Webinar recording and transcript – Second questionnaire and data access process

The second project is different from that. It's a machine learning project, not with academics, but people in industry. This is PrecisionLife, who are based in Oxfordshire.

You may know that they have a proprietary, combinatorial genetic analysis method and they have published their thoughts on genetic associations in both ME and long covid this year.  

They have their own view as to how they can analyse the data differently from DecodeME. We would be very interested to know whether they are able to, not just find associations, but whether those associations can be found in different people.  

So if, they analyse 2,000 people and they find things and they analyse another 2,000 people who are different and they find the same things then there is greater likelihood that these are true and important findings.  

So they want to extend what they've previously done with analysing UK Biobank data, extend it using DecodeME data, to look for these combinatorial risk scores. So are there different genes that, when the genetic variants combine, can predict people with ME and different types of ME too? And that's, an interesting aspect to what they wish to do.  

We're in the contractual stages with PrecisionLife. And they they wish to have questionnaire answers and they'll need the DNA data, from consented individuals only clearly.  

I'll pass you back to Sonya.  

 

SONYA 

Thank you, Chris. And thank you, Andy, and also thank you to everybody who's sending questions through.   

Just a reminder we can't answer personal questions. We will be focusing on the genetics and the DecodeME study. If it's possible try and keep your questions succinct because it makes it easier for me to ask them and we can get more in.  

To finish off before we move to the questions, we want to highlight some key dates and deadlines for you. 

  

• On the 7th December, the paper invites were sent for the second questionnaire.  
• Between 18th December and 7th January we're actually going to have a complete holiday shutdown over the Christmas period and the new year. The team have worked so hard. It's really important that they take a break. So if you do send questions in, please be aware that you won't get responses during that time. And also we might have a bit of a backlog when the team come back into the office.  
• To start the new year on 10th January we'll start sending email invites for the second questionnaire. And just a reminder that we do have the 25% ME Group for providing support and I have to say that in our first round questionnaires they supported 750 people with very severe ME to be able to participate in the study. Those are individuals who didn't have members of family or their support network available to help them. I think that's a phenomenal achievement. I just want to say a huge thank you to Helen who supported that work from the 25% ME Group. We're really committed to making our study as accessible as possible.  
• By the 31 January 2024 if you've got a spit kit please, please, please return it.  We're desperate for you to to get that back to us so that we can analyse your DNA. But just a reminder that all of you that completed the questionnaire, whether you've been invited to submit a DNA sample or not, you are still a participant in the study. And you still have the opportunity to participate in the second questionnaire.  

• By the 15th February we're asking people to make sure that they've posted back all their copies of the second questionnaire, the paper copies.  
• And finally on the 29th February at 5pm we will we will expect everybody that wants to, to have completed their online second questionnaire.  

Now I’m going to stop sharing my the slides and you will see Andy and Chris too who will join me for the Q&A's.  

I'm going to start by asking you a question, Chris. It kind of brings together some of the questions that we've had. One on the chat said, will my children get ME? We can't answer that question, we have no way of knowing, but Chris, I'd like you to tell us a little bit about what we do know genetically about the inheritability of ME.  

 

CHRIS 

So we do know that there is a genetic component to ME. And the reason we know that is from previous work by others. If you have ME then there's twice the usual likelihood that your second and third degree relatives also have ME. But this is not a definitive. So, if you have ME, then it is not 100% sure that your relative is going to have it. So that means that there isn't an inheritance pattern which, says, with, 100% certainty that your offspring and your relatives are going to also have this awful disease.  

If it were to be so, then it would be something called a Mendelian disease. And that often occurs in single genes and you can pinpoint where the genetic issue is. That would really lend itself to a genetic test and it would be then rolled out across the National Health Service.  

Unfortunately, it is not as simple as that in ME.  

There are lots of different places around the genome that will together contribute to risk. And one place may tilt the balance just a little bit, and another place till the balance, perhaps in the same way or the opposite way, and so it's quite a complex mixture. And that is why we believe it to be a complex, genetic disorder.  

Rolled up in that is obviously the environment which makes it even more complex. The greatest contributor that we already know about is the fact that two-thirds of people with ME report an infection just prior to onset of their first symptoms.  

So we know that that aspect of the environment is very important, but we also know that genetics plays a part. But not individual genes. So that means it's not predictable.  

 

SONYA  

Thank you, Chris. I'll take a question here. Do you think with the DecodeME study, the government will finally take notice of this serious disease?  

