Science webinar transcript: Your scientific questions answered

Your scientific questions answered:

So what we’re going to do now is look at some of the questions that have been posed to us already via email. And I’ll start with one that was sent in earlier. And I have to say at the start that I’m not a clinician, so I won’t be able to answer any questions relating to clinical aspects of ME/CFS. So actually, I’ll take one, which has just come in, which is,


Can you explain a bit more about what is meant by genome wide association? So I’m going to put Shona on the spot with this because I don’t think I’ve done a good enough job on that in my presentation. So perhaps she can give it a better go than I did.

Shona: I can have a go. It is quite complicated, and there’s a lot of terminology to learn as well. But the way I understand it is the genome is every bit of our genetic material, and there’s no pre-judgment beforehand. Everything is thrown into the experiment. And we’re looking for, as Chris explained, a difference between one group of people and another group of people. Here cases of ME/CFS and controls that are otherwise closely matched to those people but don’t have this condition. And we’re looking for these letter differences that Chris mentioned.

The problem is we all differ in lots and lots and lots of letters in the genome. That’s what makes us ‘us’. So we have to work out which differences in these letters are statistically significant and between the two groups. And there’s a lot of clever ways to do that. But the statistics eventually pan out that unless the probability of this happening is by chance is really low, then we can’t say it’s genome wide significant. And that’s what happened in the Norwegian paper – solid paper, interesting, really great preparation for DecodeME. But what the statisticians would say is underpowered. And that simply means it looks like there weren’t enough people in the study to give a genome wide significant result. By designing DecodeME to have many more cases and good numbers of controls, we hope that we will start to uncover these genome wide significant signals.

Chris: Thank you very much, Shona. So there have been questions that have come in about whether we are looking across the whole genome, and the answer is yes. So we are looking at mitochondrial DNA as well. And then there’s also a question about whether we are looking at not just letter changes, but word and paragraph and chapter changes, larger genetic deletions, micro duplications. The easiest answer to say is no, we’re not, except when the letter change near to it actually is a good predictor of those. It tags it. So it’s a complicated answer, but we won’t be able to look at everything in this part of the study. But we have kept to one side, we will keep to one side, half of everyone’s DNA sample so that when there is enough money, we will do the whole genome sequencing. That will enable us and others to find the more complex changes to the genome.

So there’s a question asking whether people with Long COVID or post-infectious Lyme disease can take part. So the answer is if you’ve got an ME diagnosis, then please do take the questionnaire, see whether the criteria fit with you. If you’ve got diagnosis of Long COVID or post infectious Lyme disease and not M.E, then you won’t be considered to be a good participant for this study. But of course you will be for other studies. So there are Long COVID genetic studies that are ongoing and we are talking with those people running those studies actively.

Fantastic question asking why does ME affect more women than men? So we don’t know the answer to that. It is true not just of ME/CFS, but diseases that are autoimmune, which makes us ask the question is ME/CFS, autoimmune disease. And there is active research ongoing as to why there does seem to be a female bias for immune diseases, but we actually don’t know the answer to this question.

So there is a question about whether we will be able to identify risk factors that are in common between ME/ CFS and other diseases such as multiple sclerosis. The answer is that when we get all of the data and we see what are the genetic signals for ME, then we’ll be able to compare them with any disease and we will compare them with all the diseases for which we have the data. And then in the comparison, we’ll say are the genetic signals overlapping with the genetic signals in multiple sclerosis and other diseases, or do they not overlap? And that is part of our analysis plan.

There’s a question about how the UK Biobank will have people who pass the selection criteria or might do so. Is this something you’re happy taking, Shona?

Shona: Sure, yes. I think the UK Biobank is a remarkable resource. Half a million people volunteered to give up, really a lot of personal and health data and their DNA and sometimes other samples. And many research projects across the world are benefiting from that resource. And DecodeME is one of them. We have the permissions in place to use so-called control people from UK Biobank so we’ve got 5,000 to choose from, so we can be quite choosy and try to get the absolutely best match set of people to our cases. And that in itself is actually quite a big project, quite a complex piece of work.

