 Thanks very much, and it's a great honor for me to present. My name is Patrick, and I represent a number of different institutes in Singapore. And I think in the next 15 minutes, what I'd like to do is to give you an oversight of what we're doing in Singapore and how we're trying in an early way to try to move some of the research that we've been doing into the clinical practice. And I do like Dr. Manelio's point that a lot of this must be pitched as an evolution of current practice rather than as a revolution, and I think you'll see some of that here. Speaking from an even smaller country in Belgium, where we have a population size of about 5 million, I think you will see that this presents some opportunities, but also challenges as well. So how do I move this? So just one slide on the overview. So this will be a very pragmatic, practical talk, I think, compared to maybe some of the high level stuff that you've been hearing before. Just one slide. So our foray into biomedical science really began about 10 years ago. And it is over the past five years. It's seen steadily increasing support from the Singapore government. And the last tranche was about $2.6 billion in biomedical funding for the past five years. And this, the funding arises from three major ministries, a trade industry, education and health. And while that's good in the sense that there are many different grant agencies, it can be a challenge trying to align the different types of needs of these different ministries when you're trying to talk about something like genomic medicine. And one positive aspect is that this has resulted in a lot of research institutes. Some of you may be familiar with the Singapore Biopolis and also a number of academic medical centers. And some of my colleagues in Singapore are here representing those. So I think that there is this receptacle, I think, for the use of a German genomic medicine. And I'm going to try to use stomach cancer as a basis for that in terms of some of the experiences. So the area that I think Singapore has tried to position itself is as a receptacle for understanding Asian-specific conditions. And one of these is obviously Asian cancers. This is the main area that we've been working in. And this is stomach cancer and the incidence of stomach cancer in different parts of the world. And you see that it's primarily present in many parts of Asia. I think my colleagues from Japan and South Korea will agree. But globally you will see that stomach cancers are actually the second highest cause of global cancer death. So what this means is that this is a disease that we need to figure out how to treat better. And I think the intersection of this with genomics presents some very interesting opportunities in being sort of like poster children for how we can use genomic medicine. Just two studies that I think highlight this and more how do we use this in a way that builds on current clinical practice. So this is just one study that highlights what is that basically this paper published in the Lancet highlights the use of Trastuzumab targeting gastric cancers that are amplified in the HER2 oncogene similar to breast cancer. And this is the first targeted therapy in gastric cancer. And this actually is a positive for these patients that have amplification of HER2 but for other 90% of cases there are no targeted opportunities available. So this is where genomics can come in where we can do a landscape survey, find new opportunities. In this particular work what we find is quite interesting for a cancer point of view is that besides the HER2 population there are distinct segments of gastric cancers that actually amplify different components of the RTK-RAS map kinase pathway. And this obviously is a pathway where there are significant targeted therapies available. So in one sense this is a very simple way of genomic medicine where we can stratify patients. Validation is very important to have all of these studies giving the certainty that this is not one of finding. And this is just a comparison of the data from the Chinese gastric cancer patients to the TCGA cohort primarily patients from Europe and Caucasia. And for the most part you can actually see many if not all of the similar amplifications being seen in both. So in a sense I think that for many of these conditions we have the validation and prevalence but how do we move this into the clinic is I think another challenge that we need to think about. Another study that I think highlights how do we use this as a way of evolving our current knowledge rather than as a revolution comes from a transcriptome profiling study where I think it really highlights the challenge of how can we position this sort of work as an improvement on current pathology rather than a let's kick the pathologist out of a job. And so this is a study where by using consensus clustering we can find three distinct subgroups of gastric cancers and by doing the standard pathway analysis we can find distinct pathways associated with each cancer type and also these different subtypes actually have different preclinical at least drug sensitivities this has yet to be validated. But what is interesting from this is this particular subtype over here that I think represents how we can use this as an evolution. So it's been known since the 1960s that gastric cancers and I apologize for those who don't work on stomach cancer but this is the only thing that I know is that gastric cancers can be divided into intestinal and diffuse and this is the standard pathology practice. However what's interesting is that a number of years ago it turns out that this what pathologists have known for a while but it's sort of embedded in the pathology world is that intestinal subtypes actually there are two particular variants one type that has markers of normal gastric epithelia and one not so this actually there's third hydrogenary here and when they map it to the gene expression subtypes it's possible and that this actually may correspond to one of those molecular subtypes and one of the different ones. So I think that by talking to pathologists and asking them how does this reflect your own personal experience we can begin to build bridges between the genomic sector and standard pathology. And so this is currently the consensus being done this is the pathway that most of us will learn in medical school about how gastric cancer develops but by intersecting pathology information there may be a separate subtype over here that represents that new