the high risk pregnancy specialist and an ultrasound. And we’re going to recommend invasive testing and amniocentesis or chorionic bill sampling to confirm the findings that we have. Now maybe we can, by ultrasound, we see something that’s suspected, it raises suspicion, we’re still going to recommend confirmation.
Saul Marquez:
Sure. So then, you know, with a positive result, just wanting to understand this further, it’s positive, so does that likely indicate that it’s 90 percent chance that that is the case?
Russ Jelsema:
That’s how to word it to you, yes, if you are with significant other in front of me today, I’d say, sure, you know, this is like there’s a 9 out of 10 chance with Natera’s current technology that your baby, in fact, has trisomy 21. And we would recommend, now, that’d one out of 10 chance it doesn’t.
Saul Marquez:
Yeah.
Russ Jelsema:
So it’s not a 100 percent vote to confirm it. So you need to have amniocentesis.
Saul Marquez:
Yep. Makes sense. And then case of a negative, it’s a negative. People usually don’t do additional testings or do.
Russ Jelsema:
Correct. So no, that’s correct. So if you have a negative test, you take a deep breath of reassurance just like a negative mammogram.
Saul Marquez:
Yeah.
Russ Jelsema:
Again, say this doesn’t mean your baby doesn’t have trisomy 21, there are false negatives, but a greatly lowered your risk, and if you have a normal ultrasound, that’s going to further lower your risk. So it’s not zero, but on the order of one and a thousand or one in two thousand, it’s going to be very, very low. So be reassured, but it’s possible. And again, this gets back to that differences between the placental cell-free DNA and the fetal cell-free DNA. The fetus can actually have trisomy 21 with the cell-free DNA from the placenta has gotten rid of it simplistically the 21st chromosome and it comes back negative. So we call that a false negative.
Saul Marquez:
Yeah, yeah. Back to that placental fracture idea, right? Where the difference comes in. Yep.
Russ Jelsema:
Yes.
Saul Marquez:
Fascinating super educational. And so we’re diving into the next step here. You know, you guys are always, Natera, you guys are always coming up with the neatest things thinking ahead, really, I mean, you guys are thought leaders in this space. So what are the latest you guys have come up with in, in IPT?
Russ Jelsema:
Well, I think the biggest has been the large study that’s been done prospectively. That means going forward looking at NIPT in women of young age and older age and looking at chromosome problems like trisomy 21 as well as 22Q, Which is a micro deletion. That particular work had almost 20,000 patients from around the world, patients were enrolled where they had NIPT, but they also, also, all the pregnancies had what’s called chromosomal microarray, so karyotype tells us how many chromosomes there are and if they’re missing big chunks or have additional chunks, that’s how the terminology I use of DNA, my genetic counselors, our colleagues, are probably cringing right now, but that’s how I talk. But there’s something called chromosomal microarray, where you’re looking at a more of a microscopic for smaller pieces of chromosomes, we call those micro deletions that are there, or maybe there’s additions as well. And so the study of those 20,000 patients looked at patients NIPT and then compared their microarray, which is the gold standard. That study resulted in a number of papers already, but three major presentations at my specialty, society maternal fetal medicine, last year. The first demonstrated that their ability to screen patients who are 15 years of age or 25 or 30 was just as good as those for 35 or older. And then we applied something called Panorama Artificial Intelligence, which was looking at our prior couple of million, two million, tests that we’ve done developing and improving the algorithms, as we say, and applying it, and showed we still had a very high positive predictive value, as I said, over 90 percent. The second study, which I think is the most landmark, was the presentation of 22Q, which we’ll talk about more about 22Q, but 22Q is a micro deletion, these kids look perfectly normal at birth and often look perfectly normal on ultrasound. But we can do things that birth to improve their outcomes, that positive predictive value went from one in five to one and two, 50 percent, which are very impressive, and both of those papers are just published online and will be published in the American Journal of OB-GYN in the last two weeks.
Saul Marquez:
What accounted for that? That drastic shift in accuracy.
Russ Jelsema:
Our ability to, again, with the artificial intelligence, that Panorama and having, and as well as having the results available, knowing so yeah, it improved so quite, quite dramatically. The third part, which I think will come back and talk another day, maybe, is that for an OB, one of the, we much more commonly for OB-GYNs to see pre-eclampsia, high blood pressure in pregnancy, preterm birth, and this study also showed that for women whose fetal fraction was very low and just like if you don’t have enough cells on a pap smear, we can’t give results, you have to have repeat pap, for women who had two consecutive no calls with their panorama, they were much more likely to have developed preeclampsia, preterm birth or stillbirth. Because probably these placentas are crummy, if I can use that term, they’re small placentas. So I think you’ll see NIPT being used not only to predict risk for aneuploidy, but also for adverse pregnancy outcomes. So very exciting from my standpoint as a high risk pregnancy specialist.
Saul Marquez:
Yeah, that’s super, super amazing. And this is where it’s going, and one of the things that I admire about the work that you do, Dr. Jelsema, and also the work of Natera is that the path is not fully paved. So, you know, like just the reimbursement side of things, I know it’s together now, but there’s so many things that you guys are, are laying the path on that we need in order to do this type of pre-predictive care that doesn’t seem to be commonplace in our industry. So kudos to you and the team for the work that you’re doing. So when you talk about micro deletions, you know, what are they and why is it important to screen for them?
