US NIH: Responses to NANDS Request for Information: How to advance ME/CFS Research

Wow that's a lot of responses. I counted 328 pages of responses in total.

Some are thoughtful, some are weird. Either way it shows a great public interest.

PS: a very rough estimate is 8 responses per page, or 2624 responses in total.
 
Hopefully they will be making an effort to group responses into broad categories, to make it easy to gain an overview.

Although the responses have, where needed, been anonymised, I think I could probably guess who might have submitted this.
I have recently done this exercise, together with Derya Unutmaz and Maureen Hanson, for UK MRC as an advisory board so I thought I would just offer some bullet points along the same lines here. Vicky Whittemore knows that I am a retired biomedical scientist with a major interest in ME research as a sort of 'disinterested uncle'.

Chris Ponting has convinced me that pushing genetic studies is worth doing. We need to draw on the really big datasets (hundreds of thousands or more if possible for 'first pass' trawling. We also need to verify using smaller carefully recruited population based cohorts like the UK ME biobank cohort. I think there are likely to be serious confounding ascertainment factors in cohorts that are not truly population representative and I am not yet convinced that people are aware just how serious they are. But I don't think they preclude getting a valid answer with careful methodology.

The other idea is something that came from a 'citizen scientist' patient. The key clinical problem in ME/CFS is exertion intolerance. I think we need to be able to measure that objectively. I think there is an analogy with the inability to move rapidly and smoothly in Parkinsonism. The neurologists have made progress in documenting this with actimetry - including describing on-off phenomena. Actimetry in ME/CFS has mostly looked at just quantity of activity but I think it needs to be used to look at PATTERNS of impaired activity so that these can be tracked objectively over long periods. The technical term for this is apparently 'motor fatigue'. That is to say not a sense of fatigue but a behavioural pattern that can be studied objectively. Only when we understand these patterns will we know what we are trying to explain. I think it very likely that if we really knew what the activity deficit was we would know we are not looking for a metabolic defect, for instance.
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Andy said:
Hopefully they will be making an effort to group responses into broad categories, to make it easy to gain an overview.

Although the responses have, where needed, been anonymised, I think I could probably guess who might have submitted this.
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That response makes it sound like we are a long way away from anything that will help us. Glad to see the input but it seems like we are looking at a long road ahead. Any thoughts? Also hundreds of thousands.. We don't have info on hundreds of thousands of patients and unlikely will for another century considering doctors can't even diagnose ME.
 
Sunshine3 said:
That response makes it sound like we are a long way away from anything that will help us. Glad to see the input but it seems like we are looking at a long road ahead. Any thoughts?
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I think we are undoubtedly in the early stages of getting any proper level of funding from government bodies. Although we would like to see far more from the NiH at least they are providing some, and the amount that they provide is still far far greater than the UK and EU does. However, the quote does hint that perhaps the UK's MRC is starting to take it more seriously as a topic as not only did they form an advisory board, but they also recruited Unutmaz, Hanson and, I suspect, @Jonathan Edwards to be part of it. So it suggests that some progress is being made, but as to when that will translate in to something substantially beneficial for us patients - I would be surprised if it was less than a decade.

Sunshine3 said:
Also hundreds of thousands.. We don't have info on hundreds of thousands of patients and unlikely will for another century considering doctors can't even diagnose ME.
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It's true that we don't have data on that many ME/CFS patients at the moment. My guess would be that, with an international effort, it could be possible, but it would require time, education (of officials and patients) and money.
 
Samuel said:
> Public comments received in response to a Request for Information from the NANDS Council Working Group for ME/CFS Research are now available: https://www.ninds.nih.gov/node/18206
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It is impossible to sift through those comments and not conclude that everything is yet to be done, that we are still firmly at step 1 and absolutely nothing of value was accomplished in the 3 decades lost to the psychosocial ideology. An entire generation, tens of millions, wasted on the pipe dream of pseudoscientific delusion. Few tyrants in history have ever managed to destroy this many lives so effectively and without resistance.

I'm only skimming through but cannot find a single comment that reflects that any progress whatsoever has been accomplished so far. It confirms that the status quo is disastrous, unfit for purpose and has been a complete waste, amounting to a human rights disaster.

This is a clear 0/100 grade on the last 3 decades and the CFS debacle. Absolute failure, top to bottom. Not a single redeeming positive thing has come out of the creep of pseudoscience, as advocates have strongly warned about the entire time. The rejection of all patient perspective, favoring instead the gut feeling rhetoric of people with no legitimate expertise, shows itself as a massive part of this failure.

So it will be interesting what is done with this present patient perspective making loud and clear that initially rejecting this input lead to the current disaster.
 
I've read some responses and the usual themes reappear.

I liked this comment.

