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Skip to 0 minutes and 10 seconds Let’s start off talking about genetic tests that already in use. Are there things that you use in your day-to-day practice that are making a difference now to patient care. Dr Thalange - Well, in Paediatrics, which is my field we use a lot of genetic tests and, broadly speaking, we use guided missile tests with very specific reasons. So we suspect a diagnosis or there’s a very important question that is a resolved with a single gene test. For example, if we have a newborn baby with ambiguous appearance to the genitalia then we need to know is that a genetic male or female because that’s crucial in terms of management.

Skip to 0 minutes and 54 seconds So we would do a very specific test for Y chromosome sequences using fish. Then we have broader diagnosis. So for example, I see children with short stature and one of the causes of that is the condition Noonan syndrome and there’s a host of genetic causes of that and I might well request genetic testing or get the patient to be seen by my genetics colleagues, and they may or may not agree to test but it is very useful if you can confirm genetic testing both for the individual in terms of how we manage them but also prognostically in the future.

Skip to 1 minute and 35 seconds Dr Jennings - So did all of these tests really fall within the classical genetics service - so a clinical genetic service. Dr Thalange - Largely, yeah. So the microarray screening is the current test that has replaced the karyotype and we use that a lot now and it’s better but it still gives us quite limited information, and it also generates a lot of noise, and I think one of the things that we as clinicians need to understand is how we deal with that noise - the mutation of unknown significance. And it also leads to a lot of false hopes you know, for parents that the answer is known potentially and you know, but we have to screen both parents.

Skip to 2 minutes and 17 seconds Sometimes it’s difficult to actually get both parents to agree to testing. There’s a lot of misperceptions and misconceptions around blame. I think a lot of parents feel guilty about the possibility of a genetic diagnosis in their child and and therefore actually don’t want to be tested themselves, even if the child is tested because they don’t want to feel it’s, as it were, their fault. So I think you know, it is an issue that we have to deal with ethically and we involve our genetics colleagues in those discussions.

Skip to 3 minutes and 0 seconds Dr Jennings - So variances of unknown significance present problems to the clinician but what about the general public - how do patients respond when they’re told information about having a particular genetic variant and it’s not known whether this is phenotypically important? Dr Shakespeare - I think the evidence is that patients want to know - they want to know everything that a clinician knows and so a lot of clinicians and researchers feel that obviously, if there’s a mutation or or a sequence which they know has an effect, they should disclose that particularly if it’s actionable.

Skip to 3 minutes and 30 seconds But a lot of clinicians and researchers feel that look, if we don’t know what it is, we should just keep that to ourselves, so it’s no point in telling people and that’s understandable because why would you as it were, want to make somebody anxious when you can’t tell them what the reason, or the issue is. But the evidence shows that patients are very keen on that they don’t want clinicians researchers to be paternalistic. They want to make up their mind what to do with the information, and it’s similar to the experience you must have had which is about when parents want to know diagnoses, so they want to know genetic information about their children.

Skip to 4 minutes and 8 seconds In clinical genetics, we’ve had a tradition you don’t test children for things that are not actionable during childhood. You leave it to the child to find out later. Yet, increasingly I think it’s true that parents are aware that you can find stuff out and they want to know it, on behalf of their child, and they feel it’s up to them when and how they disclose it, not up to the clinicians. So the combination of this new genetic knowledge, much of which is uncertain, and a sort of consumerist ethic that it’s our data, we want it, and we can decide how to use it, I think that throws up some professional and ethical problems. Dr Jennings - Yeah.

Skip to 4 minutes and 44 seconds I mean one of the professional problems is interpreting data that comes out of genetic reports and it’s one thing if you’re a hospital specialist who is used to dealing with genetic tests and giving genetic information to patients regularly, but how do general practitioners respond to some of the reports. Dr Thalange - Well, I think most genetics is requested by specialists rather than by general practice, so I suspect few general practitioners are the direct recipients of genetics reports.

