Shortening the Diagnostic Odyssey

Despite advancements in genetic testing, people with rare diseases often face a prolonged diagnostic odyssey involving multiple physician visits and misdiagnoses. Genetic testing company GeneDx is working to shorten the path to a diagnosis by expanding access to sequencing, collaborating with researchers, and accumulating data to better understand gene-disease relationships. We spoke to Katherine Stueland, CEO of GeneDx, about the state of genetic testing, what its 2022 acquisition by the AI-drive genomics company SEMA4 has meant to it, and what she thinks it will take to make meaningful change to the diagnostic odyssey.

Daniel Levine: Katherine, thanks for joining us.

Katherine Stueland: Happy to be here. Thank you.

Daniel Levine: We’re going to talk about the rare disease patient odyssey, genetic testing, and how GeneDx envisions changing the diagnostic landscape. Let’s start with the diagnostic odyssey. Despite growing access to genetic testing, people with rare diseases still face a diagnostic odyssey that can extend for many years and involves the need to see multiple physicians and face often wrong diagnoses for several times. Why is that?

Katherine Stueland: You described it perfectly that there is a diagnostic odyssey that can last many, many years. Right now it’s on average six to eight years for a child with a rare disease to get an accurate diagnosis. And what happens is if you just put it through the lens of what a parent’s going through, they have a child who has an unexplained symptom, they’re, of course, first going to go to a pediatrician, and that’s where the trial and error odyssey begins. Very rarely are genetic tests used in the pediatrician setting today. And historically, genetic testing was really relegated for providers who are called medical geneticists. And it takes a long time to actually get to see a medical geneticist. It can take six to 18 months. So right now, these families face the lack of utilization of testing in the general pediatric setting, but we’re trying to solve that problem by getting some of the specialists, who pediatricians refer out to, to start utilizing testing. So think about pediatric behavioral specialist, pediatric developmental specialist where many of those general pediatricians will refer out to, that’s who we’re focused on today, trying to ensure that we can intervene as early as possible to be able to get these kids a diagnosis.

Daniel Levine: I think patients understand that it can take a while for a physician to recognize that someone may have a rare genetic disease and to actually refer them to genetic testing. But I think what often surprises people is that genome sequencing doesn’t always provide a definitive diagnosis. How good a diagnostic tool is whole exome sequencing or whole genome sequencing today, and what needs to be done to improve the rate of diagnosis.

Katherine Stueland: So, when you’re taking a genome’s worth of information and interpreting it into whether or not there’s a positive finding or a negative finding, I think what you’re referring to are the many cases where we’re getting a variant of unknown significance, meaning there’s not enough data out there that’s shared in the general medical community to say whether or not this particular variant within a gene is indeed positive or if it’s negative. So, when we talk about exome sequencing, what we are doing is we’re analyzing the protein coding regions of the 20,000 genes in somebody’s genome. The exome really covers where the majority of disease causing variants reside. So an exome is a very efficient way to be able to figure out if there’s genetic disease. When you go deeper into the entirety of somebody’s DNA, that’s called [whole] genome sequencing, and that is where we believe we’ll be able to have the most definitive information. And in rare diseases, it’s been shown to be an increased diagnostic yield or an increase in diagnoses by about 10 to 12 percent from a genome versus an exome. So getting to the entirety of a genome is indeed the holy grail. Part of what sets GeneDx apart, we have fewer variants of unknown significance compared to other exomes and genomes out there. And the reason for that is we have sequenced more children with rare diseases as well as more parents. So, in about 60 percent of our cases, we’re not only taking a look at the child’s DNA, but we’re also taking a look at mom or both parents. And so we have a very complete and robust database that is enriched for rare disease. And what that means for testing with us is with every patient who we’re running through our interpretation platform, we’re either upgrading or downgrading a variant of unknown significance. So the testing that we provide is actually much more definitive than other exomes or genomes, and most definitely from other multi-gene panels or other types of genetic testing. So I would say we are closing that gap in terms of the unknown parts of the genome very rapidly as we continue to rapidly accelerate the utilization of our testing.

Daniel Levine: There have been some efforts to overlay genomic data with other patient data to zero in on a diagnosis. Is GeneDx exploring any efforts like this and do you think these hold additional promise?

Katherine Stueland: Absolutely. I think getting as much information for the individual patient as well as for the family helps us every single day. Here at GeneDx, we actually collect a lot of the clinical information from the provider who’s ordering the test. So they’re taking note of additional symptoms, other observations, but the more information, the more precise we can be. And I think what’s really helpful is we think about the future of how genomics connects with drug development. If you can really start to take a look at a person’s genetic makeup and also have a complimentary data set of the journey that they’ve been on to get diagnosed, what kinds of tests, what kind of medications they’ve been on, you can actually do analysis that we’ll take a look at what the very best path forward is going to be based on both the patient’s genotypic information as well as the clinical data that accompanies it. So I am very encouraged and hopeful for a future where we can do an even more robust job. I think we’d love to get to a place where we are automating surveys that go to parents so they can share with us the totality of what they’re seeing day to day as they’re caring for their child with these symptoms.

