 Welcome, everyone, to the first event of our Healthcare Provider Genomics Education Week. My name is Donna Messersmith. I'm one of the co-chairs of the Inter-Society Coordinating Committee for Practitioner Education in Genomics, or ISCCPEG. NHGRI is proud to host ISCCPEG as well as this upcoming week. ISCCPEG, as you can see on our slides, is made up of over 250 members. We're open to individuals, organizations, and industry interested in healthcare provider genomics education. Membership is free, and we support different project groups that have a specific need, as we will see later in this webinar today. The project groups identify specific educational needs and solutions, they share best practices, and they develop educational resources. One of NHGRI's roles is to facilitate the dissemination of products from those project groups. As one of our most recent examples, the Direct-to-Consumer Genetic Testing Project Group, which is led by our co-chairs, Dr. Tracy Weiler and Dr. Haria Ayubia, who we will hear from in a few minutes, have created a new resource that's posted on genome.gov. And this is the Direct-to-Consumer Genetic Testing FAQ for healthcare professionals. You can access it here through this link, as well as through the QR code. So for more information about ISCCPEG, please feel free to visit our link to the web page for ISCCPEG. And I want to also point out that this webinar will be recorded for future use, and you can listen to it later, and your questions can be posted into the Q&A on the webinar. Okay, next slide, please. So just a brief overview, our Healthcare Professionals Genomics Education Week. This is our second year, and we will have events throughout this week, June 6th through the 10th. Our events include panel discussions, webinars, Twitter chats, and Q&As. When I last checked this website, we had over 10 different events, and we encourage you to check out the events and register and participate. Importantly, we have additional information coming through the hashtag MenGeneEd22. So keep an eye out for events and activities through your Twitter feed. The themes for each day are listed here. As you know, today is Direct to Consumer Genetic Testing, Tomorrow Pharmacogenomics, Wednesday Inclusive Genetics, Thursday Cancer Genomics, and OBGYN, and on Friday the 10th, rare diseases. You can see more information from this flyer. So please enjoy the upcoming panel discussion, and we can move on to our next slide. Thank you. Good morning all. We will be discussing Direct to Consumer Genetic Testing case studies. My name is Haria Ayubiay, I'm a clinical geneticist and an assistant professor at Texas Tech University Health Sciences Center in El Paso. Next slide. We have an amazing panel for you today, and I will ask the panel members to introduce themselves before every case. So next slide. We have no conflicts to disclose today. Next slide. So as a reminder, we actually, this project group had a seminar, a little webinar about Direct to Consumer Genetic Testing for Healthcare Professionals in 2021, where we ironed out the different details about Direct to Consumer Genetic Testing. To re-familiarize yourself with those details, please watch the YouTube video. The link is here on the slide, and we are happy to answer any questions that you may have in the Q&A. Next slide. So Nguyen is going to be taking over. Hi, my name is Nguyen Park, and I'm a PA. I'm also an NIH ACMG Genomic Medicine Program Management Fellow and the president and founder of the Society of PAs in Genetics and Genomics. So today we're going to be looking at Direct to Consumer Genetic Testing in greater depth. And we'll start off with the definition, which is a genetic test that can be completed without involving a healthcare provider. Next slide, please. So there are many different genetic testing models, and we can divide them according to three separate categories. One who orders the test, two how is consent obtained, and then three how are the results disclosed. So in direct to consumer testing, there's not a healthcare professional involved that's ordered as it states in the name by the consumer. And the consent is obtained by the written information directed to the consumer. And results go directly to the consumer. There's also provider-mediated genetic testing in which the consumer initiates it, but there is some healthcare professional involvement, and that may differ depending on the company. The consent may be obtained with or without the healthcare professional, and the results can go directly to the consumer, and they can have optional access to healthcare professionals. In clinic-based genetic testing, which is the type that most clinicians are most aware of, it's usually ordered by a healthcare professional, and the consent is thus obtained by that healthcare professional, and the results are discussed with the patient by the healthcare professional themselves. Next slide, please. In our webinar, however, we'll be focusing directly on the direct to consumer genetic testing, and the case studies will allow us to get some really great in-depth information about that. Next slide, please. So there are obviously benefits and limitations for direct to consumer testing. Obviously, we like in genetics, we like that there's more awareness about genetics. Direct to consumer testing can be much less expensive since insurance or medical systems aren't involved. People find their results frequently entertaining, or they may find that it empowers them. If they're able to look at their ancestry or look at some aspects of their health, they can also find out information about paternity, look at things like sports and fitness and nutrition, and certain benign genetic traits. However, we know that there are limitations to this, and a lot of caveats. So they're looking frequently at segments that are analyzed, and it's very targeted so you don't get full sequencing. The results then can be misleading, and because there's not a healthcare provider directly involved, you can end up having patients who have a lot of questions and concerns, and then this can cause even a potential burden to the healthcare system. Most of the time, we need clinical confirmation. And