genomic subtype we're seeing and we're currently working with these pathologists to see if we can improve that. So this is a way of getting them used to understanding genomic data. This is just one sort of approach and you know this is not just stomach cancer I think that over the past number of years Singapore has done pretty well in identifying genes, gene polymorphisms associated with different types of Asian cancers. I just highlight this is a very nice one where this is a deletion and 2.1KB indel so very hard to see by standard NGS sequencing in BIM in only present Asian populations that seems to predict inferior responses to tyrosine kinase inhibitors and also this paper from the Cancer Science Institute looking at prognostic markers in liver cancer and other Asian-specific cancer. So I think from a discovery biology point of view we've been doing a pretty good job at finding things to translate. So the next question is that how do we move that to the next step and this way it comes intersects with the medical system and this is where we have challenges but opportunities. So one of the things that we've tried to do and this is not the solution but it's a pilot thing is to establish a program called Polaris which is the North Star this is where we want to get to in future where we can try to see can we have a national structure to look at how we can implement genomic medicine. It's funded for 3 years about $20 million from the Agency for Science, Technology and Research so one of those three agencies and the idea is to pilot the use of clinical use of genomic testing starting with cancers and genetic disease and in terms of operationally what it really means is a nationwide network of college medical and pathology certified genomic laboratories running the same tests running common informatics systems sample preparation systems so that we can standardize across the whole island and it's a tall order so we're starting in a very pragmatic small way and I'll show you what I mean and we're about one year old into this program. Some operating principles that we feel is important and I'd like to raise these for discussions is something we felt that would be important for genomic medicine to work. The first operating principle that we thought would be important is that genomic medicine labs running your high CX on your my CX should be deployed within an existing clinical framework so as opposed to setting up your center as a stand-alone center and the main one reason for that is purely financial if you're going to be trying to reimburse if you have a stand-alone that center is going to be bleeding red right from day one but if it's parked in a pathology department pathology departments can cross cover a true poison lab medicine and so on so I think that's one thing that and this allows them to see it not as a threat but as an evolution of their current practice. The second thing is that you know single gene tests probably have had their heyday but I would say that for people that want to start genomic medicine you need to have the framework to do basic genetic testing single gene testing before you can even start to think of doing a whole exo and I think that is so we need to learn by doing it finding out where the pressure points are and moving on from there the third point is that genomic tests should leverage on existing competencies and I think this is where the genome England started is that you know when you want to set up a new center if there's already a lab that's redoing really good Sanger sequencing you can use that lab for validation rather than having to set up your own system but that requires trust and how do we get the funding to flow across different centers to reimburse that lab for that and so I think that this is a more cost-effective way but it does take more teamwork and more effort in place so a lot of my time is spent meeting people and taking them out for lunch and I think lastly I think it's one is that starting with tests as initially proof of concepts that provide true clinical utility will lead to collision bias so what we try to do is to highlight disease champions these are people working in a particular domain they are very influential and we ask them what would you like to measure that would make you change the way you treat your patient and we start there and we build a test around that and that we use that as a basis to learn and they themselves participate in how the clinical report is being generated so this is the current status after one year our first Polaris test without spending the next two slides talking about is a very simple single test but I think it has identified certain issues that we need to fix and it's going to be launched at the end of the month the genomic labs themselves are going for national certification in mid-24 it's going to be based on Illumina and I'd like to talk to people here about what do they think is the necessity for reflex validation when you see a new variant called by, let's say, on a MySeq how important do you think that is the test revenue so these pages are actually being charged for these tests and what happens is that the revenue that is incurred from this test is equally split among the different centres contributing to the test on a cost recovery basis and so this was important for sustainability and finally the next Polaris test that we're going to do by the end of this year is a 90 gene GI gastrointestinal cancer test that has all of your favourite players on it so let me talk about this test over here because it's a Sanger test, it's a very simple test but I think there are certain... it led us to identify certain things that we need to fix in the system the test is targeting a condition called stromal corneal dystrophy and most of the patients with this condition have a mutation in this gene, it's one gene so it's very easy to do by Sanger but I think it hits the flavours of the things that we can use to prove the use of genetic and genomic testing for instance, by testing these patients we can clinch the disease diagnosis the location of the mutation in the gene directs different therapeutics that... therapies that the eye surgeon has to use and it's important for screening of unaffected family members because these patients that have the test even though they don't have symptoms should not go for LASIK so I think it is all the flavours of something that has true clinical utility and the fact that we have a national centre for eye diseases allows us to find out