Daniel Levine: We’ve seen the cost of this technology falling. How do you see the relationship of cost of these tests to access and is there some price point that’s necessary to make this a universal newborn screening tool?

Katherine Stueland: So, the cost of our tests have continued to decline, which means that more people have access to them. I think this has been a really important phenomenon that we’ve seen since the historic ruling by the Supreme Court in 2013 that nobody could patent DNA. So, between the cost of sequencing continuing to come down, thanks to our friends at Illumina, PacBio, and other sequencing companies, as well as our ability to lower the cost of our interpretation, we are able to ensure that we can continue to open up access. And right now, the customers who are paying for this, of course, are insurance companies. They’re state by state Medicaids, and in some cases there are families who are paying out of pocket. That’s a very small percentage because we’ve been able to generate so much access across all of these different payer types. So we want to continue to drive down the costs so we can continue to bring these to broader and broader populations of people, including as you mentioned, newborn screening is something that we’re starting to take a look at. We’re doing a study here in New York state with the Department of Health and Columbia to take a look at how the breadth of whole genome sequencing might be able to help us prevent the progression of diseases early as possible in that newborn setting. So, as we think about different ways to bring whole genome sequencing to every baby at the time of birth in order to be able to prevent disease progression, we want to be able to make sure we can continue to drive down the cost of testing so all have access to this testing in an equitable way.

Daniel Levine: You mentioned that GeneDx has amassed enormous amount of genetic data that’s helping to drive an understanding of gene disease relationships. Can you explain GeneMatcher and GeneDx’s involvement in it?

Katherine Stueland: Certainly. So to give you a scope of the scale, we have run more clinical exomes than anyone else in the United States. So we have data from exomes from about 700,000 patients. Three years ago that number was 270,000. So it’s been a very rapid clip of an increase in utilization. Key to all of this, of course, is our ability to continue to, as I mentioned earlier, upgrade or downgrade variance of unknown significance, but also ensuring that we can take new gene disease discoveries and be able to bring those to the clinical community so we can continue to diagnose patients who may have had a variant of unknown significance. So GeneMatcher, it’s a platform that really helps facilitate that gene disease discovery among patients, clinicians, and researchers. So, when we think that there’s a gene that we expect—that we have a suspicion that may actually be linked to a disease, we submit it to GeneMatcher, and then it’s validated through a network of researchers and clinicians who can work together to really bring what we believe to be a positive gene-disease correlation to a conclusive result. So

Daniel Levine: I think people might be surprised to learn how prolific GeneDx is. As a publisher or a contributor to scientific literature, how many articles have you been a part of to publish the relationships between genes and diseases?

Katherine Stueland: To date? The research that we’ve been able to do through GeneMatcher has impacted more than 22,000 patients. We have been the contributor of a quarter of the contributions to Gene Matcher and we’re routinely making new gene disease discoveries.

Daniel Levine: You were the chief commercial officer of Invitae prior to becoming CEO of GeneDx. I’m wondering what you learned from your time there that’s informing what you’re doing now at GeneDx.

Katherine Stueland: Invitae was really centered around opening up access to as many patients as possible. So, what I like to say is that we’re bringing the best of the ethos of Invitae with us at GeneDx, but we’re doing it with a degree of practicality and with financial, I’d say, an eye towards financial discipline to ensure that we can continue to really run a financially healthy company. So, we have really taken a look, since I joined several years ago, we’ve built out a team that’s focused on opening up access for more patients. I think we’re succeeding in doing that. As I mentioned, when I arrived, there were 270,000 clinical exomes in our database and today there’s 700,000, all of those representing families that we’re impacting. So opening up access is critically important. Being able to contribute to health economic and outcomes research to show how valuable it is, not only clinically, but also in saving the health systems and the healthcare system valuable dollars. And I think the other really important element is thinking about the diversity of our patient population. Most genetic testing companies really have a largely Caucasian database of patients, and the diversity of our database is reflective of the US population, and that’s something that we’re very proud of. I think it represents the way that we’re ensuring that no matter what one’s socioeconomic background is, they have access to testing. So we are intending to do good in the world, not just by way of opening up access, but ensuring that we can help. We can help a very diverse group of people.

Daniel Levine: Sema4, an AI driven genomic and clinical data intelligence platform, acquired GeneDx about a year after you joined. The combined company took the GeneDx name and you remained CEO. What did that acquisition do for GeneDx?

Katherine Stueland: When Sema4 acquired GeneDx, what that really enabled GeneDx to be able to do is move into the public sector as a company that was publicly traded. So we really brought a lot of focus and discipline to the organization with an eye towards ensuring that we can drive the company towards helping more patients and doing it in a way that helps us achieve profitability. And the importance, as I say to our employees of achieving profitability is that it ensures that we can continue to reinvest into our platform, reinvest into the important partners that we have, like at GeneMatcher, to contribute to an ever-growing understanding of genetics and their relation to disease and ensure that we can continue to help more and more families. So, the acquisition of GeneDx by Sema4 really was a conduit for us to be able to put the company on the map as being one of the leading companies in genomics focused on improving the lives of families.

