Rania Habib, MD, DDS (Host): Genetic research is becoming the forefront of really tackling these rare diseases in children all over the U.S. This is Transformational Pediatrics with Children's Mercy, Kansas City. I'm your host, Dr. Rania Habib. Joining me today is PhD Dr. Ana Cohen, and she is an ABMGG certified clinical laboratory geneticist and researcher at Children's Mercy, Kansas City, who focuses on genomic analysis of individuals with rare diseases. She is here to discuss Children's Mercy's cutting edge genetic testing and how they're improving access by expanding research to rural communities. Welcome to the podcast, Dr. Cohen. We are so excited to listen to your expertise on this topic.

Ana Cohen, PhD, FACMG: Thank you so much for having me. I'm excited as well.

Host: Children's Mercy Kansas City is leading the way in genetic testing, using next generation sequencing to revolutionize the speed of rare disease diagnoses. Can you briefly tell us about the Genomic Answers for Kids program?

Ana Cohen, PhD, FACMG: So Genomic Answers for Kids, which we call GA4K for short, is a large scale genomic rare disease program based here at Children's Mercy, Kansas City. And we're actually housed in this brand new shiny glass building that has a beautiful view of Kansas City, Missouri, and we get inspired by that every day to do better for our kiddos.

So, Genomic Answers for Kids is collecting genomic data and health information from families affected by rare genetic disorders. So we're focusing primarily on children, but usually we collect information and samples from their family members as well, because that helps us with the investigations that we're doing.

 There are two main sides to Genomic Answers for Kids. One is what most people think about in rare disease research, which is just trying to find the diagnosis for these families. And we do that in multiple ways. One of them is trying to always be at the forefront of the technologies we use. So we do use standard short read genome sequencing as most other research programs do.

And we have now also been able to develop on grid genome sequencing through a platform that is created by PacBio. And with that, we're actually able to interrogate a lot more different disorders affecting the genome in a single test. And that's really exciting. And we've actually launched that as a clinical test here at Children's Mercy Kansas City as well recently.

And then there's also another side of Genomic Answers for Kids, which is, complimentary and it's helping us also advance the diagnosis, but in a different way. It is looking into the consequence of the mutation. So one of the ways is, for example, doing functional assays to try and see what is happening in the actual body to see if there's an intervention that could be done. And another really cool thing that one of my colleagues is looking at is doing in the lab, in one experiment, you could actually screen multiple therapeutic options to see which one might be the best for a kiddo. So, for example, if you are trying to treat a child with seizures that has a very specific genetic mutation, we might be able to tell you the exact medication that would be appropriate for that, rather than the standard care, which is just trial and error to see which one they respond to.

So there's different sides to Genomic Answers for Kids. We're always trying to innovate and do better and just helping these families with rare diseases. And me personally, I focus more on the diagnostic side as well as more recent efforts to increase access to the testing in the first place.

Host: That is fantastic. I really love the fact that you are testing the child, their family to get answers, and you're using this genetic research to not only try to find out the disease, but then also help find the correct medication to help with whatever symptoms you're trying to treat. So that is fantastic.

Now as we know, Dr. Cohen, not everyone has access to genomic medicine and research, which can contribute to health disparities. According to the U.S. Census Bureau, nearly 20 percent of the population lives in a rural area. These patients often face challenges accessing cutting edge medical technologies like the ones you described.

Tell us about your pilot study to expand access to those who are underserved and underrepresented.

Ana Cohen, PhD, FACMG: So, like most research studies, we are also based in a large academic center that is in an urban location. And so, families that are coming to Children's Mercy Kansas City, automatically have a leg up in finding out that this program exists and being introduced to the program and having the option of being part of this research initiative.

Now, we know that there's a lot of families out there that would also highly benefit from our program, and we have been very conscious about trying to find new ways to make these families aware that they can join the research, and importantly, they don't necessarily have to come all the way to Kansas City just to join the research.

And so that is actually what I tried to explore in my pilot study. We partnered with one physician that had trained actually here at Children's Mercy Kansas City, Dr. Zuccarelli. She was very familiar with Genomic Answers for Kids already. She currently practices in Salina, Kansas, and that's about a three hour drive from here.

