 Good morning everybody, no, hello everybody, I recognize it's not the morning anymore. My name is Serene Haydar. I am the clinical pharmacy, one of the clinical pharmacists at St. Jude Children's Research Hospital and I did the implementation along with my team members for the implementation of pharmacogenomics at our institution. What we're going to talk about today is about the clinical, just clinical pearls for implementing a pharmacogenomics if you're interested or are about to start or have recently started implementing pharmacogenomics, what are things that you should keep in mind or things that we have learned along the years that may help you as you're going through your implementation story. So throughout the next hour what I'm going to talk about is really, I'm going to discuss three stories. The first one is going to be how to report incidental findings and have a process for discussing familiar implications of pharmacogenes and pharmacogenomic testing. The second story we'll talk about is how to update pharmacogenomic test results and considerations for that and finally we'll end with adapting and migrating to a new electronic health record which is something we had to deal with at St. Jude over the past year and a half. Just quickly before we get started I just wanted to give you a landscape of what St. Jude's pharmacogenomic program is. The protocol that we currently genotype patients or the majority of our patients on a protocol called PG4Kids, the goal of this research protocol is to migrate pharmacogenomic tests from the laboratory into routine patient care for the results to be available preemptively into the medical records as well as for clinicians to utilize this information routinely as they are thinking about pharmacotherapy in our patients. Sorry to interrupt, your video is off. Oh, my video is off. Can you see me better? Can you see me? Yes. So we elected to return and genotype patients on a protocol instead of clinical care because we started this program about 13 years ago and we wanted oversight from the IRB for incidental genomic findings that could have occurred as well as oversight from the IRB to have a process because we were currently are also withholding results for pharmacogenomic tests that are on our array until they become clinically actionable. So our process is as follows. Patients who are eligible for genotyping are approached by a group of trained research nurses who approach the patients and discuss pharmacogenomic testing with them. Patients are, there's a consent discussion that occurs with the patients and their parents at their minors after which genomic DNA is obtained from a blood sample. The patients are then genotyped on an array of pharmacoscan array by Thermo Fisher. We receive about 1200 gene test results on this, on this array. The majority of the genes remain in a research database and are migrated into the electronic medical records when they are available, when they are clinically actionable and then migrated into the EHR where they are available for clinical use, available for clinical decision support, and at that point we return results to prescribers and provide patient education about the results. We currently return results for 15 pharmacogenes. We did not release every, we did not return all these gene test results at once. We started with two genes in 2011 which are the two genes we were the most comfortable with and then added on over time and availability of CPIC guideline and as the evidence for pharmacogen, for relationship between a pharmacogen and the drug became strong in the medical literature. So we are at 15 genes that are implemented. We currently, we have implemented length 74 drugs to these genes over time and we'll talk about them. We've had to update pharmacogenomic information. So we've genotype, we've linked 74 genes to, 74 medications to 15 genes but over the, over the years have had to unimplement certain medications and these are the ones that are in red that are crossed off with a year that they were D or unimplemented at our institution. The first story we're going to talk about today is how to deal with familiar implications of pharmac, after pharmacogenomic testing. So just to kind of understand where familiar implications comes, these are the genes, these are the most common pharmacogenes that are available currently in clinical practice. The first one that I'm going to talk about related to familiar implications about pharmacogenomic testing is related to G6PD because G6PD is located on the X chromosome and this allows us or causes us to be able to identify or have suggestive findings of sex chromosome abnormalities. So the only gene that is currently the only pharmacogenes that is on the X chromosome is G6PD. So just a quick overview about what G6PD is. G6PD deficiency is an X-link disorder that manifests as patients developing hemolytic anemia most of the time when they have a triggering agent or exposed to certain stress, foods or medications that can cause hemolytic anemia. It is the most common genetic disorder worldwide about 400 million people globally are thought and estimated to be G6PD deficient. It is most commonly seen in Africa, Southeast Asia, the Mediterranean area, and the Middle East. So why are we talking about G6PD deficiency as a pharmacogen? So as I mentioned, G6PD is located on the X chromosome. So males will have one copy of this gene. So it's easy to assign a phenotype for these patients. Males will have a single allele and one allele will determine the phenotype that the patient has. Females have two alleles, which means that we will... That the relation... Both X chromosomes are important in determining genotype for patients, for female patients, and then when we find... When we have a patient who reports as a female and we know how to X chromosome, it is expected