Skip to 5 minutes and 20 seconds It could just be me reflecting my background in paediatrics and that I’m unaware of what goes on in other spheres but my wife is a general practitioner, you know, I don’t think in general, that general practitioners have much either awareness, or expertise, in genetic tests and their interpretation. It’s challenging, even for those of us who use them regularly I think. Dr Jennings - And what about other hospital physicians - do you, as a clinical pharmacologist, do you use genetic tests at all or are you used to interpreting data from reports. Dr Loke - Almost never, I would say.

Skip to 5 minutes and 55 seconds Because we are not familiar with looking at the test results, we don’t know what the implications are of the results that come back, so I would say we would never, never rely on this, and we would consider it to be in the specialist domain, as Nandu has said. I think one of the issues is that most most physicians are very comfortable with the existing other types of that test, so you can have standard tests that GPs can do and and the usual physicians can do anywhere.

Skip to 6 minutes and 25 seconds We are are skilled in interpreting those but if something comes out of blue, we are going have to go into the internet, or the textbook, and look at what it is because we we can’t keep up with the amount of tests that’s becoming available, and I gather we’ve got something called next generation sequencing coming up that’s gonna throw up hundreds or thousands of new things of which we have a little understanding of, and I take Tom’s point that, yes we should give all to the patient, but actually we don’t understand it ourselves. Dr Shakespeare - And I’d like to raise another point. Last month I had my markers sequenced by 23andme, so I have loads of data now.

Skip to 7 minutes and 4 seconds It’s on my computer. I don’t understand it. Could you explain it to me? Could you explain to me? I want to have an appointment and understand what’s happening. Dr Jennings - Well we have got that and there is that potential that you know there’s direct consumer testing, results will come back from organizations like 23andme, and other, lots of other companies now, and the person that’s requested those tests will take their data to their general practitioner and say can you help me interpret this and also with next-generation sequencing, not just a target marker, but the whole - all of the sequence with an inevitable number of variants which will have phenotypic impact will be there but we can’t interpret everything.

Skip to 7 minutes and 54 seconds But going back to clinical pharmacology - are there any tests for adverse events say, that you think you would consider using in the near future? Dr Loke - Well ideally in preventing adverse events, we’ve got to concentrate on the serious, rare serious ones that we can’t predict from any other means, or any other tests that we use. Why would we want to do an extra test on the patient if we are able to predict the adverse events through clinical skills, or symptoms or science, or whatever.

Skip to 8 minutes and 24 seconds So it is such a commitment to say to the patient about, we know you need this drug but you’re gonna have to wait a little while, while we get this extra test done and if the test is fine that we think you’ll be safe to have the drug. So it only really works in a condition where we can say actually you can - we can wait a week or two before we get the result and I wonder how how many patients would tolerate that sort of a situation, if they had a serious illness and you say, we’re going to wait another week or two before we get the results.

Skip to 8 minutes and 55 seconds So it’s relatively limited in its application, at the moment, because of the logistical issues. Dr Jennings - Can you see some tests that might become essential, so that you have the notion of never events with some areas of pharmacology, so you know the very rare idiosyncratic but really important outcomes that you need to know about. Dr Loke - Sure.

Skip to 9 minutes and 16 seconds I mean I think there’s a role for that in in the very serious skin reactions, what we call hypersensitivity reactions, where you you can get a fatal or life threatening rash from drugs like carbamazepine or abacavir, and those reactions we cannot predict in any other way but we also need to know what the the prevalence of the genotype in the population is - the particular alleles we need to know. Is it a high prevalence issue because if only one in 1,000 or 1 in 10,000 patients had it, does that mean we have to test that about 10,000 patients to prevent one reaction?

Skip to 9 minutes and 56 seconds Dr Jennings - Okay let’s look into the future now and consider, say you could actually do your genetic test as a point-of-care test, right on your bench next to you with your patient, because there are new sequences that are coming out where that you know that that potential is there, in the quite near future, would you consider using those sorts of tests for the very, very rare but clinically really important… so technology can be important.

