MEGA 'Why broad definition should be used as a starting point - by Prof Stephen Holgate'

[Jan]

I actually do not see this as a problem. The point of this kind of in depth analysis is to identify subgroups. That kind of group will separate out. So will ME patients. So this kind of study might well validate ME as a separate disease. However the recruitment issue with respect to severe patients is not answered. Its been evaded. It needs to be specifically addressed, with specific mechanisms to ensure that severe patients are sufficiently represented.

For me the main concern is not only lack of inclusion of the severely affected, but also the lack of inclusion of long term sufferers. Imo, the majority of ME patients probably fall in the category of moderate-severe (severe post exertion) and are long term sufferers. Eg moi, ME 26 years, moderate-severe daily, severe-nearly dead post exertion

 

[alex3619]

For me the main concern is not only lack of inclusion of the severely affected, but also the lack of inclusion of long term sufferers.

Duration of illness might be very important, particularly if the disease switches at about the three year mark if other research is correct. At least a few ME and CFS docs have observed changes over time.

What would be really good are some longitudinal studies that observe changes over time in the same patients, though an analysis based on duration of illness could be done in the current proposed studies.

 

[Cinders66]

I will just make one short point on entry criteria - if you want to do an epigenetics study looking at biological mechanisms of illness - I'd head straight for the sickest patients with the least chance of mis-diagnosis - ie long standing clear ME/CFS with no other explanation. Two studies on referrals to CFS clinics have shown a rough 50% error rate in referrals - 50% wrongly diagnosed with CFS and sent back; these studies didnt follow up to see if the 50% kept on for CBT-GET actually had ME/CFS (this was accepted on face value).

Saying we need to keep the net wide to look at all possibilities is fine, but you have to decide what fish you want to catch too, otherwise you'll have a mixed bag of fish and crabs.

As a patient and researcher could you approach the CMRC to be part of the patient liaison

For me the main concern is not only lack of inclusion of the severely affected, but also the lack of inclusion of long term sufferers. Imo, the majority of ME patients probably fall in the category of moderate-severe (severe post exertion) and are long term sufferers. Eg moi, ME 26 years, moderate-severe daily, severe-nearly dead post exertion

For me the main concern is not only lack of inclusion of the severely affected, but also the lack of inclusion of long term sufferers. Imo, the majority of ME patients probably fall in the category of moderate-severe (severe post exertion) and are long term sufferers. Eg moi, ME 26 years, moderate-severe daily, severe-nearly dead post exertion

I agree there's absolutely a need to have a good portion of the long term and also the entrenched , precisely the type of people who don't attend NHS clinics otherwise the study will predominantly be newly Ill, GET amenable ambulant. They should start considering a way to out reach these, recruit from outside the nhs fatigue clinics. Also Holgates version of severely ill seems to mean meeting Fukuda or Canadian consensus criteria , which isn't pwMEs version. The truly severely ill ie those housebound or worse have to have more representation
In a 12,000 study than the 50samples at the uk bio bank which in a study this size is far too small and could get seen As tokenism.

 

[Countrygirl]

Couldn't resist this! (It was posted by Dr Speedy)

 

[Arc]

Imo, the majority of ME patients probably fall in the category of moderate-severe (severe post exertion) and are long term sufferers

I wonder if that's right. Certainly wasn't for me: I was severe within a couple of years. I'm guessing that most of us who wind up here have been ill for a long time, like me, but we might not be a very representative sample.

 

[Simon]

If that's true it would totally undermine the study. But is there any data on it? Not on the severe cases who by definition aren't well enough to make the clinics, but the idea that the vast majority of NHS clinic cases are just fatigued. with very few with mecfs.

 

[eafw]

If that's true it would totally undermine the study. But is there any data on it? Not on the severe cases who by definition aren't well enough to make the clinics, but the idea that the vast majority of NHS clinic cases are just fatigued. with very few with mecfs.