We mentioned that DecodeME was referenced in the Government Delivery Plan. I think that there is definitely more genetic research that we have, the more that we find, then not just the government but others will take ME seriously.   

And, as Chris said, we're doing everything that we can to accelerate the research.  

Both Chris and I were with a Minister yesterday and their interest is there. We have a Government Delivery Plan but the key to moving things forward is accelerating the research.  

 

We've got questions here about results.  

We do not have any genetic results that we can share with you at the moment. We want to do all that we can to get the results as quickly as possible, but we haven't had all the kits back yet. And as soon as we are in a position to share results that we have confidence in, we will do that so we really, really appreciate your patience around that.  

 

Chris, we've got quite a few questions around ME and pregnancy. Is there anything that you want to share with us that we know from research and that you know might respond to some of those questions?  

 

CHRIS 

Thank you.  

So I'll deal with the question about pregnancy.  

But I also want to make the point that, it is incredibly important to receive the kits back. And what it isn't easy to do and quick to do after that is to read out the DNA. And we've also got questions from people over the phone and emails, etc, about how quickly the results will come. The process of reading out the DNA by an external company actually takes months. And so it isn't the case that immediately the DNA is extracted we can just read it out and add it to our data files and do the analysis.  It takes longer than that.  

So, back to the main question here about pregnancy.  

We know that there are many places across our chromosomes that predispose people to pregnancy issues through genetic factors. So this is a really interesting area. We know IN our study, 84% of people in our study are female. And so that, sex bias means that there could easily be many issues that overlap with sex bias conditions, pregnancy and to do with hormonal imbalance.  And if we look at the genetic signals from those imbalances and from pregnancy issues, and we look at the genetic signals that come from our study in ME, and if we see that they overlap, then that would provide evidence that there is indeed a biological explanation that covers both.  

And that's why I think genetics is really important. Not just because it causally explains things. But we're able to cross reference what we find with ME with actually anything that has a genetic signal. and make use of the fantastic advances and discoveries that have been made across genetics for you: for people with ME.  

We keep on saying it, but it's absolutely true, to accelerate towards new therapies.  

 

SONYA 

Thank you. Chris.  

We've got several questions about whether we're going to widen DecodeME to other illness disease areas and also whether we're going to open up to other countries?  

We are funded to undertake the DecodeME study in the UK. We do not have any other funding to either replicate this study elsewhere or to look into other illnesses. As you will know, we did include hose people who had a diagnosis of ME following COVID infections.  

So we do have some people involved in our study. But recruitment is now closed. We have no further funding to do any more research at this stage but we will always work with researchers and have been having discussions with others who might be interested in replicating DecodeME elsewhere.  And we will share all our knowledge and understanding and the process of how we've delivered this project and support people where possible.  

 

We've got several questions around data protection as well and concerns that the government might be able to access people's data and also concerns about data protection, legislation changing.  

Chris gave a very thorough kind of outline of how we keep your data safe and how we ensure that everything is anonymised in the presentation.  

Chris, is there anything you want to add to that as a reminder?  

 

CHRIS 

We just take this really seriously and know we don't provide a link between your identity, your name, where you're from, etc, your age, with your birth date. We do provide age but not your birthday.  

We don't provide identifiable information to others. And that is for this reason. We also don't want any other agency to make the link between the answers that you've entrusted us with and your DNA data that you've trusted us with any other agency.  

So we break the link.  

And that is with great purpose. To ensure that you feel safe in the ways that we're handling and storing your data and sharing it without that ability of others to identify who you are.  

 

SONYA 

Thank you, Chris.  

Sorry, another question for you, Chris. This is about the statistical power.  

What happens if we don't get enough kits back?  

 

CHRIS 

Well, everyone so far has just been absolutely fabulous. And the rates of participation of engagement and talking to us and the rates by which kits have come back, it's just been fantastic!  

We're at this 80% level. 

 So I would understand if people can't return their kits.  

And if that is the case, then we will have less ability to identify the genetic signals that underlie ME. But there will be good reasons, and I'll understand that. It's just that the more that we get back, the more likely it is that we're able to make these discoveries that should matter in the future.  

 

SONYA 

I'm just sticking with the spit kits, Chris.  

I want to send my spit kit back soon. If it rides over the break will it be usable or should I wait to post to you until after we come back from our Christmas break?  