that we will have two alleles for the G6PD gene. And then what usually happens is that... And not usually what can sometimes happen is when we have male patients who are phenotypic males and we have two X chromosomes reported on them, which means that these patients are supposed to have one X chromosome, they have two, and then the question is what do we do with that? So just defining that the patients may have an extra X chromosome after confirming, obviously, that the results from the lab are actually correct and there was not a sample mix-up. So what does it mean for a male patient to have two X chromosomes? This is a syndrome known as Kline-felter syndrome. So 47 XXY is one of the manifestations of Kline-felter syndrome. It is a chromosomal condition that affects males, physical and cognitive development. These patients tend not to produce enough testosterone, they have delayed puberty, they have breast enlargements, and fertility is also a hallmark of Kline-felter syndrome. Children who usually are younger tend to have learning disability, delayed speech, delayed language development, and compared to individuals who have an XY karyotype, patients who have Kline-felter syndrome are at increased risk of female-related disorders such as breast cancer, systemic lupus and osteoporosis, and throughout their lifetime will have to be monitored for these conditions, which is something that you also would evaluate in a male patient that probably less, because of the lower incidence, it is not something that people will tend to think about. So we consider, and the medical community, considers Kline-felter syndrome as an incidental finding when you're genotyping patients for G6PD and you notice and you find an extra X chromosome. But what is really an incidental finding? By definition, an incidental finding is a result that is not related to the indication why the test is being ordered, but nonetheless it may have medical value or utility to the clinical team and to the patients. Incidental findings are commonly referred to have different names. The most common terminology that you will see would tend to be either secondary findings or unanticipated findings or an unexpected positive finding. Incidental findings in pharmacogenomics are more likely to be discovered when panel pharmacogenomics testing is ordered, as opposed to single gene, because when you're going to do a single gene test, it is easy to explain to the patients what are the possibilities of us finding certain results that we may not have expected. When you do a panel test, there's a lot more genes that are going to be reported, and this tends to be the context in which patients are discovered to have client filter syndrome. Our experience at St. Jude has been with X chromosome abnormalities. We have genotyped about a little bit more than 6,000 patients on our PG for Kids protocol. We have had four phenotypic male patients who have had a suggestive finding of two X chromosomes. They had a 47 XXY karyotype. All patients were younger than 18 years of age. We discussed with their parents the possibility that the patients may have client filter syndrome gave them the option of confirmatory testing and also patients have been confirmed as having a client filter syndrome. We have one phenotypic female patient with one X chromosome and one Y chromosome who has diagnosed, who also had a flyer syndrome. If you are going to consider genotyping your patients to determine a G6PD phenotype or their G6PD status, this tends to be our recommended steps of action for managing patients who may have either client filter syndrome or any of the other sex chromosomes related abnormalities that may occur on, in our case, the X chromosome because of G6PD. So, first step would be that if a patient has a suggestive finding for G6PD to inform our process, it's to inform the genetics team as well as the primary care teams of the G6PD genotype finding. Pharmacogenomic testing at most institutions, including ours and most clinical laboratories, is a clear certified test for pharmacogenomic testing. It is not clear certified for karyotype testing, so there's a need for confirmatory testing to confirm that a patient may have client filter or confirm that a patient may have an extra or missing X chromosome. So, after the genetics team and the primary care team are informed of the finding, we sit down and offer genetic counseling to the patients and their family members. If they do consent to consultation with the genetic counselor, then the genetic team will counsel the patients on client filter syndrome offer confirmatory testing, and when confirmatory confirmation of client filter syndrome is obtained, the patients are referred to a specialized team for follow-up care, such as with endocrinologists or follow-up for other age-appropriate follow-up tests for patients who may have client filter syndrome. So, this is the first case that I wanted to discuss, patients in whom we may discover sex chromosomes abnormalities when we're genotyping for G6PD. The other case I wanted to discuss is the case of malignant hypothermia and familial implications to pharmacogenomic testing. So, let's discuss this as a case. A six-year-old boy who undergoes preemptive pharmacogenomic testing is found to have a high-risk variant in the RYR1 gene, and this high-risk variant predisposes the patients to developing malignant hypothermia when they're exposed to triggering agents and we'll get into that in a minute. The patients and the three siblings have not had pharmacogenomic testing ever in their life. So, for those of you who may want to refresher on what malignant hypothermia is, it is a potentially fatal disorder that occurs due to an acceleration of metabolism in skeletal muscles. It leads to a prolonged contraction of muscles which can cause muscle destruction. Rhabdomyolysis