Okay, well thanks for having me today. I think I saw in the, I was billed as an MD-PhD, so while I appreciate the honorary degree, only a PhD and an MS, and I'm basically a bench scientist who does a lot of translational research. So that's my perspective. I'm going to talk a lot about molecular pathways and that sort of thing today. So anyway, let me launch in. I'm going to talk about pharmacogenetics today. And I think probably one of the best compelling stories for pharmacogenetics is this paper right here. It's a case report about a two-year-old boy who went, underwent a tonsillectomy. After his surgery, everything went fine. He was an outpatient. He went home, took codeine to manage the pain, and died a couple of days later of respiratory depression. So didn't really understand why this had happened according to the paper because he had taken the correct amount of pills. There was nothing, no overdose due to the pills. But somebody got smart and genotyped him and found out that he has, instead of two copies of a gene that activates codeine and demorphine called CYP2D6 right here, he has three copies of this gene. So everybody inherits one chromosome from mom and dad. In general, you have two genes. This kid had a duplication on one of his chromosomes that gave him three copies. So he was considered an ultra-rapid metabolizer of codeine and demorphine. And while there's probably about 5% of the U.S. population has this ultra-rapid metabolizer genotype, this probably indicates that this kid had some other confounding issues. It wasn't just that, nonetheless, had he been genotyped, codeine would have been avoided and he probably would still be alive today. On the other side of the coin, people go to the dentist. They get dental work done. They are given codeine to manage the pain when they get home. They go home. Sometimes they take the codeine and it doesn't really have much of an effect. This is because there's a lot of people in the population who are deficient in CYP2D6 and cannot turn codeine into morphine. Codeine has very little analgesic effect. It's really the morphine conversion that is needed for that. So the same gene can cause inefficacy and it can cause severe toxicities. So I work at the NCI, so a lot of my slides have cancer drugs on them, so this is no different. There's a lot of variation in most drug therapies, especially in cancer. But you can see three to 50-fold variation in certain drug therapies and this variability is partially oftentimes attributed to genetics but not always, which leads to the next slide. A lot of people in this room can probably think of more sources of variability, but I'm just going to go through them each here. So drug-specific dose, schedule, the dosage form, how the drug is formulated, et cetera can affect the variability, body size, body composition. Demographic variables such as age, race, sex can affect drug therapies. Physiologic, especially disease states, hepatic and renal function can affect how drugs are handled in the body. Environmental interactions like drug-drug interactions, drug-food interactions, these sorts of things can affect. In genetics is just one of these many variables that will affect drug therapy. So we see this more as a useful tool and not the end-all be-all of determining variability in drug therapies. Now sometimes the genetics is extremely important and sometimes it's not important barely at all. So today I'm going to be primarily talking about cases where the genetics really contributes a lot to the variability and is actually useful for making clinical decisions. There's several types of pharmacogenetic endpoints that we use at the NCI. Like I said, I'm more of a wet bench kind of guy, so I've been handling a lot of the – mining a lot of the samples in our clinical pharmacology program, primarily from cancer patients. And we will notice from time to time that there is an association between a gene SNP and some sort of clinical outcome that we can then go and figure out why this is happening. So here we had a group of patients with prostate cancer treated with dosetaxel. We found that a polymorphism in a gene, CIP1D1, was related to the outcome. So men carrying the wild type, Star-1 SNP, had a double overall survival compared to people carrying the Star-3 SNP. This gene does not metabolize dosetaxel, so we had to do a little investigative work to figure out what was going on. We found out that estradiol is actually metabolized by CIP1B1. CIP1B1 is also up-regulated in almost every single prostate tumor. Those carrying the Star-3 allele turn estradiol into a very reactive metabolite that binds to dosetaxel and adducts it. And this form of dosetaxel is not very potent at all. It also interferes with microtubular polymerization because this reactive form of estradiol will bind to practically everything in the cell and it really likes the sulfhydro groups on tubulin. So we never would have found this interaction without the use of pharmacogenetics. So we use it in a discovery capacity. We're also doing a lot of clinical trials at the NIHs, I'm sure you will know. And so we're often looking at variation in phenotype. So there's a molecular pathway that feeds into a variation in phenotype. So here we were studying an investigative drug that was shown to cause QT prolongation. We knew the drug was handled by a transporter that existed in the heart and basically the transporter functioned so that when the drug got into the heart it was pumped back out. Patients who were not able to pump the drug out as effectively because of a genetic polymorphism are shown here. They had QT prolongation whereas patients who were more effectively able to pump the drug out had barely any at all QT prolongation. So here we're looking at variation in phenotype. We had the molecular pathway sort of characterized. Now both of these feed into clinical trial inclusion and exclusion criteria. You can take people who are responders, non-responders or you're going to get significant toxicities. You could take them out of your population and treat them with other sorts of drugs and subset your population for people where you think the drug is going to be more effective. And all of this of course leads into actual translation of these findings into clinical practice. So today the objectives are to review the molecular and physiological basis for drug-drug and our gene-drug interactions to appreciate the impact on drug therapy to discuss the future of pharmacogenetics and drug development and treatment. So basically I'm going to sort of give you a bird's eye view of pharmacogenes and what they do. I'm going to talk about how the molecular pathway will alter phenotype which will then alter drug therapy. And then at the very end of the talk the NIH has instituted a pharmacogenetics program where a patient comes into the hospital, they're genotyped and that genotype follows them around the hospital in our computer system. So if a doc wants to give them a drug they will have to put it into this system. The system will flag if there is a genetic issue with administering that particular drug. So I'm going to talk about the drugs that we've flagged as important at the NIH at the end. So just launch in with the types of pharmacogenes. So probably when people think of pharmacogenetics they tend to think of these sorts of interactions where you have phase one metabolism which tends to be just redox reactions that oxidize drugs, sorry the arrow got scooted over there. So here you just have a drug that's oxygenated and it becomes more polar. Now this can have two effects. One it can activate drugs like with codeine but in general it deactivates drugs and makes them more soluble, readily excretable. Phase two metabolism is also the chemical modification of a drug. Here you take a polar R group and add it onto the drug so you have drug, drug R, the R is polar it's more soluble and easier to detoxify the drug. Before I go into the SIPs that I'm going to talk about it's helpful to think about what are the major SIPs that metabolize most of the pharmaceutical armamentarium. In general it's SIP 3A4, 3A family probably metabolizes 40 to 60 percent of the drugs that are available right now. This is an old slide but little has changed in the last 13, 14 year. This gene really does not have very many genetic polymorphisms that are very predictive. So I'm not really going to talk about SIP 3As today, however the next two most frequent metabolizers of drugs SIP 2C9 and SIP 2D6 do have some very important genetic variants that will alter their activity so I'm going to talk about those today. These two metabolizing enzymes tend to be the UGTs. You have these UGTs in the liver that glucuronidate drugs and make them more readily excretible in the bile and urine. Then your sulfal transferases and then a host of others that are more or less important in the major metabolism of multiple drugs. I'm going to talk about TPMT today, even though this is a very small sliver this particular gene is quite important in pharmacology. So I'm going to give you the first example here, SIP 2D6 and Tamoxifen. So I already mentioned CIP 2D6 will activate codeine, SIP 2D6 actually also activates Tamoxifen. When Tamoxifen was developed people were thinking I believe that the NDM or the 4-hydroxy were the major metabolites that were actually active. Relatively recently some studies at Georgetown proved that it was endoxifen. It's really the active compound of Tamoxifen. It's formed through endosmethyl Tamoxifen which I'm going to call NDM and it forms this compound which is 3 to 100 fold more active than Tamoxifen or NDM alum. Also when Tamoxifen was being used people noticed that SSRI actually inhibited the hot flashes that people would experience when they were undergoing Tamoxifen therapy and I don't think people really understood why until recently when they found that really what they were doing was inhibiting the enzyme that formed the active metabolite so you had less active metabolite and less hot flashes due to that. So it's kind of useful to think about how does the population break down in terms of 2D6 genetics. We would expect just to back up that people who were deficient in this would have more endosmethyl Tamoxifen to endoxifen ratio. People who were very rapid would have more endoxifen to NDM. The poor metabolizers who do not form as much of the active metabolite comprise probably about 10% of the population roughly and they're at the top right here. On the bottom right you'll see about another maybe 5 to 10% who are ultra rapid metabolizers. They form a lot of endoxifen and the drug is actually probably more effective in these people especially. When the drug was developed though these two extreme ends of the genetic spectrum here were not the general population. The drug was really developed for people sort of in the middle and the people at the ends unfortunately don't benefit as well for the drug or they have more hot flashes, more toxicity to deal with. So you know this is how the population breaks down. Go ahead and talk about the plasma concentrations of the drugs now. So if you look at the endoxifen to NDM ratio and you take the population, you look at their plasma concentrations, you put it on a normative plot which is sort of the statistical method to figure out what groups of people comprise this population. You'll find four bell shaped curves that are very distinct of endoxifen to NDM ratio. These people on the left end here have little endoxifen to NDM, these have high endoxifen to NDM. So what you would expect then that if CYP2D6 was really an important genetic predictor of endoxifen concentration that you would see this curve enriched for poor metabolizers and this one enriched for rapid metabolizers. And that's exactly what you see. Draw your attention to the right hand side of the table here. The poor metabolizers over here are