Search for tag: "genetic testing"

Interviewer: With the power of computers behind them, scientists are solving the mysteries of undiagnosed diseases, up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Aaron Quinlan, associate director of the USTAR Center for Genetic Discovery at the University of Utah. Dr. Quinlan, you recently had some really exciting results using technologies that your group developed. They may have helped solve a health mystery. This is about infants with a particular condition. What was going on?

Dr. Quinlan: We were studying infants with seizure disorders, and the genetic basis of those seizure disorders was unsolved.

Interviewer: So, the idea is that . . . I mean, obviously they had seizures, presumably pretty severe ones, but doctors didn't know what was causing it. So, there were about a dozen or cases, and you were able to possibly find the cause for most of them?

Dr. Quinlan: Yeah, for the majority, I guess 90% of the cases we have a pretty clear candidate that we feel strongly about, and in 9 or 10 of those cases, it's a mutation in a gene that is known to cause this phenotype but was not picked up via standard clinical diagnostic tests, and in a handful of other cases, we think we have discovered new genes that underlie this phenotype.

From a clinical perspective, there's a transition, certainly removing very rapidly from gene panel tests, where we only look at a very, very small subset of the genome to interrogate genes that we know cause a given disease phenotype to, I think, in the coming years, it will be a standard course of care to use exome or genome sequencing to do this diagnosis because it's so effective, and I think the clinicians that we were working with were very excited about the accuracy and the rapidity with which we could make these predictions.

Interviewer: The role of you and your group in this is that you've developed a computational tool called Gemini, and that's what led to these results. What is Gemini?

Dr. Quinlan: So, we used genome sequencing of both the infant and their parents to try and identify genetic mutations, essentially, that cause the disease phenotype in question, and this process requires a broad spectrum of computational methods, everything from rapidly and accurately processing the sequencing data to identifying genetic variants that exist in these families, and then finally to essentially get back to a needle in the haystack problem of what is the single genetic mutation that causes the phenotype and isolate that from the potentially millions of genetic variants that are benign but exist in these infant genomes.

So, the idea is that Gemini takes all the genetic variation that's observed in the genomes or exomes of all the individuals that you're studying, and it integrates all that genetic variation information with the extreme wealth of genome annotations and reference databases that we have. For instance, some people might be familiar with OMIM. It's a list of all the known mutations or genetic variants and genes that are associated with diseases.

Interviewer: Right, so keeping up with the pace of research, the pace of knowledge.

Dr. Quinlan: Right. It's an incredibly demanding problem because there's probably 50 to 60 reference databases that we try to use, and they're all evolving. They all have mistakes. Those mistakes are fixed, and you've gotta propagate those fixes to the mistakes as quickly as possible so that . . . what we're trying to do here is empower discovery for human genetics, and so, having the latest and greatest information, obviously, empowers that process.

Interviewer: So, is there somebody who's monitoring each of those databases and saying, "Oh, gotta update, gotta update, gotta update"?

Dr. Quinlan: Yeah, we have people in the lab who monitor that, but, believe me, the research community that uses this software, they monitor it as well.

Interviewer: And so, the real tricky part is that a lot of us have scads, you can give me the numbers, you know, scads of variations in our genome, and so that the problem is finding the one or ones that increase risk for a certain disease.

Dr. Quinlan: That's right. I mean, any two individuals differ by about 3,000,000 to 4,000,000 genetic variants. So, when you look at a family, do a whole genome sequencing of an entire family, you're going to find on the order of 3,000,000 to 10,000,000 genetic variants that you have to sift through. Now, many of those, admittedly, are very simple to ignore, especially for rare disease phenotypes. We typically focus on genetic variants that affect protein coating genes. But even when you do that, you're talking about on the order of 18,000 to 20,000 genetic variants that need to be considered, and so, we need to be able to do that in a quick and reproducible way, and we want to minimize false predictions, but I think even more concerning are real genetic variants that may be associated with the phenotype that you miss. So, we want to essentially find everything but don't over-predict.

Interviewer: I imagine you spend a good part of your day in front of a computer screen. I'm wondering do you think about how this sequence of letters you have in front of you is actually a real person.

Dr. Quinlan: Yeah. Admittedly, I am fairly disconnected. I'm a genetic researcher that spends 12 to 15 hours a day in front of a computer, and I'm not a clinician, so, I don't interact with patients on a day-to-day basis. However, I mean, that is our motivation here, is, you know, that was the main reason I moved my lab from the University of Virginia to the University of Utah was to have that connection.

We have a very nice interaction between researchers and clinicians here at the U, and I think it really helps to bring home the reality of these cases. We meet with the doctors who actually work with these patients, and when you understand their plight both in terms of the diagnostic odyssey and also the impact on these families, both in the short and long term, it makes it very real.

I would like to be able to provide a resource to try and solve rare disorders in Utah, nationally, and not only retrospectively for families that are sort of pursuing this diagnostic odyssey, but also to have a system where this can be done in real time in collaboration with clinicians in our hospital and other hospitals so that when there's an infant that comes through the NICU or there's some pediatric genetic disorder that is perplexing, we have a system in place where we can sequence the genomes and actually bring our tools to bear on solving that problem quickly and as accurately as possible.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.

Interviewer: Managing medications through genetic testing, up next on The Scope.

