Intro: Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Melanie Cole.

Melanie Cole, MS (Host): Welcome to UAB MedCast. I'm Melanie Cole. And joining me today to discuss Undiagnosed Diseases Program at UAB Medicine, finding answers to mysterious conditions is Dr. Bruce Korf. He's an Associate Dean for Genomic Medicine at UAB Medicine.

Dr. Korf, thank you so much for joining us today. The Undiagnosed Diseases Program really can provide answers to patients with mysterious conditions that have long eluded diagnoses. Tell us about the program, how it came about. Why did you see a need for this type of program?

Dr. Bruce Korf: The program was begun in 2013, and it was modeled after a program at the National Institutes of Health. And the idea is that there are people who have conditions that nobody seems to be able to figure out. And they frequently go from doctor to doctor, sometimes over a period of years, searching for answers and just unfortunately don't get any. So, the program was set up to serve people in that situation, to provide multidisciplinary evaluations and use cutting-edge technologies, including genome sequencing, in an effort to achieve diagnoses for people who have been searching for answers, oftentimes for years.

Melanie Cole, MS: What kinds of patients are appropriate for the program?

Dr. Bruce Korf: The program sees both children and adults. And the criteria for entry are that they have a chronic condition, is defined by having been present for six months or more, that they're not acutely ill. In other words, they can't be in the hospital requiring intensive care. And that there has been a strong effort already to try to achieve a diagnosis that has been unproductive. So, we're really looking for patients who have eluded what you might say is standard medical evaluation.

And then, finally, we take a look at the information provided in terms of the medical history and are looking to see if there are sufficient objective signs that there's, you know, an illness that we think we can actually help with. There are many people that have things like chronic pain and chronic fatigue, and we're really not set up well to handle those kinds of problems.

Melanie Cole, MS: Dr. Korf, how have advances in radiologic imaging augmented your diagnostic and therapeutic capabilities for these undiagnosed diseases? Because it would seem that complementary with genomics and really your speciality. Tell us a little bit about imaging and some exciting advances that are helping with this.

Dr. Bruce Korf: We use whatever cutting-edge technologies we think are going to be helpful to solve a patient's problems, and certainly imaging is very high on the list of things. Obviously, things like magnetic resonance imaging, sometimes various radionuclide imaging approaches that might be appropriate for a particular diagnostic entity. So, we work with radiology here, trying to identify the mode of imaging that will be most productive and then make arrangements to work with them to use it for answering specific problems. But, you know, the ability to look at both structure and function with new approaches to imaging has certainly made a big difference in our ability to achieve diagnoses.

Melanie Cole, MS: What about genomic medicine? How are you using that to help these patients?

Dr. Bruce Korf: Most of the people whom we see end up having their genomes sequenced. I say most, there are occasions where we think we can make a diagnosis without that, and not everybody that we see necessarily has a genetic problem. But that being said, if you were to look across the diagnoses we've made, the single most productive test has been genome sequencing, where we either identify a genomic variant that is known to cause a condition similar to the one that the patient is presenting with, sometimes with a kind of presentation that may be a little bit unusual, which is why it wasn't thought of clinically. And sometimes, we've actually discovered new gene disease associations, in other words, identify a genomic variant in a person that has never been reported before, but where we can identify potentially other individuals around the world who have somewhat of a similar genomic change, either a change in the same gene, or sometimes the exact same change, which validates that it's associated with that particular patient's problems. So, genomics has been probably the single most productive diagnostic approach.

Melanie Cole, MS: So, what's the experience so far in establishing diagnoses?

Dr. Bruce Korf: We've seen, first of all, over 600 referrals, but not everybody who is referred is seen in the program. We find in some cases, for example, a person, let's say, has a neurological problem and they've never seen a neurologist. And we think the first stop for that patient is a standard neurologic evaluation. So, those patients are referred appropriate services. And as I mentioned, there are some people where we get referrals and you just can't sort of understand exactly what the problem is, or make a judgment that the kinds of approaches that are at our disposal are just not likely to make a difference. And so, those patients are not seen in the program.

That being said, over 300 have been seen in the program. And among those that have completed their diagnostic workup, I would say it's just under half in whom a diagnosis has been made, oftentimes by genome sequencing, but not always. Sometimes with more conventional tests or imaging studies. And very often because our consultants get together on a regular basis, talk about undiagnosed patients, frequently out of those conversations will come ideas for doing tests that we had previously not thought of. And then, sometimes this results in a diagnosis.

