Discussion of suggestions for the ME/CFS Priority Setting Partnership, deadline 5th July - extended to 7th July.

I am doubtful that it is worth setting up another GWAS study. If the UK GWAS study comes up with no genes I doubt further studies will find anything very crucial. If it comes up with some strong candidates then the next thing to do is targeted studies on those candidates. Repeating the expensive technical exercise of a GWAS with adequate numbers and well-enough controlled recruitment protocols seems to me unjustified.

I am also wary of international genetic projects. Ensuring unbiased recruitment and tightly validated control populations is going to be the single most important methodological factor in getting a GWAS right. Spreading an analysis over more than one country seems to me a bad idea. Yes, it would be important to confirm findings in other populations but those should be done from within tightly defined population boundaries.
 
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I've just looked at the thread about @Simon M's excellent new blog article:

For faster progress in ME/CFS research, funders and researchers need to treat patients as partners, not subjects
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and read @FMMM1's comment:

Outcomes of value would include actimetry, walking times, return to work, level of benefit requirements, NOT questionnaires.
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It strikes me that if we are going to measure improvements in function following interventions, we need to think now about ways to establish baselines. I've worn a Fitbit for the last two and a half years, but I'm not sure how much reliable data I'd have. Perhaps heart rate information would be useful, but the step counter isn't reliable, as it tends to count certain arm movements as steps.

So perhaps one research priority could be to work this out, since (a) before-and-after data collected over lengthy periods is crucial in evaluating treatments, and (b) ways to capture it automatically can be worked on ahead of the development of a drug or other intervention.

What is the most useful information to collect, and which affordable devices record it accurately enough to give a reliable indication of changes in level of function? Do we need to look out for new devices that measure different metrics, such as time upright, or can that be inferred well enough from heart rate variations? Etc.
 
Kitty said:
I've just looked at the thread about @Simon M's excellent new blog article:



and read @FMMM1's comment:



It strikes me that if we are going to measure improvements in function following interventions, we need to think now about ways to establish baselines. I've worn a Fitbit for the last two and a half years, but I'm not sure how much reliable data I'd have. Perhaps heart rate information would be useful, but the step counter isn't reliable, as it tends to count certain arm movements as steps.

So perhaps one research priority could be to work this out, since (a) before-and-after data collected over lengthy periods is crucial in evaluating treatments, and (b) ways to capture it automatically can be worked on ahead of the development of a drug or other intervention.

What is the most useful information to collect, and which affordable devices record it accurately enough to give a reliable indication of changes in level of function? Do we need to look out for new devices that measure different metrics, such as time upright, or can that be inferred well enough from heart rate variations? Etc.
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Wearables are flavour of the month for PhDs, perhaps charities could promote more illness specific ones ?
 
Amw66 said:
Wearables are flavour of the month for PhDs, perhaps charities could promote more illness specific ones ?
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Yes, possibly! The question was prompted by the thought that it might be possible to extract more useful information than we realise from easy-to-gather data such as heart rate variations. If it hasn't already been done, I'd like to see some work on this – and any other useful data collection solutions that can be can be hacked together using easily-accessible devices. One day we will probably have potentially useful drug candidates, but we can't evaluate them properly without reliable ways to establish baselines.

It's particularly important for PWME because of the history of using subjective outcomes in research, but it's not only relevant to us. Tracking changes in activity levels over long periods using objective means would be useful in a lot of chronic illnesses. It's relatively easy to record exercise done at the gym, but what really matters when assessing general function is all the activity that's not formal exercise – the pottering around that people do without even thinking about it when they're well, but which is the first to be cut out as an unnecessary drain on energy when they're not.


ETA: added 'that can be' in second sentence.
 
Kitty said:
I've just looked at the thread about @Simon M's excellent new blog article:



and read @FMMM1's comment:



It strikes me that if we are going to measure improvements in function following interventions, we need to think now about ways to establish baselines. I've worn a Fitbit for the last two and a half years, but I'm not sure how much reliable data I'd have. Perhaps heart rate information would be useful, but the step counter isn't reliable, as it tends to count certain arm movements as steps.