with direct to consumer testing, because it's through a company, there's not necessarily understanding about privacy and the use of that data. And again, a lot of times patients don't understand because they have either limited or no informed consent that goes into ordering the test. So, Huan, we'll be presenting the next segment. Next slide, please. All right. Good morning, everybody. My name is Huan Lee. I use she, her pronouns, and I'm a genetic counselor and assistant professor at the University of Minnesota's Genetic Counseling Program. So we'll be doing, I'm starting my video here, sorry about that. And so we're just going to be going on to the cases next. Next slide, please. So the first case about direct to consumer testing we have is DTC in the clinic. So we have a 28-year-old patient. She uses she, her pronouns, and she's establishing care in your clinic. And she discloses she's adopted and has no known biological family history. And she also relates, she took DTC, and she mentions that her results were negative for BRCA1 and BRCA2. And so these are, have a lot of different components here, and we think about, like, what are the different issues that we should be thinking about? Next slide, please. So a few things. So first, we really want to elicit the reason why the patient is doing the direct to consumer testing and any underlying concerns. So for adoptees, many adoptees who have no biological family health history, this direct to consumer testing is the only link that they have to their genetic ancestry and family medical history. So it can be very meaningful and important to them, maybe different from people who have a bio-advantage and actually know their family history. So one of the things we want to talk about is that, you know, she had a negative result. And so we also know that negative results with DTC, it's not comprehensive, it may be a false negative. Now, let's say she had come to you and said, I have a positive result. And so we really want to say, OK, let's make sure we can actually confirm and detect and make sure this is actually a real pathogenic variant. We might need additional testing to confirm or refute the results. And then we have to also recognize that some of this testing may not be covered by health insurance. Or it might be so it's really great to kind of go to a genetic health professional like a genetic counselor, geneticist, et cetera. One of the other things is that, you know, with genetic testing and adoptees is it can bring up a lot of loss, it can bring up frustration grief about not having that biological link. So that's another the psychosocial element that's really important to consider when adoptees or people without family health history come to see you with these results. Any other kind of comments that you might want to be considering? I want I have something to think about. My name is Rachel Mills. I'm a genetic counselor and assistant professor with the UNC Greensboro genetic counseling training program. And I teach my students about direct to consumer genetic testing. And during that class, one of the counseling strategies that we talk about is the importance of not dismissing patients whenever they present with DTC results as health care professionals, you know, we know that the DTC BRCA results are usually limited to just a handful of variants and they're not clinically valid. So it might be, you know, we might feel like we just want to be dismissive and like, oh, you don't need to worry about that. It's just direct to consumer testing. But you don't ever want to be dismissive in that way, especially as this case includes for adopted patients. They may have no other way to know about their family history. So it's really important to approach these cases with empathy and openness and follow, you know, the first recommendation that he won provided here of figuring out the reason for pursuing testing and making sure that you're being responsive to that. Absolutely. Thank you, Rachel. I would like to add this is for you at UBA. You know, I I agree with both of those excellent points is that, you know, because because this person is concerned about their risk for breast cancer and we know that there are many other genetic changes in our information that can cause breast cancer in addition to BRCA 1 and 2. So discussing this person's concern with a genetic counselor directly would be useful so that they could potentially pursue clinical genetic testing. Now, from a clinical geneticist's perspective, being adopted is not necessarily an indication to see a clinical geneticist, but they could definitely benefit from talking to a genetic counselor and seeing what their options are so that they do get comprehensive testing and not just a snapshot that might give them incomplete information. That's an excellent point. And many of the adoptees that I've seen are people with limited family history or those who have been donor conceived. We often want to do a broader panel just because we don't have that bio advantage. We don't know the biological family health history. So excellent points. Thank you so much for that discussion. We'll be going on to our next case, please. Next slide, please. All right. So this is Harie Yubi again. So we have a 50 year old man using the pronouns he and admitted to the hospital for acute exacerbation of heart failure. He has limited family history and no other chronic artery disease and that risk factors you perform an EKG and echocardiogram. And there is a pseudo infarction pattern and there is a preserved systolic function with left ventricular hypertrophy. The patient's daughter mentions that he had dark consumer genetic testing showing that he has a genetic condition that could damage his heart. His report says that he has hereditary amyrolydosis to TTR related with two variants detected. So in this scenario, we have a patient in the hospital with dark consumer genetic test results that are potentially related to his presentation. Millions of people have have undergone genetic testing and there are 30 plus million individuals who get hospitalized every year. Invariably, if you ask a hospitalized patient, they might have had dark consumer genetic testing. Most