*Diagram not to scale*

So the number of people in the each circle are not the same, though they're drawn with the same area (~250,000 in UK diagnosed, ?? some fraction of them at clinics). The point of the picture is that we keep having "broadness" used as an explanation as to why they can claim to be studying the disease but "broad study" is not an adequate response to the questions around patient selection from NHS clinics - and all the data they will be missing if the majority that they pick up are short term, mild, recent, and mixed in with those who have some other fatiguing condition

Ironically, by using NHS patients from clinics rooted in the NICE/BPS school of thought they are narrowing the field in the way George Davey Smith highlights as a problem in his paper here:

http://ije.oxfordjournals.org/content/42/4/1022.full

It becomes a type of "self selection" - his example of the well-off, middle-aged drinker is the NHS cohort. They don't represent the patient population adequately.

(edit to add correct link)

 

[Jan]

I wonder if that's right. Certainly wasn't for me: I was severe within a couple of years. I'm guessing that most of us who wind up here have been ill for a long time, like me, but we might not be a very representative sample.

I was going under the assumption that 25% are the most severe. Then in my limited experience of ME where I've very rarely known anyone who has recovered, I imagined the largest group would be the moderates and mod-severe), whose illness course may have peaks and troughs, but they never recover enough to go back to full time work or full time life, at least not on a permanent footing. Then there are the mild, I find these the hardest to get my head round, having never been mildly affected. I imagine this group has the best chance of lasting recovery and are much more likely to still be working. I struggle to understand that this group is suffering from the same illness, I'm not saying I'm right, just that I find it difficult to comprehend.

I think there are already enough differences within true ME , without adding other fatiguing illnesses into the mix to study along side it. I don't imagine that many of us have exactly the same symptoms and illness severity throughout. It seems that some aspects of the illness appear/are progressive. Pain has got continually worse for me, as have neuralgia and neuropathy, headaches, OI and multitude of other symptoms. I now have under active thyroid, is this due to the ME? So many questions we don't know the answers to, and won't until large scale in depth studies of the illness are carried out.

 

[potbatch]

Blog post that ties in with what is being discussed here



https://spoonseeker.com/2016/10/14/making-the-most-of-mega/

We received swift (but brief) replies from Prof Holgate of CMRC and Sonya Chowdhury of Action for ME in response to the email in the above blog. Full details here: https://spoonseeker.com/2016/10/15/some-response-from-mega/
There's a bit of good news. Holgate says "I am already aware of a discussion of how to include very severe house-bound patients", while Chowdhury assures us that she expects the patient advisory group to be "representative and recruited transparently" rather than just selected by Action for ME.

So far so good but the devil is in the detail of course. Holgate adds "finance will be a limiting factor", something they keep on coming out with whenever the severely affected get mentioned. In the context of a study involving 12,000 patients and seeking funding of over £5m, it seems rather strange. I fear the danger is of a massive contingent of mildly affected patients and a small sample of severely affected included as a peace offering to the patients. I shall respond to Prof Holgate along these lines when I've had a chance to reflect a bit more. But at least there will be some severely affected and a 'transparently recruited' patient group will hopefully ensure that we have a real say in what happens.

 

[eafw]

An attempt to put some numbers together:

Using the 250,000 number for pwME in the UK, and from this study there are 408 pwME in England considered severe at the clinics.

http://bmjopen.bmj.com/content/4/6/e005083.full

We then get (round numbers and old data for UK as a whole) about 500 severes at the clinics, though it is stated that many of these are merely "on the books" and not in any sort of active contact. In reality how many of them will be in the study ? On experience of other work done on these patients - talk given at recent CMRC - there is a particularly low take-up from this group. Not suprising (I think it was about 5% or less but will go back and check later)

Using those figures, even if they contact every severe they have, we then are looking at something like 25 patients (at best) from the NHS clinics who may sign up for MEGA, and 25 out of 10,000 is seriously inadequate representation.

 

[Cinders66]

We received swift (but brief) replies from Prof Holgate of CMRC and Sonya Chowdhury of Action for ME in response to the email in the above blog. Full details here: https://spoonseeker.com/2016/10/15/some-response-from-mega/
There's a bit of good news. Holgate says "I am already aware of a discussion of how to include very severe house-bound patients", while Chowdhury assures us that she expects the patient advisory group to be "representative and recruited transparently" rather than just selected by Action for ME.

So far so good but the devil is in the detail of course. Holgate adds "finance will be a limiting factor", something they keep on coming out with whenever the severely affected get mentioned. In the context of a study involving 12,000 patients and seeking funding of over £5m, it seems rather strange. I fear the danger is of a massive contingent of mildly affected patients and a small sample of severely affected included as a peace offering to the patients. I shall respond to Prof Holgate along these lines when I've had a chance to reflect a bit more. But at least there will be some severely affected and a 'transparently recruited' patient group will hopefully ensure that we have a real say in what happens.

