 Chris Conraddy, also going to be a senior resident of ours, and he will be talking on assessing the role of genetic risk factors in lifestyle changes. Okay, thank you Dr. Orozco. So today I'm going to be talking about a project I've been working with Dr. Bernstein on. It'll be, it's a pilot study that I'm going to show you, but you'll see that as we kind of go. And basically we're asking if we can cause some lifestyle changes using genetic testing. I have no financial disclosures to declare. However, Dr. Bernstein and Dr. Gellerman in the University of Utah do own a patent on the Resonance Rheumatist Spectroscopy, which we'll talk about here in a second. So I do need to declare that. And so the project is based on age-related macular degeneration. We all know that it's a degenerative disorder of immaculate with known genetic and hereditary risk factors. Basically with these single nucleotide polymorphisms, otherwise known as SNPs. We also know from groups around the country and based here as well that AREDS2 was a randomized control trial that showed that PO supplementation reduced progression of AMD to the advanced form. There are some other kind of larger parts of that study, but that's at least one point of that that's key to what I'll discuss here. Then we also know from subsequent studies that patients with diets high in zeaxanthine and lutein have a reduced risk of developing AMD. And those are just two of the macular carotenoids. We also know that patients with lower serum carotenoid concentrations, so kind of on the other spectrum of that, are at an increased risk of developing AMD. We also know that from a lot of Dr. Bernstein's work and others that most of the carotenoids come from plant-based foods, specifically things like kale or orange fruits and vegetables. Resonance run spectroscopy is a way of measuring skin carotenoids. You basically put your palm on the scanner, takes longer to turn on and turn off than it does to actually make the measurements. And you basically get what has been correlated and nicely associated with actual skin biopsy results. So it's a very valid measurement. And we know that from a paper that Dr. Bernstein and I currently have under revision and then also some of his other subsequent work, that these skin measurements seem to correlate with serum concentrations of carotenoids, as well as what we're showing in this paper we have under revision with macular pigment carotenoid concentrations. We also know that skin carotenoid concentrations seem to be a biomarker for fruit and vegetable intake. So no surprise there that the more fruits and vegetables you take in your diet, the higher skin carotenoid concentrations you have. If we then look at just a patient in repeat measurements of their skin carotenoid concentrations over time with no sort of intervention, fairly stable. This is over basically almost six months with repeat measurements four times same individual. Then if we kind of shift gears and talk about kind of the crux of this project, the more controversial aspect in medicine, not just this project, but genetic testing. So what is the role of genetic testing in medicine and in the future of medicine? So we know at least from just simple blood draws that there's really little physical risk from the actual blood draw. Groups have hypothesized that if we can identify patients, pre-symptomatic patients, we can maybe increase surveillance of those individuals with higher risks. We can maybe tailor preventative treatments to those individuals. We can target resources to those patients at risk based off of their genetic results. However, that comes with the caveat that there has been some major concern raised with genetic testing. We're all fairly familiar with them. The first, probably foremost, is the emotional toll. So you can have survival guilt. So one family member in the family that doesn't have the gene or the genetic risk factor can get pressure from the family or even just have the survival guilt. It obviously comes with anxiety or depression, or at least people have proposed that. Then probably the biggest concern just in overall medicine is the discrimination that can come from that in the workplace, mainly associated with health insurance or the ability to get health insurance. So what do we know about genetic testing in AMD? So most of the things we know now, so we know specific genes, SNPs. As I've already kind of mentioned, but most of the data in targeted therapy comes from post hoc analyses. It's been from two different groups and they have shown completely separate and very different results almost from the same patient profiles. They've used the same patients and done analyses and basically shown some groups respond better with specific gene profiles to AREDs or antioxidants while the other group has shown that they behave exactly the same. So at the end of the day, we really have no good information, at least from using genetic profiles to target therapy in AMP. If we look at other chronic diseases, and this kind of puts a little bit of a cloud on the anxiety portion of genetic testing. Back in 2009, a large study was performed looking at basically looking at Alzheimer's patients, genetically testing them and telling them of their risk, and it didn't seem to induce any sort of additional anxiety knowing that you are at risk of developing Alzheimer's versus the patient that was told that their genetic profile did not predispose them to that. So walking into the study, we basically asked, could genetic testing improve patient carotenoid intake? And maybe the kind of larger question that wouldn't necessarily be answered by this study, but maybe subsequent studies, would be, could this alter the course of the disease with pre-symptomatic treatment? So this is, like I said, a pilot study, and so we basically walked into this, taking 16 patients, and I'll kind of describe to you the study itself as we go, that were tested by Dr. Hageman's lab, and then risk stratified into low, medium, or high risk for developing A and D based on their SNP profile. The groups were then subdivided into early and late disclosures, so a group found out as soon as their genetic results were available what their risk factor was, and then there is the late disclosure portion of the group that still does not know their genetic risk at this point. So within four to six weeks they're told of their genetic results in that early group. Then both groups met with a genetic counselor basically discussing healthy diet, cessation