of the time, the results may not be related to the reason for hospitalization and they may not be relevant to the hospitalization. There is the, you know, the acuity of being hospitalized limits the health care professionals time and ability to ask about dark consumer genetic test results like here in this circumstance, I want to show that typically the results might be shared by the patient or their family member and you do not want to disregard them. Not all hospitals have direct access to geneticists or genetic counselors to discuss this with and to confirm the clinical genetic testing. So what I would do and I was a hospitalist in the previous lifetime, I would look up the dark consumer genetic test report, see where it was performed, was it performed at a clear certified lab? Is this a report that I can trust? And if it is, I'm going to look up this information and see if this is relevant or not. And it turns out that this could be that hereditary amyloidosis could present as heart failure without other coronary artery diseases factor in younger individuals. And at that point, I would see that the way to evaluate this would be ordinary cardiac MRI, which confirms the suspicion for amyloidosis. And there are other clinical testing that could be pursued. Next slide. So for an individual who is presenting with a positive or a variant detected for a dark consumer genetic test result that is associated with a genetic health condition, you would want to evaluate the patient for those signs and symptoms if if they are relevant to what they are presenting with. You would ideally want to order confirmatory clinical genetic testing. That may not be possible acutely during a hospitalization, but that's where after the hospitalization, you would want to refer them out to a clinical geneticist or genetic counseling so that they can proceed with this testing. In the meantime, while hospitalized, you can proceed with other clinical evaluations that are relevant to confirm or refute the result. And another test result that would be of interest and would be of concern and value in somebody who's hospitalized are for macogenomic variants. And that's when Christine Formea from D would take over. But I'll open this to to the general discussion. Any comments from the from our panel members? Doesn't look like it. So let's move on. Christine, would you like to take over next slide? That's great. Thank you so much, Rhea. Wonderful. So we're going to move on into DTC testing for pharmacogenomics results. And I'm Christine Formea. I am a clinical pharmacogenomics pharmacist and associate professor at Intermountain Health Care. And that's located in Salt Lake City, Utah. Wonderful. All right. So a 65 year old man using he him pronouns is admitted for myocardial infarction. The physician plans to discharge him on clopidogrel when reviewing discharge instructions. The patient happens to mention that he had a DTC test that showed that he cannot process certain medications. And his his results show a poor metabolizer for CYP2C19, which is a metabolism enzyme. You verify that this result is cleared by the FDA for clinical use without additional clinical validation. So the care team decides to use tocagrelor, which is not dependent on the CYP2C19 pathway. We think so. What issue should we be thinking about now? Well, some things that come to mind include being very aware that almost all directed consumer testing for pharmacogenomics are not repeat, not cleared by FDA for validation for other than CYP2C19. So in this particular patient vignette, this is OK. This has been we found out that his his test is OK to use for this purpose. However, with other pharmacogenomics results, which will be almost all other result types, the pharmacogenomic results need to be confirmed in a CLIA certified testing environment in a clinical laboratory. And I do recommend reaching out to your pharmacist colleagues for additional help and insights if you bump into questions about using a pharmacogenomics test result. Next slide, please. OK, so what are the steps we should be thinking about when patients present with a directed consumer pharmacogenomics test result? First, we should be thinking about looking into the pharmacogenomic variant specifically and looking at the effect that variant can have in that there's information you can look at using FDA approved drug labeling and also their online dated resources that are available. And we'll we'll talk about a couple of them in the next in the next slide. Not yet, though. And we look for this information where it's available from reliable sources to understand the genetic the pharmacogenetic effect with this medication, the medication in question. Next, we review the pharmacogenomics test result to determine the need for additional clinical testing in a clear certified clinical laboratory prior to any medication change. And this is really important because we should not be using in almost all cases, pharmacogenomic test results from directed consumer tests. Now, if this was a pharmacogenomic result that is not FDA cleared for use, we do need to have to order a confirmatory testing be done. Sometimes we're stuck in time sensitive situations where we don't have time to it's going to take us a while to get from confirmatory clinical genetic testing such as situations where patients get hospitalized and we have to make some quick decisions. So I do recommend that you reach out to your clinical pharmacist colleagues for information and consider using an alternative medication that is not related or are impacted by pharmacogenomics or used an adjusted dose that you do have information from the FDA approved drug label until you can get that confirmatory testing. So those are a few things that to consider when stuck in a scenario where there's an acute need to make some decisions. And that's important until you can get those results back from a clear certified laboratory. And as always, third point is to refer any questions to your pharmacists who are they are becoming knowledgeable and many are knowledgeable about applying pharmacogenomics to medications. Next slide, please. Lastly, on this slide, we have listed some resources to help