the major constituents of group one which has low endoxifen. The ultra rapid or extensive metabolizers are those that comprise group four which have high endoxifen. Here's another way to look at the data and I wanted to point something out here. The poor metabolizers tend to cluster low on the endoxifen to NDM ratio whereas the extensive metabolizers are high on it. However, you'll notice how much the data really spread here. There are several extensive metabolizers that look like poor metabolizers. This is because this gene is not a perfect predictor of anything. However, it is still a very useful predictor. So if you look at patients with extensive metabolizing versus poor metabolizing, how long it takes them to have recurrent breast cancer, you'll see this where patients with extensive metabolism are benefiting much more from tomoxifen than patients who are poor metabolizers. So basically, we think that the poor metabolism group here really is not benefiting as much from tomoxifen. They should probably be given another drug such as an aromatase inhibitor or something else whereas people who are extensive metabolizers probably benefit more from tomoxifen than they do from other drugs. So when you think about this issue in terms of how does tomoxifen stack up with one of these aromatase inhibitors, for example, tomoxifen is causing a little bit more recurrence. However, this part of the Kaplan-Meier analysis here is composed of a lot of poor metabolizers who are sort of dragging down the efficacy of tomoxifen. And right now, studies are really trying to compare these two curves to see if taking poor metabolizers out of here and moving them to here will actually improve this curve. And some early data from one of these trials is indicating that poor metabolizers that are switched to anastrosol after two years of tomoxifen experience no increase in breast cancer recurrence. So the poor metabolizers who were switched are actually doing better than they would have done on tomoxifen is really the idea. So I talked about a phase one metabolizing enzyme, C2D6. Now I'm going to switch gears and talk about phase two metabolizing enzymes. And I'll talk about thiopurine methyltransferase and six more captopurine and its analogs. So thiopurine methyltransferase just simply methylates drugs and deactivates them through methylation. Sixth bicarbicaptor purine and its analogs are used to treat ALL, inflammatory bowel disease and autoimmune disorders. They're fairly heavily used in the transplant community as well, especially azothioprine in the transplant community. I'll mention that in a minute. These drugs basically just incorporate cytotoxic thiogwani nucleotides into the DNA which causes the cell to die. However, they also do a second thing. They inhibit de novo purine synthesis. So the cell is not as able to synthesize DNA and divide as it otherwise would be. So they're very good drugs. Sixth bicarbicaptor purine was heavily used in childhood ALL. And some of the initial pharmacogenetic studies actually were very concerned with this drug because this drug can cause severe hemotoxicity in childhood patients, can cause death. So St. Jude was very interested in it and it was heavily developed at St. Jude. So the TP-MT, which basically functions to take azothioprine which is converted into 6MP, right? And then it goes to either one of two fates inhibiting de novo purine synthesis or incorporating it into DNA and leading to cytotoxicity. But before they can do that, it will see a lot of TP-MT in the blood and other tissues where it just gets methylated and inactivated. So when the drug was developed, the dosing was based off of people who were very able to metabolize rcaptopurine through TP-MT and inactivate it. So the metabolism of these rcaptopurine drugs is decreased with polymorphic TP-MT variation by up to 200-fold. So 200-fold is a very large number in any therapy and it has a lot of cytotoxicity in patients who are not able to methylate it and get rid of it. And these are the kids that are really experiencing some very severe toxicity from 6MP. So I'll talk about the SNPs in a second. The rapid metabolizers are resistant to the drug. The slow metabolizers are at risk. So the rapid metabolizers are these wild type individuals who have functionals of TP-MT. They're about 80 to 98 percent of the population depending on which population you're looking at. The intermediate metabolizers, they carry one wild type allele and one allele that's not functional. And they're about 65, they need about 65 percent of the dose. But they have some toxicity, but it's not nearly as severe as this group down here of slow metabolizers who carry two copies of these two TP-MT deficiency alleles. And they require about 10 to 15 percent of the original dose. And if you're talking about kids, these people are also at risk for secondary malignancies. So if you give them these drugs in childhood, they can develop cancers later on because they were just administered too much for what they needed. I've just got some results back from the largest pediatric cohort treated with azothioprine. And the results are very positive. The exact same thing is going on with azothioprine as it is with 6MP. And the results should be published within the next year. So it's not only 6MP that's affected, it's these other drugs as well. And it's not just pediatric patients. It's also adult patients. Oh, by the way, I wanted to mention one other thing. The genetic variation in TP-MT explains 95 percent of these hemotoxicity issues with the 6MP. So all of this information is high level of evidence. I'll talk about levels of evidence in a minute. But it's made it into the package insert of 6MP, at least. And the package insert says substantial dose introductions may be required to avoid the development of life-threatening bone marrow suppression in these patients. Now, I'm not a clinician, but I have heard that there is not a lot of genotyping in these patients going on. And this is something that probably needs to be translated clinically to avoid some of these severe toxicities, especially in children. So I'm going to switch gears again. We'll talk about UGT-1A1. This is also a phase 2 metabolizing enzyme. Very important. It is involved... First, let me talk about the SNPs. These TA repeats in the promoter of UGT-1A1. Normal functioning UGT-1A1 has 6 TA repeats. A gene that carries 7 TA repeats is expressed much less effectively in the liver. And if people carry two copies of this allele called UGT-1A1 star 28, they have a decreased expression in function of UGT-1A1. UGT-1A1 is the primary glucuronidator of bilirubin. So these patients have a slight jaundice phenotype known as Gilbert syndrome. And this is about 10% of the U.S. population has this deficiency. There's some other SNPs also that are predictive. I'm not going to go through them, though. These SNPs explain about 40% of the variability in glucuronidation reactions as a whole. Glucuronidation is absolutely key in arenothekin toxicity. So arenotheking is administered IV. It goes into the blood. These carboxyl esterases cleave certain groups off of arenothekin that turn it into its active metabolite called SN38. SN38 is rapidly glucuronidated by UGT-1A1 and is completely detoxified when that happens. If a patient's unable to glucuronidate their SN38, the drug becomes very toxic and you can see some severe ADRs again. However, this is very dependent on the arenothekin dose. This is really what I wanted to bring up. At high dose, almost 100% of the patients who carry this SNP get severe hemotoxicity. Whereas, you know, a moderate amount of patients with wild type alleles get the hemotoxicity. However, if you go down to 125 megs per meter squared, this SNP no longer really matters at all. So this is a very dose-dependent situation. And so sometimes when we think of pharmacogenetics association, we have to consider other issues other than just the gene.  So arenothekin toxicity through glucuronidation reactions is made its way to the package insert of the drug. The package insert, this one says that the glucuronidation of Billy Rubin, such as those with Gilbert syndrome, people with that, will be at a greater risk of myelosuppression. I think the updated one actually does list UGT1A1 star 28 now. Switch gears from phase two metabolizing enzymes to transporters. I'm going to talk about one transporter in particular that's been very highly studied in the past five years and I think is on its way to making it into pharmacogenetics directed therapy. It's this OATP1B1 here. So a patient receives a statin, it goes into the gut, goes through the gut wall into the portal blood. It can be metabolized in the gut wall by CIP3A4 or pumped back into the gut wall by MDR1 and MRP2. Once in the portal blood, it basically needs to see an OATP. OATP1B1 is the primary transporter of simvastatin. There are some other OATPs that are very important. But unless this statin sees an OATP, it does not very effectively get into the liver cell. Once in the liver cell, it's metabolized and eliminated. Some of it makes it into the bloodstream and you have varying levels of AUC exposure in these patients. What happened there? Here's a slightly more complex version of what's going on in the liver cell. There's a SNP in this gene, a single-nucleotide polymorphism SNP in this gene that affects how much statin actually gets into the liver cell. The SNP is what's called a non-synonymous transition. In most people, it's the wild type allele. A position 130 gets changed to a D. And this actually has a great effect on AUC exposure of statins. We knew this back in 2006. A very good paper was published showing that this thing is heavily linked to the AUC of statins. Now, greater exposure to statins can lead to statin-induced myopathies. So in patients carrying the SNP that can't get their statins into the liver cell as well, you worry that they're overexposed and they're going to get a myopathy. Another study was published more recently looking at 500,000 alleles in the genome. I love this study. It shows that only one polymorphism was associated with statin-induced myopathy, and not only was it associated, it was several orders of magnitude over the association threshold, which is denoted by that brownish line there. This SNP is almost in 100% complete linkage, meaning it's co-inherited with that N130D SNP. So this SNP is probably just a passenger that's riding along with the N130D SNP causing overexposure to statins and statin-induced myopathies. This group also took these data into a validation cohort where they had cumulative percentages of myopathy, and they found that, again, they see the same SNP is about 20% of the patients are getting statin-induced myopathy, and about 60% of statin-induced myopathy cases could be attributed to this SNP. So this is a very predictive allele. And the present SNP has a 15% representation in the U.S. population. So this is a very frequent SNP. There's a lot of people getting statins that are probably at risk for myopathy just due to this issue alone. At this point, the FDA has not really weighed in on whether or not we should genotype for this one yet, but I think it's coming soon. And at the NIH, we are genotyping for this. I'm going to talk about targets today as well.   