of smoking, ARED supplementation, or at least taking in more fruits and vegetables into diets to decrease developing AMD or even progression of AMD. We then did baseline measurements at, baseline eight weeks, six months, and we're still waiting on the one-year measurements, but basically the skin carotenoid concentrations is a surrogate marker of carotenoid intake. All the patients in this study were ages 20 to 59, and the SNP profiles have all been validated in Caucasians, so all the patients are Caucasian, and then you see in the bottom of this kind of the just general outline that I've kind of already discussed. The actual demographics of the patients included in this study, 15 of them were female, one was male. Like I said, they were all Caucasian and all of the family history of AMD. Seven were low risk from genetic testing. Four moderate risk and five high risk. And then if we look at their skin carotenoid concentrations over time, so the high, moderate, and low risk, those are all early disclosure. And then it's kind of a grab bag in the late disclosure of low, moderate, and high risk patients in the late disclosure that still did not know their genetic results. We can see some interesting trends, at least from this small study. So if we look at the high risk or moderate risk, you can see most patients actually had an increase, or at least half the patients in the high risk, most of the patients in the moderate risk had an increased carotenoid concentration. Like I said, with that previous graph that I showed you, these remain fairly stable without any sort of intervention. In the low risk group, half of them obviously changed their diet or did something additionally to increase their carotenoid concentrations. That's in kind of comparison to the late disclosure group, of which none of them have obviously changed anything lifestyle-wise or carotenoid consumption-wise. So while this is a pilot study, and I realized that, this would suggest that we need to further pursue this. So, at least from what we're seeing, the higher genetic risk factors, profiles, and patients knowing that seem to make these patients more amenable to altering their lifestyles in positive ways. And while this is only a pilot study, we are currently in the process of submitting a much larger grant by this further to the VA, in which we're going to enroll two to 300 patients over an 18-month time period and follow them for a year, just like we have previously. What we've also learned from this pilot study is that we also know that that eight-week time point that I plotted previously doesn't seem to be the most beneficial because most patients may not even have their genetic profile known at that point, just from the genetic testing. And then we're also going to add in measuring macular pigment with a spectralis, and I didn't talk anything about that. I just mentioned that our value chart very early on, but we also know that we can measure macular carotenoid concentrations very well with a spectralis. And so I need to make some acknowledgments and thank several people, so obviously there have been several labs involved in this, Dr. Hageman's lab, Dr. Gellerman's lab, and then, of course, Dr. Bernstein and his lab. Then the clinical studies department, specifically Kellyan and the rest of the clinical studies staff, and then, of course, funding kind of makes the research world go round. Then if you care to look at citations later, here's some interesting things. Of course, the non-ophthalmology literature of this reveal study with Alzheimer's disease is actually, I think, maybe the next step in medicine, but we'll see what genetic testing ends up becoming in the future. Then to kind of shift gears to a QI project that I've been working on was Dr. Feist and Dr. Ferguson. There's been, unfortunately, I don't know if this is a trend or maybe this has been much longer than just my residency here, but it seems like as a resident here, there's been kind of a gradual decline in paging practices. What do I mean by that? We don't have enough information to actually either identify the patient that we're being consulted on, or even identifying the team to get a hold of to identify the patient. For example, we'll get a four-digit number, that's the only thing that we get in the page that literally is a non-working number, so we have no information, possibly compromising eye care from our standpoint. So a fairly big deal when it comes to eye care, presumably. So our kind of solution to that was to kind of take a step back and figure out ways that we could force other services to give us the information that we needed to, I guess, perform consults in a timely fashion. And so we've gone in and had them create a smart web template, and I'll show you that here in a second, where you have to fill in specific information, patient name, MRN, and a specific question, and a 10-digit callback number so we can get a hold of the team and know the patient for each consult before the page will go through. Unfortunately, bureaucracy is a bad thing, as we've already heard. So this has been readily adopted at the U. However, Primary Children's has been giving quite a bit of pushback in regards to adopting this, and I'm not quite for sure why, but it seems to have improved at least my experience on call, and I think several other residents would agree as well. And so this is what the current template looks like now. It used to be a single box that you could basically free text anything you wanted into, and now it's multiple parts, and you can still go around this. I don't think smart web, if you're smart enough, you can just put in a single letter, and that's enough. So it's not quite the solution, but it's better, and I think we're seeing some improvement with that. So with that, any questions? Yes. Students that were identified early at the eight-week point were being at risk, and they were told to increase their prognoi intake. Right, and change their lifestyle, yes. Were they, was that quantified in any way, whether by food or by supplement, or how much, they were to increase it? No, so there was, basically they were giving general information on age-related macular degeneration and what's known in the literature. So not in a quantifiable, you know, there's A-REDS vitamins, there, you know, if you smoke, it should stop smoking, it shouldn't pick up smoking, it's a midlife crisis, you know, things along those lines. So it wasn't quantifiable, it was just kind of a blanket statement with the genetic