So we won’t include people who report ME/CFS, and there’s a couple of other exclusions, and we’ll try and do things like age and gender match. So I think, without sounding like I’m passing the buck, it really is just a complex process to get the best match. I think the question is perhaps when we talk about the 16% and controls, I think, Chris, you had that on one of your slides. I think that was a hypothetical difference between cases and controls. It’s actually if you read some of these GWAS papers, and I have to say they’re often very very densely written, the differences between cases and controls in the frequency of these key letters in genes is actually sometimes really quite small. But because everything’s done so carefully and the cases and the controls are so well matched, this can still be meaningful and statistically significant. But it’s very much pointing to a signal which then further work really unpicks.

But one of the reasons I’m such a fan of genetics is that it is hypothesis free. Every gene in the body is being surveyed. And I think it’s true for all sorts of complex conditions that all the predictions just got blown away once the GWAS results started coming through. And really whole new avenues of research and eventually treatment do get opened up as a result of this amazing GWAS technique.

Chris: Thank you, Shona. So there’s a question about the criteria used, and the questioner says, presumably not Fukuda. No, not Fukuda. We’re not using Fukuda, we’re using Canadian Consensus Criteria and the IOM, they are two criteria. You would have to pass the Canadian or the IOM or both, and some other criteria that we put in place.

So there’s a question as to whether DecodeME is expected to have as an outcome, a diagnostic test. So no we don’t expect it to generate a diagnostic test. What I expect it to do, however, is to improve diagnosis. By that, I mean that people will be believed more when we hopefully show in this study or in subsequent studies that there are definite genetic risk factors for ME and that will help to overcome what people quite rightly consider to be that people are stigmatizing individuals with ME, and we’ll be able to overcome that stigma with the scientific evidence for genetic risk factors for ME, and that will help the diagnostic rate and overcome what is this appalling delay of median eight years between initial symptoms and diagnosis.

So we’re just looking to see what other questions that there are.

Shona: I’m just going to say, I think a few questions came in asking, will we be collaborating with this researcher and that researcher, and I think it’s really interesting to see how participants are so engaged with the scientific literature and are reading papers and wanting to know that we’re all working together. And I think that is a really important point for DecodeME is our transparency and our plans to be as open as possible.

So, yeah, I think maybe there’s a few questions we could answer there. One of the slightly complicating factors is that we do have to be very careful about sharing data because it is private personal data. And I think Chris already mentioned the number of agreements and contracts and safeguards we’ve put in place for all data handling and de-identifying samples, for example. But when it comes to actually reporting results, our aim is always to make these in the public domain. And, in fact, GWAS is arguably one of the most collaborative fields of scientific research, certainly of biomedical research. And it’s partly because from the early days, it became clear that to get this power, groups did need to work together.

And one of the quite complicated things to explain is that we don’t need to share necessarily share individual data. We can do analysis, generate so-called summary statistics, and then these can be added together in a de-identified way, there’s no personal information there, and that can allow other findings to be made. So DecodeME is going to be an absolute step change in the numbers, but it will by no means be the end. There will be other projects after it that will just clarify and expand on the current work.

Chris: Thank you, Shona. There’s a question about the pre and post COVID, whether it refers to the onset of symptoms or the form of diagnosis. It’s the onset of symptoms. So if someone had any symptoms prior to the pandemic and was diagnosed after the pandemic, then they would be part of the pre-COVID set, the 20,000.

Question, does ME/ CFS have a neurological basis? That’s why we’re doing this study.

A question that came in before we started – do we have a rough timeline when results might be published? So this year is the data year. We’re collecting the data, the samples and the data. Next year will be the analysis year, and the final year will be in 2024 will be the dissemination year. That’s the rough timeline.