I'm not only going to talk about that today, because I'm really concerned more with the germline variation, the DNA that mom and dad gave us, not mutations in tumors. There are other types of targets that are subject to germline variation. And I'm going to talk about that instead. So, before I get to the targets, here are two cytochromes P450 that take warfarin and convert it into an inactive form of warfarin. So, these, more hydroxylation through 2C9 and CYP4F2 leads to less active warfarin in the bloodstream. But I'm not going to really focus on the CYP story. I'm going to focus over here. Warfarin is designed to bind the vitamin K-oxidoreductase C1. By doing so, it reduces the amount of reduced vitamin K, which reduced vitamin K is pro clotting function. So, warfarin binds to this target. There's a snip in this target gene, VK or C1, that causes the expression of the gene to go down by many fold. So, if a patient lacks sufficient expression of VK or C1, warfarin will bind it all up and cause bleeding events. Brief aside on CYP4F2, it was fairly recently discovered using a platform I'm going to talk about in a minute called the DMET platform. Here's the association. It's very strong. The FDA has again not weighed in on this one, but I think it's going to be up and coming. So, here's the incidence of warfarin sensitivity. I like this paper a lot, showing basically what causes warfarin sensitivity in the general population. And you can see this sort of red-pink piece of the pie chart and this yellow piece of the pie chart correspond to CYP2C9 and VK or C1. So about 40% of warfarin sensitivity in the general population can be attributed to these polymorphisms alone. Incidentally, the CYP2C9 polymorphism, which metabolizes warfarin, is about 1 to 15% of the U.S. population. VK or C variants are more frequent, especially in Caucasians, about 40% of us carry these SNPs that lower VK or C1, and it's about 12% in African-Americans. If you look in the package insert, you'll find this little table, which gives you a warfarin starting dose based on these two SNPs in... Actually, it's three SNPs in VK or C1 and CYP2C9.  It's pretty neat. In this case, if the warfarin was already... Dose was already decided upon based on INRs, then obviously you don't need this information, but it still is useful as a starting dose to decide on a starting dose. Okay, I'm going to switch gears again. So I talked about targets. Now I'm going to talk about genes that have effects that are not necessarily related to the target but are sort of ancillary targets themselves. Okay, so I'll show you what I'm talking about in a second if that doesn't make sense. So you have tumor lysis syndrome. You have cellular breakdown, which spills out a lot of DNA. This DNA is catabolized into a lot of purines. These purines can cause hyperuricemia. This uric acid can precipitate in renal tubules and cause renal failure. So this is known as tumor lysis syndrome. A drug is given to avoid this. Actually, two drugs, alpurinol and raspiricase can be used. Raspiricase here takes uric acid and converts it into a readily excretable form of uric acid called allantoin. Here is the actual reaction up here. When urate is converted into allantoin, it produces a lot of hydrogen peroxide. This hydrogen peroxide is cleared by glucose-6-phosphate dehydrogenase. Now there's a group of people that do not have functional G6PD. They tend to be Mediterranean in origin and it's the same group that cannot eat fava beans, which is why I have the broad bean up here, because the toxin in fava beans will actually cause the exact same thing to happen. They'll get severe hemolysis due to too much hydrogen peroxide. Just an interesting aside, it's thought that this population has this deficiency because they want to produce a lot of peroxide in the bloodstream to combat malaria. It's kind of an interesting idea. So anyway, genotyping for G6PD is a very, very good predictor of G6PD function, and so this is a genetic test as well. And the last type of gene-drug interaction I'm going to talk about are these hypersensitivity reactions, which are becoming increasingly important, I think, in pharmacotherapy. So a drug like abacavir goes into a antigen-presenting cell where it sees one of these major histocompatibility complexes. These MHC proteins are encoded by human leukocyte antigen, which is called HLA. These are the genes in the genome, so I'm going to say HLA referring to these proteins here. The genes for these proteins, anyway. These proteins will bind to your drug, go out and start to amount an immune response to the drug itself, which causes hypersensitivity. And it's a Stevens-Johnson syndrome in general. And here's a kid with Stevens-Johnson. This is really considered... It's starting to be considered malpractice to not genotype for this before you give some certain drugs, especially abacavir. There are similar results with carbamazepine and allopurinol. It's still only recommended by the FDA, but it's still extremely predictive of hypersensitivity reactions. Just a simple genotype test can really tell you who's going to get it and who will not. About 5% of patients get a back of your hypersensitivity. If they have one of these HLA loci, you can have up to 103-fold odds ratio of risk of getting hypersensitivity reactions. It's 100% positive predictive value. If a patient has this genetic background, they're almost certain to get a hypersensitivity. It also has a 97% negative predictive value. If they don't have the SNP, you can be 97% sure that they're not going to get hypersensitivity. Here's a conclusion of one of the seminal papers investigating this. I'm just going to read it. In our population, Australians, withholding abacavir and those with HLAB star 5701 or these other HLA should reduce the prevalence of hypersensitivity from 9 to 2.5% without inappropriately denying abacavir to any patient. I think that's really a very good summation of the power of these HLA genotypes. So, I'm sort of giving you the bird's eye view of all the pharmacogenes that are currently out there and are probably moving towards the translation side. Now I'm going to just briefly mention one of the platforms that we use to actually get the genotypes in these patients. Just talk to you a little bit about it. This chip, it's an array-based technology called DMET, which stands for Drug Metabolizing Enzymes and Transporters. It has 2,000 variants and 235 PKPD genes. So, you can see all of these Phase I enzymes. You'll see the ones that I mentioned in there, the Phase II enzymes. You'll see the ones I mentioned in there. Transporters, you'll see the ones, again, the SLC01B1 is in here. And then these other genes that can have effects on PKPD. So, here's G6PD, for example. Cytodine deaminase, which is important for certain other drugs, et cetera. This chip is actually, it only costs about $500 to do the chip. And if you batch a lot of samples, as we've learned, it actually costs only about $50 a patient. So, it's not some outrageously costly thing to do. However, it does have one major deficiency that we've identified. And that is that it takes three days to actually get data out of this. And that's a fast turnaround time. So, for a lot of these drugs, if you need the information right away, you cannot get it. It's just not possible. This isn't CSI Miami. We can't just genotype something in 15 minutes. So, basically, what we've done at the NIH to combat this issue is we have made a policy where a patient gets admitted and then they get this genotyping test done. The information follows them around so that if a clinical decision has to be made rapidly, that this information is there and available and will be flagged to the clinician who is going to give them the drug. We've based the... So, now I'm talking about our experience with PG testing at NIH. We've sort of used this website called FarmGKB, which is run by a lot of the pharmacogenetics experts in this country. They're all part of a network called PGRN. And they have really curated the pharmacogenetics literature very well. So, if you're interested in this, FarmGKB is an excellent resource for learning more. They've published levels of evidence. So, we have only selected those that have the highest levels of evidence that are available. Published control studies of good quality relating to phenotype and or genotype patients, healthy volunteers, having relevant pharmacokinetic and clinical endpoints. Pretty much everything I'm going to discuss today has that high of a level of evidence. It also has a very high level of clinical relevance. So, even though maybe you have a high level of evidence that a SNP is associated with some outcome, that outcome may not be that clinically important. So, they've also curated the clinical importance of this. And all of these genes I'm about to talk about have a high level of clinical importance as well. So, I'm just going to go through the list, because I think you may see some of your favorite drugs on this list, and keep it short so that I don't keep here for too long, but here we go. Abacavir, I already mentioned this one, HLAB5701. This one is recommended, so if an investigator will get flagged, this says you really need to get this genotype before you can administer abacavir. And even though it says the test as TBD, our laboratory medicine branch actually runs this test all of the time. So, we're currently processing this SNP through that branch. Anybody treated with abacavir. Allopurinol, another drug with hypersensitivity reactions. Same story. It's recommended and can be run through the lab right now. Azathioprine or any of these mercaptopurine drugs. I already mentioned these, so I won't go through the mechanism. This is also a very, very highly strongly recommended SNP to test before administering any of these drugs. And we can actually use the DMET platform to do so. Carbamazepine is another HLA. The FDA recommends testing this in Asian populations. Now, this is an issue here. So, I have a friend, I'm from California, I have a friend whose grandfather was one of the original Japanese immigrants to the United States. He doesn't look at all Asian, but he has a significant part of his genome that is Asian. He wouldn't identify himself as Asian, he would identify himself as a Caucasian. If he was treated with this drug because he wasn't Asian and we decided not to genotype him, then he could potentially experience some severe reaction here. So, we've decided that really looking at a person's self-identified race is not the way to go about this. We really need to actually genotype a SNP or not. So, this one is actually very recommended. The test is again through the laboratory branch. Clopidogrel, Plavix, the poor metabolizers have non-responsiveness to clopidogrel. Hyrodosis may be needed in these patients or there's new, there's new anti-platelet agents out that can be used instead of clopidogrel. This one we consider optional available, but we assume that since the information is already available in the clinician that they will just opt for one of those other anti-platelet agents. Coding, I already mentioned it. We don't use a lot of coding at the NIH. This one still is optional or available. The DMET will give you the information. Fluoroprimidines metabolized by DPYD. Patients with deficiencies of DPYD will have some potentially fatal toxicities. So, this test is recommended and it's already available to the clinician via the DMET chip. Irinterferonone-alpha has an association with an IL-28 beta SNP. This is, one SNP is very predictive of who is going to respond well to this drug and another is predictive of who will not respond well to the drug. We consider this optional or available. We have to go outside of the NIH to lab core to really do this one. Renathekin already mentioned it. DMET chip already test UGT-1A1. So, this one's already being used. Isonizid with NAT2. NAT2 is a phase 2 conjugating enzyme that acetylates isonizid and gets rid of a very reactive intermediate metabolite. If people are slow acetylators, they have a three-fold increase in drug-induced liver injuries. This one is considered optional or available. The DMET tests it. CYP2E1, similar story. It's available. Finitoin, difficult drug to dose. There are some variants in CYP2C9 which affect the toxicity and efficacy. This information will be available for dosing of finitoin. Finitoin also causes some hypersensitivity reactions and there's an HLA that's predictive. So, this one's strongly recommended and the test is done through the laboratory branch. Razburacase, which I already mentioned. G6PD genotyping is already available through DMET. Statins and OATP1B1 mentioned it. The test is available through DMET. Tamoxifen, 2D6, test is available through DMET. Warfarin, same snips, DMET test. And then we have the molecular pathology laboratory who is already doing all of the somatic mutations for these targeted agents. So, just run through the targeted agents and not mention much about them. Tristuzumablopatinib, disatinib and nalatinib. Anatmatinib also affects kit so we have the molecular pathologies test kit for us. Jafitinib or latinib and these others. BRAF inhibitors, EGFR inhibitors, RAT inhibitors, alkylating agents. And that's it. So, those are all the drugs that we have implemented at this point at the NIH and the PG testing arena. So, just a couple of final thoughts. How many drugs have pharmacogenetic markers in the label? Well, at this point there are 114 of these drugs and if you go on to this website at the FDA, you can look at all of these drugs. How many drugs have FDA recommendations that are actually actionable? Seven have boxed warnings where the testing is very important. 