10 years of the NIHR Leicester EXCEED Study

Professor Martin Tobin and Dr Catherine John talk to Professor Turi King about the first 10 years of the NIHR Leicester EXCEED Study, from its original aims through to the research questions its data is helping to answer today.

EXCEED (Extended Cohort for E-health, Environment and DNA) is a longitudinal health study that looks at the causes of long-term health conditions by collecting information about genes and lifestyle. More than 11,000 people have already taken part in our research which is leading to discoveries that can improve and save lives.

Based at the University of Leicester, EXCEED is a uniquely valuable resource for health research as it combines genetic, environmental and lifestyle factors to offer researchers a detailed picture of how health is influenced by people's DNA as well as what's happening in their lives and the world around them. www.exceed.org.uk

Transcript

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Hello and welcome, you are listening to an NIHR podcast. I'm Professor Turi King,  your host, and today I'm talking to Martin Tobin and Catherine John,  who are the principal investigator and scientific director respectively,  of the EXCEED Study, which is a longitudinal health study that looks at the causes of  long-term health conditions by collecting information about genes and lifestyle. Martin and Catherine, the EXCEED study has recently celebrated its 10th anniversary. So,  let's start at the beginning, what is the EXCEED Study and what was the original vision for it? So, the EXCEED Study is a study of 11,000 local participants to Leicester, Leicestershire and  Rutland, who've chosen to give their time, complete questionnaires, give a sample of their  saliva, for DNA analysis, and consent to link with electronic health care records, as well as consent  to be called back for future studies to enable us to better understand long-term conditions. So, it sounds like you've got lots of sort of information there that you're linking. So,  you've got things like patient health records, but you're also able to look at their genetic  data. So, is that new to be able to do that? And what's the thinking behind doing that? So, when we designed the study, we wanted to be able to answer questions which were relevant to  understanding how long-term diseases are caused and why they progress in different ways. So,  in conjunction with the public and participants locally, we designed  the study in such a way that we were able to utilise the relevant pieces of information,  but also make it tremendously convenient for participants to be able to take part in the study. So, for example, we are able, utilising linked electronic health care records,  with participants consent, we're able to see how long-term conditions evolve and progress without  needing to recollect that information from participants on a frequent basis. Are you teasing out the differences in terms of disease, I suppose the way it arises,  but also how it progresses, in terms of what the genetic causes might be, plus also  lifestyle factors. Is that what you're trying to look at, the difference between those two? Exactly, we're able to look at the same time, lifestyle influences on how diseases evolve  and how they progress and at the same time look at genetic influences on diseases, and how the  two work together to influence risk of disease. So, if you look at a long-term condition like  chronic obstructive pulmonary disease, a really important long term lung condition,  then smoking and one's genetic makeup act together to influence one's risk. And by being  able to study both in detail, we can understand how that works and how best we might be able to  intervene in such diseases in the future. So, you're actually adding, it sounds like,  another layer of information, because quite often if you're looking at things like lung disease,  you might go, right, well these people all have lung disease, these people don't. What  are the kind of genetic variants that these people have got that might make them more prone towards  lung disease, that these people don't have. But now you can add that extra information  in about, okay, so this is their genetic predisposition, but also, we know that  this person is a smoker, or they live in this particular environment or this kind of thing. So,  you're adding an extra layer of information which helps inform you in your studies, isn't it? That's absolutely right. And of course, many people who have one long term  health condition actually have one or more other long term health conditions as well,  and utilising electronic health care records, that enables us to establish what's going on in  terms of combinations of diseases, but also things like response to treatments as well. Not all people respond equally to particular treatments. For example, drugs that are used  to treat high blood pressure, some people find a better blood pressure response than others,  some people have adverse responses like, developing a chronic cough with  certain types of blood pressure medication. So, when the project started, what was your  aim? So, I know Melanie Davies, who's the Leicester NIHR BRC director, said recently,  it takes a huge amount of vision, strategy, resilience to set up a study like EXCEED. So, tell me, what does it take to get a study of this nature off the ground? That's a really good question and it requires a long-term perspective. It requires building  trust with participants and the public locally, but also building trust with health care workers.  