Then there have been questions about timing, about have all the participants been selected yet? No. We have only started with a few people to stress test our systems. And, boy, are we glad we’ve done that, because it has become clearer to us that we’re not doing a good enough job with the questionnaire. And so we’re doing a root and branch revision of that. And the latest thing that we’re going to do this week is to pass it back to see whether that requires a thorough ethics review or not.

But the whole reason why we’re doing this is for people with ME and so we have to do as good a job as possible. And so we really do appreciate people’s patience that we’re not yet going out to everyone who would wish to participate. But the initial participation has uncovered so many things that are going to substantially improve this study and give a much greater likelihood of success. And that’s such an important message for us to give you today.

So there’s been a question before we came online as to whether we’re going to group patients or people with ME So we have 20-25,000 people. Are we going to be able to use questionnaire data to say this person is part of a type one or type three or whatever ME/CFS? So we are going to do that analysis and find out whether we can basically say whether people are in one type or another and then compare the DNA of the people and the different types to see whether the different types have a different DNA basis to them.

How confident are we that there is a genetic signal for ME/CFS? Well, there is this likelihood, this greater chance that someone has a diagnosis of ME/CFS if there is a close relative with ME/CFS, and that’s what’s giving us some confidence that there will be, that there is, a genetic signal. The other thing to say is that there have been so many different conditions over the years that have been thought of as not having any genetic basis whatsoever, but in recent years have been found to have an abundance of genetic evidence for contributions made. I don’t know if you’ve got an example of that Shona?

Shona: Yeah, I think it is a really important question because we are biological creatures and of course nurture is important, but nature really does underpin so much of our development, our illnesses, our health. And I remember seeing a slide. So different conditions have been known for a while to have different amounts of heritability. And people can produce slides showing how from twin studies, for example, how heritable different conditions are. And there is a spectrum. And basically it’s really hard to find something that kills you or something that gives you ill health that isn’t genetic. And I remember someone once saying, well, being struck by lightning is not very genetic. And actually they said, well, no risk taking that’s got a genetic component.

So there will be a genetic component to ME/CFS. I think the slightly more challenging question is will DecodeME find it? The study has been designed to stand a very good chance of so doing. If it doesn’t, that doesn’t mean it’s a failure actually. In itself that is interesting information. And there have been one or two other conditions where initial results haven’t shown and then people have thought hard and tweaked things and gone back with more people or slightly different categories of people and have got there.

Chris: And we will work with anyone around the world to make sure that we have as large a number as possible to find these genetic signals. And that’s what’s happened in other conditions previously. So thank you, Shona. You’ve answered another person’s question about whether the 25,000 will be enough.

Then a question about whether there will be an incentive for pharma to risk R&D (research and development) investment for a new treatment. Well, there isn’t anyone from pharma here today, but I would expect and hope that you will join us to go and knock on their doors and insist that they risk such investment. A quarter of a million people in the UK, and growing, who have this devastating appalling disease, all deserve for there to be a lot of investment. And those companies that are listening, and there are several, are very interested in DecodeME and are waiting its results.

Thank you for personal question to me about what led me to research ME Yes, I have personal links, so I have a friend, a very good friend who has ME But it’s much more than that now. It is something that I wish to learn more about before I reach the end of my scientific career.

Will we compare the genetics of me with any other diseases like endometriosis? Yes, we will, because there is a genetic study, several actually, of endometriosis. So we can do that, and we will do that.

So if someone has been diagnosed with ME and Long COVID, please do participate. Absolutely.

Another question was who can provide the diagnosis of ME? And it’s a health care professional. I think so. A GP, a consultant, a nurse. I think in our Frequently Answered Questions, I think we provide the answer to that.