29 have indications in usage information and 24 will give you information about the dosage. So, a subset of those are actionable. And the last slide here is just considering the prevalence of use of pharmacogenetically affected drugs. There's about 24 million people. This was in 2008 using drugs that have pharmacogenetic information that's available that you can just genotype them and know what, you know, no more information anyway about what to do, make clinical decisions. There's a lot of people using these drugs. This number is just ever increasing and eventually they think this stuff is really going to be important in clinical medicine. And Doug Fig, my boss, always ends his talk by saying, at one day he envisions a child is born. The child gets a DMET chip-like genetic test and that test can be carried with them through life on a thumb drive and they can go and it's their doctor one day, put it into a database, it'll tell them don't give this drug, do give this drug. That seems to be the way that things are going. And so that's all I have to say and thank you very much. Comments or questions? Yes. Could you paraphrase the question? Yeah. So the question was how do you find out if a patient is at risk for clopidogrel in efficacy? And you can use a few options. The first option is you can send it off to have it genotyped by a private company. There are several private companies out there right now doing this. The test really needs to have I think three different alleles and each one of those alleles can cost a certain amount of money. We found that it's actually cheapest to just have the DMET chip run on people. You can take the blood sample, you can send it to the Coriel Institute, they will give you the information back. The guy named Norman Jerry, the guy we run through, he's doing all the NIH studies. You can send the information back and then make the decision based on that. Yes. Thank you for a great talk. You raised a lot of important issues. I'm sure I see at least one patient with either a slow or rapid metabolizer that's not doing well clinically. There was a Dr. Flockard in private practice who used to do consults. So how can we get a consult in terms of private practice to help us? One is a specific drug, but one is metabolizers slower that might affect many, many drugs and that might be beyond the expertise of a private practice doctor. I know there's some agencies that are springing up that offer pharmacogenetic consulting to clinicians. It's a very new thing. You can Google search it. I know that Doug Figg was approached by one of these agencies. I can't really get the name of it. But we're also at the NIH and I'm sure we can direct you in the right direction. I think my email is up here. If we can't help you, I'm sure we can put you in touch with somebody who can at this point. Those of you who are entrepreneurs, it sounds like that's an opportunity. It is, definitely. I want to reiterate the excellence nature of this program Interestingly enough, just from an historical point of view, the 6MV Discoverer is one of the Nobel Prize and you may be aware of that. But to take that a step further, there have been some recent guidelines that have been published by our national organization suggesting that HLA B5801 profiles be obtained and certain groups of patients who are going to be administered in Alapurano. That happens to be the Ham Chinese and certain Thai subgroups. But getting back to your California story, you wonder how many of these particular groups may be here and vulnerable because this is so important for the Alapurano Hypersensitivity Syndrome. So from bench to bedside, this is recommended for looking at the economics of this as we speak. And for the practicality and bench to bedside we are told that this HLA B5801 is now available commercially. Is this an area that you have studied more than your slides? I'm not an expert on HLAs by any stretch of the imagination. But I do know the Alapurano story and I agree with the sentiment that we really need to genotype everyone. So I'm not sure exactly is there... Did that answer your question? Well, it was a statement. Yeah, so yeah, I think that this needs to be genotyped in clinical practice. It absolutely needs to be done because it's so predictive of who's going to get these toxicities. It's very important. That's true. I looked up what came here. I always look to see if there has been yet a lawsuit from Alpractice about one of these things popping up. Nobody has yet sued anybody in one as far as I can tell from Google for not doing one of these HLA tests. However, I have found you mentioned Alapurano. A woman was misdiagnosed with gout, was given Alapurano, got Stevens Johnson sued and won $6 million. So clearly it is something that needs to be addressed clinically. Well, you'll see it. It's on television very quickly on its matter, I think. Boyers are entrepreneurs too. I have a point. I'm reminded that Marlon Seanaway in response to a congressional question that a hearing made the observation that none of us are purebred. That's definitely true, especially in America. We are very ad-mixed. Yeah, thank you. By the people at St. Jude who came up with the TPMT observation and they talked about genetic excellence. The genetic tests are held to a higher standard than your standard clinical assays just because people want them to be so predictive of everything, although they never really will meet that benchmark. So I think that there is a lot of resistance out there right now to implementing a lot of this stuff because of that issue. Similarly, the CYP-2D6 tamoxifen story has been recently stalled by two published studies that came out at the San Antonio Breast Cancer Suposium showing no relationship between CYP-2D6 and tamoxifen outcome. Now, these two studies were fundamentally flawed. There is an editorial by Mark Retain in Cancer Letters talking about how these two studies both violate a fundamental law of nature, the random sorting of alleles amongst populations. And the reason for this is that these folks genotyped tumors and did not genotype the germline DNA. The tumors get mutated and it's not an accurate reflection of what's going on in the liver, how much endoxifen is actually being formed. So these studies have a lot of impediments to them that are outside the control of a lot of us who are doing the science. I think that our group would be partially interested in it. Doug Price here has come for some moral support. He's a fellow staff scientist in our lab so I think we could probably talk to Doug Figg about that, maybe doing some of those studies. Juan Lertora is the guy that runs the PG program right now at NIH and I think you could definitely approach him and ask he's always interested to talk about this sort of information. Would you comment on the role, the traditional role of pharmacists in protecting patients and how you see that role? Well I mean for this I think pharmacists are not geneticists and I know that very well because I am a geneticist and I have to deal with pharmacists all the time. I think that what needs to really happen here on the pharmacy side is that we need to have some very good curated databases where you can just put in genotype information and the people who are experts in genetics and all the other fields that are needed to understand this information. This database just spits out a clinical decision that should be made rather than having the pharmacists do it all. So in fact at the end of the day one could conceive of a system that doesn't lead to alarm fatigue which happens now a lot in pharmacies. They have a bunch of interaction messages and eventually the pharmacist ignore them. It's going to take a lot of work it seems. I don't know of any but I am more of a cancer researcher so I can't say that there is not. I was actually recently diagnosed with psoriatic arthritis and my doc actually mentioned that to me when I went to him. Oh I'm sorry the question was basically there is secondary malignancies in certain cases and there is a secondary malignancies in certain diseases like arthritis inflammatory bowel disease and the question was do you see secondary malignancies that are related to those diseases I think is basically what you are saying right? Or a genotype that is predisposed so that's more of a risk allele less of a pharmacogenetic allele I could see maybe that if you were treated with azathioprine for inflammatory bowel disease that you might see secondary malignancies in patients with certain variants but the disease alleles I just don't know much about. You raised an important issue in terms of clinical trials and that is you know maybe we should lower the patient population to the people most likely to benefit one example that I see every day is leucosmic and jointing works in a subset of the population it's said ineffective when you look at the whole population are we any closer to using genetics and clinical trials to make those more effective? There are several out there in the literature right now that are finally doing this which is exciting I mean we really needed the prospective side of this now I know that there is some resistance to drug companies to do from drug companies to do these sorts of studies because they want their drug to work in the whole population and want to subset it so often times you'll see these prospective studies already being done on approved drugs I'm not aware of any drugs that are being developed at this point with pharmacogenetics in mind but I also don't work for drug companies so I don't really know for sure I don't think anybody has ever done a study like that I think we primarily assume that a generic and an on label or I'm sorry I forget the name a drug that's produced by a drug company are the same compound so I don't think we ever look at generics versus the drug companies drugs I think that a I think that this is a really important field for the future practice of medicine and b felt very incompetent in being able to use it and it seems to me that revolves around competency rather than knowledge and one of the reasons we were very interested in having a pharmacogenetics talk here is that this one is very very close to the clinic on the bedside and it seems like maybe we ought to do some more of this what do you think I see hands mounting maybe we should do a little bit more but I want to thank you very much thank you very much yeah hi