And because she was very familiar, she was very enthusiastic to bring this program to the patients that herself and her colleagues are seeing all the way in Salina, Kansas, which primarily serves rural families in the surrounding area. And so through that, we were able to communicate with these providers to educate them a little bit more on the value of genomic testing and also what types of clinical presentations most benefit from genetic testing because it's not actually that beneficial for every single type of clinical presentation. So we really wanna offer testing to the families that will benefit the most. We don't wanna just blind recruit people to expand our program. And so we provided the support. And then we also, one very important thing was to make sure that our team was basically doing all the work because we know the providers are often overwhelmed and don't have a lot of time with their patients.

And we were specifically working mostly with primary care providers, so PCPs rather than specialists. And these are typically the exact providers that have the least time with their patients and a lot of constraints. So by us here at Genomic Answers for Kids providing all the support in terms of doing the actual consenting to the research, explaining what genetic testing means and what are the possible outcomes of participating in the program; but also smaller things like coordinating the sample collection and having that mailed to us.

And all of that, that was all taken care of by our team to make it easier on the providers and the families. And what has been really exciting is that the results that we found through that were very encouraging. So we really found that, first of all, the diagnostic rate for rare genetic disorders is around 25 to 30 percent, in general, and that's exactly what we found in our pilot study with Salina. Out of 21 families, we were able to provide a definitive answer for five of them.

But even more exciting than that is that traditionally, most of these families might actually need referral to come to Children's Mercy, Kansas City, to then initiate testing, and that whole process, in terms of referral, then there's a wait list, then there's the testing that happens, can easily be over a year, and for all of these families, we were able to provide an answer in less than four months.

So, we really were able to speed up the diagnosis and also provide testing to families that maybe would not have had access, maybe they would have been referred here, to Children's Mercy Kansas City, but we hear from a lot of families in distant regions that it's really difficult for them to even travel to come here.

It might be because you know, it's a full day off work for the parents or they have other kids that they can't leave behind. There's a lot of logistics that come into coming to an appointment so far away from home. So by us coming to them instead, we're really hoping to get rid of that barrier of just local access to genomic testing.

Host: No, it's really a fantastic program because we've all been there where we're trying to get these patients from the rural areas to come into the main hospital, and that's really difficult, so I love that you're bridging that gap for these patients and also for the providers who are in those areas who don't have access to the same technology that you have.

Dr. Cohen, why is it important to foster greater diversity and equity in research?

Ana Cohen, PhD, FACMG: My personal belief is that it's important to foster diversity and equity in all aspects of life. But as a professional in genomic research, obviously that is one of my focuses. It is very well known in our field that efforts in genomics in general have been extremely biased to white populations of European descents and also of just higher socioeconomic status.

And what that does is that actually we rely a lot on databases for our data interpretation. We use these databases, one of the main ways we use them is to filter information. So, we all have our genomes, there's actually a lot, a lot of variants or mutations in our genomes. That just makes us unique individuals, that doesn't mean that it's causing a disease.

And so we need filtering systems. And one of the main filtering systems is we can say, Oh, if this change that I'm seeing in this individual, I've also seen in another 2,000 individuals. Well, I know this is not causing a severe disease in this child, because otherwise these other 2,000 individuals would also have this severe disease.

So that's where databases really are very helpful to really reduce from hundreds of thousands of variants to analyze to maybe a hundred. That's sort of where we're around. That's the first step. And so if you think about just diversity in these databases, the less diversity there is, the less effective the filtering is going to be.

And we see that. There is, unofficially we can see that it's much easier to do the interpretation of the data for individuals of white European descent versus any individual that is from a more diverse background. And so by adding more diversity to these databases, we're actually helping all patients, through the interpretation.

But then, just another layer is just, we want to see equity in research because we want every family to have the same chance. Just because you live in a certain place or have a certain level of education or a certain socioeconomic status shouldn't mean that you are more likely to have access to a resource compared to another family.

And so this is really where we're trying to think outside the box and bridge that gap. It is very difficult because there is so much information to convey and distance really does pose a barrier. If I'm able to talk to a family one on one and explain the benefits and the drawbacks of research, I think that comes across much more clearly than if I'm trying to explain that over the phone or via email.