There’s a question about the heterogeneity, the diversity of ME/CFS, and everyone that I’ve talked to agrees that it is a heterogeneous disorder with very diverse symptoms. That doesn’t necessarily mean that it won’t have a very narrow set of causes. There are some diseases that affect many parts of the body but have a very specific cause. On the other hand, it could be very heterogeneous because we can split apart me into these different types. And that’s probably likely, too. But this is why we’re doing a genome wide study, because we’ll be able to see, if we have enough people, enough participants, we’ll be able to see that there are these different contributions made and that might be separable for individuals that have particular symptoms over others. Rather than going narrow and focused, which will be very good for finding causes for those individuals, but not everyone will be able to look at as many people as possible, for as many causes as possible that contributes to ME

Will we communicate with all participants with their individual results? We will not be passing back genetic results to participants. And we decided this early after a lot of conversation. And can I ask Shona to summarize why we thought that was a reasonable approach in this case.

Shona: Yeah, I fully support that decision. It’s also the decision that was taken by the UK Biobank. And we’re at a really interesting time in human genetics, where there are new initiatives, government led, NHS led, really starting to bring genomic medicine at scale. And then separately, there’s research initiatives looking to return individual results, how to explain that to the volunteers, how to deliver that within the NHS, how to respect the wishes of the participants, either to know or not to know their genetic results. It’s a really complicated area and I think we felt it would just dilute the main purpose of DecodeME, which is to look for these genetic signals that differ between cases and controls. So there’s no return of results. And if that was ever to change, there would have to be a big program of re-consenting and re-explaining. So I think that’s really way down the list of priorities. But the genomics world, the human genetics world, is moving fast, and I think in a relatively small number of years, there will be a lot more genomic medicine available to people. But before that can happen for something like ME, a huge amount of basic research has to happen first.

Chris: Thank you, Shona. A really important question about diversity. Do we in DecodeME have a sufficient diversity of population in the study? Eg ethnicity? We are inviting anyone who has been diagnosed with ME who’s over the age of 16 years or above to register. And that doesn’t mean to say, of course, that certain parts of our population are less likely or more likely to participate. But we will go out of our way to try and ensure that we are as unbiased as possible in ensuring as many people of all persuasions, all backgrounds, all parts of the UK, who can contribute to this study. And the UK Biobank has taken a similar view and so has sampled from across demographics across the country. And that allows us to match the controls that we have with respect to their genetic ancestry, et cetera. But it’s a very important point that indeed, many people in genetics have paid not as much attention to as they ought to have.

There’s a question which says that an individual has not received anything in terms of a testing kit or an email or call. They don’t know whether they are part of DeccodeME or not, despite, I assume, having registered for the study. So we have not fully launched because we have only opened ourselves up to a small number of people to trial our processes. And when we go to the full launch, then people will be told that they are now invited to log on to the DecodeME website and to answer questions or to request a paper questionnaire. And then everyone will be told whether or not they pass these criteria. So, again, we are doing the best we can. It’s taking longer than I would have liked. But we are working around the clock to do the best we can for this project for people with ME

Is M.E a weakened or overactive immune system? It could be an autoimmune condition. We’ve discussed that. We can find out using genetics, whether it has genetic overlap with other autoimmune conditions.

There was a question before we came online about Long COVID and whether we are working with people who are studying Long COVID. Yes, we are. We can ask whether Long COVID and ME/CFS share genetics links. We will do that analysis, and we want to continue to find as many people who are working in Long Covid genetics as possible to work with them.

There’s someone who asked the question about their concern that they’re worried that DecodeME might use embryonic stem cells. DecodeME does not use embryonic stem cells. And so we hope that your mind is at rest about that. But if you have any worries whatsoever about this, then please go to the DecodeME website and look at the Frequently Answered Questions, because we’ve covered some of this there. But I also need to say that if having read everything, you don’t want to participate, then you’re free to do so, to not participate. That’s exactly what should happen. That given all the information that we provide to you, that you are able to give your consent or not give your consent to participate. So, Shona, would you like to carry on?

