 Thank you very much for the invitation. So I'm talking to you as an academic in the UK, which is still part of Europe, just to out. But also, as somebody who works with the International Serious Adverse Event Consortium. So what I do is, as an academic, I direct the MRC Center for Drug Safety Sciences. For those of you who do not know, the MRC is the equivalent of the NIH in the US, except we have much less money, of course. But we haven't been stopped from giving coffee to people. So if you come to us and see us, we will give you some coffee. This is the mission of the MRC Center for Drug Safety Science, to really undertake a leading-age science, train the next generation of drug safety scientists, understand the mechanisms of the type of serious adverse drug reactions we're looking at today, and to develop strategies to improve the benefit-to-risk ratio of current and new medicines. That means developing diagnostic tests, predictive tests, but also using the chemistry of the drug to be able to design new safer drugs, as was suggested earlier on. So we work with academics, other health care groups, plus also industry and other types of organizations. And that was why we started working with the SAEC. The SAEC is set up by Arthur Holden. The mission is shown there, which very much aligns with what we do with the MRC Center for Drug Safety Sciences. That is identify DNA variants useful in understanding the risk of drug-induced serious adverse events. That's the ISAC's mission. Now, the SAEC has been looking at various different phenotypes. Serious-cutaneous adverse drug reactions, drug-induced liver injury, and also recently started the drug-induced renal injury. The important aspect over there is that because there are different patients being recruited to all these different phenotypes, one can actually start looking across the phenotypes to see whether there are common genetic factors, so that common genetic factors, which leads to skin versus liver, with the same drug. And that's going to be very important as the work of the SAEC in terms of undertaking all the autogenome studies comes to fruition in the next year or two. Also, within the same particular group, for example, within the serious-cutaneous adverse reactions, then we also have different phenotypes. So I have been leading the serious-cutaneous adverse reactions, but we called it itch international consortium on drug hypersensitivity, for obvious reasons. And this is what we have managed to do, have 12 international centers, 50 UK centers, and over the last four years have collected 1,500 patients. These includes Stephen Johnson syndrome, toxic epidermin necrosis, but also Dress, but also some AGEP cases. But also we've been interested in type 1 hypersensitivity reactions, anaphylaxis, associated where there's been immunological testing done. And all of these cases are collected to specific phenotypic criteria, but also we have an independent adjudication of these cases. And Dr. Neil Scheer sitting in the front and Peter Friedman in the UK are two dermatologists well-known in this area. I think you are well-known, aren't you, Neil? So who then undertake the adjudication? And they spent many hours on the telephone with us undertaking the adjudication after having received the case reports. So in terms of the SJSTN, so the data I'm going to show you is unpublished. I'm not going to show you some of the specific alleles that we've identified largely because we need to validate those alleles in some replication sets. Apart from the end case study I'm going to show you. But these are the SJSTN cases that we've collected in terms of the different drugs the patients were exposed to. And it includes many different ethnic groups. But if you just look at the Caucasian cases, what we have are mainly northern European population but also a Spanish and Italian population. And if you look at the clustering there, you can see that the clustering of those Caucasian populations from Europe in association with the controls that we've utilized within the GWAS studies. So the question that we've been asking is that are there any drug-specific associations you can identify, which is what everybody else is doing, but also are there any disease-specific associations you can identify? You could hypothesize that the disease association with SJSTN irrespective of the drug is probably there but it's going to be a much lower effect size as in a complex disease. And therefore you are going to need much larger number of cases, for example, as in type 2 diabetes. And these are data which have just come out. Now, this is data which still needs further work on it. But what we're finding when we actually look at all Caucasian SJS cases is that there is something appearing in the HLA allele area. And it is a very low-frequency HLA B allele. But also in chromosome 8, we're finding a protein kinase. Now, we do need to validate this, but it is nevertheless interesting to be able to show you that. Now, I don't know whether this is not drug-specific at the moment because there are certain drugs which are appearing, but there are many other drugs also in there which are showing the same allele in there, which is interesting. Now, when we actually start then stratifying by the different self-reported ethnic groups, we find that this is mostly driven by Italian SJSTN cases with 40 cases. And the HLA B allele, which is the rare allele, is appearing with an odds ratio of 133 with the 95% confidence intervals as shown and a p-value, as you can see there. And then when we actually exclude the Italian cases and look at the northern Europeans and then look at the Spanish populations, there is no other population-specific signal appearing. So it is being driven by the Italian cases, and that is why it is also important to look at ethnicity when you do these kind of analysis. But again, we need to be able to do further work, whether it is being driven by one particular drug or a couple of drugs in that population. Now, in terms of drug-specific associations, we are obviously, there are associations, we're finding which are already well known. For example, with the allele-pyrinol in only nine cases, Caucasian cases, we are beginning to see, again, 5801 associated with allele-pyrinol. But then there are other drug-specific studies we've done. I've only have time to show you one particular example, and that's with trimethyprimesulfo-methoxazole. Again, 17 SGS cases against 5,000 controls. We're finding some genome-wide associations with a nice stack on the Manhattan plot, as you can see, on chromosome 3, chromosome 6, 13, and also on 21 and 22. And again, these need to be looked at in more detail and validated or replicated in other populations. And what we need to do is now find some replication cases. And obviously, when you are looking at something that rare, it is important to be able to collaborate globally to be able to identify new cases so you can replicate. These could still be positives despite the fact, these could still be false positives, despite the fact that they are above genome-wide significance. And so, just to give an example of how we tried to do this with nivirapine in the African population, we undertook a prospective study in Malawi where we identified individuals prospectively or who had had some degree of hypersensitivity. I was either a macular, popular