counselor. Yes, Dr. Olson. So it's interesting, as we look at the genetic risk profile, and there are not patients in the study now to look at subgroups, but there are about 30 patients who are homozygous risk at one in 10. Right. So both HR1 and chromosome factor, or component factor agent, and of those that have reached 70, all of them have been legally blinded both by themselves. So I mean, some of these genetic profiles are just absolutely blind. Right. And then we have protective groups who, you know, in some populations, they're just never going to get it. So this is a big deal, and the controversy about whether knowing this is important or not is interesting. Clearly, there has to be a difference in what's happening. I just think no one has been able to look at it real carefully as far as our nature side, the nurture side of this, our lifestyles and the rest. And so clearly it's a subject, but it's going to be important. Right. And when we get to gene therapy and targeted therapy, we're going to be testing all of our patients for this and then striving to likely do a gene therapy to prevent the problem down the road. That's what I see. Yeah. And I think we all assume theoretical risks of anxiety, depression, survivor guilt. They haven't been well studied. We've all just hypothesized that these are risks. You know, so is it really a risk worth prohibiting the avenue of genetic testing? I think that's going to be the biggest question in probably the next five to ten years of medicine. No question. This is a very emotional thing. I mean, I've had patients break down in tears, obviously, young and seeing their parents or grandparents suffer. So doing your genetic risk is really quite bad. So, you know, I mean, no question. There's a certain, but long term is this better and you make a difference. And that's important work to do. Right. Have you shown studies where people have had that diet of high protein whites and still have a high chance of getting AMT even though they haven't? Yeah. So there's the genetic risks. So those two authors that I showed you earlier that have basically shown two totally different kind of results, even with the same patients. They've both analyzed the data in different ways. So the question, people think have been answered, but I think it's much more debatable in the literature than to say, yes, it decreases risk. The AREDS II trial has shown, yes, it decreases progression, but patients still progressed. So it wasn't every patient responded as well. So I think there's a genetic component that we don't understand. The question you ask is, if you're at risk but normal, if you have the appropriate lifestyle, can you change that risk over time? That study has never been done. Yeah. It's not been done. And theoretically, probably, I mean, as you look at populations who have these good habits, you can see there's a difference in regards to, you know, the incidence of macrogenetic advance. So the answer is probably, but believe it or not, that particular study has never been done. Yeah. So there's a few big studies that have never been done to answer some of those questions. Dang it. There's no answer to that at this point. This would presume, I mean, this would have to be a 50-year study where we followed patients for 50 years to see, that was kind of the sub-question that I asked with our initial question. So I think the only way to do that is to do this study but prolong it to 50, 60, 70 years when patients would be developing AMD to see if that alters development or even progression of AMD. I'm going to give you my scientific answer to that because I get that asked that all the time. There is no downside to having the good lifestyle that we're talking about. This is a diet rich and particularly cruciferous vegetables that have been shown to be good in a whole host of ways. Lots of fruits and vegetables, whole nuts, fish. I mean, that's a good diet. So there's no downside to be doing it anyway and then exercise has also been shown to be important. The one thing that I recommend probably not is the ARIDS, it's very high in zinc and there are studies that show that high zinc levels decrease your high-density low blood pressure, your protective cholesterol. So probably not ARIDS unless you actually have change but all of the rest. I say there's no study to prove it but if this were me in that situation, I'd do it and frankly I'm doing it anyway even though I don't think I have unusual risk. So I recommend and if you look at the epidemiological studies of large groups and what happens and this would be over a period of time, those who've had those habits tend to be doing better. That's the best evidence we're going to have until somebody really does at least a 20 to a 30-year study of 50 likely to be able to answer that question. So I'd say absolutely but I would not recommend the ARIDS until we know more about long-term high zinc and its impact on high-density live protein. That does come with one caveat. There has been a lutein crystalopathy patient that Dr. Bernstein has seen. So you can take enough lutein that you actually get crystals. I think you can take that in diet. Yeah, she was on lutein supplementation plus taking basically a shake of kale, strawberries and oranges every single morning. So you can take too much. There's so little that's done from a long-term perspective on overall incidence of the disease. Remember, when Greg Hageman submitted his first grant, the head of the National Institute called him up on the phone and said we are never going to fund a grant on macular degeneration because everybody knows this is just light exposure and age and that nobody will ever do anything about this disease so you're wasting your time. That wasn't that long ago. That's kind of the mindset that we had back when I was a resident. So you didn't want to give a diagnosis if they're doing all right. What do you want to know? So we're really getting incidents and things now but the genetic risk and lifestyle, the genetics are overwhelming if you're at super high risk and then your lifestyle becomes more important than some of the intermediate and then you've got the protective and if you're protective you can smoke three packs a day and eat horribly and you're never going to get it. So you've got to remember that interplay. Interplay of all of this and that almost anything that has lifestyle as a negative impact on our future we're not doing very well. You know what they call the American diet? The standard American diet. The sad diet.