Shona: Yeah, just following on from that, people are also free to withdraw from the study. But actually, we’d almost rather, if you’re unsure, ask and try to bottom out the reason that you’re considering not joining, because it’s almost better not to join than to join and withdraw. Again things change and if something happens and you think, actually, no, I don’t want to be part of this anymore, that’s absolutely fine. You don’t have to give a reason. I think the key thing is we’re doing our best to provide information to help people make the choice. And we’re very much there at the end of an email or as Chris says, lots of information on the website and that will evolve also. We’ll be adding to that and have been adding to that ever since the website launched. So I think that ask questions, and it’s very much we want volunteers. There’s no coercion here whatsoever.

Chris: Thank you, Shona. And to follow up on someone else’s question about being recontacted for future research, we ask people whether they don’t want that to happen. And so you don’t need to opt in to that. You can say, no, I don’t want that. But I do want to still be part of the DecodeME, and that’s absolutely fine. Those people who are happy to be re-contacted in the future for future studies, of course, that would be great. And we would make sure that only studies that have proper ethics, approval and et cetera are ones in which people would then be re-contacted for.

Shona: And that helps us to be agile. If new developments arise, people are asking, well, are we going to ask about infection with such and such a virus or some other comorbidity? And if a good hypothesis comes up, we can create a new questionnaire and we can go back to the people who’ve said they don’t mind being re-contacted. And we could say, look, we think it’d be really useful, really helpful, really interesting, if you could answer these new questions. And that way we really start to build a deeper picture and a deeper understanding and allows us to be agile and responsive to other research that might be coming out, whether directly from ME/CFS or perhaps from Long COVID and ME/CFS post-COVID.

Chris: So there have been several questions about Epstein Bar virus, glandular fever, multiple sclerosis. This is testimony to everyone’s interest and being able to follow the literature and to read up on the science, because this is indeed one of the major findings of modern times. In January, there was this paper in the Journal of Science suggesting, with very strong evidence, a link between Epstein Barr virus infection and multiple sclerosis, basically saying that individuals who are later diagnosed with multiple sclerosis will have to have been infected with an Epstein Bar virus, although the majority of people, of course, do not proceed to multiple sclerosis having been infected. Does this help ME research is the major question? Because, as you well know, people with glandular fever have a higher likelihood of going on to being diagnosed with ME than others who have not. Well, we need to do two things. First of all, we need to be buoyed up by the success of the multiple sclerosis findings and the fact that the genetics played a part in those discoveries and for understanding how the virus predisposes people to multiple sclerosis. Secondly, it might indeed present evidence that there are biological similarities between multiple sclerosis and ME For example, they might both be autoimmune diseases, not just MS, but ME as well. And they might have genetic DNA letters that are in common that contribute to each of those separately. But each of them is a complex disease. So there won’t just be one letter that we’ll then be able to be looked at and go, yes, you will get MS or yes, you will get ME if you are infected with this virus. Both are complex diseases, and it will be the rest of the letters, the rest of the genome that will tilt the balance as to whether people will later be diagnosed or not.

So there are questions about vaccinations that unfortunately lie outside of my expertise, and I’m sorry, I won’t be able to answer those. Then there are questions such as whether some therapies and treatments, perhaps for cancer, might lead to people being excluded. I won’t go through all of the exclusionary criteria. The major reason is that it would take a long time to go through them all and I would just hope that people will answer the questions on the questionnaire and find out whether they go through to receiving a saliva collection kit or not. And as I said before, if you’re not picked, it doesn’t mean to say you don’t have ME. It just means that for this particular study, you don’t fall into the narrow set of criteria that we have to use.

There was a question about essentially showing are we looking at the whole genome of each sample, or are we just looking at individual parts because of genotyping and using a microarray? Is this something you’re wanting to respond to, Shona? What shall I?

