RARE Daily

Bringing Genome Sequencing to Rural Populations

July 4, 2024

For people in rural communities, access to genomic testing can require getting on a waitlist, delays in clinical assessment, and multiple visits to urban medical centers. A pilot study from Children’s Mercy Research Institute in Kansas City, Missouri, found that by partnering with a rural clinic in a direct-to-provider model it was able to more than double the historic rate for rare disease diagnosis among the rural population and also cut the time-to-diagnosis by about five months. We spoke to Ana Cohen, assistant director of molecular genetics at CMRI, about its direct-to-provider model, how providing local support to patients at their regular clinics allowed them to bypass bottlenecks, and how the approach can shorten the time to a diagnosis for people with rare diseases in rural communities.

Daniel Levine: Ana, thanks for joining us.

Ana Cohen: Thank you.

Daniel Levine: We’re going to talk about the challenges rural populations face in getting access to genome sequencing, a pilot study from Children’s Mercy Research Institute and how this may point a way forward to improving access and care. Let’s start with barriers people in rural areas face, though particularly when it comes to being diagnosed with a rare disease. What are some of those?

Ana Cohen: So just to clarify, every single person out there with a rare disease is facing many obstacles. However, for patients in rural areas, the obvious additional barrier is just geographical isolation. They are further away from medical care in general, but when it comes to genetics specifically, there is a nationwide shortage of genetic specialists and those that are available tend to concentrate in the larger urban academic centers such as Children’s Mercy Kansas City, where I am based. And so those that are located far away from these urban centers are automatically at a disadvantage. And these families tend to just seek care from their local primary care providers that tend to be closer and in these rural clinics. And what that looks like for them, if they’re suspicious of having a genetic condition, is that they will see their primary care provider, then they get a referral to a genetic specialist. They have to wait about six to 12 months to get to that first appointment in an urban center, have to deploy resources to travel, possibly take time off work, possibly have to find care for other children that are not coming to the appointment, and then come to the main hospital just to initiate testing. And then on top of that, they have to add on possible insurance issues for approving tests. Then the test itself tends to take about two to three months, and then they get a report back and only then they actually initiate proper care for whatever genetic disorder they might have. So it really takes a very long time as well as a lot of traveling. And this is incredibly burdensome for these families, and naturally it’s going to affect those that have the least resources in their day-to-day life, and this is really something we wanted to focus on helping these families with.

Daniel Levine: There’s growing concerns about issues of diversity, equity, and inclusion, but often this is conceived of in a narrow way. How did Children’s Mercy come to focus on the issue in the context of rural populations?

Ana Cohen: Danny, that’s a great question. And indeed, there’s a lot of talk about this diversity, equity, inclusion in, I think, all fields, but in genomics specifically, the reason that has been discussed a lot recently is because it is clear that in keeping medical care and genomic research focused on the same types of population over and over, which tend to be predominantly white and socioeconomically comfortable populations, means that the type of genetic variation we are capturing is always the same. And so this is really narrowing our ability to do the best work that we can. Now, a lot of other genomic centers are positioned in cities that are much larger and have a lot of what most people think of as diversity, which is ethnic and racial diversity. However, children’s Mercy is actually located in a natural geographical position that would make us think of thinking about diversity in terms of geographical diversity and not necessarily that traditional diversity that most people think of. If you think about where Children’s Mercy Kansas City is located. So, Kansas City is on the border of Missouri and Kansas, and we have a very wide catchment area. Yes, we are primarily serving Missouri and Kansas, but also a little bit into the neighboring states. And the closest pediatric center actually to us is in St. Louis, Missouri. But you can drive all the way through Kansas State, which takes about nine hours and not find another pediatric focus care center. So just think about all of those families that are in these states that don’t have access to specialist care. We are very lucky that Children’s Mercy Kansas City has developed incredible resources through both the clinical side and the research side, and we really felt a responsibility to reach out to support these rural families in the areas around us. And that’s really why we decided to invest in diversity in a different way.