Announcer: Examining the latest research, and telling you about the latest breakthroughs, The Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Diana Brixner, Professor of Pharmacotherapy and Director of the Outcomes Research Center, and Director of Outcomes for the Programs and Personalized Health at the University of Utah. I wanted to talk today about a study that you led recently looking at the elderly who, amazingly, on average take at least 14 prescribed drugs each year. What are some of the concerns about that?

Dr. Brixner: All of us have different variants of drug metabolizing enzymes, and this will have an impact on how many drugs are, in fact, metabolized. So as you can imagine, in individuals where you are not aware of what the drug metabolizing enzymes can do, you may likely under-dose or overdose an individual. It could lead to adverse drug events. It could also lead to increased drug interactions where two drugs may be overactive where you did not anticipate that.
With the elderly, they do, in fact, take many more drugs, and because they're on more drugs, then the risk of drug-drug interactions or drug-gene interactions between the drugs that are on is much higher. And therefore, using a test to determine their variants in drug metabolizing enzymes can be very valuable.

Interviewer: So what kind of test did you perform on them? I mean, it was more than just a test.

Dr. Brixner: Yes, and that's what makes this product really very interesting. It's a combination of the test, which is done via a buccal swab, and then the gene analysis is done in a certified laboratory. But the results of that test then are run through a clinical decision support tool, and the combination of the test and the support tool is called YouScript, produced by Genelex Corporation in Seattle.
And what the clinical decision support tool does is it takes in account not only the drugs susceptible to these enzymes, but in fact, all the drugs the patient is on. And therefore you get a very complete picture of drug-drug interactions, drug-gene interactions and drug-drug-gene interactions. Let me give you an example, if a patient is on a drug that has an interaction, and then has a drug metabolizing enzyme that affects another drug, it's very likely that that could lead to a drug-drug interaction you would not have ordinarily expected without knowing the genetic information from the patient.

Interviewer: And so, by taking together the results of the test with the results of this clinical support tool, you can modify somebody's drug regimen based on what you think will be least likely to have adverse reactions for that patient?

Dr. Brixner: Yes, that is ultimately the idea, and that, again, comes back to the idea of the clinical pharmacist, and the role that the clinical pharmacist can play in actually interpreting the results of the clinical decisions support tool with the provider and the patient, to then make the appropriate modifications in their therapy regimens so that the patient gets the best benefit with the least exposure to adverse events.

Interviewer: So you got some really striking results from this study.

Dr. Brixner: What we found was that, in the group that was tested, there were significantly lower emergency department visits and hospitalizations than in the group that was matched and not tested. What's interesting is that we also saw actually an increase of outpatient visits in the patients that were tested, which was counterintuitive at the outset. However, when you think about it, in fact, these results make a lot of sense. If patients are tested upfront, it's likely that patients would come in to the provider and have additional outpatient visits then, not only to review the results, but make any appropriate changes to their therapeutic regimens.

Interviewer: And the decrease in hospitalizations and emergency department visits that you saw actually took place over a pretty short follow-up period, right?

Dr. Brixner: Yeah, that's a very interesting point to bring up. Our study looked at a four-month follow-up. And, in fact, we are now currently looking at extended data out to nine months, and we would anticipate that the impact of the savings would be even greater at nine months out to a year, granted there is a point where there are no additional savings. But the other interesting point is that you only need to be tested once, and this information then can be put into the elderly patients file, and then as they bring on new drugs, or change drugs going forward through the rest of their life, this information can be used to guide appropriate treatment.

Interviewer: And you talked about savings. You mean costs savings?

Dr. Brixner: The savings was, in fact, there is the cost of the test and the clinical decisions support, but there is also then cost savings by the emergency department visits and hospitalizations avoided. So what we did using some national costing data is demonstrate that, in fact, the majority of the cost of the test is offset by the savings and fewer emergency department visits and hospitalizations.

Interviewer: So this is a test that, at this point, probably is not covered by most insurance policies, or at least by Medicare, who most of these patients would be with.

Dr. Brixner: And that was exactly why we set out to do this study in the first place. It is a very dynamic environment right now with when looking at how data should be considered for making reimbursement decisions around diagnostic tests. And that includes the test that we're talking about today, preemptive pharmacogenetic testing, as well as the gene testing for targeting drug therapy. It's a different process to look at reimbursement for diagnostic test than it is for drugs. And Medicare and other insurance companies are struggling with how this evidence should be evaluated.
Our hope was to generate enough evidence that would look potentially favorably at the inclusion of this type of a test and clinic decision support tool in managing elderly patients on several drugs or polypharmacy, that we would then go ahead and validate our findings in a larger prospective randomized trial design. It's exactly that type of study that we're working on now, based on our preliminary results to demonstrate the validity of our results in a unified population within one health care system.

Interviewer: What's your hope for where this type of work is going?

Dr. Brixner: Well, that's great question. What I would love to see is that when we do the validation study that we see trends along the same line as what we saw with our preliminary results. I then think it would really be worth considering that when the elderly come in for their annual well visit, as they enter into the Medicare health system, that they should, in fact, have this test done once, so that it's in their file to guide their future treatment regimens. To me this would be a great step forward in improving care for the elderly, and greater involving clinical pharmacists in the role of medication management.

Announcer: Interesting, informative, and all the name of better health. This is The Scope Health Sciences Radio.