 

CHRIS 

It's really stable. So do provide a sample and it can be posted back to us whenever you can.  

 

SONYA 

And just in terms of the results, Chris, can a gene or blood biomarker be established from this study? 

 

SONYA 

 So a single marker, no. Because it it's related to what I said about a single gene being explanatory of of ME. Because it will be that there will be lots of places in our genome that together will be explanatory, it won't be a single gene marker and so it's not easy. It won't be the possible to easily have a single genetic test.  

Now that's not to say in the future that won't be possible.  

But we do not say that this is going to be an immediate outcome of DecodeME.  

 

SONYA 

Thanks.  

we've got lots of questions I'm just reading through about what the results may or may not show. So rather than take all the individual questions, Chris, can you just remind us what we are hoping to find and also a reminder about the potential outcomes of the study full-stop?  

 

CHRIS 

So this is research.  

Doing research means you never know what the outcome is going to be.  

You do it to the best of your ability and then you see what the outcome is.  

The size of the study, for the 20,000 or so individuals, indicated that on average this type of study would find five places in the genome that would begin to explain people's ME. Now, imagine that each of those five places all points to the same thing that is going wrong in people with ME. If it's immunology, if it's neurology (so something wrong with the nervous system or mitochondria) ...  

If everything points to one thing then that's where future scientific activity should focus.  

That would be a key outcome.  

Now, science is very messy. And there is heterogeneity as people know, diversity of ME symptoms, so it could easily be that those five things point in different directions; one to mitochondria, another to the immune system, for example.  It may be that one or two of them we can't even explain in those terms.  

Then those individual lines of enquiries should be followed up as soon as possible by the experts around the world so that their experience and background and expertise and technologies can be brought to bear upon these different lines of enquiry that DecodeME has uncovered for you using your data.  

 

SONYA 

Thank you, Chris.  

And, Andy, you can maybe answer this one.  

In relation to the data we're collecting and the access that we're giving, are we going to be charging applicants for it?  

 

ANDY 

No we're not charging is the simple answer.  

I can't even think why we would charge.  

We're not set up to charge and quite frankly, I would be completely against the idea of us charging anyway because obviously that would be an additional barrier to the value of DecodeME.  

The value of all the effort that the DecodeME team is going to, and you as participants are going to in expending your energy and filling our filling in our questionnaires and sending them back. That’s a long longer answer, but in short, no we are not.  

 

SONYA 

Right, thank you, Andy. Have we got any plans to undertake any other questionnaires after the second one?  

 

ANDY 

Simply, again, no.  

Essentially it goes back to funding. During the creation process for our second questionnaire, we we still had many more questions than we eventually settled on as forming the second questionnaire.   

So there would be the potential for us to ask many other things from you, the participants. But there obviously has to be a limit on what we can do. How much funding we have and how much time we have to do it all in.  

So the second question now will be it from us. But obviously, you are all participants assembled as a cohort. So, we are hopeful as well as having researchers coming to us requesting the data: genetic and questionnaire data. That was explained earlier. But we're also open to researchers coming to us and saying that they would like contact those participants who have consented to being recontacted.  

So again, that's another long answer for what was quite a simple question. But from us, no, there is no further questionnaire after the second one. But hopefully in the future we might be able to connect those people who have consented with other researchers who want to find out more about you.  

 

SONYA 

Thank you, Andy.  

Chris, we've got quite a few questions here. Can you just give us a reminder, why not everybody that completed the first questionnaire was invited to then provide a DNA sample? And also why some people that were initially not invited were then subsequently invited?  

 

CHRIS 

In every study that has ever been put together in genetics there are criteria. Criteria for inclusion and exclusion.  

So people have to be more than 16 years of age, for example, and that's due to aspects of the law that we needed to adhere to. And there are other aspects, such as we wanted to be reassured that people with ME have a medical diagnosis. And that is so that we can go to others and say we have a firm belief that the cohort that we brought together is one that medical practitioners would recognise as being a cohort of people with ME.  

So there's, there was always going to be a set of exclusionary criteria and inclusion.  

We wanted to make sure that these criteria were internationally acknowledged, and this was part of the PPI process, we agreed on the Institute of Medicine, the NAM criteria, and we agreed on the Canadian Consensus Criteria. So one or both of those.  

That means that some people don't come through in our process, which means that we don't ask everyone to provide their DNA.  

Now, at the at the very beginning, we wanted to include as many people as possible. We still do, and we set out our criteria in a particular way.  