Hey everybody jr. Fisher here want to say good morning to you. We're gonna have a great session today I've got some really cool stuff lined up for you And I appreciate you being on this live broadcast. I want you to make use of this chat I have a iPad right here, and I can talk back to you. I may just verbally talk back to you But if you're live on here, why not introduce yourself say who you are today is a really cool session I'm gonna provide you guys with a quiz that you can take And it's all about the imposter syndrome and we're gonna talk about that today And I'm also going to talk to you about An illness that I got that that one that hit the whole world. I Want to talk to you about that But I want you to feel confident that you can ask any questions you want you can put any you know Suggestions, you know just be part of it. Tell me where you're at where you're coming from I know we're live on YouTube but Facebook, I don't know if it's working on there I got an error message on my screen. So who knows if that's working, but that's okay. Hey, I'm loving being back live with you guys I'm gonna do more and more of it. I promised I would start a cooking channel and I'm gonna start that very soon I know I keep saying that I've got no excuses right now Okay, because I'm healthy now, but I do want to talk to you about that I got that that virus that was going around the world And I want to share that with you real quick and what happened I got sick. I guess at the end of September. I was in Cleveland, Ohio My son was in the hospital. I went there to see him because he was in bad shape they had They had botched an operation a simple operation and it made it a whole lot worse He ended up having two more operations while I was there and now that I think back on it You know, that's it's just really horrendous what he went through and all the pain He had to go through because a doctor didn't do her job properly But that's neither here nor there. I wasn't feeling well And I left there on the 28th of September And when I left there, I will flew back to Austin, Texas I live in Georgetown, which is just north of Austin, Texas And I wasn't feeling well. I mean, I didn't have an appetite I just I felt kind of hot and kind of cold and just didn't feel right And I got back on the 28th and the 29th. I got worse and by the 30th I felt horrible and I thought I had the flu. I thought I had the flu something like that and So my wife took me to the emergency room and I was shivering Well, we first we first went to a clinic and they took my temperature And they said you need to go to the ER to get checked for COVID And I probably shouldn't have said that word because I'll get demonetized or something But I did want to share with you what I had and I went to the hospital and I was in the ER and When I was in the ER, they gave me the test for the flu, but they also tested me for COVID and They came back after about two hours of sitting there. I was very uncomfortable and they said, you know, you have a fever of about 102 and Yeah, you don't have the flu. You do have COVID So, you know, I didn't have any breathing difficulties, but I felt really awful and they sent me home and My fever started to spike. My fever went up to a hundred and four and a half Which was miserable. I gotta tell you it really was miserable. I had zero appetite. I couldn't I couldn't eat any food whatsoever But I took some time at all after about two weeks of this I started to feel better. I started to feel better again. I started to feel like myself again And I and I got through it and I was very grateful. I was very grateful that I got through it And about a week later A friend of mine from gosh 30 some odd years ago Sent me a message and he said I have a family member that's ill How long did it take you to get over, you know, what you had And I said, well, you know, it was a couple weeks or something like that And he says he and he finally said, you know, my son's in the hospital With the same thing and his son is 40 years old And this was probably yeah like a week after so I'm thinking the first week of october and His son was in the hospital and he was getting progressively worse What is this now? This is november and this was the first week of october. He got progressively worse and worse and worse They ended up saying his o2 was low So they put him on a ventilator about a month ago I would say something like that And then they said at this one hospital that he was at that they couldn't help him anymore They need to send him to another hospital. So they flew into another hospital They were going to put him on a ECMO machine, which you can look that up But basically it cleanses your blood and oxygenates it again And they said he wasn't a good candidate and his kidney started to fail And as of two days ago, he's passed away Um, and it's a very sad story and and I want to share it with you guys because You don't really have control Over what's going to happen in your life. The only thing you can really control Is how you react to things both physically and mentally. That's it. That's all you can really do Uh, and I'm going to talk to you today about imposter syndrome Uh, and it's a syndrome that actually 70 of the population have so if you're in a room of 10 people There's seven people in that room going through this And I'm also going to provide you with a test that you can take. It's totally anonymous because all you do is You go to a page and you download it and you take it in the privacy of your own home So it's not online or anything like that. You don't have to worry about that But it'll let you know, you know, what's going on in your brain a little bit And I want to talk to you about the syndrome What it is uh, why it affects us all that good stuff So we can kind of you know, zero in on it, you know and and see, you know, do I have this thing?  You appear to be powerful You appear to be very independent But on the inside you kind of feel weak on the inside you feel unsure on the inside you feel scared But nobody around you really knows that they don't see that You kind of have this feeling of am I good enough? You have a lot of self-doubt a nagging feeling that you know, maybe you're a fraud You know, maybe all the things you've done really don't matter And that is really descriptive of what um imposter syndrome is Um, and it's something that can really hinder you if you don't get a grasp on it According to a study as a matter of fact an international journal of behavioral science Um, you know 70 of the population has this The term itself was actually first coined in the 70s by psychologist Dr Suzanne Imes and and those are the ones that did the test i'm going to give you uh, and dr Pauline rose plants And it refers to really It it affects more high achieving people than it does anybody else people have achieved a whole lot People who exhibit imposter syndrome remain convinced that their own success and achievement are attributed to luck and timing Because they were able to fool others into thinking that they're smarter and more competent Than they actually are. I've been through it myself You know, I've I've been on stage and I've been talking to groups of people A couple hundred people at a time sometimes and i'm thinking why would they want to listen to me? I mean, why me? I don't know anything You you kind of get that feeling And I think we are all affected by this a little bit But I also want to go over some of the top people very famous people that struggle with the same thing To kind of share with you, you know, if you're feeling this way if you're feeling insecure That there's other people feel the same way and I also want to You know, I want to let you know that feeling this way will prevent you from doing a lot of the things that you could accomplish Thinking that you're not good enough or that, you know, you don't do Well enough It's really going to stop you from getting a lot of places you want life And one thing I forgot to ask you to do Please do me a favor and subscribe to this channel. I don't forget to turn on Wait a second. Hang on. Hang on. Hang on. Hang on. Is the bell in the picture now? Yes Turn on all bell notifications. So you notified each and every time I go live Okay, I got got to get my commercial out of the way, but that's that's pretty important stuff Um I guess the bell needs to be here to show up. Well, I just saw it on my screen and read Okay, so there's other factors that lead to feeling the sense of being a fraud And How you feel different from everybody else and how you feel different from your peers, you know It could be your appearance. It could be your gender. It could be your sexual orientation. It could be your race It could be any defining characteristics. Um, as a matter of fact, they say millennials Actually be a crippling type thing now this this syndrome is not listed in any Or That um, but it exists why they don't I don't know but it's it's just it's a thing. Okay Um, it could be how you were brought up. It could be, you know, maybe you had a parent who you know Would tell you how lousy you are in the next moment. They would tell you how great you are and it was confusing to you I know I had a parent like that Um, while some people may see adaptability as a good trait to possess It can also make others feel like they aren't equipped to Deal with life and deal with stuff One attribute that commonly occurs in high achieving people And often accompanies imposter syndrome or is perfectionism. We think we're perfectionist.  We all know this. I mean deep down inside We know that you know, we can't be a perfectionist, you know, we can't do things perfectly We're going to make mistakes. We're humans. Okay And I mean life doesn't always happen fairly.  Uh, he had two daughters And a wife and he passed away and and and that seems terribly unfair Um, but the reason I share that story with you is that you're still here Okay, you're still here.  Okay This perfectionism thing is a crippling thing and it it'll manifest itself a couple different ways You will way over prepare for everything and waste tons of time Um, or you will procrastinate not do anything because you're afraid you're going to do it wrong So perfectionism is not an admirable trait. It really is a lot of people say, well, I'm a perfectionist and and I say it with this Such pride and I'm thinking to myself.  