 All right. Good morning everybody. So thank you so much for joining us today. So we're going to be giving a presentation on pharmacogenomic resources, what clinicians should know. Today we'll be covering CPIC or the Clinical Pharmacogenetics Implementation Consortium, and then my colleague Michelle O'Carillo will discuss at FarmGKB. And then we've got Kristen Cruz on here as well who will be helping us with our questions and answers. So if you have a question, please put it in the Q&A box within the chat. All right. So CPIC, just a little bit about CPIC. So CPIC was formed in 2009 to provide freely available evidence-based and updated pharmacogenetic clinical practice guidelines. To date, we are a consortium. We have over 600 members from 260 institutions and 36 countries. We now have 26 guidelines. Most of these have been updated at least once or twice. And now our guidelines cover 25 genes and over 90 drugs. So what is a CPIC guideline? So CPIC guideline answers one question. So I think when you're thinking about ordering a genetic test or how you interpret that genetic test, there's really two different questions. One is, should I order this test? But the other question and the question that the CPIC guidelines answer is, should I use this pharmacogenomic result and how do I use this result? So CPIC guidelines are really based on the assumption that the test results are in hand and not to discuss the merits of doing the test. Each CPIC guideline uses standardized formats. So I'm going to review kind of one very briefly today. But you can, if you go look at another guideline, you'll see that there are very similar. We have a system for grading the evidence and for grading our recommendations. These are peer reviewed, not only through the journal peer review process, but also we send this out to yes all 600 plus of our members. These are freely available and we'll be able to show you a few places today where you can find these guidelines. These are updated as I mentioned, we do update these guidelines on the ongoing basis and really the evidence base grows every day and so we do find a need to continuously review evidence to make sure our recommendations wouldn't change based on new evidence. We have a strict authorship policy for conflicts of interest because these do closely follow the IOM or the now I guess the National Academy of Medicine standards for writing clinical practice guidelines. And so today we're really just giving just a really brief overview and just really telling you things that we think a clinician should know, but I do think it's important for you to understand the entire CPIC process. There's a reference down here where you can go and you can really see the entire SOP, but we also do have a table in this where we align it with the standards from the clinical practice guidelines we can trust and you'll see that we do align quite nicely with these. All right, so where do you find a CPIC guideline, you can go to CPICPGX.org. This will land you on our homepage. There's lots of great resources on this, but again today we're just doing a high level review so we're going to talk about the guidelines. So if you click on this tab up at the top, the guideline page, it will take you to a list of all of our guidelines. Again, we've got about 26 guidelines, so of course this list is much longer than I'm showing you here. But we can click on each one of our guidelines, so let's say we wanted to click on, you know, when a CYP-2C19 clopidogrow, we click here even though I think my example is NSAIDs, but it takes you to a guideline page for this example NSAIDs based on the CYP-2C9 genotype. On this page you can find our full PDF of the guideline and our supplement, and at the bottom of this page you'll see a lot of other great resources which I'll review here in a moment. So as I said, we have 26 guidelines that covers 25 genes and over 90 drugs. One thing I wanted to point out, so I know this is a busy slide, so this is all the genes and then the drugs or the drug groups that we have guidelines for. One thing I wanted to point out is we do have a level called a no recommendation. You'll note that when you order a pharmacogenomic test and a lot of times you have a lot of genes on that, it's usually a panel of genes. However, not always are these considered what we consider actionable, which means you can act on this, you know, that genetic test result while prescribing. And so we would assign these a C-PIC level C or no recommendation, and this means that our author group has gone through the entire process for the C-PIC guidelines and is really deemed at this time with the current evidence. These are not considered actionable. So let's walk through a little bit about how to utilize the C-PIC. And again, I'm just doing a very high level. So there's some details that we're going to kind of leave out today. So I highly recommend that you at least go read at least one C-PIC guidelines so you can kind of get a feel for what's all included in each guideline. But the important parts that you need to know. Each recommendation in the guideline is based off of a phenotype. So the very important part of the C-PIC guideline development process is the translation of this genotype to phenotype, and this is generally the table one in the guideline. I'll show you an example of this in a moment. And then our table two and table three, depending on how many recommendations are in the guideline will be our recommendation. So again, a big part of here is being able to understand and interpret that genetic test result that you might get from the laboratory. There are a lot of steps, but