can lead to tetany, fevers, and patients can die because of it. It is a genetically-inherited disorder in two genes that we know of at this time, RYR1 and CATNA1S. These two genes have an autosomal dominant pattern of inheritance. So, people who have a high-risk genotype have inherited one high-risk allele are at risk of having that susceptibility. And if a person has that one high-risk variant, it means that one of their parents has passed this down to them, meaning that one of these parents is also susceptible to developing malignant hypothermia. So, as we were thinking about how to return RYR1 and CATNA1S, there were some key considerations that we thought that we had to think about. So, it's important if you are going to return these two pharmacogenes to have a process set up and approved at your institution before you start returning these results. If a patient, should your institution offer genetic counseling for the patient's family member because this is a gene that has an autosomal dominant inheritance pattern. If you find a patient who has this high-risk, potentially fatal condition, what is your responsibility? What is our responsibility as an institution? Should we offer counseling to the family members and let them know that they may be at risk? So, should we offer counseling? Which family members should we offer counseling to? Should genotype testing of family members be offered at our institution? Or should we just inform them that there's an option for genotype testing and who will perform that? Where will that be performed? Where should the testing occur? And again, who is going to pay for the genetic testing for the confirmatory testing in the family members? So, what we elected to do at St. Jude is that we will offer genetic counseling and confirmatory testing at our institution We will offer cascade testing, which means testing of all the patients first-degree relatives, so mom and dad, and full biological siblings. And testing will occur at our... The testing cost will be assumed by our institution. So, this patient that we had, the parents decided to undergo pharmacogenomics testing and confirming pharmacogenomics testing to the whole family. The patient had two sisters, a brother and obviously, and at the time mom and dad were available. So, they all opted for genotyping, and it was found out that dad and one of the sisters was also a carrier of that high-risk R1 genetic mutation that the patient had, which meant that all three individuals were also genetically predisposed to developing malignant hyperthermia if they're exposed to triggering medications such as inhaled fluorinated anesthetics or succinylcholine. So, after we found out about the results, we counseled myself as well as the genetic counselor, sat down with the patient, and discussed what it means for the patient, as well as the family members to have this R1 genetic mutation and offer genetic counseling related to that. So, again, what are our recommended steps or the steps that we have created for managing pharmacogenomic test results that may have familiar implications? Once we receive the pharmacogenomic test result, if it has a familiar implication and it's a high-risk result, the first step for us is to inform the primary care team and the genetic counselors of that high-risk pharmacogenomic test result. We return the results to the patient, offer genetic counseling to the patients and if they would like to speak to a genetic counselor to learn more about family inheritance patterns of this high-risk result. And then if the patients agree to genetic counseling, genetic counseling is performed as well as confirmatory testing within our institution. So, these are just two examples of familiar and incidental findings that are related to pharmacogenes. There are others that I wanted to quickly mention. Genes that have dominant expression patterns include MTR and R1, HLA and NHLA, in addition to R1 and CSNZ1S that we discussed, and then the gene that is linked with X-linked inheritance is D6PD. What are key takeaways to take out of this first story for familiar implications of pharmacogenomic testing? So, just remember that most pharmacogenes have a co-dominant inheritance. They are not dominant genes, so there's no direct implication for family members. Some pharmacogenes, as we discussed and showed, have dominant inheritance patterns that have familiar implications, and it is important to have a process set up and approved by your institutional leadership and oversight committees before you start returning these results to patients. So, moving on to story number two, how to update pharmacogenomic test results. So, we have been genotyping patients for about 13 years, and as you can imagine, pharmacogenomic testing and not just the testing platforms, but information related to interpreting pharmacogenomic test results has changed over time. So, we currently report pharmacogenomic test results in the lab sheets and the flow sheets of our medical records, and we made the decision many years ago when we started this process that clinicians may not necessarily understand what a, let's say, CIP-2B6-STAR-2-STAR-5 genotype is. So, every single one of our results is coupled with an interpretive consult that is written by a pharmacist that is associated with each one of these results, and for example, you will explain what the phenotype assignment is for that patient as well as explain clinical implications of that test result. So, also, what we do is that whenever we return the results, place them in the medical record, in addition to the consult, we also add phenotype-specific genomic indicators and problem miss entries into the EHR as applicable and when it's applicable to add that information. So, over time, we've had to create a process for updating pharmacogenomic test results, and this