Daniel Levine: Did it change at all the way the company thinks about or incorporates AI?

Katherine Stueland: So, one of the most important tenets I think of Sema4 was how do you deploy AI to be able to combine genomic data and clinical data from an EMR? And that, without a doubt, as we talked about, is something that we want to be able to do in the future. The way that we’re using AI today is ensuring that we can scale our interpretation platform. So if you think about the manual process that may exist for our team who are looking through highly curated databases, we can now, as an example, be able to have variants that are ranked. And so it becomes a much more automated process that makes the job easier for the clinical geneticist who is working for us. It lowers our costs and it ensures that we can turn around our answers quicker. So all of the benefits that we’ve been able to really pull through on the AI side of things come from a patient-centric place to improve the overall experience.

Daniel Levine: GeneDx is addressing multiple markets. How does GeneDx work with providers?

Katherine Stueland: So, when we think about the importance of using an exome and a genome to diagnose patients, it’s critically important that this test is used upfront as early as possible. The sooner that you’re able to give a diagnosis to a family, there’s a child suffering from a rare disease, the sooner that they can do something with that information, meaning they can get on an FDA approved therapy, they can join a clinical trial, they can get into the right sorts of occupational therapy, physical therapy. So there’s so many different types of action that can be taken that can prevent the progression of disease. So our entire strategy is centered around how do we get providers to utilize this testing as early as possible. Ultimately, we talked about getting into newborn screening. We want to be able to get to that point where every parent has access to this, to clinically actionable information as soon as there’s a symptom. But today we’re trying to really drive utilization earlier in their journey. So we’d like to see a day when general pediatricians are using testing. Their guidelines are about a decade out of date right now. And so we’re focused on the next referral set of clinicians and providers who are really using this testing effectively to not only get a diagnosis, but to ensure that these kids get into a clinical trial or connected with an FDA approved therapy as soon as possible.

Daniel Levine: My understanding is you’re using a subscription model for doing that. Does that encourage utilization?

Katherine Stueland: So, the way that we utilize our testing today, it is ordered by a provider and it is paid for by an insurance company or a Medicaid program. So there’s not a subscription service today. But in the future, what we’d love to be able to introduce is being able to sequence at birth and be able to, on first presentation of a symptom, be able to have a provider query GeneDx, and then we can provide an answer about whether or not the symptom that they’re noticing, whether or not there’s an underlying genetic condition. So, we think that a subscription approach in the future is one that could really ensure that, again, we’re getting to a faster diagnosis, faster clinically actionable information, all really designed to prevent the progression of disease.

Daniel Levine: And how about with academic researchers, which is another market that you’re pursuing?

Katherine Stueland: Academic researchers are critically important to all of the work that we do. There is some really important research that happens across all of the different conditions that we look at, whether it may be rare forms of epilepsy, if it may be in autism, or if it could be for children with hearing loss. And so right now, our number one job is making sure that as many providers and researchers who are seeing these children with symptoms are aware of GeneDx, they’re aware of our exome and our genome, and they know that we are able to be here to provide a definitive and comprehensive answer about whether or not there’s an underlying genetic condition. We’re also publishing with many of these researchers new data, whether it’s on diagnostic yields, if it is related to the newborn screening study that I mentioned, or if it’s health economic and outcomes data. We’re doing research with the University of Washington to really take a look at how this testing is utilized and the impact that it has on patients. So academic researchers play a critically important role in really further establishing the clinical actionability and utility and validity of the tests that we provide and the answers that we’re giving to these families.

Daniel Levine: The last market I wanted to ask you about was drug developers. How do you work with them?

Katherine Stueland: Drug developers are playing a really important role in educating families and providers about new treatments and gene therapies that are being contemplated and that they are developing. And so what’s really interesting, I think, is this ecosystem of diagnostics companies, researchers, biotech companies, the FDA, all working together with a single goal in mind, which is how do we make sure that we can get children on the right medication? It’s the promise of precision medicine that lies as a shared responsibility within this ecosystem. So for drug developers who are aiming to have an impact using their discoveries, they can’t do that unless there’s a diagnosis and there’s nobody who diagnoses more children than GeneDx.

Daniel Levine: How hopeful are you that there will be a meaningful change to the diagnostic odyssey anytime soon and what do you think it’ll take to make that happen?

Katherine Stueland: I’m very hopeful that we’re going to be able to significantly reduce that diagnostic odyssey. I would love to see us eradicate it completely. As I look at it, for a family to go through six to eight years of a diagnostic odyssey where we can provide an answer within weeks, if not days, is unconscionable. And what it requires is more education for families, more education for providers about the actionability of this information. And it requires that payers continue to expand coverage in their medical policies. So we still have a lot of work to do on the educational front, but we are working relentlessly day in and day out to ensure that we can really do our part in putting an end to the diagnostic odyssey for as many families as possible.

Daniel Levine: Katherine, CEO of GeneDx. Katherine, thanks so much for your time today.

Katherine Stueland: Thank you so much. I appreciate it.

This transcript has been lightly edited for clarity and readability.

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