My fear exactly and tbh I'm pretty narked that the severely affected are still the after thought in U.K. Research compared with fatigue and might be added in in a very small number. That just sums up the entire problem with the whole uk nhs approach -drown out ME with CFS and the fatigued, then ignore the severely affected who now constitute a small minority of a vast umbrella. Heck we even have services that don't even cater for the severe at all. I personally want to see how that 10,000 adult figure is thought to be broken down - what % are thought to be meeting ICC & what percentage the severely ill, if it's just 50 borrowed from the existing bio bank it's about 2%?

 

[Cinders66]

An attempt to put some numbers together:

Using the 250,000 number for pwME in the UK, and from this study there are 408 pwME in England considered severe at the clinics.

http://bmjopen.bmj.com/content/4/6/e005083.full

We then get (round numbers and old data for UK as a whole) about 500 severes at the clinics, though it is stated that many of these are merely "on the books" and not in any sort of active contact. In reality how many of them will be in the study ? On experience of other work done on these patients - talk given at recent CMRC - there is a particularly low take-up from this group. Not suprising (I think it was about 5% or less but will go back and check later)

Using those figures, even if they contact every severe they have, we then are looking at something like 25 patients (at best) from the NHS clinics who may sign up for MEGA, and 25 out of 10,000 is seriously inadequate representation.

If the study looks worthwhile I think you will find the severely ill desperate to be included but there has to be will, proper outreach e.g. Involving the 25% group charity where the severely ill can be reached and with proper attempts at accommodation e.g. Don't expect someone bedridden to have a blood test, an interview, an examination all at once or without much advance notice etc. I had issues with the MERUK funded physio presentation at how virtually impossible stepping into the deep and dark world of severe ME was presented, although I've only seen it once so maybe that's unfair. Ron Davis set up his 20-30 very in depth, multi bodily fluid severely ill study in USA, probably a limited area, very quickly.

I think the 50 severe samples borrowed from the bio bank in existence already is what they're planning to use, which would also be very cheap, but I would probably (unless wise heads explain otherwise) like to see a good size more than that so we can learn meaningful things about this population when the study is as a whole so huge.

 

[Cinders66]

An attempt to put some numbers together:

Using the 250,000 number for pwME in the UK, and from this study there are 408 pwME in England considered severe at the clinics.

http://bmjopen.bmj.com/content/4/6/e005083.full

We then get (round numbers and old data for UK as a whole) about 500 severes at the clinics, though it is stated that many of these are merely "on the books" and not in any sort of active contact. In reality how many of them will be in the study ? On experience of other work done on these patients - talk given at recent CMRC - there is a particularly low take-up from this group. Not suprising (I think it was about 5% or less but will go back and check later)

Using those figures, even if they contact every severe they have, we then are looking at something like 25 patients (at best) from the NHS clinics who may sign up for MEGA, and 25 out of 10,000 is seriously inadequate representation.

That paper, on a positive note did show quite a lot of English clinics using Fukuoka to diagnose.
Just as an aside,
One of the authors of this paper was George Lewith, wasn't he the dr who spoke strongly in favour of the PACE trial to the press recently?

 

[char47]

eafw thats such a brilliant illustration!

 

[char47]

This needs to be posted on the Q&A

completely agree, its perfect, and the heart of the point that MEGA/Holgate are missing

 

[eafw]

Another one, bit more to scale, and slightly different focus, using numbers from links below and assuming about 400 people per clinic, at 49 clinics. (also assuming I did the rest of the sums right). The CMRC should be doing this - as part of an honest appraisal of their own proposal - as they have the numbers better than we do.

http://bmjopen.bmj.com/content/4/6/e005083.full#ref-1
http://www.meresearch.org.uk/information/publications/misdiagnosis-on-a-grand-scale/

 

[Cinders66]

Another one, bit more to scale, and slightly different focus, using numbers from links below and assuming about 400 people per clinic, at 49 clinics. (also assuming I did the rest of the sums right). The CMRC should be doing this - as part of an honest appraisal of their own proposal - as they have the numbers better than we do.

http://bmjopen.bmj.com/content/4/6/e005083.full#ref-1
http://www.meresearch.org.uk/information/publications/misdiagnosis-on-a-grand-scale/

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Isn't the percentage of mild 25% too? I can't remember where the stats come from but I'm sure some research recently found a minority's in work, is that the definition of mild?. Not that it matters, especially for the point of the discussion but I thought it quite interesting that the majority were moderate as it emphasises the severity.