interpret and apply clinical pharmacogenomic test results to your patient care. At the top, there is a list of useful pharmacogenomics variants that are included in FDA approved drug labels and they can be found on the website that is that is listed here. It's a quick reference to understand what biomarkers are matched with drugs. This is helpful. Secondly, there's an evidence based clinical practice guidelines group and that's information. Those guidelines are available through the clinical pharmacogenetics implementation consortium, also known as CPIC. These are great guidelines. I use them all the time, a bookmark, a bookmarked on my computer. Pharmacogenomics test results should always be interpreted in the context of other clinical variables that may influence drug response. It's always important to remember everything else is going on along with the pharmacogenomics test results as well. Please note that CPIC does a great job with these and their purpose in these guidelines is to help clinicians use test results that are currently available. A CPIC does not tell a clinician when to order or not to order a test. So it's when you have a test result available. And finally, the pharmacogenomics knowledge base, also known as FarmGKB, is a searchable database of curated pharmacogenomic information and includes a lot of great information, primary literature, drug labels from around the world and other guidelines besides the CPIC guidelines of the consortia. And it's very helpful and clinicians may search for drugs, genes or other drug gene combinations for additional information. And with that, I will now pass the baton to Rachel. Next slide, please. Thanks so much, Christine. There was actually a question in the Q&A about the pharmacogenetics case. If we can go back to that slide real quick that I wanted to answer before I share my case and get other folks to weigh in on. So Andy Cosgrove asked, does direct to consumer pharmacogenetic testing require counseling before, during or after the results are in? Because it seems like this could be incorporated into the medical record without complicated discussion. And I agree that counseling for pharmacogenetics is not usually as intensive as counseling for other types of genetic tests. But I think that there is benefit to some level of counseling for pharmacogenetic testing, if nothing else to help set expectations. There are some limitations to the clinical utility of pharmacogenetic testing, particularly among non-European or individuals without European ancestry. And so having a discussion upfront about what a pharmacogenetic test result can actually say and how it can actually impact clinical care would be helpful to do during the consent process for pharmacogenetics. So again, not a super labor intensive counseling process, but still helpful to kind of set some groundwork in under understanding expectations for the test. Did anybody else want to weigh in on that question? Absolutely. Yes. This is Harie, a UBA. Thank you for this question. As Christine pointed out, doctor's tumor genetic testing that includes for macogenomic testing may not. Well, one, it you in most situations, you still need to clinically validate the results before you do any any medication change based on that result. So I would not incorporate that into the medical record and perform any medication change before it is actually clinically confirmed through clinical genetic testing, except for one caveat, and that's for CIP to C-19, where it was actually FDA approved for use. And I will ask Christine to comment on that as well. The other aspect of it, it's not just that you need to confirm clinically at a clinical in a clinical lab. The other aspect of it is that for a specific drug, the dark symptom genetic testing variants may not be adequate. They may not be all the variants that we would test for clinically for that medication. So that is why if you're if if you're patient or an individual is is interested in for macogenetic testing or the health care professional is concerned about for macogenomic effects of a certain medication, I would review the FDA labeling and see if there is a specific for macogenetic testing that should be pursued and then clinically ordered that test rather than ordered our consumer genetic testing for the patient. So, Christine, would you like to comment on the CIP to C-19? Nitta is asking, do any DTC companies offer other FDA approved PGX genes other than CIP to C-19? Thank you. Actually, there's not currently it's only the only FDA cleared test is for CIP to C-19 and two drugs, clopidogrel and citaloparam, and that is specifically for 23 and me direct to consumer testing. Everything else needs to be all other results, all other tests should be confirmed through a clear certified clinical laboratory. And this is really important because just as just to highlight some of the things that hurry and Rachel said, absolutely. I mean, we we need to understand the different diversity of genetic variants that could a patient could have. It's especially important in our patients with diverse ancestries and this is there may be some fall some false negatives that are present with our with these test results. So it is if we're going to be managing medications, we really do want as much genetic information pulled into the test and that is useful for managing medications as possible. And it is really difficult because our patients do often go have these direct to consumer testing done. And at that point, it's really difficult because there's no one there to help counsel them for medications. And for this reason, FDA has been very, very vigilant and is really looking out for our consumers in that they do want they do have they do encourage and you want us to be using confirmatory testing to make sure that we are looking at a diversity of genetic variants and applying this in the best possible way to manage medications. And it's really important to also mention to our patients that they should not be using direct to consumer testing or pharmacogenetics results in general to manage their own medications. They need to be talking to their health care providers about this and getting more insight. And I always