And then, obviously, if we add to that, language barriers or, distractions during that communication that the family may have, or there's just so much to take into account that, we're really just dipping our toes in.

Host: Now, Dr. Cohen, you mentioned that one of the major outcomes of your pilot study was that you were able to diagnose five of these families in the rural community. You were able to bring them to Kansas City in four months instead of a year. What are some of the other outcomes of your pilot study and what impact do you hope your research has on the rest of the research community?

Ana Cohen, PhD, FACMG: So I just want to clarify on something that you mentioned, so we were able to provide a concrete diagnosis to families, to five families. We did not at any point have to bring them to Children's Mercy Kansas City, which is actually a big aim of ours is to be able to provide the same level of genomic testing and care for these families without having to bring them here.

At least, in what we call the pre test phase, which means just everything that's leading up to the genomic test and to that potential diagnosis. We really cut out basically, a wait list time. We cut out the need to travel. We cut out the waiting on top of that for a test. And I didn't even talk about insurance, but sometimes that's another barrier and doing this through research, there are absolutely no costs to the families whatsoever. So we're cutting all of those barriers. So the main outcome is the reduction in what we call time to diagnosis for these families. We really shortened that to under four months for these five families.

Obviously, the other families remain without an answer at this time. That's based on current knowledge. But because they enrolled in our research study, they remain in the study as long as they want to. And we routinely reanalyze data and look for new information out there in the literature or even pursue functional studies like I mentioned earlier.

We don't like to call those as negative results, we are saying right now they're not positive yet. So the main outcome was really that. Now I do want to point out the one very enlightening thing that came out of the study as well was that as much as we want to provide equivalent care to these families without them having to come to a big urban academic center like Children's Mercy Kansas City, it turns out that in the phase post test; so after they receive their result, there are still a lot of barriers to accessing the care that they need. And that is something that at this time we're not equipped to really help as much as we want to. We're starting as well, having a lot of conversations in terms of the roles of, for example, local community health workers or just doing more telehealth consultations so that these families, wouldn't have to travel.

But, that part is still a little limited. So there's a lot to learn. But what's exciting is we have found other clinics that are excited about these results and also want to start telling their patients about our program. And we are honestly open to partnerships with as many clinics in rural areas as would come to us.

So if anyone listening, resonates with the situation and wants to contact us, we are definitely open to that opportunity.

Host: That's amazing. Now, you have provided us with a wealth of information about all the amazing work you're doing at the Genomic Answers for Kids program. As we wrap up this episode, what is your final take home message for our audience, Dr. Cohen?

Ana Cohen, PhD, FACMG: So a take home message for our audience is that there is a lot of power in genomic testing, but there's still a lot that remains unknown. So we are doing our best and we're innovating, and we're trying to reach as many families as possible, but we also want families to understand that at this time, there's only about 30 percent of families that walk away with a concrete diagnosis.

However, as I mentioned before, having more diversity in information and databases actually helps with the analysis of every other family that is being tested. So by participating in the Genomic Answers for Kids program, you are not only helping your own family and your own child, you're actually helping every single other individual that is enrolled in our program. And I know that that might seem not as exciting as having answers; but, we do find that over time we are getting new diagnoses that we're able to provide sometimes for families that have waited, even like 10 years. So, we like to tell people to not lose hope.

We are continuously innovating, the adding of long reads genome sequencing that we've done in the last couple of years is really bringing a lot of new information. We think that we're going to be able to reach a diagnostic rate of above 40%, maybe up to 50 percent soon. So this is just the beginning. We're excited for what's to come and we're excited to help more families.

Host: Absolutely. You really have a really special program at the Genomic Answers for Kids program at Children's Mercy. Thank you, Dr. Cohen.

Ana Cohen, PhD, FACMG: Thank you.

Host: Once again, that was Dr. Ana Cohen, a clinical laboratory geneticist and researcher at Children's Mercy, Kansas City. To refer your patient or for more information, please visit childrensmercy.org to get connected with one of our providers. I'm your host, Dr. Rania Habib, wishing you well. This has been Transformational Pediatrics with Children's Mercy, Kansas City. Please remember to subscribe, rate, and review this podcast and all other Children's Mercy podcasts.