Rizwan Hamid, MD, PhD, Professor of Pediatrics and Director of Division of Medical Genetics at Vanderbilt, also one of the Principle Investigators along with John Phillips and John Newman of the Vanderbilt Undiagnosed Diseases Network talks about the program and the process from application to completion.
Interview conducted by Ivanhoe Broadcast News in March 2018.
We hear a term like undiagnosed diseases and it doesn’t really resonate with a lot of people or they don’t understand. Is this a big issue in this country?
Dr. Hamid: When we think about undiagnosed disease I think we think about three different types of problems. One are diseases which are common diseases and they present in unusual ways. One of the ways we think about for example is a patient who has Lupus, which is a reasonably common one, but the disease presents in such an unusual way that the physician has difficulty diagnosing that patient with Lupus. And that can obviously lead to a long expensive odyssey. The second type of undiagnosed disease is disease which is very rare; which means that these are diseases which by definition are maybe one in two thousand people have something like this. And, they are so rare that our normal physician or internist or a pediatrician or a neurologist may not ever see a patient with that condition. It is never on their radar. The diagnostic odyssey is long and complicated. The third type of undiagnosed diseases are diseases that we don’t know exist. These are diseases which nobody has put a label on. These are a combination of symptoms or presentations whether they happen in a child or they happen in an adult. But, it’s such an unusual combination that they either get mislabeled or not really labeled at all. These patients have another sort of complicated long diagnostic odyssey because even with the best of care at the best medical centers these patients never receive a diagnosis because nobody has labeled that condition, nobody has recognized that combination as a disease. The idea of the undiagnosed disease network is to actually help patients in each of these three categories.
Explain for us what is the Undiagnosed Diseases Network, how does that work? Because as you mentioned before there’s a center for that and then there are other sites around the country correct?
Dr. Hamid: Yes. The Undiagnosed Diseases Network actually grew out of the Undiagnosed Diseases Program which is at the National Institutes of Health under the direction of Dr. Bill Gahl. This program at UDP as we call it or Undiagnosed Disease Program was started about now eight to ten years ago. And the purpose was the same: help patients with these three categories that I just described. What they found was that the program was very successful. But the demand was such that the site (or the center) at NIH could not handle it. Plus it was very inconvenient given how big the United States is for people for example from the west coast to go to NIH to get there. So the idea then came around that maybe the experiences that UDP and the protocols that the UDP developed can be further implemented at several centers across United States. You increase the type of patients you see, and you increase access. That was one of the major objectives. About two and a half years ago the network was expanded in to seven clinical sites. One in Stanford University, California, one in UCLA in California, at Baylor College of Medicine in Houston, Vanderbilt, Duke University in North Carolina and Harvard Medical School. So now the centers kind of range in the United States and now not only that we can see more patients but we can see bigger diversity and patients have better access.
Before I get to how this works, what’s the protocol? Does the family come to Vanderbilt, do they go through testing. Is there an estimation of how many people are affected by this?
Dr. Hamid: There’s some estimation and given that many of these undiagnosed diseases don’t have a label I would say this is a very rough estimate. But various studies have suggested that maybe there are about two hundred thousand individuals both adult and children in United States which have an undiagnosed or rare disease. In terms if you think about population in the United States that would be about one in seventeen hundred individuals. So while individually these problems or these undiagnosed diseases seem rare, as a combination all of these rare diseases together is quite common. One in seventeen hundred is not that common. The problem with undiagnosed disease is it’s the burden they carry on the health system, on the families, on the patient their self. And the long diagnostic odyssey with really no answers in site.
We should make mention, of course I would speak to the family about that, but obviously I would imagine the frustration on both sides, the physicians and the family. But you’ve seen it firsthand. How difficult is it for families dealing with this situation?
Dr. Hamid: It’s very difficult because they know that something is wrong and something is causing significant symptoms. Let’s say for example, if it’s a pediatric patient, a common type of symptom we see in these children are they’re delayed. They are developmentally not where they should be. So for example, a normal child would be walking at twelve months of age and these children are not. They have seizures. They have other problems with their body. Parents know that, doctors know that, but for the child there is no diagnosis. All the testing that has been done comes back negative. The parents see the child getting worse and worse and worse. So as you can imagine for a family how devastating that can be if you have a sick child like that. On the flip side we see that sort of situation many times in adults too. We have seen patients here who have been in perfect health, or they think that they’re in perfect health at twenty years of age and find out that they have gone through college, and find out by thirty years of age they cannot even hold a food bagging job at the local grocery store. So what that means is that for within a period of ten years there’s a significant deterioration of their mental status or their neurological status. That is very devastating to not only that person but their close families, if they have children their children. It’s in many ways quite devastating. And also for the physician because when these patients go and see their physicians the physicians are very frustrated because with all the high tech medicine that is available in the United States and all the fancy scans, all the fancy blood tests, they still cannot pinpoint what is wrong with the patient. And these patients undergo a million dollar workup without any answers.
When a family comes to Vanderbilt like Gia and her daughter what is kind of the process?