Okay, they dwell on all the negative stuff This trait often translates into a deep running fear of a person's failure Being exposed can limit your chance to really explore And take a leap of faith and try a lot of things you want to try Let me get a sifter real quick All right, guys put whatever comments you want in that chat section there I love to hear from you and I know some of you may be you know watching this and it's not live It was recording but you know put put your comments below if that's the case and I'll come back and answer you Ah, that's some good tea. I don't drink coffee tears up my stomach, but that's some good tea so Another great reflective tool that many people use Includes, you know to really get you out of the syndrome it includes but making a list of your successes accomplishments All your positive experiences Where they stood out or where you felt like you truly deserve accolades that you achieved I know a lot of times, you know people will say well You know, I just happen to be in the right place at the right time I don't really deserve this, you know And I'm going to go through some of these famous people and what they were thinking because it's it's pretty darn interesting Um in the name of cutting in or cutting out the isolation that comes with uh the infamous imposter syndrome I'm going to go through a list of highly successful individuals and their respective fields Who at some point have or still experience these crippling insecurities? Let's start off by a guy named Albert Einstein Every even a male like Einstein's caliber or caliber In genius was not immune to feeling like a frog Perhaps one of the most influential scientists of the last 500 years Albert Einstein was known to have faced imposter syndrome later on in life He was once quoted as saying and i'm going to read this quote here. I don't want to get it wrong The exaggerated esteem in which my life work is held Makes me very ill at ease. I feel compelled to think of myself as an involuntary swindler So he didn't even think highly of himself. It's really kind of weird. Uh, I want to take another example Maya Angelou Maya Angelou, uh, lusibachimas is one that could hardly be replicated by somebody else. She was a poet She did civil rights. She was a memoirist She was an actor. She was director producer. She even authored and published seven autobiographies three books of essays countless books on poetry And an extremely impressive literary career Where she actually Was credited with writing a long list of plays movies television screenplay she did all these things all the while Facing her own personal hardships now a woman of such substance and Ability yet Maya Angelou was once quoted as saying and I will read the quote here I have written 11 books, but each time I think uh, oh They're going to find out now. I've run a game on everybody and they're going to find me out That's how she felt about herself. It's craziness, right? Uh, another guy you've probably heard of John Steinbeck another brilliant actor Steinbeck was the winner of two of the most prestigious awards in the world The 1962 Nobel Prize in literature and the Pulitzer Prize for his famous work the grapes of rap not only Not only okay are his literary works inspiring generations You know after his death his books are also being adapted into movies Namely the one in 2016, which is in dubious battle Which starred James Franco and Selena Gomez and contrary to successful others Uh or contrary to how successful others thought he was Steinbeck wrote in his journal. This is what he wrote to himself I am not a writer. I've been fooling myself and other people. John Steinbeck. What? What? Okay, so it's not just you guys if you're struggling with this um Cheryl sandberg now you may on the surface may not know who Cheryl sandberg is but you will in just a second She was the first woman to serve on facebook's board of directors She actually Had been linked to other impressive organizations and the past she had also been the vice president of global online sales and operations at google And had an active role in launching google.org Which is the company's uh philanthropic vertical Her long list of achievements further includes serving on the united states secretary of treasure chief of staff and being named in the times 100 most influential people in the world list and She also established the lenient foundation and became an author She said to be worth over one billion dollars. Thanks to her stocks and facebook. Okay, that was a good investment Um and several other profitable companies even after achieving that even after achieving that She said there are still days when I wake up feeling like a fraud not sure where Excuse me. Not sure. I should be where I am Okay, even her if that if that stature, uh, and I want to pull out an actress here that we all probably know meryl streep She was probably hailed as one of the best actresses of her generation And she was really famous for her ability to adapt to different accents and her versatility in all these roles Streep is said to be one of the only six actors who had won three plus competitive oscars for acting and 20 nominations Okay, she had 30 golden globe nominations which she won eight. Okay, so that's pretty pretty big accomplishment Now she was awarded the national medal of arts in 2010 and the president's medal of freedom in 2014 by president obama And she's managed to secure accolades and fame internationally too Wherein the government of france made her the commander of orders of arts and letters in 2003 Even after Breaking all these records and winning the highest and most prestigious awards possible across the globe meryl street Still has been quoted as saying this is her quote. You think Why would anyone want to see me in a movie? And I don't know how to act anyhow. So why am I doing this?  Look at all these people. I'm going to share with you a few more and show you what you can do about it Tina Fey Tina Fey who I love. I think she's awesome A female comedian, I mean to make it in our Sexism society is pretty tough anyhow, but Tina Fey Has truly carved out a niche for herself while silencing anybody who was a critic. She is an actor She's a writer. She's a comedian. She's a producer She's won nine prime time Emmy awards two golden globe awards five screen actors guild awards Four writers guild of american awards and throughout her career so far. She's been able uh been awarded the associated press entertainer of the year in 2008 furthermore She surpassed any remaining glass ceilings that she was awarded the mark twain prize for american humor in 2010 Okay, so that was making her the youngest recipient of the word or excuse me of that award ever She talks candidly about her encounter with imposter syndrome and here's a quote from tina fe the beauty Of imposter syndrome Is you vacillate between extreme egomania in a complete feeling of i'm a fraud Oh god, they're on to me. I'm a fraud So you just try to ride the ego name egomania when it comes and enjoy it and then slide through the idea of fraud That's what tina fei had to say. Okay, so if you're feeling this way guys if you're feeling this way It's it's something that so many people feel sharyl strahan She was an incredible one She had a really tough past her mother died of lung cancer and she took to heroin to deal with it She took heroin, okay This eventually led to the end of her first marriage strahans and I know you don't know her yet I'm gonna tell you who she is strahans journey to self healing and self discovery Let her to hike solo along the 1100 long pacific coast trail without any proper knowledge or experience of hiking at the age of 26 she was able to Capture the parallel natives narratives of the experiences during the hike and her personal challenges in life in the book She wrote a book on this. She is a memorized. She's an sas. She's a podcast host and she's an author of five best-selling books Even though she was triumphant in the face of adversity and difficult situations that got her through by herself Nobody helped her. Okay. She was also dealing with imposter syndrome. Here's what she wrote Writing is always full of self doubt But the first book torch is really full of self doubt And it was much more of a struggle to keep faith by the time I wrote wild I was familiar with that feeling of doubt and self-loathing. So I just thought, okay This is how it feels to write a book Okay, so she was messed up. Okay I mean I could go through a list. I'll give you a couple more. Emma. Emma Watson She's an active model activist With a net worth of 70 million dollars At the age of 27 she had accomplished that her accomplishments include graduating from brown university with a bachelor's degree in english literature All the while handling a professor acting career as well Okay, the british academy of film and television arts honored watson with the british arts Excuse me the british artists of the year title in 2014 and in the same year She was appointed as a un woman goodwill ambassador with her role at the u.m Watson launched The he for she campaign that actively encourages men to take up the role of gender equality advocates Reaching such heights of success at such a young age sometimes made her feel like an imposter because here's what she had to say When I was younger. I just did it. I just acted It was just there. So now when I received recognition for my acting. I feel incredibly uncomfortable I tend to turn in or myself. I feel like an imposter. It was just something I did Okay, now there's a great story here and I want to find my notes here Uh, I I have a couple other people. What time is it? We get a little bit long on time. So, um, let me let me uh Look at here's here's how to know if you have imposter syndrome Okay, I want you to think of these things and then I'm going to give you the link for the quiz It's going to be in the description of this video. So if you look in the description, you're going to find the link But if you have a marginally higher level of stress than most people do If you get anxiety over the smallest things If you procrastination that leads to even more anxiety Uh, if you're constantly living in the fear of someone finding out about the lack of experience or skills Uh, if you feel like they you don't belong Uh, always either understanding or completely disclaiming your achievements and experiences Do you shy away from asking for a raise because they feel that somebody else may deserve it more than them? Uh, you know, are you in that boat? Uh, not applying for jobs extreme nervousness Overpreparing for task. Excuse me. I make these It's live. What are you going to do? Looking for perfectionism and everything you do These are all traits of this. These are all traits of this guys Humility is not thinking less of yourself, but thinking of yourself less. Okay. That's what that really is now Let's take a moment here and I want I want to talk and I find I want to find my story here Uh Where is my story or I got a bunch of notes here on my screen Okay So there was this guy He's a pretty famous podcaster and he got invited to a group of super Super Achieving people big big room of super achieving people and he sees a guy in the hallway and uh, he starts to talk to the guy in the hallway, uh, and He says to him why you stand out here. He says well because I don't belong in that room and he says well, you were invited He says I know but I just don't belong in the room because why do you feel that way? He says well, all those people in that room All those people in that room really accomplished something He says me I was just there And it turns out it was the first man to set foot on the moon That's all of it And and you think about that, you know in his mind He had forgotten about all the training all the work all the physical stuff all the book smarts You know all the tests he's passed and all that he just thought you know He would just happen to be there. He just happened to be there Um, so it's incredibly enlightening if you if you look at this guys And you see what's going on in your head and other people's heads Um, and if you if you feel like this put put up put something in the comments I will you know, I'll tell you I felt like this many many times Put your comments in there say hey, yeah, I felt the same way before It's nice to know that other people feel the same way And it truly is guys, um, you know that we go through so much of life And we're just always worried about things. We're always concerned about things And we're not really just enjoying ourselves, right? and I think back to um The friend of mine whose son passed away and for some reason, you know I was talking to my wife and I was saying for some reason I lived and he died We had the same thing. Okay. I got sick. I didn't feel good. Well, what was me?  It may be to talk to you today It may be so that I can share this message with you today It may be and I know we're I normally talk about making money online But it's not just about making money online You got to get your head right first if you don't have your head right You're never going to make money online.  I'm going to care about that money in the bank. Okay, you're going to care about what you did The only thing you're going to only thing you're going to do at the end of life I think is look at all the regrets all the things you didn't do Okay, all the things you wanted to do that you couldn't do I think that's what's really going to happen at the end of life. I really do believe that So if you if you want to take the test Look in the description of this video There's a link there. Are you good? All you gotta do is click on the link It'll take you you download the test and you can take it and you can see where you stand on there This test was devised By these psychologists who actually coined the phrase imposter syndrome So it's it's a really good test. I think it's very informative. I took it myself I won't give you my score, but yeah, I got imposter syndrome So a lot of us do it if you have it, you know, you can work on it You can google things that you know, and I don't want to get into a whole lot of detail So I could talk for two hours on what you could do about it But the first thing I think we all got to realize and that's why I shared the story with you Is you're alive.  I promise you you're going to regret it later on So make sure you do it.  I'm going to be going live a whole lot more I know I missed a little bit. I had some illnesses. I moved blah blah blah. They're all excuses.  Thank you so much for being here guys I really do appreciate it. Um, like I said, give me a thumbs up if you don't mind. Don't forget to subscribe Don't forget Bring the bell turn on all bell notifications. See you're notified each and every time I go live Thank you so much for being here. Don't forget grab that quiz that test whatever you want to call it It's in the description. I'll talk to you later