Skip to 10 minutes and 20 seconds Dr Loke - I think that will work in a specialist clinic, where the particular allele is well defined, the a clinician’s experienced in managing those patients but again for a general practitioner, who’s probably has to prescribe 100 drugs or 200 drugs in the space of of a week or two, and to be able to test how many could they manage to remember to test. I think it works in especially setting, I think much less so in primary care at the moment.

Skip to 10 minutes and 51 seconds Dr Thalange - I think it could work in that context because I I think it’s one of the interesting things to me about the consumer approach to genetic testing is that actually, those companies are going to have to present the information in an intelligible way to consumers. They’re not going to produce a report that’s strange lots of you know, lots of letters and numbers in a sequence you know, incomprehensible to most of us.

Skip to 11 minutes and 14 seconds And actually, it would be helpful to know that you’ve only got a 15% chance of responding to an ACE inhibitor, you know, you could hypothetically, have a you know, a hypertension analysis that says you’re most likely to respond to these three or four treatments and less likely to respond to these one or two. Dr Shakespeare - What happens … I can see how that would be useful and there’s a - let’s call me the patient in this instance, you know, I want a drug which works for me and which I respond to effectively. I don’t want to waste time because it could be a waste of time to take drug for a few weeks and have no response.

Skip to 11 minutes and 52 seconds What worries me is, let’s say, I have some complex cancer and there are drugs on the market to deal with it and then you test me ,and you say well look, you know, it would help you a bit but you’re not really in the target for this drug, and I’m saying but my friend down the street’s got the drug and they’re doing brilliantly - why can’t I have it? Dr Jennings - Well, there are some good examples of drugs like that, that we do take a test for …

Skip to 12 minutes and 11 seconds Dr Loke - Well yes absolutely and there are new new drugs for cancer where they know that a certain group of patients who have a genetic mutation have a lower response rate than other patients but would it be acceptable to the public, if let’s say, hypothetically we say, ‘oh, so your friend down the street’s got a 40% chance of response,’ and the NHS says, ‘yes that’s a good response, we will go ahead with a drug,’ but you’ve had a genetic tests and they say, ‘oh you’ve only got a 30% chance of response, so you can’t have the drug,’ but you might feel that a 30% chance is it’s a good chance for you, rather than no chance.

Skip to 12 minutes and 46 seconds Dr Shakespeare - And ethically we should treat like cases alike and we don’t know whether this friend of mine is in the responding group or I’m in the responding group. Tt’s less likely I mean the responding group but I could be and you’re not even giving me the chance to find out, so I’m going to write to my MP and I’m going write to the Daily Mail.

Skip to 13 minutes and 3 seconds I’m going to be very cross about it and some people are going to say, well it’s a very expensive drug, we don’t want to waste it on people like you, and I think when we start having those discussions, I know we already have them through NICE but we’re actually stratifying the people - we’re saying the drug is in clinical use but we’re stratifying to people who we believe could merit it, and I think that’s quite a difficult thing for the public to understand, and sometimes, to accept.

Skip to 13 minutes and 41 seconds Dr Jennings - Well, here’s an interesting thing - this course is called Pharmacogenetics and Stratified Medicine but research has gone on recently into, if we roll out stratified medicine into general use, what do the public think of it, and one thing they don’t like is the name ‘stratified medicine’, probably for the reasons we’ve just been talking about, and research has shown that they much prefer the term ‘personalised medicine’ so actually you can have exactly the same thing relabeled and it becomes more acceptable to people because it’s seen as something individualised, or personalised.

Skip to 14 minutes and 16 seconds Dr Shakespeare - Well, as we know, there’s this idea of the Four Ps: preventive, predictive, participatory, and personal. And yet this is not a mirage but this is a goal. We don’t know if we’re going to achieve this, and in the NHS where we’re we’re strapped for resources and you know, increasingly, we can’t offer everything that is possible.