process is led at our institution by the pharmacogenomics program, and it includes information such as updating the patient's phenotype when applicable, updating the interpretive consult note that I just showed you. We, once that interpretive consult note is updated in the medical record, it shows up in the EHR as a corrected result. This is the only capability that you have in the medical record system to update information that is already posted, and so the information that we update in the consult note includes the phenotype, the activity score, as well as the ideal function, as applicable to the update and to the specific updates. We also update the genomic indicator if the phenotype of the patient has changed and also update or add a pharmacogenomic problem is when applicable, depending on the change in phenotypes. Clinicians and patients are notified of the update only if a phenotype change occur. If an activity score changes but the phenotype hasn't changed, we tend not to inform patients and the prescribers because it's going to confuse them a little bit more and it's not clinically actionable. So, we have worked on updating phenotype-specific results in the medical records for the clinicians, so in our current EHR, but also made it a point that the patients also be able to see their updated results in their online portal, so they are also available in the portal and when the results are updated, patients get a notification in the portal that says that their pharmacogenomic results have been updated. We decided that we will update any results on any patient who remains enrolled in our protocol and is alive, irrespective of when the original test results was generated. We had a lot of discussions about this through discussing what is our responsibility. Should we update the results from 10 years ago? Maybe the patients are not looking at their portal. They don't even know that they still have a sentient portal. What should be done with older results? We decided that we will update results independent of when they were generated at the institution. We published on this about four years ago. In June 2019, most of the results that we had updated were related to CYP-2C19 and a phenotype change in CYP-2C19 for the ones of you who are in practice then, if you remember, there was no CYP-2C19 rapid metabolizer phenotype. There was only a CYP-2C19 ultra rapid metabolizer phenotype. About 3% of all of our results had to be updated to assign the new CYP-2C19 rapid metabolizer phenotype in the patient category. Again, we went through all the updates and updated the consults, the genomic indicator, the problem list, as well as notified clinicians and patients about this update. Flash forward five years, four years now, and we are again dealing with an update to the CYP-2D6, so not CYP-2C19 this time, but a new update. In November of 2022, there was an update to the ideal functionality of some CYP-2D6 variants that are listed on this slide. The platform that we currently use, which is the Pharmacoscan platform by Thermo Fisher, interrogates two of these ideals, Star-9 and Star-41, and this update led to a downgrade of activity score for CYP-2D6 Star-9 and CYP-2D6 Star-41, where the activity score was downgraded from 0.5 to 0.25. Nearly 16% of the patients that we genotype for CYP-2D6 would have had an activity score update based on this Star-9 and Star-41 change and an allele functional assignment, and so this is where you can see it on our patients. We would have we will have a process to update these consults and the wording and the activity score that is mentioned in the consult for the 1,000-plus patients who are affected. However, the good news is this does not result in a phenotype change for 1,000 patients. It actually only resulted in a phenotype change for three patients out of the 1,030 patients who would have had the Star-9 Star-41 and yellow. So it's not a huge change a huge number of change in phenotypes it is mostly a downgrading of activity score that does not change phenotype and so it's not very at this time clinically burdens for clinicians as well as patients because they're not going to have a phenotype change. So the question I get routinely asked about is well, how do you know that there are patients genotypes? How do you know that there are updates that are available? How do you know that Star-9 and Star-41 were downgraded? And so there's two places free to go if you want to do this. The first place is if you go to the CPIC websites on the bottom right of the screen click on contact which will be as one of your tabs and you'll be directed to this page that shows you options for CPIC communication click on the where it's under I want to get announcements. This is a link. This is a sign up email that functions even if you're not a CPIC member. So sign up you'll get email notifications whenever there are new guidelines that are published, whatever there's CPIC news or whenever CPIC wants some feedback. You don't get a lot of these emails so don't think that you're going to be spammed. It is only tailored to whenever there is something that is important to announce through the CPIC website through CPIC. Another place to get that information from is going to FarmGKB. So if you were on the earlier MedGNED talks and NHGRI talks from this morning you would have heard Dr. Cotto and Dr. Will Carrillo talk about CPIC and FarmGKB. If you go to the FarmGKB website again bottom right of your screen here scrolling all the way down to the bottom of the website there is a link there is a button that says get latest news by email and you'll receive the latest FarmGKB blog news and again you don't get tons of them you won't get spammed it is just when there's information that is important to circulate out to the membership and the people who have signed up to email. So this is