erythematous eruption, dress, SJST, and all drug-induced liver injury. And I took GWAS studies, but also been undertaking some proteomic studies, and I don't have time to be able to show you that. But although our mission has been to identify predictive biomarkers, what we're also interested in looking at prognostic and diagnostic biomarkers, and we've been looking at this particular protein called HMGB1, High Mobility Group Box Protein 1, where you can look at the total levels, which, by an ELISA test, but much more important is to actually look at the isoforms that stratify, which stratify populations according to most mechanism release, the acetylation status of HMGB1, but also function in terms of radox status. And there's some very interesting data which are coming out with HMGB1. So here's the sort of ingest in SJSTN, 51 SJSTN patients and 182 total controls, and the only sort of association that we get is on HLAC. We've undertaken sequence-based typing, and we see that this is HLACO401 associated here with the navirapine. And obviously, what we wanted to do from this was to go and replicate it. So we started identifying cases, again, in African population, some in Malawi, but also some in Uganda and some in Mozambique. And when you put it all together and do for this particular hit, RS hit, which is RS number up there, you find that it is genome-wise significance with an odds ratio of 5.17. Now, so we think the HLACO401 in the African population does increase the risk of SJSTN in that African population. So what we want to go on to do is to undertake sequence-based, next-gen sequencing of these particular HLA region in a subset of patients with SJSTN. And what we identify is that there is a non-synonymous variant which is in complete LD with the RS number I showed you before. So this is in complete LD and this non-synonymous variant leads to an amino acid substitution which is present in the alpha-1 subunit of the peptide recognition site of HLACO401 and we're just undertaking some molecular docking studies to see how noviropine or potentially metabolites might be able to fit in there and how they lead to the SJSTN. Although we've talked about the parent drug being responsible, it is also important to note that metabolism may still be important and this is done in such patients whereby we've been actually looking at whether patients bio-activate noviropine to toxic metabolites and we've done that with various other drugs by looking at whether there is binding going on to human serum albumin and using mass spectrometric methods. And you can see that noviropine does form addicts in patients who've taken noviropine chronically and the binding occurs particularly on histidine 146 on the albumin molecule. So that just gives you a flavor of the work that's been going on with the SAEC. I think SAEC is a public-private public partnership that has worked well and has managed to recruit well-fina type patients. Genowide approaches are now beginning to bear fruit and there'll be much more coming out. We're furthest ahead with type 1 hypersensitivity reactions and we've got some very interesting hits coming up, hopefully going to be published in the near future. Global collaboration I think is very important to be able to further some of these findings but I think although we are looking at genomic data mostly and that's what we mostly looked at today, I think it is important to identify diagnostic and prognostic biomarkers and some acknowledgments there and to many others who are not mentioned on the slide. Thank you for your attention. We have time for a couple of questions. Yes. So I may have missed this and I'm sorry if I did but in the Italian SJSTN, did you say what Bialio that was? I didn't because we need to validate it. It's a rare variant. Rarely occurring at less than 2%. In Italians. In Italians. Thank you. Are there common alleles for that crossover from SJSTN to some of the other skin reactions which are more common or more frequent where the finding of a disequilibrium or finding of a signal would actually also imply that SJSTN could also be included. That is, are these allele markers always specific for the particular disease? You mentioned one slide where we actually pooled different kinds of skin reactions. So I was wondering whether you found certain markers which actually cross over to different kinds of serious reaction. So that is further work that needs to be done and with 1502 and FluCloxacillin, sorry, 5701 and FluCloxacillin, we've not only identified with liver injury but we are also identifying some patients with 5701 who have type one reactions, anaphylaxis, as well as AGEP as well. So there is some crossover between alleles and the occurrence of different phenotypes. But with 1502 and carbamazepine, that seems to be very specific for SJSTN. So I think it does vary with drug and the kind of phenotypes you're looking at. So I don't think there is one specific rule for everything and certainly with, if you look at 5801 with allopyrinol, there is association with SJSTN, but also with Dress as well. So if you were developing a drug and you saw a signal, let's say, with even maculopapyrin, erythema, and would that be for you a cause of concern for this particular disease? We're usually not. Given the point, the problem that powering is what is so challenging for this disease, you need really a lot of post-market exposure before you can see something. Yeah. I guess your question is does a maculopapyrin erythema act as a kind of signal for the occurrence of more severe reactions and whether the same HLA association? The problem is that there's not enough been done on the maculopapyrin exanthems and the genome-wide association studies. And part of the problem there also is the causality assessment because getting a maculopapyrin exanthem may be not entirely drug-related. There may be other factors there. And the causality association is much more difficult to assess in maculopapyrin exanthem than it is in SJSTN. We're gonna have two more short questions and two more short answers. Okay. How much of your case finding has been amenable to structured queries of electronic health marker data as opposed to manual? All of this was manual. I did do some work on electronic health records and looked at the phenotype and I won't tell you which country it was. I won't tell you which particular provider it was. But I did 150 records and not one of them fitted in with the criteria that we had. David. David Margulis, University of Pennsylvania. When you're grouping people as Italian and Spanish in English, is it all based on the location of origin or is it genetic ancestral markers or it's self-reported answers? Okay. So when we're classing them as Italian, Spanish, et cetera it's self-reported ethnicity including the grand parental background. However, what we have also done is obviously the GWAS we've done some population stratification analysis and I showed you that data in terms of the plots on there. And those are the northern Europeans, Spanish and Italians according to the principal components analysis. Okay. Thank you very much. Interesting acronym you picked since itching doesn't come along with Steven Johnson or a TEN, at least in my limited experience. Now we're gonna hear from Thailand. Dr. Chantratide from the Rama Thibodi Hospital in Mahidol University in Thailand.