We said to everyone at the beginning, we're going to tell everyone at the end of the process what our criteria are. We will still do that. But we're not going to say it upfront because we feel that others may believe that we are allowing people to change their answers given so that they would be included or not. We didn't want that to happen. We don't want criticism of our approach by others, by other scientists.  

So when we set down our criteria we were upset.  But not as upset as many people who were excluded initially, by the reality that not everyone was being invited to give DNA. In fact very relatively few. It was one in two people at that point. And because this is science, we hadn't appreciated that. We didn't know exactly how many people are going to be included and excluded.  

Sorry for this long answer, but it's very important to explain this.  

We then made sure that we, as scientists, wanted to repair this situation in a robust scientific way.  

And that's what we did.  

We went into a scientific huddle for several months and worked out good scientific practices to allow the inclusion of some who have been excluded, but without having any subsequent impact on the quality of the findings that we would then come up with.  

We did this by then ensuring that people's comorbidities, etc, can be accounted for in this scientific method. 

Now that took time because we needed to think it through. But we also then wrote up a data analysis plan that is online, everyone can read it, hopefully it's accessible. So that anyone could understand what we're going to do, how we're going to do it and why we're going to do it.  

I wish that we could turn back time and repair the situation and have invited all of those people at the beginning. But, hopefully, we've taken the right steps for the right reasons to ensure that as many people as possible could be included in this important study.  

 

SONYA 

Thank you, Chris.  

We've got quite a few requests coming through - Can we make recommendations? Can we comment on other papers? We're not in a position to do that. That's not what today's webinar is for.  

If you have questions, you want access to information, advice, you need some support in accessing health care, please contact Action for ME. We have a support line, we've got things on our website, we have health care services. 

There are also other charities, the ME Association, 25% ME group who may also be able to assist.  

A reminder that the recording will be available for people afterwards as well.  

I've got a question here, in addition to the powerful genetic analysis, is there any opportunity to analyse other biomarkers which may vary during periods of remission and relapse?  

 

CHRIS 

If such biomarkers would be accessible in saliva, then the saliva samples that are being held as part of the samples you provided and would allow such analysis.  

But they would need to be present in saliva and we're told by many people that it's more likely that such biomarkers would be in the blood, which we haven't collected, for reasons that are hopefully obvious.   

It would be far more costly, far more difficult and people didn't want to do that often. But the recontact method, so that in future studies that people could be able to donate their blood samples or any other type of biosample, would then enable that kind of study to happen and and such biomarkers to be discovered.  

 

SONYA 

I've got a question around consent. Somebody's asked if they can change their consent from no to yes? And how do they go about doing it?  

 

CHRIS 

People have changed their opinion about the study to say that they do not wish to participate any longer and we withdraw people from the study and that is absolutely fine. And we said that at the beginning of the study, in the consent form and the participant information sheet.  

If anyone wants to change their details in any way, please can you get in touch with us? And on our website there are contact details of how you are able to stay in touch with us. And we'll see what we can do. Thank you for that question. 

 

SONYA 

We've had a question on Facebook around whether we wanted to do extra questionnaires, could participants help fund any other work by contributions?  

It's a really generous suggestion.  

We've got the funding, £3.3 million to deliver the DecodeME study with the two questionnaires that we've talked about today. So we don't have any plans to do any further studies and further questionnaires at the moment.  

If you want to make contributions to research, Chris, Andy and I are all working within the Genetics Centre of Excellence that we've set up between Action for ME and Edinburgh University.   

The ME Association funds research.  

ME Research UK funds research.  

There are several charities that you can contribute to.  

 

We've got lots of questions around the links between ME and long COVID, and other things like ADHD, fibromyalgia.  

Chris, can you just tell us a little bit about what we know genetically about links with other illnesses and particularly around long COVID?  

 

 

CHRIS 

From the genetics, we don't know about any shared genetic predisposition between ME and any other disease.  

We know from symptoms that there are shared symptoms, sometimes.  

The exciting thing from, my point of view as a geneticist, is this ability to ask the question whether the genetic signals that we hope to see in ME overlap with the genetic signals seen and for any other disease or traits or anything which might therefore provide evidence for commonality: for the same thing contributing to risk for the different diseases.  

So we will do as much as we can on that. And of course by sharing data, then allow others to do as much as they can on questions that we haven't yet thought about or have not cropped up yet. And that's the reason why we want to share the data as much as possible is to ensure that anything that we do is complemented by anything that anyone else could do.  