So many of the EXCEED participants were invited to take part via their general practitioner. So, it was building those partnerships with local general practitioners. So that they  could see the value of the study. And in fact, we were really overwhelmed by the support that local  participants and the public provided, that local GPs were able to come on board as partners so  effectively. And to a certain extent it involved a leap of faith on the part of the participants  who consented to take part in the study. We've been going for ten years now and it's  only towards the latter part of that ten-year period that we started to see so many research  publications and research uses coming out of the EXCEED Study, out of that resource  that participants helped to build. So, it sounds like a really nice  collaborative study between, sort of, scientists, GPs, and the public. Absolutely, and I think developing those partnerships at the beginning is crucial  and has been important to make sure that we got the design right, to make sure that we got ongoing  feedback from participants into how the study evolves and progresses, that's been really key. So, Catherine tell me about the design of the study, what are you interested in looking at? So, I think there's a couple of aspects that are important there. One is about being able to  study a really broad range of health conditions and diseases, and the other is about being able  to look at them over time. So, the way that the study was designed, we asked people to consent  to being followed up for 25 years. So, we had that ability to follow up over quite a long  period and see what changes with people's health. And the other aspect of the design that helped to  address that, was linking to people's health care records. So, particularly their records  from their GP, which means we can see when they go to the GP with a symptom or are diagnosed  with a new condition, without us needing to go back to participants and keep asking them those  questions over and over again. So, in the early days,  who were you looking to recruit? So initially when the study began,  we recruited people who were aged between about 40 and 69, and there've been a couple of changes  to that, particularly when COVID happened. We extended recruitment to the study out  to anyone over 18, so that we could really contribute as best we could towards all of  the urgent COVID research that was needed. And the other important thing was that we  were asking people to agree to be followed up, potentially up to 25  years. That's a really important part of the study because it allows us to see how  conditions and diseases develop over time. Historically, there have been lots of really  important examples of longitudinal cohort studies like that, that have provided really  fundamental shifts in our understanding of health and disease, even down to kind  of the risks of smoking and lung cancer. And this sounds like it's one of the really  key things to the EXCEED Study, when you were thinking about setting it up,  is that you want to be able to follow people for the long term because you're trying to understand  about that disease progression alongside health and lifestyle factors. And that's one of the  things that makes the EXCEED Study so great, isn't it? You've got this longitudinal outlook for it. It does, absolutely. And if we combine that design with participant consent to be recalled  for further studies, then we also have the opportunity for participants to be able to  come back, who've developed either a particular condition or a combination of health conditions  or responded to a medicine in a particular way, to come back for more detailed evaluations when  further research questions, that perhaps weren't even anticipated at the beginning come along. I think the other really important thing, in relation to that, is that it's not just about  our ideas, it's about working with researchers who look at a whole range of topics. So,  researchers who look at heart disease, at mental health, at a whole host of conditions, are able  to come to us and say, we think this is a really important piece of research that needs to be done.  And because EXCEED participants have shared that health care information, which has information  about all of those things, we're able to help undertake a whole really wide range of things. So, it's not just the EXCEED Study itself, you're able to then feed into other larger  studies because you have this resource. Yeah, exactly that. And it might just  be looking at the information that's already been collected or it might be writing out to  participants and saying, we think this study might be of interest to you. Would you like  to come along and join a new study? So, what were the sort of diseases  and conditions you were looking at when you first started the study? And  how has that broadened over the last ten years? So, it was always planned that the study would be  able to be really broad and look at a whole range of things. There was a particular focus early on,  on looking at lung diseases. So, people who came to an appointment to join the  study and did that face to face, they had measurements taken of their lung function,  how well your lungs work. So that was one of the focuses, but because of those links to the health  care records, we're now at a stage