So perhaps one research priority could be to work this out, since (a) before-and-after data collected over lengthy periods is crucial in evaluating treatments, and (b) ways to capture it automatically can be worked on ahead of the development of a drug or other intervention.

What is the most useful information to collect, and which affordable devices record it accurately enough to give a reliable indication of changes in level of function? Do we need to look out for new devices that measure different metrics, such as time upright, or can that be inferred well enough from heart rate variations? Etc.
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You seem to have set out a very good suggestion i.e. respond to the request, for ideas for future research areas, by outlining a study on the use of actimetry in ME/CFS.
I'd caution that the perfect should not be the enemy of the good. There's already studies showing that questionnaires overestimate activity, i.e. compared to actimetry, so even the currently available actimetry technology beats questionnaires.
 
FMMM1 said:
I'd caution that the perfect should not be the enemy of the good.
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100% agree.

It would be good, though, to have validation from people who know what they're doing when it comes to actimetry. Otherwise, researchers working on drug candidates – who might be familiar with analysing biological samples, but know little about monitoring activity – are likely to be hesitant about including it as part of a study protocol.

It doesn't need to be specialised or expensive. It just needs to work well enough, and to have been shown to do so.
 
Kitty said:
100% agree.

It would be good, though, to have validation from people who know what they're doing when it comes to actimetry. Otherwise, researchers working on drug candidates – who might be familiar with analysing biological samples, but know little about monitoring activity – are likely to be hesitant about including it as part of a study protocol.

It doesn't need to be specialised or expensive. It just needs to work well enough, and to have been shown to do so.
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Fluge and Mella used actimetry in the rituximab trial.

I assume that those reluctant to use actimetry may be running studies on a very limited budget [poor quality studies shouldn't be used for public policy] and those who know actimetry won't give the right i.e. +ve answer [PACE authors could give some tips on this!].
 
FMMM1 said:
I assume that those reluctant to use actimetry may be running studies on a very limited budget
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True! This is why the research perhaps ought to be done separately. If evaluated protocols using inexpensive technology are available to researchers doing small studies, there's little reason not to co-opt them, especially if the only alternative is subjective self-report. Previously tested approaches must be used in the majority of lab procedures (everything from what PPE is required for a particular task onwards), so it's hardly an unfamiliar concept.

And, unlike a study on a drug candidate, it could be worked on now.
 
Kitty said:
True! This is why the research perhaps ought to be done separately. If evaluated protocols using inexpensive technology are available to researchers doing small studies, there's little reason not to co-opt them, especially if the only alternative is subjective self-report. Previously tested approaches must be used in the majority of lab procedures (everything from what PPE is required for a particular task onwards), so it's hardly an unfamiliar concept.

And, unlike a study on a drug candidate, it could be worked on now.
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Yes, an actimetry study might e.g. look at off the shelf equipment [you mentioned fitbit] and more specialised equipment - there's a review, on this website, of a study using a "time upright" sensor (more sophisticated).

I wouldn't be surprised if even the basic kit (fitbit) was better at monitoring versus questionnaires.
 
FMMM1 said:
Yes, an actimetry study might e.g. look at off the shelf equipment [you mentioned fitbit] and more specialised equipment - there's a review, on this website, of a study using a "time upright" sensor (more sophisticated).

I wouldn't be surprised if even the basic kit (fitbit) was better at monitoring versus questionnaires.
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I created a new thread here re Actimetry:
https://www.s4me.info/threads/actimetry-studies.20638/
 
These are my questions and comments:

I have grouped my questions into 7 main questions. There is space for three questions and one comment on the form, but I understand from @MEMarge we can make more than one submission, so I will make three submissions. My main questions are:


  1. Is ME best understood as a form of cardiac dysfunction?
  2. What is the pathophysiological basis of post-exertional malaise?
  3. What is the pathophysiological basis for drug intolerance in ME patients?
  4. What is the epidemiology of ME?
  5. What food, drink and supplements can help with energy production?
  6. What are the best objective ME-specific biomarkers?
  7. Can we have an urgent review of clinical testing?
My comments will be:

  1. We don’t need more psychological or psychiatric research, not one more £1 spent on research into CBT, GET or similar psychosocial-based therapies.
  2. All research involving patients should have a robust scientific (i.e. falsifiable) basis and use objective monitoring.
  3. There should be no trials in children that have not first been conducted in adults.
  4. We need an urgent inquiry into why there has been very little ME research in the UK, and what funding is needed to achieve parity with similar diseases.
 