do recommend talking with pharmacist colleagues to to gain more insights, especially looking into some of these drug gene interactions. Thanks. I'd like to add a comment to if that's possible. This is when I'm just letting you know that we want to emphasize, I think you've heard it ad nauseam, but just to make sure you are not putting any direct to consumer genetic testing results into a patient's medical record unless you have confirmed it. And so it's not just with pharmacogenomic testing. It is with all other tests as well. And so because patients are not aware and if you're not looking at the direct to consumer genetic testing results specifically, as previously mentioned, if your patient doesn't fall within the ancestry group in which the variants apply, then you could be making and also people who come after you who see this result in the medical record could make judgments and medical decisions that is that are based on information that has not been confirmed. Thanks so much for all of the wonderful questions about PGX and we'll certainly take time to answer more at the end if they come up. But we'll go on to the next case. If you'll go to the next slide, please. So for this case, we're going to be talking about third party interpretation of direct to consumer genetic testing results. And before I go over the case, I want to give you a little bit of context of what I mean by third party interpretation in case that's something that you haven't heard of before. So third party interpretation refers to tools that are outside those provided by the direct to consumer genetic testing companies that customers order from. So you can go into your direct to consumer genetic testing company account and download your raw data from that company and then upload that file with your raw data to a separate interpretation tool. Most of these third party tools are online. A lot of them are free or fairly inexpensive, but there are some that has these comparable to the cost of testing originally. These third party interpretation tools gained popularity back around 2008 or so whenever the FDA began restricting the types of results that direct to consumer genetic testing companies could return. And they've just continued to remain popular since they provide that additional information beyond what's returned to the direct to consumer genetic testing company platform. And I'll talk a little bit more about what that means, but wanted to provide that context because in this case, a parent has had direct to consumer genetic ancestry testing for their two year old. He's generally healthy, but he's got some speech delay. So he's seeing a speech therapist. They decide to run those direct to consumer genetic test results through a third party interpretation site and it identified four variants that are all considered pathogenic variants with a variety of conditions, a couple of tumor suppressor genes, Ehlers-Danlos syndrome and gene for cystic fibrosis. So what should we be thinking about in this case? You'll go to the next slide, please. First of all, I'll get on my soapbox here and say, please do not ever order direct to consumer genetic testing for a child. The reason that this is is, first of all, it violates the terms of use agreement for almost all direct to consumer genetic tests. They specifically say that testing is only for individuals 18 and above. And these terms are in place in part to acknowledge a child's right not to know. This concept of a right not to know is an ethical concept that allows individuals to control whether or not they receive genetic information and what type of information they receive. So by testing children for adult onset conditions, it takes away their ability or it violates their option. They're right not to know. I think for us as health care professionals, it's it's easy for us to see how genetic testing information can be really helpful for understanding disease risk and putting early interventions into place. But some patients may prefer not to know their risk, particularly if it's for conditions where there aren't any good treatment options, things like Alzheimer's or Huntington's disease, for example, patients might actually see genetic knowledge to be a burden in cases like this, something that just induces stress and anxiety. It's not actually helpful to them. So anytime we're thinking about genetic testing for a child and treatment or surveillance in childhood is not available, providers and parents should consider this idea of a children's right not to know and potentially postpone testing until the child can decide for themselves when their adults, whether or not they want to have testing. Next slide. Since this case, though, is focused on the direct to consumer third party analysis, I want to talk a little bit about considerations if someone shows up with results from a third party tool analysis. This first point about results being false or uninformative, third party tools are not regulated the way that direct to consumer genetic testing or clinical genetic testing is regulated. So there's no FDA oversight. There's really no oversight from anyone, really. So because of that reason, there's not really any assurances that the results are going to be accurate. For the second point about a positive test may be a false positive. In 2018, Stephanie Tandy Conner and her colleagues from Ambrie published a paper where they conducted genetic testing to confirm results identified by a third party interpretation of direct to consumer genetic testing results. And in that analysis, 40% of variants that were reported in the raw data were actually false positives. So you have a pretty high chance that a result identified by these third party tools might be a false positive. And we've kind of talked about this already, but a negative test can be uninformative because direct to consumer genetic testing companies usually use genotyping tests that only look at a small subset of all of the genetic variants that are available. So a negative result could mean that the patient truly is negative or it could mean that the patient is positive for a genetic variant that was not covered by the test. So it's hard to know exactly what the risk