Shona: Yes, again, sort of nomenclature. So we are surveying the whole genome. We’re looking at points along each chromosome, including the sex chromosomes, although there’s not much on the why, but we’re missing the bits in between. So we’re just looking at kind of landmarks, fence posts along the way. And as Chris mentioned, we’ll have enough DNA prepared from those precious saliva samples that people will be posting. We’ll have enough DNA leftover after the genotyping. This whole genome survey, if you like, in future to sequence everything, with new funding. Sequencing is getting cheaper. And I think the hope would be that if we can demonstrate good success from our GWAS, our genetic analysis of these samples, that there will be a real enthusiasm to find out the rarer variants and the full picture. So I hope that answers the question. We are looking at the whole genome. We’re not missing anything out, but we’re only seeing a slightly blurry picture. And we hope that in the future we can really focus and have a sharper picture across the whole genome.

Chris: Thank you, Shona. And the whole genome includes the mitochondria. We’ve had some additional questions on that. Yes, we will be looking at the mitochondrial DNA in this first part of the DecodeME study.

So there’s a question about whether the diagnosis needs to come from consultant neurologist or from a GP or other healthcare professional. Their concern, as they say, is that many people in the study with their ME may not have had access to a specialist to confirm that diagnosis. So there may be diagnoses that are inaccurate, essentially. And it is true that any diagnosis is imperfect in the sense that not everyone diagnosed will actually have that condition. I think the misdiagnosis rate in Parkinson’s disease, for example, is about 10%. So we do have to worry about this. And this is why we’re taking a lot of time and paying a lot of attention to the questionnaire that we have completely root and branch changed. So that not just do people pass with respect to whether they’ve been diagnosed or not, but they pass with respect to the criteria, the Canadian or the IOM criteria, but also that the cardinal symptom, for example, post exertion malaise. That is also evident in people who are registered for the study. We fully recognize that some people, like with any disorder, may not have been properly or completely diagnosed, and that will change our ability to find genetic signals. But because of the numbers involved, should not stop us from finding those signals.

I love this question. Do I have an opinion on whether Epigenetics may be relevant to ME?

Shona: Definitely one for you, Chris.

Chris: I was just about pass to you, Shona, so bad luck! Epigenetics is everything above the DNA. So, for example, there are four types of letters in DNA, and one of them can be modified chemically. It’s a methyl group so that it is different from the DNA that was inherited from your parent. And there are other types of definitions of Epigenetics, so it can be quite a woolly concept. So to me, Epigenetics is all about whether genes are active or not. You have the same DNA in all of your cells, essentially. And the differences in your cells, whether your liver or your toenail or your ear or your brain cell, those differences come from whether your genes are active or not. They’re on or they’re switched off. To me, that’s what Epigenetics is. And it’s a molecular explanation of those switches. And absolutely, because it’s the expression of your DNA. Absolutely, those switches matter to whether people have ME or any other disease. But this isn’t what we’re studying. We’re studying the genetics itself, not Epigenetics. But there’s so much data that already exists that is Epigenetic data. And so if you have an image that’s correct, then have this one: that you have the DNA that we’ll get from people with me and compare with controls. And layered upon that and layer upon layer, we will layer with all of the other Epigenetic data to allow us to contextualize these genetic signals and allow us to say we believe that what is going wrong is not just this gene that is in the mitochondria, for example, whose protein is in the mitochondria, but that we think that it’s the mitochondria and the immune cell that is going wrong. And we have the tools to do that. And that’s what the genetics community at large is doing. And we’ll use everything that we have at our disposal to gain insight into what has gone wrong with so many people with ME

So we have reached the hour and we’ve ended with Epigenetics. And there are still some questions that have come in, and I apologize that we haven’t covered them all. To all of those who have reached this point in time, thank you for keeping with us, and I hope that we have answered your questions sufficiently. If not, please do go to the website and see if there’s a better explanation there. Thank you. To everyone on the team who isn’t on this call, the people with ME contributions have been central and critical. We would not be where we are today without all of those, not just a week or a day but for the last few years. And thank you, Shona, for all of your insights very much. Enjoyed partnering with you today on this webinar. See you soon. Bye.