Here are my questions in full:

1. Is ME best understood as a form of cardiac dysfunction?
It is clear from the widespread symptoms that the disease involves systemic impairment. Can systemic hypoperfusion of tissues explain many or all of the symptoms of ME? If a pathogen or toxin which damages tissues is in the circulation (there is evidence for this), restriction of blood flow could be an adaptation to reduce delivery of the toxin to tissues. Evidence in support of this includes reduced blood flow, reduced cardiac output, endothelial dysfunction. The circulation could be regulated to be sufficient to maintain life whilst insufficient for normal functioning. Can the severity of ME symptoms be related to the degree of hypoperfusion? How do the symptoms of ME compare to other diseases in which there is abnormal perfusion?



2. What is the pathophysiological basis of post-exertional malaise?
During activity, particularly exercise, perfusion of tissues is increased. Is the delivery of a damaging toxin to tissues involved in the cause of post-exertional malaise, in addition to diversion of blood flow from other tissues? If so, tissues with a slow turnover (e.g. adipose cells, neurons, cardiomyocytes) should theoretically show more evidence of damage than tissues with a high turnover (e.g. white blood cells, small intestinal epithelium). High turnover may explain limited results in studies using white blood cells. We need studies which compare different tissues from the same patient. Can this also explain differences in ages, i.e. children are more likely to recover due to replacement of damaged tissue during growth and development? Can increased blood flow resulting from massage, baths and saunas, or other means, induce post-exertional malaise and are they comparable to exercise?

3. What is the pathophysiological basis for drug intolerance in ME patients?
A major problem with ME is the lack of effective drugs. Many drugs have limited or no effect, or are not well tolerated. I cannot tolerate any medications containing steroids - why? Anecdotally, alcohol intolerance is very common among ME patients. Can this be confirmed by biochemical studies? How common is alcohol intolerance in ME? Can alcohol intolerance be used as a marker for ME? Is the physiological basis for alcohol intolerance the same as for drug intolerance? Is the problem due to reduced perfusion of the liver, or abnormalities in P450 enzymes? How does drug metabolism in ME patients compare to healthy controls and other diseases? What trials of existing drugs could be performed in ME patients?



4. What is the epidemiology of ME?
We need some very basic information about ME. We need an accurate assessment of the prevalence of ME which does not rely on using GP/hospital records since this misses patients with long term and/or severe ME who no longer see their GP or attend hospital (including patients who are too ill to get medical help). Who gets it? What age? What occupation? When? What year? What time of year? Where? What causes relapses? How? How many ME patients can identify others around them who became ill at the same time, but recovered and perhaps did not progress to ME? Can incidence be related to known outbreaks of infectious disease? Does regular physical exercise at the time of onset affect outcome? Can complete rest early in the course of ME prevent long term illness or induce remission (this would need early diagnosis)? The disease severity needs more accurate descriptions e.g. “moderate ME” is not moderate in its effect.



5. What food, drink and supplements can help with energy production?
Given that abnormalities in energy metabolism have been reported, what is the best food to eat or drink to maximise energy production? Which supplements should we take and which should we avoid, if any? For example, it has been reported that there is reduced glycolysis and increases use of amino acids for energy in ME patients. Can this be confirmed and if so, would a high protein diet help? We need trials, with objective biomarkers, to investigate the best dietary management for ME patients. What role does liberation of amino acids from muscle have in the disease and can it explain the lower prevalence in men?


6. What are the best objective ME-specific biomarkers?
The symptoms of ME are non-specific and wide-ranging. There is therefore an urgent need for objective ME-specific biomarkers which can be used both in the clinic for diagnosis and monitoring, and in research for accurate case definition. Several studies have identified biochemical and physiological abnormalities, e.g. reduced flow mediated dilation and post-occlusive reactive hyperaemia, which could potentially be used as biomarkers. These urgently need to be replicated and examined in large patient populations.

