Pursuing Elusive Diagnoses for Rare Diseases

Undiagnosed Diseases Program

Laura A. Stokowski, RN, MS; William A. Gahl, MD, PhD


February 26, 2015

Editorial Collaboration

Medscape &

Medscape: The UDP is undergoing an extension. What led to the decision to extend the program, and what does that mean for patients? Will this primarily increase capacity? Will the centers differ in the types of patients who are evaluated, or will patients be accepted to centers purely on a geographical basis?

Dr Gahl: Extension of the UDP occurred in large part because the NIH as a whole wanted to expand the model of the UDP to other academic medical centers for the benefit of more patients. As a consequence, the NIH Common Fund, in the Office of the NIH Director, took on this project, and we were asked to do two things: (1) extend the UDP to other centers; and (2) try to do some teaching of the analysis of exomes or genomes for rare disease diagnostics. That's how the network was born, and it has provided funding for at least 5 years.

There are six new clinical sites, with a coordinating center at Harvard Medical School. There are also two sequencing centers. Now all of those are funded, and there will be some functional study groups for metabolomics and animal models as well. The new centers are enthusiastic because it's a mark of some prestige, and it will bring patients to them, but it is really about research and discovery for their investigators.

The patients will all be registered and apply through a gateway at the coordinating center. They will be distributed to the geographically closest location of the clinical sites. That site will look at and make a decision about whether to accept the patient. Some sites might have expertise in a particular area, so it is possible that a patient might be shunted to that site rather than the center closest to the patient's home, but for the most part, the patient will go to the nearest clinical center for evaluation. Sometimes a patient might already have been evaluated at that center, so it makes sense for that patient to go elsewhere.

Medscape: Will the Clinical Center at NIH be part of the same pool of centers, once the other six centers begin to take patients? Will the opening of the new centers increase a patient's chances of being accepted into the UDP?

Dr Gahl: The current Clinical Center will continue as one of the sites, but we have a requirement to see more patients than other sites. The other six centers are each required to see 10 patients this year (2014-2015), 25 the next, and then 50 patients annually for subsequent years. We are required to see 120-150 patients each year. We see about 150 patients a year. When the expanded network is up and running, the other sites will see 300 patients in total every year. So, altogether, patients will have three times the chance of being accepted as they do now.

Medscape: Do you ever reconsider patients for acceptance if you didn't accept them into the UDP the first time they applied?

Dr Gahl: Yes, but it has not happened very often. A small subset of individuals—perhaps 5% of applicants accepted—have received a letter saying that we would reconsider their application at a later time. What happens more often is that people reapply a second or third time without our telling them that they should. Sometimes there will be a change in the patient's medical condition or some clue that we can go after at a later time, and that's fine. But for the most part, the reapplicants are patients who never had too much objectively wrong with them and just keep saying, "Will you reconsider me?"

Medscape: Do you find that the community practitioners who send patients to the Clinical Center are happy and relieved to have a second opinion, or skeptical that any stone has been left unturned in seeking a diagnosis for their patient?

Dr Gahl: They are happy. Almost universally, they are anxious to have us take a look. Occasionally, physicians will mention that their patients asked them to write to us. These physicians are not reluctant to refer because they don't want anyone else to see their patients, but because they have already given the patients diagnoses that the patients haven't accepted. Physicians have been very pleased to have us offer another opinion, get some tests done that they perhaps can't get done for insurance reasons, or sometimes just to be able to say that the NIH couldn't find out the diagnosis either. Overall, they have been very accepting of the UDP.

There is another element to this. Approximately 20% of the time, when we send back a rejection letter, we will say, "You might consider this." I used to think that physicians would be annoyed at that—that they wouldn't want advice from someone who had never seen their patient, whom they have followed for years. But I haven't received a single note or letter back saying, "Who do you think you are?" The physicians have been very appreciative.

One thing to consider is the fact that these patients have been occupying the waiting rooms of doctors for years, and as physicians, we want to help our patients. If you don't have a diagnosis, you are in a very awkward position.


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