usually how the majority of us in the community know about an update in phenotype changes or updates to guidelines or new CPIC guidelines that are published. So key takeaways for update of pharmacogenomics test results keep in mind that over time as information matures in the medical literature there is a possibility that the leo functionality and phenotype assignments of certain pharmacogenes may be changed. Consideration should be in place for when to update results, how to update results and interpretation of these results as well as how to discuss them with prescriber and patients and how to notify patients about them and how to update the CPIC and FarmGKB communication emails are a tool to learn about these pharmacogenomic updates. So last story we're going to talk about is lesson learns from adapting to new EHR so at St. Jude we started returning preemptive pharmacogenomic test on an institution-wide basis back in 2011 as I mentioned earlier we genotyped to release two genes into the medical records when we started the EMT and CYP2D6 so and then and then quickly added eventually added other genes by the time we migrated to a new EHR in October of 2022 we had 14 genes that were already fully implemented into the medical record system and then we were told in October 2022 that this whole thing is changing we were going to switch to another EHR add these 14 genes that we had already implemented we were implementing a new one at the same time at the EHR switch and then there was the shift to the new EHR so what was asked for us and it took about 18 months was really recreating a 10 years period worth of implementation from one electronic health record into another one we created about 200 close to 300 post-test alert rules that had to be recreated in a new medical record system about 30 pre-test alert rules were recreated and then other in-basket notifications had to be created and this was something new for us something that we quickly learned is that the logic to create notifications and interruptive alerts in the medical record system although the logic is the same there are specific things that are different between one EHR and another we learned that we could not combine multiple drugs into a single rule meaning that if we were going to write a logic saying if a patient is an ultra rapid metabolizer of CIPTC-19 for example there are recommendations to adjust the dose of voriconazole and proton pump inhibitors but the alert could not be written so that so that each PPI and voriconazole were embedded in one alert and we had to create new ones which is something that was we had to create individual ones which was something that was different for us the other thing that we had to switch from was transitioning from problem lists into genomic indicators so we previously had used only problem lists to return pharmacogenome to post and display high-risk pharmacogenomic test results in the medical record we now display all pharmacogenomic phenotypes in the genomic indicators section so this was a switch for us because we used the only return high-risk pharmacogenomic results in the problem list whereas the genomic indicator we would also return normal metabolizer phenotypes to normal risk phenotypes and so we thought that's a great place for any clinician so one stop shop to see the phenotype of every patient did that on every patient and then on probably week one of implementing a new medical record system we had a patient who had a g6pd activity test that was returned as deficient so previously in our old medical record system we would have returned we would have placed a g6pd deficient problem list in the medical records in this case because we moved from problem list to genomic indicators we put we added on this patient a g6pd deficient genomic indicator and then as we did this because the patient had a deficient activity test a deficient genotype test we quickly noticed that the things that we had put in place did not really work for patients who were deficient by activity testing because our genomic indicator section as it indicates is an indicator for genomic testing and all the information that we have related to our genomic indicator relate to patient education and prescriber education about genotype testing including a statement in the result in the notifications that we sent patients and where we tell them you have been the test was performed to look at variations in certain gene and g6pd was one of these genes which made this note incorrect in our patients so what we did notice is that we needed a problemless entry for g6pd deficiency and not a genomic scenario where there would not be a genomic indicator needs in patients who are found to be g6pd deficient without having been tested for g6pd by genotype testing so we did that and then noticed that when we created this we also had to have our decision support alerts fired differently we wanted a patient who was g6pd deficient to have an alert notifying them that they should not receive high risk medications that are related to g6pd however our current CDS alerts do fire off of genomic indicators so we had to modify the logic for our decision support alerts in patients who are g6pd deficient to also look for a problemless entry because you could be g6pd deficient either by testing a few g6pd genotype but also more commonly by g6pd activity testing in the same scenario applied to malignant hypothermia where a patient could have been susceptible to developing malignant hypothermia either because they had a strong family history of that or they had a personal history of being exposed to a triggering agent and develop malignant hypothermia or maybe just because they were susceptible to developing malignant hypothermia because they had been genotype for pharmacogenomics but had not had the MH episode themselves but still we needed