today we're really just going to focus on how do you get from that Diplotype to the phenotype, because I believe most laboratories are going to report out using this star allele nomenclature, which is really just a way to define haplotypes for pharmacogenes. But again, we're just going to focus here because I think this is where a clinician needs to go. I don't think it's as important for you to really understand how we assign these Diplotypes. However, there is a table in the guideline that really explains this process out and how we do assign a phenotype based on that Diplotype. But for you and for a busy clinician, I think this is where you can go. And I think also Michelle, when she starts speaking here later, she's going to show you in a better way that you can find these recommendations on PharmGKB. So here I'm showing you the guideline page for Clopidogrel and Cip2C19. And again, I talked to you a little bit about those implementation resources that you have down here at the bottom of the page. I'm going to blow this up for you here. So you can see here we've got an entire translation table that translates every possible Cip2C19 Diplotype to phenotype. And there's a full table here. I think some genes have over 10,000 combinations. I can't remember exactly how many Cip2C19 has but there are quite a few. This is a big file. But really all you do is you find your Diplotype on this table. And here you go, here's your phenotype. So from our example, it was Cip2C19-2-2. And we know that this individual is a four metabolizer. So again, very important step. So now that you know what the phenotype of your patient is, you come back to the guideline. And again, usually it's that table too. And you'll see here for a Cip2C19-4 metabolizer, if you were to prescribe Clopidogrel, you would want to avoid that drug and use a different drug. We also have a classification or really a strength of that recommendation. And you can see here, I'm going to point out some differences in some of our guidelines. Some of our guidelines are indication-specific. So you can see that even though the recommendation is the same, the strength of the evidence is different because there's just a different evidence base for different indications. So what does that strong, moderate, optional, and no recommendation mean? So strong, this really is we do have a system for grading the evidence. So we found that the evidence is high, high quality, and that we think the desirable effects clearly outweigh the undesirable effects of using that information, that genetic information for prescribing. And then moderate is where we have a closer, uncertain balance as to whether the evidence is high quality or desirable clearly outweigh the undesirable effects. And then we have optional recommendations where we feel like the desirable effects are really closely balanced with undesirable effects. Sometimes these recommendations are based on extrapolations or really the evidence base is weak. But really, we think that you could use the information for prescribing, but it would be optional because there really are room for differences in opinion as to the need of the recommended force of action. And I talked to you a little bit about no recommendations here, so really we found that there was really insufficient evidence, confidence, or agreement to provide a recommendation to guide clinical practice at the time of the guideline. All of our guidelines also have at least a paragraph on pediatric dosing. In some cases, there's enough evidence base where we can have a specific recommendation for the pediatric group. And so this I'm showing you here our CIP-2C-19 boy conazole guideline. And you can see here we have a specifically, there's another table for adults and then we have one for pediatrics. And this kind of gets me to my next point. If you know that your patients to CIP-2C-19 for metabolizer, for example, you also need to know that you may be just prescribing clopidogrel, but the patient needs to know about this result because of course there's several drugs are impacted by CIP-2C-19 variation. So just wanted to conclude here and big things. So again, big picture here. I highly recommend you go pull the CIP-2C-19 guideline, get yourself familiar with it. But once you familiarize yourself with one CIP-2C-19 guideline, they're all pretty standard moving forward. And again, I use some basic examples here for drug metabolizing enzymes. So there are quite a few caveats for some other genes, but really just wanted to give a high level and report to you today. But really just to remind you to be mindful of some limitations. So the genotype to phenotype translation. Sometimes you might get back that genetic test result. And they've actually translated that genotype to a phenotype for you. But if you're going to be using a CPIC guideline for your recommendations, you need to make sure that they've translated the way CPIC translates it. So you still want to jump on online and make sure that, you know, if they're calling them a poor metabolizer that CPIC also calls them a poor metabolizer. And we're getting a little bit better in that area, but I have seen some lab reports recently that they're not really using CPIC standard translations. What does star one mean? So star one is really what we consider wild type or the reference. And most cases this means the patient is more of a normal function. But remember that in most cases that your genotype result is from targeted genotyping testing, which focuses on the tear getting previously described star alleles and sometimes not even all of those. So you just have to make sure that