Daniel Levine: Before we talk about your recent study that was published in the American Journal of Human Genetics in April, I think it might be useful to talk a little about the Genomic Answers for Kids program. Listeners interested in taking a deep dive on this can listen to an interview we did on this podcast in October 2022 with Tommy Pastienen, director of the Genomic Medicine Center, Children’s Mercy. For listeners not familiar with the program, can you explain what it is and what it’s seeking to do?

Ana Cohen: Absolutely. So, the Children’s Mercy Research Institute, back in 2019, established a large care genomic rare disease program that is called the Genomic Answers for Kids, or we call it GA4K for short. Now just to clarify, we call it Genomic Answers for Kids because our primary focus is on helping children. However, we also have a lot of adults, primarily parents of the children, but also other family members that are part of the study. So, it’s not just children, but the goal really, over multiple years, is to collect genomic data and health information from 30,000 children and their families and create a shareable database of nearly a hundred thousand genomes. And in parallel, the Genomic Answers for Kids program is continually investing in expanding our diagnostic capabilities, and we’re doing that through innovative technology and research. And it is something that we like to emphasize that our recruitment has no exclusions based on prior genetic testing, on availability of parental samples, or insurance coverage. We are very happy that we’ve had a lot of success. As of April 2024, we’ve already been able to recruit over 14,000 individuals, and we are already surpassing 1,700 diagnoses, which is truly incredible.

Daniel Levine: The program is using state-of-the-art sequencing technology. Even with cutting edge technology, though, many patients still go undiagnosed. What kinds of diagnostic rates are you able to see?

Ana Cohen: Danny, that’s a great question and something I think a lot of people have trouble grasping, and it just comes from the fact that there’s still a lot of work to be done. So, we in Genomic Answers for Kids utilize multiple technologies and we’re continually trying to innovate beyond what is currently utilized. So, the baseline diagnostic rates are around 25 to 35 percent, and we have been able to establish a very strong partnership with Pacific Biosciences, and they have developed a technology called Long Read Genome Sequencing, also known as Five Base or Hi-Fi genome sequencing. And with that partnership, we’ve seen our diagnostic rates surpass 40 percent, and we’re really confident that in the near future we’re going to be able to cross the 50 percent threshold. And it’s just really encouraging and we think there’s a lot of innovation that’s going to come, particularly as we expand our recruitment.

Daniel Levine: I think a lot of people think if only they could get sequenced, they’d have the answers they’re looking for. But why is it that even with sequencing technology we have today, so many people still go undiagnosed?

Ana Cohen: Absolutely, it is, let me tell you, frustrating for us as well. You might think of us as specialists, but it turns out our knowledge of the genome is still very limited to this day. So for example, we rely on what is considered a reference sequence to tell us what we expect is the normal looking genome for any individual. And we’re definitely missing some variation in human beings. The tricky part when we find new variation in our studies is understanding: is this new variation causing disease or is just normal variation that no one had seen before? And maybe they hadn’t seen it because they weren’t using the right technology, which is why we’re testing multiple technologies and constantly trying to innovate on that side. Or it could be because a specific subpopulation had not been tested and that variation is specific or enriched in that population. And that is why increasing diversity, we believe, is going to help us also increase that diagnostic rate. So, the more people we sequence, the more information we collect, and the more we’re going to learn about the genome. And in parallel, the Genomic Answers for Kids program is always sharing the data. So everything in a de-identified manner is shared with other groups that are doing the same type of research. And we believe that all together we can collaborate to understand more about the genome. Now this is assuming, obviously, that we’re talking about individuals that actually do have a genomic or genetic condition. There are for sure individuals that have a suspicion of having a genetic condition that actually don’t and the cause of their disease is different, or it could actually be a combination of genetics and environment. And that is something that is also very poorly understood still in our field, but there’s a lot of research going into that.