where we've been involved in studies of not just lung disease,  but heart disease, mental health, liver disease, hormonal conditions. And in fact, there have now  been about 54 studies that have used information from EXCEED, and 21 of those have published  their findings in scientific journals. So, it's really exciting to see the results coming out. And the other thing you've been doing, I know, is not just looking at single diseases, but how  diseases are interacting. So that's another thing that's, kind of, come out of the EXCEED Study is,  it may have started originally just looking at kind of individual ones, but now that you've  got all this data, it allows you to look at diseases as groups, I suppose as well. Yes. So, we can think about which diseases tend to happen together. If you already have a condition,  what puts you at risk of developing others that might be related or what can be done  hopefully in the future too minimise the risk of those things happening. So, one thing that comes across from talking to the both of you is just how interdisciplinary  the EXCEED Study is, but also the global reach of the study, because you can feed  in and be part of these other wider studies, which increases the power of those studies. So COVID is a really good example of that. So this was a new phenomenon that the scientific community  understood very little about, really, and studies like EXCEED and others like that, were in a really  good position, because the study is already up and running, we've got participants already there,  you know, we'd really like to collect some more information about your experience of COVID. We'd  like you to do some COVID tests and see if you've had it. And by gathering that together with other  studies who could do the same thing and working really closely with them. So we were trying to do  it in the same sort of ways and gather the same sorts of informations, meant that quite quickly  we were able to feed into some really important research, that helped us to understand more about  the genetics of COVID and the wider impacts of the pandemic and everything that came with it. So, what are you most proud about the study? So, I think it's about how people have worked  together really. So we've got a fantastic team working on the study, who have spent 58  years of their lives collectively bringing the study to the point that it's out now,  and that includes our admin team who are really the first point of contact whenever  participants need to speak to us, you know, the researchers who are working on the study. But of course, the participants are a really huge part of that again,  and just really appreciative of people giving their time and sort of agreeing to work with  us in this way and continuing to engage with the study over ten years really. And I hope  will continue to do that over the next ten years. So yeah, next ten years, where are you going next? So, I think we need to continue to have those conversations but take them out wider. So,  talking to those people who might not have thought about participating in health research or genetic  research, for lots of reasons, you know, lots of people have questions about this kind of  research. Because it's not something that people come across every day. And we know, for example,  that people from minority ethnic communities might have more questions, more concerns, for really  good reasons. So, it's really important that we hear those things and start to address them and  start to really build that trust for people to come and participate in studies like this. Have you been surprised by anything around the EXCEED study? Well, when we designed the study, we designed it in such a way that it could be used for  the broadest range of health conditions, but one never knows when one sets out that it's actually  going to succeed in doing so. So, we're now at a stage where awareness has been raised in the  scientific community about the value of EXCEED as a resource. And we've been receiving proposals  for health conditions that, for example, our own team hasn't contemplated studying. So,  for example, endometriosis, inflammatory bowel disease are newer proposals coming in. But amongst the studies that have already completed, we've had conditions that we  didn't necessarily envisage being able to study. And EXCEED has played a really  important part in demonstrating the feasibility of using linked electronic health care records,  to study things that we didn't necessarily know would definitely be feasible at the beginning. So, for example, understanding thyroid disease by utilising routinely measured thyroid function,  which GPs measure on participants, avoided the need for participants to have a blood test, and  avoided expensive new laboratory investigations, and yet was able to contribute to the largest ever  study of underactive, overactive thyroid, and also understanding of thyroid cancer. So, we've been  delighted to see the range of conditions and the range of approaches as well, that those studies  have used in answering those scientific questions. Martin and Catherine, thank you so much for  talking with me about the EXCEED Study. This was an episode of the NIHR podcast,  I'm Turi King and thank you for listening. If you have any thoughts or comments on this  or any other episodes, please contact us via our X channel @NIHRresearch, or @ExceedStudy. For more information about the NIHR, you can visit our web site nihr.ac.uk.