 

SONYA 

Several questions around ME and potential links with ethnicity and increased risk to certain ethnic groups. Can you say again, with a focus purely on genetics, is there anything that might respond to those questions?  

 

CHRIS 

So we don't know.  

Again, it's early days about understanding the genetics of ME.  

Across the world, 8 billion of us, we share so much of our genetic code, that I would be incredibly surprised if there were to be strong differences between people from different genetic ancestries. Not saying it's impossible, I'm just saying to my mind, it's highly unlikely.  

But what I do think is that it's highly likely that different communities around the world are diagnosed at very different rates. And that is a key thing that I think governments and health systems need to focus on. To ensure that everyone has the right access to being diagnosed by well-trained and empathetic professionals.  

 

SONYA 

Thank you. And again, we've got several questions around viral trigger for ME and what we're expecting to find in our study but also what's known about whether or not viruses trigger ME.  

Is there anything you would like to say on that, Chris? And Andy, do chip in if there is anything you want to to add as well?  

 

CHRIS 

So two thirds of people say that they experienced an infection prior to their first symptoms. I think that's a very powerful piece of evidence. Obviously one third have not and that may be asymptomatic infection or no infection at all.  

Now, imagine that what we find is that these genetic signals for ME focus on genes that make proteins that are the first point of contact between a virus and our own cells. And that they are genetic differences that change that contact between a virus and ourselves.  

Now that would immediately shine a lights on it on what is going on  and what is going wrong with people with greater risk of ME.  

We have no evidence for that today. But this is one possible outcome of this type of study.  

The beauty of doing I study like DecodeME, which looks across all of the genes across the whole of the genome, is that we are essentially asking questions of everything. And so all possible outcomes are still on the table.  

 

ANDY 

Not sure I can add anything much to that.  Chris will be better placed to talk about the science. From a patient community point of view, obviously, the information that we've gathered through the questionnaire, where people have indicated that they did experience an infection before the symptoms started, is really a confirmation of what anecdotally was known in the patient community already.  

And it's just more evidence to show that that is what is reported by patients, is not cast iron proof of that link, but, as Chris says, is a strong piece of evidence to indicate that infections do often lead or relatively often lead to chronic consequences.  

They should be taken more seriously than just the short term consequences that might come from any infection.  

 

SONYA 

There are lots of questions around long COVID and ME, and Chris touched on on that in terms of response earlier on, but what we are seeing as a charity is a number of people with ME-like symptoms with a diagnosis of long COVID that are needing support.  

There is research out there that's indicated around 50% of people would meet an ME diagnosis but have got the label of long COVID.  

We know it's a very confusing picture for people, doctors included.   

So please do go to the charities.  There are long COVID support charities there if you do need some support. You know many of us have websites where anybody can access resources. But people can also contact the charities to gain support if you need it and that may be in terms of accessing a diagnosis.  

We know that post exertional malaise is a key defining symptom of ME. We know that a proportion of people with long COVID have that key defining symptom. So please do access the services available.  

 

 

So I'm gonna bring things to a close.  

I want to thank you all for taking the time and energy to listen, to engage with us through your questions, to be part of our study, even if you didn't complete a questionnaire.  

Many people have reached out to family and friends to promote the study. So you've played a part in lots of ways.   

Just your support and gratitude, there are so many comments and thanks that have come through on the Q&A, we will make sure that those are passed on to the wider team as well.  

We really, really appreciate and value our thanks and your support.  

There are answers to questions on the Decodeme.org.uk website. So please do go there to access more information and there are blogs as well that you can read if you want to change your consent, if you have issues around your spit kit that you're wanting to return, or anything like that. Do contact us. the details are on the decodeme.org.uk website.  

We are going to be closed for a couple of weeks over Christmas but we will pay catch up as soon as we can and respond to any contact that we've got. 

Just as a last point as we finish, there have been several comments that have thanked us for being so collaborative.  

Collaboration is at the heart of this, as is the involvement with people with lived experience. The science is better because of the input that with people with lived experience have had either directly through Andy in the management group,  through our patient public involvement steering group but also those that have contributed in the early days responding to our consultations and surveys.  

So thank you to everybody that has played a part now, is going to play a part in the future, and those scientists that we hope will be able to access your information, your DNA.  

And hopefully together we can accelerate research.  

Thank you.