Daniel Levine: Let’s talk about the pilot study for the study. Children’s Mercy Research Institute collaborated with Salina Pediatric Care, a rural clinic in Salina, Kansas. Can you explain what Salina Pediatric is and why they were selected?

Ana Cohen: Yes. Salina Pediatric Care is the only pediatric focused clinic in the region of Salina, Kansas. Salina Kansas is located 175 miles away from Children’s Mercy Kansas City. That’s about a three hour drive each way from our center. It serves about 4,000 children a year, which is just under half of the children in that region, most of which live in rural zip codes. And about 13 percent of that population identifies as Hispanic or Latino. Now, one thing that we know is that most primary care providers don’t feel comfortable ordering genetic testing because it requires extra knowledge. But more importantly, it requires extra time with the patients to counsel them about what the testing is going to do, what answers may be found or not found. And that’s a resource that most primary care providers don’t have time for. And so, we really needed to find a way to reach primary care providers and empower them to feel comfortable to do this. The reason we partnered with Salina Pediatric Care is because we have over there someone that we call our physician champion, Dr. Zuccarelli. She is actually a pediatric neurologist who trained previously at Children’s Mercy Kansas City. So during her training here, she became familiar with the use of genomic testing and how to one, identify individuals that might benefit the most from this testing, but also two, how to properly utilize resources to order such testing. So having that person on the ground to kind of be the intermediary and teach us what support the providers are going to need was extremely important and we really wanted to focus that on the pilot side so that eventually we could use that knowledge to transport to other clinics where we might not have a physician champion onsite.

Daniel Levine: How did this study work?

Ana Cohen: It’s actually pretty simple. Usually, patients in the traditional care route would go to their primary care provider and then they would get a referral to come see genetics in a large center and then they would initiate testing and then they would wait for testing and then the care would be modified, and potentially they’d actually have to come back to the urban center. So we decided to flip it around. We wanted families that are potentially affected by a rare disease to just go see their primary care provider, be offered testing and with one visit sort of skip the line and have access to genomic testing. So how did that work in practical terms? We really recruited the primary care providers, which included physicians, practitioners, and physician assistants at Salina Pediatric Care through our physician champion. We also did a visit on site to train the providers on recognizing the best families to consider for our study. And then when the providers themselves felt that they were comfortable suggesting the study to a family, they would just make that suggestion during their regular clinic visit. And if the family was interested in participating, then the Genomic Answers for Kids team would take over and do all the work for them. So what did that look like? It looked like calling the family to explain to them what the study was, to provide pretest counseling, and really all the information and all the paperwork was done by our team. And then also do all the work of coordinating sample collection. So typically this was a saliva sample. We also work with blood samples. Sometimes that gets shipped to our laboratory here at Children’s Mercy Kansas City. And it just goes through the processes of every other sample in the Genomic Answers for Kids program in terms of DNA extraction, sequencing, and analysis. And then if we find an answer, so a diagnosis, which as I mentioned earlier a diagnostic rate is expected around 25 to 35 percent of the time, then a clinical confirmation is done. And that is possible because the research in the clinical sides here work very closely. Clinical confirmation is done, a clinical report is generated that is given back to the primary care provider. And from then on, it’s sort of on them to pursue follow-up care for the families. So really we’re looking for the family. This is a single visit to a doctor that they already know, collecting a sample once, and then we did all the work for the provider on our side in between the clinic visit and receiving the results.

Daniel Levine: And what were the results of the effort.