is there. Also, it's important to keep in mind that direct to consumer genetic testing and these third party interpretation reports include a lot of results like pages and pages. A patient will come into your office with like a stack of papers if they print everything out. So it's not really possible for us to discuss or conduct confirmatory testing on every single variant. So it's helpful to kind of engage in some discussion with the patient at the outset to understand what results they're most concerned about. So if we use the case that I presented a second ago, the parental concerns about speech delay, none of the variants that were detected are related to speech concerns. So we could potentially defer any confirmatory testing until the child is older, maybe until they're 18 and can consent themselves. But you might inquire about family history to see if there's any familial risk of a hereditary cancer syndrome, considering some of those variants in tumor suppressor genes. The cystic fibrosis gene, like that's on newborn screening in all states. So you can assume that that is a false positive or double check their newborn screening results just to confirm. So this kind of use of triaging all of these results to address the most significant concerns first can help you address a lot of information in a short time and make sure you're really focusing on the the needs and concerns of the patients. So with that, I'll check in with my other panelists and see if y'all have any other thoughts or comments about this case. Thank you, Rachel. This is Haria EVA. I think this is a great case. We often, you know, this this brings back the the the the question, why did the parent do this third party analysis? Right. What are they concerned about? And it's possible that their main concern is that the their child's delayed speech. And that's where formal evaluation can be perhaps done to evaluate if this significant should we be looking into genetic causes? Are there other features that are concerning other developmental delays, other features such as autism spectrum disorder or something else that might actually warrant clinical genetic evaluation and clinical genetic testing for the child for something that is relevant to what the parent is concerned about. But I completely agree with you for the other variants. It's not uncommon for me to see in clinical genetics, a child, unfortunately, a child who had clinical genetic testing for an adult onset cancer risk because their parent had it and their parent is concerned. So if, for instance, the the the the mother had a BRCA variant, she would ask that her child gets tested for it when the child is only five or six. You know, we do send genetic testing for cancer related risk if there is a clinical indication in a child, if the child has a cancer diagnosis, if the cancer could occur in the child and that child would require increased interventions and screenings. But in in in certain situations when the cancer onset is in adulthood, where the oldest screening recommendations are begin during adulthood, you really want to give that child the option to decide for themselves if they want to get genetic testing or not. So thank you so much for bringing up this important ethical issue. Of course. Any other thoughts or comments? All right. Well, I'll pass it on. Next slide, please. So key takeaways. And I want to thank everybody who's been putting questions in the Q and A's. We will make sure to address the ones that weren't addressed already. I I want to start with answering one question that dark consumer genetic testing while there is a fine print when you for consent, right, with everything that you sign up for online, if you want to sign up to the for. Anything you're going to have a long list of the disclosures and agreements and do the patients go through that? I know that I wouldn't. I just came through things and signed at the end. So although informed consent is supposedly in there for dark consumer genetic testing, it's not true informed consent. They are not really going understanding what are the benefits and risks of obtaining this type of testing. That being said, if your patient comes in with dark consumer genetic test results, start with the first start the conversation. Why did they pursue genetic this type of testing? What are their concerns? Once they once you look at those results, determine was this actually a report generated from the dark consumer genetic testing company? Is this company? Does this company have a clear certified laboratory or was this a third party analysis report? Remember that the third party analysis report may be false and the ones that you really want to focus on are those that are directly attained for the dark consumer genetic testing company. Then look at those results. What is clinically significant? Do I need additional medical information, additional medication history, family history? And is there clinical genetic testing that could be ordered to confirm those results? Remember that the for for a positive result, if there is something that could be confirmed clinically, that's that's the right you want to take. And you want to discuss that with your patient. And if a patient is reassured that their dark consumer genetic test results are negative, that is where you want to remind them that this is not comprehensive testing. And this is for you to to recognize that this is not comprehensive testing. And that's where you go back to your clinical evaluation and deciding does this patient need additional clinical evaluation, maybe genetic counseling referral or clinical geneticist referral for proper clinical genetic testing? Or do I need to talk to the clinical pharmacist about from our progenomic testing for this patient? Next slide, please. If the patient is hospitalized and it's a time sensitive situation, clinical genetic testing, confirmatory clinical genetic testing is not feasible or readily available. You want to evaluate for the genetic condition and you would want to research any pharmacogenomic result to determine if you need to adjust medication dosing. Remember that there are always ethical issues when it comes to genetic testing, especially in