you understand that it's not really designed to that novel variants. There could be rare allylic variants that may not be included in that genotype test and the patients with these rare variants may be assigned a normal metabolizer phenotype by default. So just kind of keep that in mind. And with that being said to pharmacogenomic results really should not be used in a vacuum because they really only count for genetic variability to drug response and as you know, there's lots of things like drug interactions, kidney function liver function and other things that can really cause variability and drug metabolism. So with that I finished up and I'm going to hand this over to my colleague Michelle. I'm starting my slides. Okay. So I'm going to build on what Kelly talked about with the CPIC group and talk about the pharmacogenomics knowledge base otherwise known as farm TKB from TKB is the largest resource of freely available pharmacogenomic information out there. And our mission is to be everything a PGX and we're financially supported by the NIH, specifically in your eye. So, here is a homepage of our website. We're at www.farmtkb.org please feel free to jump on and follow along if you'd like or please check us out at some point. The homepage is really long you have to scroll down to see all of it. You can take a tour of the homepage it will show you all the different sections of the homepage when you have a chance. And to learn more about pharmacogenomics in general on our homepage, we have this green button right here. So to click that it takes you to a page that has information that you can navigate through in basically bite size chunks from basic genetics to more details about how genetic interactions, how to next interact with medicine. And there is an FAQ for clinicians that you can that you can go view it's mainly regarding pharmacogenomic testing, how to order tests and what to do with test results, a little bit about what Kelly already talked about with test results. And I would like to point out that at the top left hand corner of every PharmGKB webpage there is this icon with PharmGKB and you click it, it will take you right back to our homepage. So let's pretend like I click that and back on the homepage we have another section that I'd like to just point out that describes the specific types of information you can find on PharmGKB. We also have a tour and automated tours of website that you can follow along and documentation on how to search on PharmGKB. And we also provide an overview of the different types of information on the website, much of what I can't cover here today. I'm only going to cover a little bit about prescribing information and drug labels. But if you forget what I talked about today, you can always come back to this page for a reminder. We have automated sources of information on PharmGKB. We curate peer reviews, published literature, information from studies, including clinical outcome studies, the PharmCoConnect studies and more. We also curate regulatory agency approved drug labels, which often contain unpublished data. And lastly, published pharmacogenomic guidelines like the ones from CPAC that you just heard about from Kelly. We also talk about each of these three kind of in reverse order. So guidelines first. So guidelines annotated at PharmGKB come from a variety of sources, but the main two sources are, sorry, I need to go back, are CPAC, which Kelly just talked to you about a little bit about. And also the Royal Dutch Pharmacist Association's Dutch Pharmacogenetics Working Group, which is a mouthful. We just call them DPWG. So like I said, there are various groups that have published different pharmacogenomics related guidelines. But CPAC produces the majority of them. PharmGKB partners with CPAC to be upfront about that. But also this Dutch group produces quite a few guidelines as well. So we highlight both of these on PharmGKB. So on the PharmGKB homepage, you can click the clinical guideline annotation button, and that will take you to the landing page for all these clinical guideline annotations. As you can see, we have a column for CPAC, a column for the Dutch group, and then a column for others. And at the top of the page, you can read more about our process for curating the guidelines. But the table down below is really long and you can filter and search based on the source of the guideline and what type of information is in the guidelines such as guidelines where a dosing change is recommended based on the phenotype or phenotype, or if a different drug is recommended. So if I sort this list, if I filter for CPAC guidelines and say ones that recommend dosing change based on the phenotype, I get this list. And I can find out more information about any of the guidelines in this table by clicking on it. And I'm going to show you an example today for amitriptyline. And this is the PharmGKB annotation page for the CPAC guideline for amitriptyline and CIP2C19 and CIP2D6 from the TCA guideline. We provide a video overview of the information in the guideline. We do encourage everyone to read those manuscripts put out by CPAC in its entirety, but sometimes people just want like a brief introduction before they read the entire manuscript and these videos will give them that. And we also have a place for users to enter a particular genotype. So you can use these pull down menus to select the genotype for Diplotypes that maybe you got as like a test result that you got back from a pharmacogenomic test. And Kelly talked about, you know, the star wheels and you can enter these Diplotypes here in this pull down menu. And what happens is we will