7. Can we have an urgent review of clinical testing?
Currently there is very little testing performed in the clinic, indeed it is discouraged. What tests can be done that are not currently being done, e.g. tilt-table testing, brain imaging. Every patient should have a suite of tests and imaging e.g. MRI, CT, X rays, and researchers should be investigating correlations between findings and severity of the disease.
 
I saw another online comment yesterday from someone who (like me) found their function restored temporarily to normal after receiving the AZ vaccine. There does appear to be a subgroup of patients who benefit significantly from stimulation of their immune system, either after a vaccination, during the onset of a mild infection such as a head cold, or at the drop-off in hormone levels in the final days of the menstrual cycle.

If we don't have a good understanding already, I'd like to see some work on why this happens, in case it offers a clue about what is going wrong in ME.
 
I've added another question:
Can we have more research into pain and its physiological correlates in ME patients, particularly in association with activity? My experience is that every physical and some mental activity incurs pain and while it is both pain and fatigue combined that generally stops me from continuing with an activity, pain is frequently the limiting factor.

I have now made four submissions. I realised that you don't have to give a name, and it occurs to me that this leaves the survey open to potential abuse.
 
Yvonne said:
I've added another question:
Can we have more research into pain and its physiological correlates in ME patients, particularly in association with activity? My experience is that every physical and some mental activity incurs pain and while it is both pain and fatigue combined that generally stops me from continuing with an activity, pain is frequently the limiting factor.

I have now made four submissions. I realised that you don't have to give a name, and it occurs to me that this leaves the survey open to potential abuse.
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Have contacted the JLA re this. (JLA = James Lind Alliance, who are the small team who run the PSPs for all diseases. They provide the survey software, send the data to the analyst etc)
I have a vague memory that URLs are monitored....but will let you know when I hear back.
 
MEMarge said:
Have contacted the JLA re this. (JLA = James Lind Alliance, who are the small team who run the PSPs for all diseases. They provide the survey software, send the data to the analyst etc)
I have a vague memory that URLs are monitored....but will let you know when I hear back.
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Thank you @MEMarge
 
Yvonne said:
I've added another question:
Can we have more research into pain and its physiological correlates in ME patients, particularly in association with activity? My experience is that every physical and some mental activity incurs pain and while it is both pain and fatigue combined that generally stops me from continuing with an activity, pain is frequently the limiting factor.

I have now made four submissions. I realised that you don't have to give a name, and it occurs to me that this leaves the survey open to potential abuse.
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It depends on what you mean by abuse.

If it is a measure of how many have participated then equating each survey to a different person may inflate engagement and therefore not be accurate , perhaps skewing category classes ( so 4 x carer when only 1 x carer- but perhaps raising issues that 3 other carers might not by having more options - with 3 questions there will be a lot of common topics . Submitting more may open up different areas ?) I think multiple submissions help when cognitive issues are so much a part of the condition .

So if success was measured solely on outreach and engagement this may be a key concern .
Category of responses are important to try and ensure that carers , clinicians and different degrees of severity are represented.

But this is not epidemiology- we are looking for ideas and concerns to generate questions for research, and we know that for severe and very severely affected many will not be able to contribute - but others could contribute on their behalf, and others by submitting many questions may cover concerns of others .

I could gather info from this thread from those outwith UK ( technically this is UK only but all responses are retained) and complete the survey a number of times, and it might actually be a good idea given some of the suggestions.

It is quality not quantity and perhaps @Yvonne's 4th submission has that bit of blue sky thinking that lights a spark with research which could make a difference.

So whilst multiple responses may skew participant data it is not participant data that is the primary outcome - its ideas/ concerns which could be researched which come from lived experience .

My aunt has a paper copy and has completed it but has other ideas - she cannot cope with another paper copy ( Even with her sister completing it it took weeks) but after a chat during a lunchtime visit I can raise a couple of points .

To be able to do this is important.
 
By abuse, I meant that if I were an unscrupulous researcher I could complete the survey as if I was a patient or carer and submit questions that suggested my field of research was desired by patients and carers. If I had a large number of collaborators and supporters, they could do the same, skewing the popular questions in our favour.
 
Deadline is todayat 5.

Any final thoughts, ideas, research questions

https://www.psp-me.co.uk/take-part/

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