UK Genome Wide Association Study (GWAS) project - draft website goes live, feedback sought on recruitment plan, and updates

My response was assuming the diagnostic criteria would still be validly applied, though I agree there might be problems with achieving that, and if so that would indeed be very problematic.

The trouble is, there likely are people who have genuinely suffered from ME/CFS and for whatever reason have genuinely recovered, or mostly so. The information lurking within data from those fairly unique patients could be important to understanding the disease; would their genetic makeup show something different from other pwME? As yet we have no way of knowing if people who recover from ME/CFS do so due to genetic and/or non-genetic reasons. But of course you are right, accurate diagnosis would be crucial, as for all other participants, else might see something that looked significant but was not.

 

Website has been through another round of formatting edits, https://mebiomed.org.uk/

Many thanks to all those who have made suggestions on how it could be improved.

 

Much has been said recently about questionnaires. My personal opinion is that much of what is being talked about goes beyond the scope of this GWAS, however I'd like to highlight

from https://mebiomed.org.uk/faqs/

So I will be looking for us to use the fewest questionnaires required for the GWAS to be successful but with the above action we will be making it easier for anybody who wishes to follow-on with any future study, whether that be questionnaire based or not.

 

Did they say why?

 

Thank you Andy. Perhaps I'm just being over-anxious about this, but is the association that the GWAS will be looking for against the genes: 'having ME vs not having ME'?

Or will it go as far as sub-phenotyping ME cases?

One big reason I suggested additional questionnaires was because ME is heterogeneous, there is a chance that it is not one genotype but several different ones, each comprised of a different cluster of SNPs?

And that lumping them all together in one 'having ME vs not having ME' phenotype analysis might not turn up (or might dilute) any statistical significance?

If this were to be the case, it might be necessary to sub-phenotype the ME cases to see whether there was statistical significance in clusters of SNPs associated with sub-phenotypes?

The only practical way to sub-phenotype ME cases on this scale, with the resources available to the GWAS, would be by questionnaires to identify symptom clusters, disease/health history, onset type, environmental exposures, etc.

I am basing this concern on the oft-cited concept that ME might not be one homogeneous disease with one genotype, but might be several different diseases with very similar presentations. In my mind it would be valuable to have data that can be used to try to sub-phenotype ME cases to see whether this turns out more statistically significant results, in case the whole-cohort 'having ME vs not having ME' doesn't identify statistically significant associations.

Because in the latter scenario it would be a lot of work for nothing, whereas if there was data to draw on to try sub-typing patients this could increase the likelihood of getting meaningful results, especially since we know ME is complex and heterogeneous.

Does this make sense?

 

@MerryB, it seems to me you are assuming that these questionnaires will be able to accurately identify sub-types. Why?

Most of the questionnaires were designed for other patient groups and may erroneously cause a different diagnosis to ME, or erroneously diagnose co morbities. So I, personally, doubt they'll accurately tell us much about sub types. If the questionnaires are optional then you may get self selecting sub types filling them in - that could skew your data.

Many of us have had additional suffering inflicted on us thanks to the use of these very questionnaires.

The GWAS is a starting point. It may be that it is immediately clear which is the ME patient and which is not and that opens up one line of questioning. If it is unclear than that will open up another. Maybe the GWAS will even help produce a fit for purpose questionnaire.

Why give yourself the extra financial burden when research funds are already scarce? Why give yourself the extra workload when the data itself may throw up other far more pertinent lines of enquiry?

 

I do see your point, but if this phenomenon exists, won't it need to be picked out of the GWAS statistically rather than from participants' symptoms?

If there aren't any visible differences at all between ME patients and controls, there's no point proceeding any further with GWAS research. It's unlikely that nothing would show up – I'd expect it to be more a question of whether any differences are significant, and which of them might be meaningful – but to answer the research question, the evidence surely need to come from the genetic data itself.

I think tying any genetic differences to symptoms, severity, and onset type is probably much further down the line. It may not be possible (or even necessary) to work it out objectively.

 

Sorry I haven't the energy to quote everyone, but just wanted to say that although I can see the point of wanting to subtype.... I agree with all the arguments against having any additional questionnaires included. At this point it should be only what is necessary for the GWAS.

 

@Andy apologies if this has been already pointed out but the FAQs have a typo

shouldn't that be either 'previously proved helpful in identifying', or 'previously provided helpful information (or some other word) in'

A big thank you for everyone's hard work on the study & on the site too.

 

I love that idea

ETA Although maybe not.
it could too easily be twisted?... (look away now if you easily upset by nasty comments about sufferers)
quite a few deriders love to use the fact that M.E. spells 'me', to suggest we are selfish/lazy etc...
"it's the ME(me) syndrome", "It's all about ME ME ME", "sufferers need to look at the name of their condition for the cause/cure of their condition"

etc etc etc blah blah blah I'm sure you've heard them all too.

 

Would a partnership with SolveME to use their registry for the purpose of registering for future other studies make more sense. That resolves the issue of who maintains the list long term, and who decides who has access to it. Those resources may not be available long term for the GWAS team (or would the Biobank maintain the list which may make more sense)?