retrieve the from CPAC database, the specifics of the guideline including the recommendation for that specific, for those specific genotypes. So the CIP2C19 guideline focused on genotypes from two genes, both CIP2C19 and CIP2D6. So this way the user doesn't have to map across all those files that Kelly mentioned. It's kind of done for you here on PharmGKB. So it's a nice way to kind of access that information quickly without having to map through all the tables on the back end that everybody has like informatics group to do that. However, that being said, all those tables that she mentioned are really important. And if you scroll down that page on PharmGKB, you would see links to all those tables. Just like you see them on the CPAC website, you can also get access to the manuscript itself and the supplementary information on PharmGKB. So we have similar pages for the Dutch group, same kind of mechanism where you can enter a genotype. The only thing that is missing is we don't have the videos for the Dutch guideline. So I'm going to switch gears to drug labels. We curate from a variety of sources, but we start with FDA approved drug labels listed on their pharmacogenomic biomarkers table. And then we try to find matching labels from EMA in Canada when we can. I will say that we have some labels from Japan and Switzerland on our website as well. But those were collaborations where we had colleagues help translate the labels for us so we can't maintain those regularly. So on the homepage, you can click on the drug label annotations link to get to the landing page there. And at the top again, you can learn more about our curation process. But like with the guidelines, we have ways to support these label annotations. This FDA biomarker sorter tag just refers to the FDA's pharmacogenomic biomarkers and drug labeling table, which provides a list of labels identified by FDA that has some kind of gene on them. And this table from FDA has the drug in the gene and the section of the label that there's some information on, but it's up to the user to basically read through it and understand what type of information is on that label. But Farm2KB basically is doing that for the user here. So you can query and sort based on the source of the label I'm using this far. And I want to point out these different color tags, the different color tags like red for testing required or green for actionable PDFs refer to the label content. So that's the part where Farm2KB goes in and pulls out that information regarding the gene on the label. So to be clear, Farm2KB only curates drug labels that have gene or variant information on them. We don't curate every single label. But the ones that we identify with gene information, we do tags based on whether the label says that some kind of testing is required or recommended. Most say nothing about pharmacogenomics testing at all, but they might contain some actions like dosage success suggestions, and that would be an actionable PGX tag. And some refer only to the gene but make no mention of how it would affect prescribing it all and they would get an informative tag. So if you look at our website for these annotations, we have links on every page with the drug label annotation. So take you to the legend to explain exactly how we put these tags on the label annotations. So here's an example. If you click on an annotation from the landing page that I showed earlier, there's an example of an annotation here from FDA. In this case, the label is on the FDA biomarker list. It's tagged with testing recommended because of language from the label. There's a quote down here that says testing should be considered in certain populations. So that's why it's got that tag. It's also tagged with prescribing info, specifically alternate drugs based on, again, language from the label saying that the drug should be avoided in patients with a specific variation. In this case, HLAB 1502. So the drug contraindicated in that population. And that's what we mean by alternate drugs. And finally, on every label annotation, you can look here way down at the bottom, there is a link to download the PDF of the drug label that we curated that we got the information from, and the relevant information is highlighted for the user there. If you're interested in FDA labels, in particular, you could scroll down the homepage here and click on this link for FDA drug label annotation. This takes you to a table just for FDA approved drug label annotations and I'm going to zoom in on it quickly. And you can see we have a lot more columns here available to see if, for example, a variant is mentioned on the label most labels don't have a variant but if they do it's listed here in the column for you. So you can sort based on whether or not the label is on the FDA biomarker list, sometimes they go off mysteriously or on the biomarker list and we keep track of that for you. The FDA also started another list a few years ago called the table of pharmacogenetic associations. They started this list is actually three tables and one, and the table is kind of sort gene drug pairs based on how they feel it meets different criteria. The FDA does curate all the information from these lists as well, and you can sort on the website on our website based on based on those FDA tables. You can also sort based on the level and the tags that I talked about earlier. As a note, FDA biomarker table and their PG X association table, those are two different tables. They don't always agree. They don't sometimes most of the time they align but sometimes they don't just as a quick example. And this particular label for amphetamine