Melanie Cole, MS: Well, then tell us how the program actually works from a patient's perspective and navigating the program itself and speak about your multidisciplinary approach.

Dr. Bruce Korf: The approach to seeing patients has actually changed a little bit because, as of a few months ago, we joined the National Institutes of Health Undiagnosed Diseases Network and they have a gateway, they call it, which is where referrals ultimately are made, or where patients need to go to be seen. So, the gateway is available. One can do a quick search online for the Undiagnosed Diseases Network. Patient will enter their own information into the gateway. We'll explain the nature of the problem and provide appropriate contact information. This is reviewed by UDN staff and those cases are then assigned depending on usually the location of the patient. So, anybody in our region here at UAB is likely to be referred to us.

We have the opportunity then to review the medical information that was provided and make a decision whether we think we can help with this particular problem. This is then reviewed at a meeting that occurs every other week with the UDN, where every case that has been suggested for a patient to be seen, is briefly reviewed, and a decision is made whether that patient will be seen in the program.

Once that's done, our nurse practitioners work with the patient to collect relevant medical records and to identify the appropriate specialists to see the patient, in addition to one of the core physicians in the Undiagnosed Diseases Program. And so, we'll then coordinate a visit with one or more clinicians, depending on what the nature of the problem is organize testing, which might be imaging or it might be blood testing or conceivably other things like urine testing. If genome sequencing is to be done, that is arranged. And so, the patient is seen. It may not all be in one day. Sometimes it's not possible to coordinate that that tightly, but we'll do the best we can to arrange a coordinated visit, somewhat depends also on how far the patient is traveling from.

Gradually, information will come back as test results are obtained. And then, we'll be in touch with the patient, either sometimes to arrange additional tests if necessary, or other times if we think we have an answer, to discuss that answer, and then ultimately to issue a report to the patient and to their clinician, whoever that may be, to explain the outcome of the evaluation.

I will say that, for the most part, the evaluations are billed to insurance in the usual manner. Consultants who might see the patient will do so as well. Tests are also done on a traditional fee-for-service basis, though there are arrangements that can be made for individuals that are not insured, for example, and are otherwise unable to afford the evaluations.

For Alabama residents, we have the possibility of ordering genome sequencing through a state-funded project that allows us to do genome sequencing. And now, it's called long-read sequencing, which is really the most cutting-edge approach to genomic analysis without the need to charge the patient for those, so that's been a major asset that we have.

Melanie Cole, MS: Dr. Korf, as we get ready to wrap up, what's your future vision for this program? How do you feel it improves the patient journey and outcomes? And what are the conditions under which you believe patients would benefit most from your experience and this program?

Dr. Bruce Korf: There are several things that we're looking forward to as this program moves forward. One is an increased use of telemedicine and earlier access to genome sequencing. So in other words, we think that, in many cases, the diagnoses that get made by sequencing were not things that we would have predicted. That leads us to believe that we actually might be wise in settings where we think there's likely to be a genetic cause to do the sequencing earlier in the course of evaluation, possibly even based on a telemedicine visit to try to reduce the barriers to patients being seen. So, that's one area.

Second area I've alluded to, which is using long-read sequencing, which is a new technology that is far more sensitive to various kinds of genomic changes than what I guess you could call traditional sequencing that has been used over the past several years. So, we think it will increase the diagnostic yield.

A third area that we're very interested in moving forward and has actually begun to, is in outreach to the community, particularly in communities that are historically underserved. So, we think that there are many people who are unaware of the program or might not be able to afford the kind of evaluations that need to occur. And we're now beginning to work with community health services in order to make sure that people are aware of the program. We can assign a nurse practitioner navigator to help them to literally navigate their way through the evaluations and understand all the things that need to happen, and also to be sure that their clinicians are aware. You know, there are many people who have had diagnostic assessments years ago in the past that were unproductive and then gave up on the possibility they could have a diagnosis. And with new technology now, we think it's really worth revisiting many of those situations. And that's another message that we're trying to convey to the community, but we're very eager to be sure that there is wide access to the program and individuals in all demographics. So as as time goes on, we do hope we'll be able to increase the volume of patients seen and increase the yield of diagnoses.

Melanie Cole, MS: Thank you so much, Dr. Korf, for joining us today. And for more information, please visit our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole. Thanks so much for joining us today.