Russ Jelsema:
So micro deletions and there are a number of them, and the one that I like to focus on today was the 22Q, which is also called the George Syndrome, Velo Cardio Facial Syndrome, and where there’s a small piece of the 22nd chromosome missing. And it has a fairly broad variety, but there’s a fairly common phenotype associated but not recognized always until the kids are three or four years old. And so comparing it to trisomy 21, which we’ve screened for in the past, if I, for example, saw a family who I diagnose trisomy 21 at birth, if the baby doesn’t have any heart birth defects, that baby can go to the regular nursery or I can stay with the mother in the delivery room. The care is no different. And in fact, if we didn’t know what had trisomy 21, if I caught that baby, I would know it had at birth. You can recognize it. Conversely, with 22Q, these babies look perfectly normal at birth, they’re about every 500 births, so I have delivered about several in my lifetime, but it never knew that I did. But if we knew they had 22Q or they’re at high risk, their care is altered significantly. So routinely babies are born, we don’t check their calcium level, but half of babies are 22Q have low calcium, which can lead to what we call subclinical seizures. They’re seizing, but you can’t tell if their brain’s seazing but their body isn’t. If we know they have that, we can check calcium and give them calcium, reducing the likelihood for bad outcomes in the future. Also, the first thing kids get is vaccinated by, by the labor and delivery nurse, they give them vaccinations. Two thirds of kids, three fourths actually with 22Q have immune problems. We don’t want to vaccinate them. So now here in the first 10 minutes of life, you’re altering this kid’s care. Third thing we want to make sure that the pallets checked by an expert because these kids have palate abnormalities and they don’t feed well. And finally, a newborn echocardiogram checking the heart. So we would do four different things for this baby. And there’s data coming out of Children’s Hospital of Philadelphia that demonstrates that for prenatal diagnosed versus those diagnosed at four years of age, typically for 22Q, the outcomes are better. So I think that, what’s impressive for me is that now we have some way to screen for a condition that we can’t even identify at birth routinely, but we can improve the outcomes for these families.
Saul Marquez:
I think that’s fantastic. My question is, is this currently standard of care?
Russ Jelsema:
Standard care, so the standard of care, it’s commonly done so over, we are the leader in terms of NIPT in over, well over half of the physicians, OB-GYNs, my colleagues order 22Q with their NIPT. So in that way you can say, well, it’s pretty standard. That being said, my specialty organization of American college OB-GYN and my subspecialty society maternal-fetal medicine at this time do not support 22Q screening.
Saul Marquez:
Gotcha. Gotcha. So there’s some work to be done there.
Russ Jelsema:
Yes, there sure is.
Saul Marquez:
Yeah, yeah. And you know, there’s gaps like this everywhere. This is just one that you guys are working on to make it better. I was recently learning about ROP, when, when infants get too much oxygen, right? Something that we could tease out and find ways to improve. And I get super excited when we have thought leaders like you, Dr. Jelsema, leading the way in finding ways to close those gaps. So appreciate the work you’re doing for, for our country and also for the world, because you guys do, do apply this stuff worldwide.
Russ Jelsema:
Yeah. So ROP, if I can just say so, that’s so, we saved, 1963, President Kennedy had a baby die at 34 weeks of pregnancy. His wife, Jackie, delivered a premature, three weeks early by C-section, and the baby died from oxygen issues, that led to the formation of neonatal. And we started giving babies lots of oxygen, which led to blindness. Stevie Wonder is an example of that, the musician.
Saul Marquez:
Oh wow, is he one of them? Oh.
Russ Jelsema:
Yeah, that’s what I’ve been told. I may be wrong, but that’s what we were told in med school and residency. But there are a lot of people who had that, but now we’ve learned that we can back off on the action. So what saved a lot of lives, the action resulted in injury, so we continually work towards improving outcomes, and that’s our goal here at Natera as well, to improve outcomes for babies, for moms, for families.
Saul Marquez:
Yeah, that’s beautiful. And that’s what we’re all about. So how does Natera ensuring patients and providers get the most out of NIPT, non-invasive prenatal testing?
Russ Jelsema:
Sure. Regarding patients, we have the availability of what Sheetal Parmar talked about on your prior podcast with regard to pre-counseling, pre-test counseling. So a patient who does, who’s thinking about having the test can talk to a gen counselor and say, hey, what’s the accuracy of this test? What’s this test tell? That’s free of charge after they get results back? Sometimes there’s a lag between getting a positive result back and being able to see somebody like myself, and they can call and hear positive, hopefully good information, from them versus finding it on the internet and a lot of educational services, pamphlets, brochures and that like for patients. From a physician standpoint, Sheetal’s team and my team, we have four medical directors in women’s health, are actively trying to educate our colleagues, family medicine physicians who do obstetrics, midwives, OB-GYNs, about NIPT and the benefits that it can bring to their families.
Saul Marquez:
Beautiful. This has been truly informative, and I know at the same time for many people listening, you’re like, wow, that was so great, but how can I learn more? So I think this is a great opportunity, Doctor Jelsema, just to say, first of all, thank you for such an informative session and to open the door for a connection here. Where can folks go to learn more and how could people learn more about you in the work that you do?
Russ Jelsema:
Yeah, I think you can go to the Natera.com website, lists all of our medical directors and you know, you can connect through that’s probably the easiest way.
Saul Marquez:
Excellent. Well, hey, really, really appreciate you jumping on today and educating us. This has been fantastic.
Russ Jelsema:
You’re welcome, sir.
Saul Marquez:
A leader in personalized genetic testing, Natera combines its cell-free DNA platform with cutting edge technology and a focus on real world data to transform what’s possible during people’s most critical health moments. Natera has applied its core technology to the areas of women’s health, oncologym and organ health, helping millions of people manage their disease from a simple, non-invasive blood test. If you’re interested in learning more about how Natera is revolutionizing the standard of medical care, visit Natera.com, that’s N A T E R A.com.
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