Ana Cohen: So, we were able to achieve a diagnosis in 24 percent of the cases, right around what we expected, which was very reassuring and showed that what we believed, which is that all populations are probably affected by rare diseases, is true. And one important thing is obviously that these results were returned to these families much faster than they would have been if the families had pursued the traditional route of having come to see a specialist in person before initiating testing. So typically what that would look like would be a wait list of at least six months with testing that takes about three months. So best case scenario, a result would be given back in nine months. All the results that we had that were positive and diagnostic were given back in less than four months. So really we were shortening the time to diagnosis significantly for these families, which is incredible. Also, a very interesting finding is that actually three of the diagnoses were found for children ages seven to 13. That is actually a little bit surprising. We typically see a higher diagnostic yield for children more in the two to three years age group. And that’s because that’s the typical age where physicians might notice that children might be not developmentally progressing as their peers, and that’s typically an age where they would pursue testing. So what that tells us or suggests is that there’s a potential lack of ascertainment of children that would benefit from this testing if they don’t have access to medical care in the right age group. So that was extremely interesting to us. Now I do want to point out the one finding that was a little bit surprising to us and a big learning lesson that is really reframing how we think about care for underserved populations, is that just giving back this diagnosis to families if they’re far away from medical care sometimes that means that they’re still going to be underserved for proper follow-up care after receiving the diagnosis. And that’s something that we are investigating, new resources that we might be able to connect families with that would have more local support that we’re not able to provide just because of that geographical isolation.

Daniel Levine: And did this study shed any light on the types of challenges people with rare genetic diseases face getting a diagnosis?

Ana Cohen: So, I believe the main challenge that we were able to uncover with this pilot for individuals with rare diseases specifically in rural areas is really that access to care is a continuing problem. And it doesn’t exist only prior to testing. It exists also after the testing. So, with the pilot study, we were really able to troubleshoot all the pieces that go into place prior to genomic testing—so all the limitations and access to a specialist, all the limitations in access to testing that could be because they don’t have access to medical care. Sometimes it’s also, I didn’t really go into detail here, but it could also be limitations in insurance coverage or limitations on even being able to make the appointments for all types of reasons. So those limitations we really tried to address with the pilot, but we weren’t able to address the challenges that come after getting a diagnosis. And that’s really one of the directions that we need to invest in.

Daniel Levine: And does this point a way forward for providing a model to address the health needs of rural populations? Does it show a way to implement a direct-to-provider model?

Ana Cohen: I believe the main thing that was learned from this is that primary care providers want to help their patients. They want to support their patients locally and make them feel comfortable to come back to the care with the providers that they already know and trust. And so, the model really supported this direct-to-provider system supported by a large center like Children’s Mercy Kansas City can exist and really overcomes a lot of the barriers that primary care providers have in terms of resources by just having us, on our side, to take over a lot of the logistics and a lot of the headaches that come with paperwork and time and sample collection and mailing, all of that that sometimes seems trivial, but can actually be a barrier, also to just initiate genetic testing for these families. We were really able to utilize this pilot to troubleshoot a lot of the logistics and visualize how a direct-to-provider model can be expanded to additional clinics. Now, is this going to meet all the health needs of rural populations? No, but we believe we are addressing one important need, which was the access to genetic testing that was previously not well distributed for rural populations.

Daniel Levine: Are there plans now to expand the use of this model to other populations?

Ana Cohen: We are definitely looking to expand. We’ve actually, through the same physician champion that we collaborated with for this pilot project, we’ve been able to recruit an additional five clinics in rural Kansas. And we are just currently starting recruitment for those clinics. We are looking for additional clinics in rural areas that might be interested in joining the study. And again, the only requirement is that primary care providers are looking to learn a little bit about the potential benefits of genomic studies and work with us towards understanding the program, introducing that program to their patients, and then our promise that we will try and take over most of the logistical burden that comes with participating in the study.

Daniel Levine: Ana Cohen, assistant director of molecular genetics for Children’s Mercy Research Institute and lead author on the study in the American Journal of Human Genetics. Ana, thanks so much for your time today.

Ana Cohen: Thank you.

This transcript has been edited for clarity and readability.


The RARECast podcast is made possible through support from the Global Genes’ Corporate Alliance. The members of the Corporate Alliance support Global Genes’ mission and programs, work to meet the vital needs of people with rare diseases, and address inequities they face. To learn more about the Corporate Alliance or how your organization can become a member, click here.



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