patients through this particular test more importantly, it's allowed us to try to integrate a number of the different academic medical centres so one, the National Eye Centre provides the patients and the consultation, the ordering, they do the blood collection so all of this is intersecting with the standard hospital practice that we're doing here the National University Hospital system provides the DNA sequencing and the mutation report and the GIS bioinformatics and the test revenue is actually split among these three places so in this cases, actually, this particular place gets the bulk of the revenue from the test and so, as a lot of this with certain challenges that I'd like to close now but just cheer for that, I'd like to get your feedback on the first one is that because we have different ministries trying to get legal and licensing agreements across the institutions is quite complex that's the first one second one, Singapore has a very interesting system that the moment a patient's test crosses an academic medical centre that test is charged at what we call a full rate it can't be and so this is sometimes something that we need to fix in the system because the goal of this is to get all of the people from different centres working together there's a general lack of expertise in genetic and genomic counsellors so a lot of the doctors have told me we would like a test, we would like to prescribe it but I don't feel comfortable with it without a qualified counsellor sitting in my clinic at the same time so this is something that we are trying to address by sending more people for training and finally I think and one of the things I'd like to get back from this one is that we lack official policies on how do you write the informed patient consent form how do you deal with these incidental findings and how do you aggregate your data from the patients that you're running a test on such that you can have a database that's itself a very valuable for future discovery and the fact that it's clinical service how does that feed into research so I'd like to close there I'd like to thank my colleagues in the audience Professor John Wong, Professor Cheung Mi Ju who are here and thanks Mark Williams Geisinger could you talk a little bit about why TGFB1 was chosen as your exemplar for a single is this a condition that's more prevalent in the population because it's not one that at least that I'm aware of in this country is being tremendously prevalent so it again I think it's very pragmatic we needed to have a poster child of a test that hit all of the bells of clinical utility and we needed to have what we call a disease champion a clinician that was willing to work with us over a six month basis to polish and build the test third thing was that there was actually research being ongoing in the center on this condition so they had all of the patients the wild type and the mutant patients rapidly validate the test so I think that we wanted something that we could at least from the technical standpoint all of the ingredients were there and we could use it as a test to see what the other challenges the framework for how do we do the reimbursement because I think that's the important part the technology we can swap it and swap out but how do we do those other bits I needed something that we could stress test the system and find out where the weak points are so we won't make a million dollars from it but I think we've done about five to ten patients already and you know though I think that's been clinical benefit from these patients already so I think that and we're going to do more once we get the framework set up we can then use the same basis to do other ones along these similar frameworks so that was the reason Teri Manolio, very neat project and I'm wondering the data that you generate from this are going to be useful to others who might want to interrogate the TGFB1 gene as well have you thought about how both you're interrogating other databases to see when you have a whole host of variants that may have no meaning at all how you're doing that and then how you can contribute to those databases such as through things like the ClinVar database at NCBI or others so speaking as a researcher I firmly believe you 100% about the importance, the value of open sharing and I think however I think that in order to reach that vision we have to do it in steps and there are significant concerns, some of them emotional, some of them from a patient privacy point of view as to what is the right version of the data that we can open up another tension is that a lot of the funding in our was from the Ministry of Trade and Industry so they're obviously interested in this from a commercial standpoint whether you have that question of open access versus not these are all I think issues that can be solved with further engagement of the different because all of us have the same vision but getting there I think just takes step by step so the vision I think is then to share all of that data that we have we just need to figure out the best way I won't let us into trouble and I might just suggest David Ledbetter and Heidi Rehm are here and are quite familiar with data sharing in ways that probably affect intellectual property and that sort of thing but might want to talk with you a little bit about getting this data. I'm here to learn on this. Thank you. George Petrinus is actually a question I wanted to ask to Tim two lectures before one important argument for policy makers to incorporate genomics into health care is that they save money the national health care expenditure so have you considered doing economic evaluation using this test so that it can become eventually cheaper for the patients? So yes and no and you may not like what I'm going to say but again I think it's a very pragmatic what we do we're going to do is that we're going to compare the cost of developing this test in Singapore and doing it versus the cost of this same center sending the test out overseas we're still working on the final pricing of the test but we can basically do it in-house at about one third of the cost particularly if you factor so that's basically the argument that we're going to say for cost effectiveness now we can talk more about this later on because a lot of this is patient pace but at the very least we can say that we're actually bringing a test to Singapore, leveraging on our research and to bring at least health care cost for the individual patient down I think we'll start there