Dr. Hamid: The process starts even before that. A patient who feels like they don’t have a diagnosis or a physician who feels like they have a patient who doesn’t have a diagnosis, the physician will encourage their patient or a patient may take it upon themselves to actually first submit an application to the Undiagnosed Disease Network Program. They just Google the term apply UDN and they have to fill out a very simple straight forward application. Nothing very complicated; mostly its demographic information name, age, date of birth. And the physician who has seen the patient writes a little letter saying why this patient’s symptoms are unusual. And that’s all it takes. We call the central location the coordinating center. Given the patient’s preference and where they are the patient is assigned to one of the seven sites. They may have a preference, they don’t want to be evaluated at UCLA or Vanderbilt or Harvard they will let that preference be known on the application. Or if they don’t then based on their geographic location they may be assigned to one of the sites. At that time the site is notified and the site then takes over the process. We get notification that hey, somebody has applied to your site. The next step is we get all of the medical records for the patient. And for pediatric patients that can sometimes be pretty straight forward. For adult patients we have had situations where we get boxes and boxes full that are delivered by UPS. Because if the patient has had a long diagnostic odyssey and been evaluated at multiple centers the amount of records that we’re going to get are going to be huge. When that happens the next step is that we actually go through each paper of that medical record. And that process in itself can take up to two to three months. What the idea here is that we want to get a very comprehensive picture of what is going on. What has happened, what tests have been done, are there any diagnoses that were missed. These record reviews take place at our team meeting. There is a physician involved; it may be me or one of my colleagues John Phillips or John Newman and a team comprised of genetic counselors and nurse practitioners. After we review the records we get a pretty good sense whether the patient that we are seeing is the sort of patient we’ll be able to help. Once that happens then we nominate that patient to the UDN as a whole saying the Vanderbilt site would like to accept this patient. And then the process moves forward. Then the patient is notified and we then arrange for a visit for the patient to come to Vanderbilt to get the process started. Since we already have a very clear idea of what has happened before and what tests were done before, the process then is to do two main things: One, to get additional investigations, original tests or additional consultations with the subspecialist(s) that the patient may not have; and, the second side is that we actually decode the patient’s whole genome. We take blood from the patient (and family members) and we decode all of the genetic code for the patient. And then we look at the genetic code and look at all the clinical information we have. Some from the medical records and some from that visit when the patient is at Vanderbilt, and we try to put it together and try to get an idea whether the genetic information overlaid on top of the medical records and exam findings and over the patient, gives us a definitive clue as to what may be going on. One of the important things to remember here is that this evaluation is free to the patient. So the patient’s don’t get charged because that’s part of the network. Some cases we find the answer immediately. Those are the great cases and patients are very happy about it. In other cases putting the genomic information or decoded genomic information or the medical records for why just the clues point to maybe three or four potential conditions which we then have to further explore. And in some cases we try to put it together and we cannot. So that gives us a clue that this may be a disease that has never been previously described in medical literature. Proving that connection sometimes is the hardest but this network was actually designed to help us do that. The network, in addition to having the clinical sites, has advanced research sites. One is at Baylor and we call it mortal organism core, and one is at University of Oregon. And the idea for these cores is that you then try to make a connection experimentally by doing lab research. The stressful thing for the patient is that there is not going to be an immediate answer. Because we’re talking about research now because now you’re experimentally trying to identify a new disease and you’re trying to connect the genomic findings with patient’s clinical findings experimentally and prove it conclusively that there is a connection and you have now described a new disease. That can take sometimes years, sometimes two years, sometimes three years, and sometime four years. One of the key things we always remind the patients when they come and see us is that if you’re lucky and we have an answer immediately which is great because that then allows the patient’s doctor to think about treatments and how do we fix it. However, on the other cases even after your visit is over the work is going to keep on going behind the scenes. We will continue to do research on these patients and you will get clues. When you get those clues or when you get more information from us maybe sometime in the future but all that work is happening behind the scenes. That’s the whole sort of goal of this network and why this network works and is able to give patients the best possible hope. As opposed to a patient going to a state of the art medical center. Because when you go to a state of the art medical center if you have a complicated disease they may be able to figure out a known disease which is a rare presentation but they will not have the resources to figure out an unknown disease. Or a rare cause of a known disease because research on these disorders can take a lot of money and a lot of time and insurance is not going to pay for the research. Those answers we never really get. That I think is the strength of this network is the combination of clinical and research and ability for the physicians in the network to put those two pieces together without having to worry about reimbursement, insurance issues, pre-authorizations and all other things that everybody has to deal with.
It makes it so unique.
Dr. Hamid: Yeah, in some ways yeah.
Is this a tool you want other pediatricians, gynecologists, other doctors, and family doctors to have? Is this a way to sort of educate them in a sense?
Dr. Hamid: Yes. One of the key goals of the network is as we diagnose new diseases, as we identify rare presentations of known disorders is to put that information out, either on our website, our social media pages and in medical journals. We present these findings in national meetings because you are absolutely correct: the idea here is that there are not enough doctors in the United States specialized in rare disease diagnosis and management to take care of all the patients. The idea is as we find things, as we gather knowledge, is to actually send that knowledge out with a defined protocol. One of the things we always do is if we diagnose something new we want to publish it so other doctors can look at it, see how that patient presented. Why was the Undiagnosed Disease Network able to diagnose the patient? What tools did they use and is this something that I can actually implement in my hospital, my clinic? And one of the things to remember is there’s nothing except for the very high tech research element. The clinical tests and investigations that we do in most patients, the genomics decoding or genomic sequencing that we do in most patients, those are resources now that are available to pretty much every state of the art hospital. Those are not special resources as they were maybe ten years ago. The majority of the stuff that we put out and publish are the best sort of knowledge that almost any physician can benefit from. The great hope, and I think this is the vision for Dr. Gahl when he started this network was, that you advance medical knowledge and the idea is then other physicians reading that information whether as fully specialized physicians or even in training as medical students, as residents, they will then use the knowledge to provide better care to their patients. Hopefully they will be able to diagnose some of the rare diseases themselves. Those are some of the very important goals of the network.
END OF INTERVIEW
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