 

[Jan]

Does this make sense, I've just posted it on the Q&A, I'm very foggy, I'll edit if needed if I worded it wrongly or it could sound better?

Jan Sussex

So, if I understand correctly, migraine patients and coronary artery disease patients were studied looking for shared pathways between migraine and coronary artery disease, which turned out to be not as expected. What if this study also included lots of patients with different causes of headaches and lots of people with different coronary diseases? This is the problem, migraine and CAD are well defined and I imagine diagnosis is pretty accurate. Our major concern is that you will be studying a big mixture of patients with many different diseases and conditions that cause fatigue. Fatigue is a symptom, and not even the major one in ME. So here you are not studying two clearly defined conditions but just one symptom.

Most of us agree that the starting point should be with CCC defined patients, to ensure you are definitely studying the right group of patients. Then the next step should be to find sub groups withing this cohort. This is what we want and desperately need. Why the need to throw in patients with fatigue and 1 or 2 symptoms, then try to separate them out afterwards?

This does not even begin to address all the issues of trying to recruit patients through the fatigue clinics and being able to ensure you actually have the right patients in the study in the first place. The study should contain a representative quantity of severe patients, moderate patients, mild patients and must contain the long term patients, not just those with a recent diagnosis of chronic fatigue.

 

[Cinders66]

Does this make sense, I've just posted it on the Q&A, I'm very foggy, I'll edit if needed if I worded it wrongly or it could sound better?

Jan Sussex

So, if I understand correctly, migraine patients and coronary artery disease patients were studied looking for shared pathways between migraine and coronary artery disease, which turned out to be not as expected. What if this study also included lots of patients with different causes of headaches and lots of people with different coronary diseases? This is the problem, migraine and CAD are well defined and I imagine diagnosis is pretty accurate. Our major concern is that you will be studying a big mixture of patients with many different diseases and conditions that cause fatigue. Fatigue is a symptom, and not even the major one in ME. So here you are not studying two clearly defined conditions but just one symptom.

Most of us agree that the starting point should be with CCC defined patients, to ensure you are definitely studying the right group of patients. Then the next step should be to find sub groups withing this cohort. This is what we want and desperately need. Why the need to throw in patients with fatigue and 1 or 2 symptoms, then try to separate them out afterwards?

This does not even begin to address all the issues of trying to recruit patients through the fatigue clinics and being able to ensure you actually have the right patients in the study in the first place. The study should contain a representative quantity of severe patients, moderate patients, mild patients and must contain the long term patients, not just those with a recent diagnosis of chronic fatigue.

As I understand it the main point, or probably one of them, of the study is to subgroup the conditions which come under the uk CFS umbrella and those diagnosed so at clinics in the NHS. IF they just started with CCC then a) it wouldn't do that b) probably most at the clmics wouldn't be eligible. I don't think this is an ME study as such but I get confused with what the primary aim is or is it 2 - to subgroup and find biomarkers.?

 

[Jan]

As I understand it the main point, or probably one of them, of the study is to subgroup the conditions which come under the uk CFS umbrella and those diagnosed so at clinics in the NHS. IF they just started with CCC then a) it wouldn't do that b) probably most at the clmics wouldn't be eligible. I don't think this is an ME study as such but I get confused with what the primary aim is or is it 2 - to subgroup and find biomarkers.?

And there is the problem, ' I don't think it's an ME study as such ' It's not it is, it's a study to distinguish the different causes of long term fatigue. This is not the bio-medical research into ME we have been waiting decades for, it's a huge multi million pound study to sort the psychiatrist misdiagnosed patients into different groups, and if we're lucky there may be enough pwme to show the biomarkers other studies have already found . This should not be taking millions of pounds from the ME research pot when so much more research is needed into the actual disease itself. This sort of study could be done later, once good progress has been made into the disease ME.