 

Would this involve signing up or committing to using their app? Some ME patients don't use smartphones. Others (like me) will not agree to downloading an app on their smartphones.

Edit- also re the app - I found keeping a diary for symptoms and activities a huge additional burden in the past. I also found it to be a wholly negative experience as it just focused my mind on ME all the time.

 

To respond I'll highlight information from the FAQ again.

 

We are exploring options.

 

While we are exploring what options are available to us, we are keeping in mind that the burden for participating in the study should be as light as is possible, in order to allow as many patients as possible to take part. Whatever platform we use in the end should make things as easy as possible, not add unnecessary tasks.

 

I understand that the me/cfs biobank questionnaire is being used to check that participants have me/cfs?

When I did the biobank questionnaire last year, there was a question like "do you have fatigue that is not relieved by rest?" I think this is not a good question because when I was less severe, I could feel okay if I rested a LOT - I'm sure that is true for many people with "mild" or maybe even "moderate" ME? The issue was that the amount of rest needed in order to relieve my fatigue was excessive. And the amount of fatigue triggered by ordinary activities was excessive.

* * *

Also, I am wondering whether the biobank questionnaire will be able to differentiate people who have PEM from people who have post-exertional fatigue but not PEM? As I think we're all agreed that the latter shouldn't be included in an me/cfs study.

This needs to be made very clear in how the questions are asked, because a lot of people don't understand the difference between PEM and PEF and will say they have PEM when they don't really. (Especially since a lot of people in the UK have been diagnosed with ME/CFS purely because they have fatigue and the doctor didn't investigate much further.)

I even have trouble articulating what the difference is. For a lot of PWME, PEM involves additional symptoms / symptoms worsening, as well as fatigue. But mine often only consists of worse fatigue... So partly I'm not sure whether mine even counts as PEM? But if it does, then how do we articulate the difference between that and PEF? We can't just say that it's different in the amount of fatigue triggered, because people with other energy-sapping illnesses also experience PEF which is abnormal in intensity compared with a healthy person.

Perhaps 'recovery time' is a differentiator? But I'm not sure, because I read that people with untreated hypothyroidism can sometimes require several days to recover from physical exertion. I do wonder whether we PWME tend to underestimate the 'recovery time from activity' required by people who have other energy-affecting health conditions? Also, some people diagnosed with ME do seem to present with a PEM-like pattern that resolves after only a day or so?

I suspect the difference is this: if you are in PEM, and you continue to exert yourself without resting enough, then you can go on a huge downwards spiral and risk eventually ending up in a long-term state of extremely severe (think of the severity of e.g. Whitney Dafoe). For somebody experiencing PEF, this is not going to happen; continued exertion will just make them more tired, and their energy level will go back towards their 'normal' once they have rested plenty. Whereas if I overexert to the extent that it pushes me down to a worse level of ME severity (this does not happen every time, just with really bad or protracted overexertions); then once I've been at that worse severity for a few days, that becomes my new 'normal' and no amount of rest can get me back to what my 'normal' was before the overexertion.

It's really hard. I wonder if you can't properly understand the difference between PEM and PEF-with-a-different-health-condition unless you've experienced both yourself and know what the difference in feeling is. And it can be very hard to articulate how something feels... it is for me anyway.

You also want to include people who rarely get PEM because they manage to avoid overexertion.

 

Does everyone get immune symptoms with PEM? I've always had this, but I don't know whether it's universal. If I've only exceeded my energy envelope by a bit, it's nothing more than slightly raised neck glands on waking, which go down again within half an hour.

Once you recognise it – rather than dismissing it as dehydration from mouth breathing, or something like that – it's unmistakable as an immune response. If it is universal, then questions would need to be carefully framed to describe it, as I'm sure some people with mild ME won't recognise it as a PEM symptom.

 

I fully agree. Questions like this are not at all suitable for diagnosing ME/CFS in my opinion; they are so very ambiguous it can be pot luck when answering a question that should not be asked in the first place. In my wife's case, yes there is some relief (what would be the point of resting otherwise!), but it is nothing like the relief if she were healthy, neither degree nor quality.

Fully agree again. My wife seems to instinctively know how to pace herself well, so her PEM is typically about feeling shattered and not very well, and will be back to her norm next day. But if she gets it wrong, or circumstances overtake her, she ends up feeling bl**dy ill and way beyond shattered, and she will definitely not be OK by the next day.

As usual these questionnaires were originally designed by people who presumed to understand ME/CFS, and what questions to ask. But ME/CFS is unique in many ways, and needs its own very carefully thought out questionnaire.

Maybe diagnosis could itself be much better if a much improved questionnaire were designed. But an undertaking not to be underestimated, let alone then proving its validity.

 

Many do get it, but a fair number don't. I ran a poll on this forum about PEM symptoms a few months or so ago.

 

Sorry, I'd forgotten all about that! Not having a great day today.