No, I think it was a well run process I would say. I think the entries obviously were in several hundreds. I think the short listing process and then making sure that the jury had been well briefed prior with enough time in between made it a very efficient as well as obviously effective jury panel process. My appreciation and thanks to obviously all the people in the wider set of almost 800 entries. I think there's a lot of good work to all the marketeers on different categories and spheres. I think the other mention is the kind of categories that we work. So besides obviously the traditional mediums, we also had now almost traditional which is digital mediums but we also had categories to do with slightly more ancillary areas. It was good to see which was AI leveraging technology in general as well as basically CSR. That's also good to see. So we got a very good flavor and spread across multiple industries. So all in all I think a very good set of high caliber entries and backed by very good, how do you say case studies that were documented in terms of not only the work that went in, the strategy behind it as well as the impact in the outcome which made it much easier for us to do the evaluation and the awards. I would say I think last I think my appreciation and thanks to my colleagues and the jury members. I think it was fruitful discussions throughout and congratulations to the winners. So I would say it this way that I think we covered almost all bases very well and it was well spread out. There was an accent because of the context in the background of the last couple of years which have been a little how do you say tumultuous as well as transformational. I am sure that larger climatic campaigns etc will gather more momentum going back hopefully once we get out of the pandemic related disruptions and that I think can be dialed up going forward. But I think the piece that really stood out was the categories that I mentioned which were I think sprouts and good to see there which was technology in use. The piece on CSR I think these were categories I think that are going to be the future and therefore I think stood out at night.


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QuickBooks Online 2023 Paypal Bank feeds import data to QuickBooks. Get ready to start moving on up with QuickBooks Online 2023. Support Accounting Instruction by clicking the link below giving you a free month membership to all of the content on our website broken out by category further broken out by course. Each course then organized in a logical reasonable fashion making it much more easy to find what you need than can be done on a YouTube page. We also include added resources such as Excel practice problems, PDF files and more like QuickBooks backup files when applicable. So once again click the link below for a free month membership to our website and all the content on it. Here we are in our bank feeds practice file. We started up in a prior presentation using the 30 day free trial. We also have open the free QuickBooks Online sample company. If you want the to open at the same time we suggest using the incognito window or another browser to open the sample company. You can open incognito if using Google Chrome by selecting the three dots in the browser incognito window typing into the search engine QuickBooks Online test drive where using the sample company to compare the accounting view the one the bank feeds practice file is in and the business view the one the sample company is in. You can compare and contrast the two views with the cog drop down and switch the view down below. We're going to be duplicating some tabs to put reports in like we do every time right click in the tab up top to duplicate it right click in the tab up top once again to duplicate it back to the tab to the middle and reports on the left opening up the balance sheet the balance sheet yes the balance sheet and then if you look at the business view by the way the reports are located in the business overview and then the reports that's where they're at over there. Let's go to the tab to the right and then also down to the reports open up the other financial report the income statement or profit and loss or P&L whatever you want to call it let's change that range I'm going from 0 to 0 1 0 2 no 0 1 0 1 2 2 tab 12 31 2 2 and then run it to refresh it and then tap to the middle close the hamburger scroll up to the top change the range 0 1 0 1 2 2 tab 12 31 2 2 tab and run it to refresh it where are those bank feeds located let's go to the first tab to find those because that's where our focus is banking on the left hand side bank feeds up top that's where they are what if you're in the business view though you know like what if I'm in the business view don't worry then they're down in the bookkeeping tab and transactions up top and the bank transactions so you could find them if you're in that view to no problem so last time we've been connecting our checking account and then we connected our credit card account so we've got the bank feeds set up the next question is well what if I have like an intermediary type of account specifically PayPal or PayPal account for any product now PayPal is kind of an interesting one because it used to be used as just like a facilitating type of transaction to receive payments and whatnot a lot of times for a lot of businesses that they would then be able to then transfer into the checking account but more and more of these days the PayPal account is becoming like another checking account because people are paying expenses and whatnot business expenses out of the PayPal account so there's a couple different ways that you can deal with PayPal one is that you can connect it like in essence a bank now there's apps for PayPal as well that might give you some more detail in it we might dive into that maybe in future courses but the the two options we're thinking about here is one maybe I don't want to connect the PayPal because it's more complex and maybe I just want to keep my checking account or two maybe I do want to connect the PayPal as baby basically another another checking account so when might I use you know either of those two options now note the PayPal transactions when you transfer from PayPal into the checking account you will of course see and your account on the checking account right so if you had a situation for example where all of your money is going through PayPal from like YouTube or something like that it was YouTube revenue and you know it's just one source going through PayPal you're not using PayPal for anything else you're not using it to pay stuff with you're just taking the PayPal as a function as a means of collecting your money from some gig platform well in that case maybe it might not be worth connecting the PayPal because you could just get the money from PayPal and then transfer it to your checking account and although the checking account then will show as a transfer and I'm not going to see in the bank detail that this came from whatever it came from like YouTube revenue I know that I use PayPal only to collect my money from YouTube revenue or whatever Amazon or whatever platform that I'm using and that could work quite well if that's like your only source of income however if you've got multiple sources of income like multiple people or platforms or whatever are paying you through PayPal then if you wait till you transfer it over to your account and record it as revenue it'll be more difficult to distinguish the different income sources so you're not gonna be able to make a different kind of income account over here if all of my income sources here went through PayPal then I couldn't really say well this is from Amazon versus Audible versus YouTube or website or YouTube because it would all be kind of mashed together when I transferred over and it would show up as just one transfer so that might be okay you might say I don't care it's just my revenue account I'm just going to call it revenue whatever that's easy so you could do that but then you'll lose a little bit of added detailed information which might be worth the added problem or issue of connecting to PayPal which is a little bit more work but gives you a little bit more of that detail and then what will certainly most likely cause people to need to actually connect to PayPal is if you're holding on to money in PayPal so that you can pay off your expenses out of PayPal because that's easy to do it's becoming easier and easier to pay things through PayPal which means PayPal is now being kind of like a checking account because it's not just a means to collect your revenue anymore it's now used as a basically a receipt and payment kind of thing so that means that what I'd really like is to have it in here as another bank feed so I can see my expenses or the payments that I'm making as well as the revenue be able to distinguish the revenue and be able to categorize the expenses in the same fashion as we've done with the checking account and the credit card account now there's also other kind of intermediary platforms you might use like a stripe or something like that but some of the other ones aren't the same as PayPal in that they stick to just really kind of the transfers of money as opposed to you might not be paying your expenses with them so if you get paid through stripe or something it's likely that the stripe is just collecting your revenue and again you're faced with the same situation you're like well I could just record all my stripe income as it comes in as just income from whatever source I know it came from say a website for example so you got you got paid through a website for things you're selling on your website maybe that's good enough for your information to record your income and your deposits when they come through to your checking account but you might want the added information that's collected from stripe such as all the customers that bought stuff from your platform and again you really want to think about that to say do I really want all that information or not because you because if you pull in you could look at applications that pull in all the people that paid you the other information from like a stripe for example but if you sell a whole lot of volume of small dollar amount things you might and they're only one time sales you might not want all that information other than their email address for your mailing list right I don't I might not want in my Quick Books account thousands of customers for that are one time customers you know I