Skip to 14 minutes and 36 seconds The question is, which are the most cost effective diagnostic procedures to introduce to enable people to have the drugs that might work for them, and in terms of the economics ,I would imagine, you mentioned hypertension, at the moment you know, you have a mass-market drug, everybody gets it, some people respond well, some people don’t respond at all, on average you know, people do okay. In the future, how are you going to work? You might have a dozen, two dozen, stratified drugs which have a smaller market, where there’s this expensive diagnostic test that we give them ahead of time. It may all work out swimmingly, or it may be actually quite expensive and difficult for the drug companies to develop.

Skip to 15 minutes and 13 seconds iDr Jennings - But is the status quo okay because, to quote somebody else, Alan Rose who is from GlaxoSmithKline once said that, for the majority of drugs, only thirty to fifty percent of the patients who received them actually get benefit from their medicines. That’s not an acceptable situation to stick with, is it? Dr Loke - No, but how much can the genetic testing improve the response. Dr Jennings - That’s a good question … Dr Loke - That’s the big problem because some of the things that you mentioned, a genetic component contributes maybe 20 percent or 10 percent to it, so we could improve the response from 40 percent to 50 percent. Is that a worthwhile thing?

Skip to 15 minutes and 50 seconds And maybe you would argue it is but why don’t we design drugs that have better better efficacy among the whole population, rather than having to stratify patients. Dr Shakespeare - I’ve seen some research from the States you know, because this personalised medicine and it’s going to tell you about the lifestyle changes you need to make, and the drugs that may or may not, work for you but the response that I have to that is actually, you know we still know what we should be doing, you know, we should be eating more fruit and vegetables; we should have more exercise, less fat, that’s what we should all be doing and this detailed, detailed prescription - how much better is it than that basic, well understood public health advice?

Skip to 16 minutes and 28 seconds Dr Jennings - I think that’s a really good question.

Skip to 16 minutes and 40 seconds Dr Jennings - So, let’s let’s return to the notion of using genetic information more and more, which we already are, and look to the future. One of the big challenges is the amount of data - we’ve talked about variants of unknown significance but there is another way that - we could consider sequencing genomes either very early on in life, it could be sort of, replace the Guthrie test in time but only actually look at the data in an episodic way and look for particular changes, where we need to know the answer about those particular variants. Is that the sort of model where genetic testing could be applied with …

Skip to 17 minutes and 15 seconds Dr Loke - So, are you suggesting that prospectively every patient, conceivably, could have a test that at some early point in their life? Dr Jennings - So this notion of a DNA passport? Dr Loke - Yeah exactly. Dr Jennings - Yeah but the point is, we don’t want to deal with all of that information because it’s probabilistic all the way through our lives but actually it can be really important, when you’re going to be prescribed warfarin, to know some things, some little bit of that information, so there’s the sort of, model.

Skip to 17 minutes and 38 seconds Dr Loke - So, on a typical elderly patient who is on ten, eleven different drugs, so every time you want prescribe a drug, you would plug in this this device, which has the variants on it and you would check that? Dr Jennings - It would just be part of the patient records in this scenario. Dr Loke - Well, patients at the moment, they don’t even bring in the drugs that they are on, we don’t even know what drugs they’re taking but to add another layer to it? What do you think? Dr Thalange - You’re dealing a very specific group of patients there Yoon. Dr Loke - But they are the majority of patients who come to hospitals.

Skip to 18 minutes and 12 seconds Dr Thalange - Yes, but obviously most patients - so most of us, at some point in our lives are patients and I think and most of us want to be healthy, and actually I am very attracted by the idea of a DNA passport. That means, that when the child comes to me with short stature, rather than me for example, doing a very expensive and potentially hazardous growth hormone test, I’m doing an appropriate genetic test that says you know, before short stature that says, this is the explanation, and you know, ideally ,in my consumer-driven model, it’ll also give me a likely benefit from different treatment strategies, so that actually it’s really helpful.