to notify clinicians about it the same also scenario applies to TPMT where there are institutions that perform TPMT genotyping and others perform TPMT activity testing if you do perform TPMT activity testing this activity test is a surrogate of whether the patient has a mutation or a variation in their TPMT gene but again it is not a genotype test result and you have to accommodate for that when you are working on different scenarios for notification and for return of results for patients key takeaways for adapting to new EHR section is really to look at to consider CDS alerts when so the logic for CDS alerts are pretty similar but you have to early on when you are thinking about changing electronic medical systems to work with your informatics team to work with your CDS experts to be able to for them to to work closely with you to explain the capabilities, limitations and enhancements of the new system that you are going to work on and also consider how to display results that have pharmacogenomic implications but are not obtained for pharmacogenomic testing and in this case it would be in our case it was G6PD, malignant hypothermia as well as TPMT activity so this concludes the end of my talk I wanted to just mention a couple of things I am one person sitting in front of you guys talking about this but this is a group effort there are many people who contribute to the pharmacogenomics program at St. Jude's some of them are mentioned here but it is definitely a team effort that everybody works together and so for my end this concludes my session but I just want to quickly thank you for attending and being part of NHGRI's health care education week there are many more education sessions throughout this week there are today's only Tuesdays so Wednesday, Thursday and Friday also have specific topics if you go to the NHGRI website you will be able to see that information if you check on the chat Donna has placed a link to the NHGRI recordings that are available one of which tomorrow is nursing genomic education day and so there is an FAQ about there is recording and presentation about what nurses should know about genomic testing as well as on Friday related to rare diseases and rare genomic diseases so with that I will conclude and check to see if you guys have any questions and thank you very much for listening in so the first question that came up is that is thanks for this great talk. Approximately how many patient family members require confirmatory testing at St. Jude per year and what is the institutional budget for this? I would say that about we probably have one patient a year or one patient maybe every other year who has to have confirmatory testing for this for mostly RYR1 and CACNA1S G6PD activity, G6PD testing for confirmatory tests because G6PD testing is a common test that can be easily performed at many institutions we do not perform G6PD activity confirmatory testing until patients to go see their prescriber for that for RYR1 and CACNA1S it's about a thousand dollar per test for both tests for RYR1 and CACNA1S so about a thousand no more than two per year or every other year. Any other questions? What EHR system? We are currently in the EPIC EHR system we were previously in the CERNR medical record system so this has taught us to be able to talk about both medical record systems and have a great collaboration with both of them actually. So while we are waiting to see if there are other questions a couple of things that we have learned over the years is that the return of G6PD results the return of results related that may have familiar and incidental findings is something that patients ask questions about the advantage of pharmacogenomic testing unlike Mendelio genetic testing is that patients are genotyped for pharmacogenes meaning that we will we explain to them that pharmacogenomics is a test that really will only tell us how their body is able to handle medications rather than this test will this test may tell us if they have if they're predisposed to developing a certain pregnancy or Huntington's in the future so we've had pretty good acceptance rates for parents to want to genotype their children because we're a pediatric institution and and so there's advantages to performing pharmacogenomics testing that is targeted rather than disease genomics because it is just related to medications and this is something that has helped us another question is is your CDS and response information in all epic systems nationally are you sharing content so we at the time that we went live with epic we a couple of institutions that we're already implementing pharmacogenomics epic EHR system have gotten together along with epic and we created and under the oversight of epic created a pharmacogenomics brain trust that comprises groups of institutions who have implemented pharmacogenomics within the epic EHR system and we are working with epic to make to work on their pharmacogenomic package and to make it available in the foundation system for epic so that it's available nationally and internationally content yes is being shared by us being shared by others and epic has a lot of this content at this time if it is not yet in foundation system it will be it just depends on what information you're looking for and whether it has already been rolled out into the epic foundation system with the epic quarterly update I think we're going to end with that if you have any questions my email information is available on the slide is available you can always email me I've ready I posted it on this earlier at the end of this presentation I'm always happy to help and thank you very much for NIH and NHGRI for hosting the session it's always interesting and really nice sharing information and comparing information with all other healthcare practitioners thank you and have a good day everyone