minors. And clinical, so dark consumer genetic testing is not covered by insurance, right? And any clinical genetic testing may or may not be covered by insurance depending on the clinical indication. So having a dark consumer genetic test result is not necessarily a reimbursable clinical indication for clinical genetic testing. But if the patient does have a significant personal family medical history, then that would be reimbursable in most situations. Next slide, please. I want to remind you all that we are we're going to be answering your questions. So please feel free to put them in the Q&A. This is how you could find a genetics professional. You could go to the National Society of Genetic Counselors website. We've had fantastic genetic professionals, genetic counselors with us on this panel today. Even as a clinical geneticist, I use their expertise about genetic counseling issues. So please reach out to a genetic counselor if you have questions or concerns. And if you need a clinical geneticist to evaluate for a clinical genetic condition, reach out through the American College of Medical Genetics and Genomics. And for macrogenomic results, I strongly encourage you to talk to your clinical pharmacist about any FDA recommendation in terms of... FDA labeling in terms of for macrogenetic testing for a specific medication. Next slide. As a reminder, we have a dark consumer genetic test frequently asked questions, resource for healthcare professionals that's on genome.gov. And you can reach that through the QR code. Many of the discussion points that we highlighted today are actually in that FAQ. And it was created by members of the IACC PEG, DTCGT Project Group, any of them are presenting today. And if your patients have questions about dark consumer genetic testing, you can provide them with information from Medline Plus that uses less medical jargon and is more patient-friendly. Next slide, please. We'll go through your questions in the Q&A. And next slide. And I would like to leave this slide up with the QR code to evaluate our webinar. So please feel free to do that anytime. We look forward to your feedback. So the first question that we got, do all states require informed consent? And for clinical genetic testing, as far as I know, informed consent is required. And I'll ask our genetic counselors to chime in. Hi, Huria. This is Wynn. And so I would like to talk about it from a clinician standpoint in terms of being a clinician who's worked in all different fields of medicine. I worked in cardiology, nephrology, environmental medicine at the VA, and now in genetics. And I don't know that there's a specific requirement by states in terms of informed consent. However, from a clinician standpoint, ethically, you would not order a test without obtaining informed consent and without discussing it with your patient first, no matter what field of medicine that you're in because you would want to be discussing the results. And one of the things that were taught in school is that you never order a test that you don't know how to deal with the results. And so in the same way, you would need to prepare your patients when you're ordering tests of any kind. And especially when it comes to genetic testing, you wanna be thinking about all the different people that are affected because genetic testing doesn't just affect the patient, it affects their family members, generations before and after and within their own family. So I don't know specifically in terms of legal, there's not a lot of, I think specific regulations about it, but from an ethical standpoint, just to reiterate, all clinicians would obtain informed consent. Hopefully that answers your questions. Absolutely, and in their position statement, the American College of Medical Genetics and Genomics stresses that consumers should be fully informed regarding what the test can and cannot say about his or her health or their health. And so we have, we just don't have, we have a lot of laws about DNA privacy, but not specifically about informed consent for genetic testing. Go ahead. Sorry, and I was gonna say in all research studies, informed consent is required, but from a clinical standpoint, I don't know that it's mandated, but definitely recommended. Right, I was gonna chime into, this is humanly informed consent as a part of our job as a genetic counselor, with every patient and with every test. Just as far as legal and mandates, again, different states have different requirements, especially for even third party, some require more than others. So it's not a blanket policy that all states have to do X, Y, Z. So there are different sites. I was looking at some governments and CGC and some of them are a little bit out of date, but it seems like there's 10 to 24 states requiring different levels of consent from third party, but absolutely from what Wyn said and from the rest of us from clinical perspective, we always have to go through an informed consent and that's just part of our ethical, moral and legal, I would say as well, process to make sure that our patients are well informed and have an idea as well as the clinicians themselves. Thanks. So the next question that I'd like to pause to our audience, R of U.S. is regularly reported in dark consumer genetic testing. And as far as I know, variants of uncertain significance are not reported in dark consumer genetic test results. The reports depend on the company that is releasing it. Typically they either say variant detected or variant not detected or result positive, result negative. They do not typically report out variants of uncertain significance. And for our other audience members who may not be familiar with this term, variants of uncertain significance is that when there is a variation in the sequence of a gene of a specific genetic instruction, but we don't know if this variation is just normal variation in the population that is not related to any genetic condition or clinical condition as far as we know, or it may be related to a genetic condition but we just don't have enough information about it. And when we order clinical genetic testing, we can get three types of results. In a clinical genetic test, we can get a positive