Skip to 18 minutes and 51 seconds Now, obviously, if you have the depth of quality of information that has real potential to personalise medicine in a really effective way and obviously, it has great potential in patients who are on comparatively few medicines, as opposed to who have very, very complex treatment regimens, but I think it even has a role there because drug interactions for example, may be unpredictable and so I think actually, in time that has real merit you know, actually going to the genetic passport and saying, well what can I find out about you from what’s known, of relevance. So, not looking at everything, but looking at the particular issue that has brought the patient to see me .

Skip to 19 minutes and 47 seconds Dr Shakespeare - That seems to me, to be very exciting but also, from a social scientific point of view, a little bit worrying because for example, let’s say that I’m an employer, and you’re coming for a job and I want to know what variants you might have that might make you, I don’t know, claim on your health insurance from the work, or take time off, or become I don’t know, have heart disease, or dementia, or whatever. You know, my 23andme results told me about ApoE and you know, I don’t have ApoE, for now, I’m okay but what if I had had?

Skip to 20 minutes and 15 seconds What if I had those two variants and what if my employer, or more importantly, my long-term care insurer said, have you got ApoE four four, you know, the two alleles - they may discriminate against me. So I think that what’s very, very helpful in a clinical setting could be worrying in an economic, or employment, or insurance setting and so we have to be - have some very much more advanced legal and ethical safeguards to make sure that it’s not disclosed inappropriately or used as the basis for discrimination.

Skip to 20 minutes and 53 seconds Dr Jennings - I think that’s sort o,f already well established in the States, where you know, development of genetic ethics has run alongside the development of genomic science and it’s illegal to discriminate on the basis of genetic data ,with regards to employment. So, those things are already being put into legislation in some countries. Dr Thalange - We have been down this road before, albeit not in genetics, but for example, in HIV testing, it used to be the case that if you even had an HIV test, you were practically uninsurable and those discriminations were all removed essentially, in law, and I think as long as there’s adequate consumer protection that is reasonable.

Skip to 21 minutes and 39 seconds Dr Shakespeare - So, I do agree that there has been action. There have been moratoria, there have been - but in my view, more of us sort of trying to create a dyke, in the in the case of a flood, than a permanent protection against abuse and so I think that, as we’ve develop our understanding clinically, scientifically, we also need to do so legally and ethically. Dr Jennings - And personally, because people may regret - you can’t put the genie back in the bottle and people may think they want to know and when they find out they don’t want to know.

Skip to 22 minutes and 9 seconds There was a study recently published about medical students ,who actually had a lot of genome data produced as part of one of their experiments and they had it annotated and they could choose whether to have that data given to them, or not, and a significant proportion of people that did the experiment really regretted having that information, once they had the information. So we don’t always know ourselves, and what we precisely want to know about probabilistic information.

Skip to 22 minutes and 36 seconds Dr Shakespeare - And I think that’s where probabilistic is very important because we are talking largely about probabilistic information and we still have what you might call, a simple clinical genetics - Mendelian understanding of you know, full penetrance, you’ve either got it or you haven’t (50%) and we’ve been brilliant at educating people - toss the coin you know, you’ve got it, will you pass … People - biology, they understand recessive and dominant. They’ve got that but what that means is that I think they’ve got a more fatalistic …

Skip to 23 minutes and 4 seconds genes equals destiny, and what we’re talking about is genes equal tiny raised risk, or combination of genes equals complex variable outcomes and we have to educate people away from the deterministic model of genetics. Dr Jennings - That’s good, and I think that’s a good place to finish. That’s covered all our questions now.

Some final thoughts

During the construction of this course we had a wide-ranging discussion about the use of genetics in medicine by today’s clinicians.

We also debated the potential utility of genomic medicine in the future; and our conclusions informed the material included in the course.

We filmed the 23 minute discussion between Barbara Jennings, Yoon Loke and Tom Shakespeare with their colleague, Dr Nandu Thalange who is a consultant physician in paediatric endocrinology.

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Using Personalized Medicine and Pharmacogenetics

UEA (University of East Anglia)