just want the mailing list right so in that case so you really want to think about do I really want to go through these other apps and pull all that information into QuickBooks or is that just going to load down QuickBooks and not give me any more added value so with regards to PayPal I would think that if you have multiple income sources and you're paying out of PayPal using it as a checking account then linking to it like a bank feed might be a worthwhile activity then we're faced with the same kind of questions well how do we link to it there's two ways we can do it we can link directly to PayPal with with an online link or we can download the the information from a PayPal however PayPal doesn't have as many sources to download so for example if I was to hit the drop-down and say that I want to upload from notice we have all these different file types we've got the dot CSV we've got the deep dot Q FX the dot QBO this one the QBO is the one that usually if you're going to upload the information from from like a checking account or a financial institution that you would use most financial institutions have that but I don't think QuickBooks or PayPal does yet PayPal does have the dot CSV file I believe that you can download but even that is going to be clogged up with a bunch of garbage in it we'll take a look at it in a little bit more detail in a second so you'd have to delete a bunch of stuff to do that so what you would really like to do is get a direct connection most of the time to the PayPal that would be the easiest thing to do but again if you're going way far back in history you might not be able to go far as far back for example with the first connection to PayPal so if you're trying to reconstruct like a whole year or multiple years it might you might have to basically download the dot CSV file and then connect to the bank so if you're connecting directly to PayPal and you can go you could go to the to the link account right here which if this was the first time you're linking to it that page might look different but most people would have already linked their checking accounts and then they would go into the link PayPal and you see down here they've got connect to PayPal so you can connect to PayPal and then you can go through the setup process to verify your account you might have to log in to PayPal to connect it but the setup process like with the checking accounts and credit card accounts is usually fairly easy that's kind of like the easy part and then you're going to be overwhelmed with all that information that comes in from bank feed limbo that we've talked about before the checking account and the other and the credit card account so for our practice problem I'm going to pretend that we downloaded this information from PayPal and upload it once we upload the information whether we upload or whether we connect to the bank will be in the same spot in essence bank feed limbo so this is a dot CSV file and so you can see I have I've actually trimmed it down already to the three fields so I believe if you download directly from PayPal you can download as an Excel file which might be the easiest thing to do because you're going to have to trim down all the data in the file and in the Excel file you'll have all of these other fields that that PayPal gives you that you don't need and then you can just select all the fields that you don't need and highlight them right click on them and delete them so that you're down to only the fields you do need which are the standard fields to upload which is a name a date field a description field which often includes like the name of the person that's paying you or that you are paying in like the bank detail the jargon and then there's going to be a number field or two number fields if you're using one number field positive numbers are increases negative numbers are decreases to the PayPal account I believe that's how the PayPal data is spit out on the Excel file once you've formatted the Excel file then you can save it as a CSV because you can't upload an Excel file you can upload a .csv if you have an Excel file and if you want to make your own Excel file just to practice with you can practice with it you can just type this into Excel something like this and then you can say file save as and then browse and then I'm going to save it as not an Excel worksheet but a .csv file so something like this or I think I used that there's another .csv it's a CSV file that's the point this one is the one I use I believe so that's what you want to save it as and then when you open it it'll look like it'll open with an Excel file but it'll be a CSV file which is a compatible file to upload it's like a like it'll open like an Excel file with all the formatting stuff in it so there's my file I'm going to upload that then to QuickBooks as another account and then we'll be in the same kind of situation as if we connected and so I'm going to say okay let's go drop down let's go upload file upload file and I'm going to just select it from the desktop it's on the top of my desk where it's nice and easy to find but you've got so much junk over there how can you find anything on top of that desk bank feed paypal paypal payup pal alright so there we have it we're going to say boom next and then an account so I don't have an account set up yet so I'm just going to create an account as we go on the fly we're flying right on that little flies back we're going to do it on the flies back which is hard because you have to have good eyes because flies are small so we're going to do it right on the fly it used to be a checking account and then I'm going to call this paypal paypal and then a sub account I think I made a cash parent account so it's a sub account of the cash parent account and when do you want to start I'm going to say other and I I believe the data started sometime last year so I'm just going to say August obviously this would be quite important if you're linking to the bank so that you pull in the proper date I think let me just make sure what happened here other I'm going to say let's make it just one month prior to that just to be super sure what your account balance so it might make that beginning account balance when I record it I'm going to deal with that later so I'm not going to worry too much about the beginning balance I'm going to deal with that that's my beginning balance bank reconciliation kind of situation we've talked about in the past I'm going to save it and close it and it looks movie B to the end so let's say let's continue and so select yes the format so is the first row of your file a header is the first row a header I don't think it is right because it wasn't a header I didn't have any headers so how many columns how many columns show so how many amounts so we only have one column that shows amounts instead of increases being one and then decreases in the other and then what's the date format used used I think I'm using month day and year like that and then the date field is going to be column one where it has the date up top so I'll say yeah the description is going to be that one column two with the teachable and I'm just mapping out and column three is of course the amount so if I had a header field then of course I can tie out to the header but I didn't have a header I just have this straight raw data raw data just like I like my clams or something I don't I don't know what a lobs oysters oysters raw eat them raw I don't really eat oysters I don't know what I'm talking about so I'm gonna so I have all of those that looks good I'm gonna pull them in it didn't like these two what was the problem what is the problem man with those two it didn't like the increases I think I have to have something in there on the description that's why so I'm gonna say let's remove let's close this out I'm gonna say no no you guys have rejected my data I am not I'm gonna go back to PayPal and that's not acceptable that's not acceptable I'm just gonna add like a description on these I think that's the problem I'm just gonna say this is a D for deposit and that should do it so let's close it save it and let's do it man let's save it as a number two and so there's PayPal number two that I have made the adjustment on all right you better recognize you better recognize now those deposits are important those are like the main thing that's what I'm doing this for Quick Books all right upload from a file and then I'll connect this thing this is gonna be PayPal number two boom let's do it again let's do it again I'm not it's not a problem I'm not upset or anything just cuz Quick Books is being stupid is the is the first row of your file a header no it's not column one column and then down here it looks like that okay just like last time it's the same thing date all right and then description is that and then the amount okay okay Quick Books are you happy now so there that was the issue I have solved it all right let's go and continue Quick Books will import 15 transaction using fields you choose do you want to import yeah I do let's do it so import completed both and now we've got another item in Bank Feed Limbo it did not put a beginning balance so we could do the same reconciliations with PayPal PayPal you might when you first look at it you're like it's not the same as a checking account it's kind of weird but it does give you reports because you kind of look at a PayPal just like a lot of people look at their checking accounts and they say well this data in the checking account I can see it real time so I don't need a bank statement but you still want to have the bank statements because the bank statements have that very delineated cutoff helping you to do the bank reconciliations so you still want to do the bank reconciliations like with the PayPal which however should be easy once again because we're probably going to be now after we get that first bank reconciliation done we have that beginning balance issue it should be just like kind of like the credit cards where we're gonna basically do everything from PayPal you know we're not we're not gonna enter the data on our side and then verify it to PayPal as we might do with some items in the checking account like deposits like checks physical checks that we write with PayPal all transactions were probably going to be electronic and therefore we're going to depend on PayPal to record them in our system and therefore the bank reconciliation should be easy but now we've got this information in bank feed limbo now which is what I would call is to hasn't been pulled into the promised land to help us to create the financial statements or double check the financial statements that we have created it's over here at this point in time and of course one of the major components are going to be these transfers that we have from PayPal that are that are also going to be on our checking account hopefully deposits into our checking accounts we've got those inter company kind of or enter bank feed to bank feed type of transactions in a similar fashion as we did when we looked at the credit cards so in future presentations we'll just populate and add this PayPal information into the system it should be you know routine same kind of thing except for a lot of small businesses the PayPal might be more the revenue side of things because you might be simply I mean a lot of people at least I started using PayPal as a means to collect revenue on these online platforms right it was one of those means to do that so you might have more unlike the checking account you're probably gonna have more decreases to the checking account expenses on the PayPal you might have different categorizations of the revenue and then you've got of course that pairing kind of thing so that's what we'll do in future presentations it will be great you will not want to miss it and so tune in next time and we'll see you then