result, a variant detected that is associated with a disease. This is called a pathogenic variant. And with variations of it, likely pathogenic, we could get a negative result or no variants detected. And we could get a variant of uncertain significance, which means that there is variation in the sequence but we don't know what it means in 2022. And we would want to reevaluate those results in the future in a year or two to see if there is updated information about that variant. Any other comments from the panel about variants of uncertain significance in dark somogenetic testing? Have you encountered any dark somogenic testing results that report out variants of uncertain significance? I have not and I wanted to share like kind of a different way to look at it. Most direct to consumer genetic testing use a technology where they know what they're looking for. So they have a predetermined list of variants that they are searching your genome for. And so it's a checklist of like, yes, they have this variant, no, they don't have this variant. And because of that approach, because of that technology, they're not gonna uncover variants of uncertain significance because you're not gonna know to look for those. I did, I do think that this is relevant to the other question about full genome sequencing being available direct to consumer for around $100. And I certainly have mixed feelings about it. You know, and on one hand, I think that it could continue to promote awareness of genetics and get testing into the hands of consumers more readily and more easily since it is challenging to get a referral to genetics or genetic counseling because of the number of practitioners in the U.S. My concern would be the question of what they're returning and how they're gonna return it. The large cost for genome sequencing actually has, my understanding has less to do with the actual technology of the sequencing and more to do with the amount of time and effort that it takes to interpret those results. So my concern would be if they are just giving you raw data and then expect you to run it through a third party interpretation tool, use another resource that costs extra money. So I would be looking really closely at the fine print of what you're actually going to get for $100 and how you can use that information. There's also a question of, is it truly full genome sequencing where you're getting things like variants of uncertain significance or are they using sequencing technology to still return a checklist of findings similar to genotyping? So I am interested to see, I've also heard that this is on the horizon and I'm interested to see what it looks like. But those are some of the questions that I would be asking before I dive in and start using that test. Does anybody else have thoughts about that question about the whole genome sequencing for 100 direct-to-consumer? That is a great question. Clinically, I have not had the opportunity to actually order full genome sequencing for my patients. One, because one, it's still very expensive and two, the interpretation is, we don't understand everything about our genome just yet. So in many circumstances when we are doing whole genome sequencing, it's really done on a research basis and potentially in the future it will become a clinical genetic test but at present time, it is not going to be reimbursed by insurance to order whole genome sequencing. What we do order clinically is something called whole exome sequencing. And what that is is that we are just checking on the sequence of the actual genes that we know of at present time. So the genome is huge and only about less than 3% of it consists of genes that we know of. And of those, these are the ones that we can order clinical genetic testing for and that's called whole exome sequencing. So ordering whole genome sequencing, if it's truly whole genome sequencing on your own, it is worrisome to me because we don't know how to interpret that outside of the research setting at present time. And that information, how we interpret that's going to change dramatically as we learn more and more about our genetic information. So many of the companies that say they are doing whole genome sequencing are in fact just performing genotyping which is what Rachel Mills talked about just kind of seeing if somebody has a variant or not. Another issue with genome sequencing if it is truly genome sequencing is the technology that is used. What is the depth of coverage? So in clinical testing, we need to make sure that every sequence is covered so many times, right? We want to make sure that we truly, that if there's a change that we saw it see it consistently throughout and the depth of coverage is valuable. And when I've looked at into some of those dark genetic testing companies that offer whole genome sequencing looks like the depth of coverage is not adequate. Then again, when you get a report you get lots and lots and lots of pages of information that is not, it is not the same quality as the clinical report. It does not report things out as you would get from a clinical report. So I would not encourage my patients at present time to pursue dark consumer genomic testing, whole genome sequencing. I don't know if the other panel members have a different take on it but that's my personal opinion. I just want to acknowledge that we are at time and we do have a couple of more questions in the chat. I think for the purposes of the event we need to wrap things up but if folks want to hang on so that we can respond to those questions via the chat we would be happy to do that and appreciate everyone being here today and asking such great questions and being engaged. Donna, would you like to close us out? Sure. Again, just to repeat your comments. Thank you so much everyone for coming and we do plan to post different aspects of the webinar on our website and please check back to see additional resources and do consider checking out our events page for additional events during the whole week and follow the hashtag MedGNED22 on Twitter. Thank you so much everyone and thank you so much to our panelists who provided excellent cases and responses to questions and overviews. Thank you to all.