is on the biomarker list, however, on the label, there's very little about anything about PG X the most it says is that to be sick, basically metabolizes the drug. That's why I got the informative tag, however, on their other table of pharmacogenetic associations, they actually have instructions here about you could consider lowering a starting dose or using an alternative agent. If you if your patient is to be six for metabolizer. So how that information is sorted out. It's unclear at this time, but you can compare and contrast that on form to KB. And I mentioned a little bit earlier that from to KB curate scientific literature like the paper from the New England Journal of Medicine. We use standardized terminologies and collect study information from each article. We curate bunches and bunches of articles, we have thousands curated on our website, and we try to aggregate this information across all the articles to curate. We add in information from the drug labels and the guidelines when possible, and use all this information to create rated genotype drug summaries that we call clinical annotations. These annotations are graded based on the amount of evidence that we have collected to support the association. You can read more about it, but basically a level one a means that that association has the support of a drug label or a guideline. But the value of the clinical annotations is really when there's not a guideline or a drug label available but you want to know more about a particular variant drug association because maybe you got it returned on a pharmacogenomic. A test, for example, you may have a test result about it, but if there's no guideline or drug label, you can use farm DKB clinical annotations to see what evidence we have found for for such an association and you can find these annotations by typing a gene or a drug name in the search box on our website, going to the corresponding page and clicking on the clinical annotations link on the left hand side and the table would be here for you. So I'm out of time, but I wanted to play now to more possibly helpful resources. For those of you who would like to dig deeper into pharmacogenomics farm cat is a pgx tool that takes patient genotype and sequencing results and vcf file assigned Diplotype and phenotype like Kelly had mentioned earlier, and then provides the CPIC and DPWD dosing guidelines and a report format. And farm bar is a central repository for pharmacogen gene variation. It maintains the nomenclature for all of those star alleles for the cytochrome P450s and other pharmacogenes. It's an invaluable resource and while it may not appear as relevant to clinical implementation as the guidelines do the guidelines absolutely depend on this nomenclature so I encourage you to check it out. Here are all the people associated with all of these projects. These are all my colleagues and these resources couldn't exist without them. Thank you. Okay, thank you to our two presenters thank you both for your presentations are our question and answer session is open you can feel free to type in a question for either of our presenters. And so I have a couple of questions that have come in. So the first one is for Dr coddle about CPIC. How often are CPIC guidelines updated. So yeah I kind of mentioned before they're updated on it we try to update on the ongoing basis trying to keep up with the evidence base but I would say each guideline needs to be at least reviewed by authors at least every five years and that keeps us within those standards for the writing guidelines that we can trust. However, I will say there's some guidelines like I don't know the HLA and carbamazepine it's a very clear example of the patient has this variant don't use the drug and so more evidence to this might make it a stronger recommendation but it really won't change the recommendation itself. So in those cases those guidelines might be, you know, they may actually go the full five six seven years before we do update them, but others where like in any kind of like the SSRI guideline or anti depressants or anti psychotic when once we get that one done. Those are that evidence base is growing every day so those probably will be updated more often. I have another question that really talks to the process of assigning phenotype based on genotype. So is it their prescribed process for that. Yes, and so we have a full SOP just written for this so I mentioned that you know some of that that I left off. For time wise, we have one process where so you say you have that allele. We use farm var to help define what that alleles that star allele. And then we assign a function to it so it's either increased function normal function decrease function or no function those terms are standardized. And then that phenotype is really based on the combination of those two genotypes so a patient who has that star two star two for example, they have to know function alleles and because of this, they are poor metabolizer but if they had one normal function allele and one no function allele, they would then be an intermediate metabolizer and another thing to note to is these can differ these assignments can differ by gene. Right, so one thing to note a star two for sip to see 19 is not the same as a star two for sip to D six. And the functions can change and actually sip to D six and sip to see 19 actually use different definitions for that genotype to phenotype so it's really important that you're pulling the correct gene tables when you're utilizing those genes great question Chris thanks. Very good and that sort of leads into the next question because this is genomics education week. So, are there resources for educating clinicians more, more in depth about how to interpret these results. Yes, they're actually quite a few and one I want to point out because there is a talk this afternoon at one o'clock Eastern time that I really hope that you can join because I think it will go over a lot of resources that you can have and I'm reading this I apologize because it's a mouthful the NIH inner society coordinating committee for practitioner education and genomics or is CC peg. They've got a learning series that they'll be discussing this afternoon but their new peer reviewed online education for healthcare professionals. I'm excited to dig into these even as a as a as a pharmacogenomics expert I still can't wait to see what they put together so I hope others do take the time to take some of these forces they put together. We just had a question come in and this one is for Dr world curio. Will there be an option someday through farm GKB to create a CPIC inherent patient specific report with medication recommendations similar to what we see in a commercial pharmacogenomics report. So, you know, farm GKB is basically research space but we are working, we're just about to release a tool on the website, which you can enter the genotype through those pull down menus like I said for like all the genes that you might have information for from a test results, and it can pull up all the CPIC recommendations for you know, if you have to see nine that could apply to multiple guidelines to see 19 results applied to multiple guidelines. So if you enter those into this landing page, you'll pull up all the recommendations specific for those unit types that are entered. So it's, it won't be quite the same. I think type of report as a commercial pgx report, but it is going to be a report that that specific for that patient that really using exactly what's in the CPIC database. So the nice thing about farm GKB and CPIC is they work hand in hand, we're kind of one big team there. And so the stuff that you pull on farm GKB is exactly what's in the CPIC guidelines and in the database. That's wonderful. That's really good news. So one other question. And this is really a doctor called you, you touched on the star one variant issue. And so, for the real case scenario of a clinician who gets back a report. The clinician, where can the clinician go to evaluate whether the variants reported back are represent the fullest of variants that should be interrogated. And so they've got a working group where they Michelle may be the better person because she's involved in each one of these. But they, they put together a list of variants that they think must be tested there's a tier one and tier two. I think these are all publications in themselves so you can go to PubMed and probably easily find these recommendations or the AMP website I'm sure they have them. But they've got these, they're all from farm GKB and on farm GK farm GKB has everything. It's the one stop shopping there. But yes, that's a great list. I do recommend that you do the tier one and tier two. I think that's, I think that would be recommended these days, but they did base some of that off of the availability reference. So there's a lot of things that went into those decisions about the testing and which alleles to include but I think most laboratories should be doing tier one and tier two. We have several more questions coming in. So regarding back to the report on farm GKB that we just discussed. Will that report be patient friendly. Also, as well as provider oriented. So the initial release is going to be more. Yeah, researcher are provided or provider oriented not really for patients directly yet. But that's, that's really an important issue because so much of healthcare is going, you know, it's becoming transparent right with patient. Patient friendly lab results available on my chart, for example, so, you know, and patients are getting absolutely well yeah we'll have to work on that just because it's more of language issues so it's making sure that we're using language that's appropriate. Okay, there is a question. Are there online free pharmacogenomic courses for basic pharmacogenomics that are recommended. I know there's a lot of certificate programs out there I'm not certain how many of them are virtual versus in person but I do believe you do pay for all of them. We're going to have a CC peg resources though we're going to are free. And I do believe it's it's pretty basic on to the more advanced so I think that would be a great place to start and St. Jude also has a website where we also have competencies that are I think really great and easy to access as well. And those are also freely available. One more question this is, is there a recommended timeline for introducing mandatory mandatory pharmacogenomic training into medical school curriculum. I really think pharmacogenomics should be really integrated into any pharmacology class. I don't know how much of that the medical students get. But they certainly need to be learning a bit more about pharmacogenomics within their curriculum is being taught in pharmacy schools now, sometimes within the curriculum but then sometimes it's a course on its own, but either way, it really needs to be worked out. So that brings us to the end of our questions coming in from our attendees. If you have any more questions go ahead and type them now. Thanks being none I think that's the end of our Q&A. If you have any questions or anything please please feel free to reach out to CPIC or form GKB that we both have links on our website where you can submit questions.