Find MDs who have been afflicted so they can speak the medical lingo to researchers & be part of a) changing mindsets and b) collaborating on a solution
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And this one

From a systems science point of view, I believe the epidemiology of ME/CFS needs a major update. ME/CFS research will not likely be fully funded until the general public become worried about the growth rate of the condition. This is really a big deal in my opinion because nobody is talking about the role of epidemiology in the sequence of power in getting funding. Here is the model:Competent Epidemiology => Public Worries => Medical Engagement (calls for action, etc) => Pressure on Elected Officials => Congressional Funding Response => NIH and related agency cooperation => Increased Funding => Increased Research Activity => Better Clinical Management => SolutionsCurrently the missing link is 'public worries'. We are a worried patient community, but patient worries do not lead to significant medical engagement or pressure on public officials. We are just another special interest group to them. That is not adequate. Think of the AIDS response, how the public fear was a critical factor, that response was not just a few worried patients or patient associations. We are missing the big splash in public awareness, and I believe a competent epidemiological study could trigger that. Yes, this is a long game and I know people want quick studies and answers, I want those too, but for the major funding we need, we have to play the long game well, not just the short game.
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There are many good comments.
 
Sunshine3 said:
That response makes it sound like we are a long way away from anything that will help us. Glad to see the input but it seems like we are looking at a long road ahead. Any thoughts? Also hundreds of thousands.. We don't have info on hundreds of thousands of patients and unlikely will for another century considering doctors can't even diagnose ME.
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The author of the response would not be quite so pessimistic.

We actually already have some data from the US as a spin off from a big epidemiology project that runs towards the million level. (The patients did the diagnosing I think.) It suggests that there is a major genetic element in ME that is not a simple Mendelian issue. It is indirect and will suffer from a lot of uncertainties but things like that can be very powerful.

Having been through the process before I would make the point that the quantum leap to a useful theory can occur when least expected and also when a very large amount of relevant information is sitting there ready to make use of. It is a bit like doing a jigsaw and having a cluster of pieces put together on one part of the table but no idea where it goes and then suddenly turning it round and finding it fits perfectly with a gap by the left hand edge. In RA we suddenly realised how some bits might fit together in 1996. By 1998 we had started testing the new model with treatment and by 2001 we had clear proof we were on the right lines. An important part of that was being prepared to completely ignore the 'received wisdom' in the field - which looks likely to be a good idea for ME too.

Picking out a single relevant gene might turn everything around.
 
strategist said:
What does not a simple Mendelian issue mean?
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Mendel described how traits are coded by single genes - either dominant or recessive. For instance I think red hair may be coded by a single gene. Haemophilia is coded by a single gene. But height is probably coded by 100 genes all making a slight difference. It looks as if the genetic component of ME may involve several genes in combination - or at least so far nobody has convincingly shown any gene that does it on its own.

The relevance is that if ME were due to a single Mendelian gene it would stick out like sore thumb even on a sample of 20 patients and 20 controls. The more genes involved the more you need genome-wide studies (GWAS) on large numbers of people.

At leas that's my level of understanding.
 
Objective measures of post exertional malaise

Just wanted to highlight the idea submitted by the famous anonymous author:

The other idea is something that came from a 'citizen scientist' patient. The key clinical problem in ME/CFS is exertion intolerance. I think we need to be able to measure that objectively. I think there is an analogy with the inability to move rapidly and smoothly in Parkinsonism. The neurologists have made progress in documenting this with actimetry - including describing on-off phenomena. Actimetry in ME/CFS has mostly looked at just quantity of activity but I think it needs to be used to look at PATTERNS of impaired activity so that these can be tracked objectively over long periods. The technical term for this is apparently 'motor fatigue'. That is to say not a sense of fatigue but a behavioural pattern that can be studied objectively. Only when we understand these patterns will we know what we are trying to explain. I think it very likely that if we really knew what the activity deficit was we would know we are not looking for a metabolic defect, for instance.​


This is a great idea. The challenge, of course, is to identify the characteristic patterns. It would be necessary to validate the patterns against self-reported PEM from patients, and also compare with the patterns of sick controls.
 
Simon M said:
Objective measures of post exertional malaise

Just wanted to highlight the idea submitted by the famous anonymous author:

The other idea is something that came from a 'citizen scientist' patient. The key clinical problem in ME/CFS is exertion intolerance. I think we need to be able to measure that objectively. I think there is an analogy with the inability to move rapidly and smoothly in Parkinsonism. The neurologists have made progress in documenting this with actimetry - including describing on-off phenomena. Actimetry in ME/CFS has mostly looked at just quantity of activity but I think it needs to be used to look at PATTERNS of impaired activity so that these can be tracked objectively over long periods. The technical term for this is apparently 'motor fatigue'. That is to say not a sense of fatigue but a behavioural pattern that can be studied objectively. Only when we understand these patterns will we know what we are trying to explain. I think it very likely that if we really knew what the activity deficit was we would know we are not looking for a metabolic defect, for instance.​


This is a great idea. The challenge, of course, is to identify the characteristic patterns. It would be necessary to validate the patterns against self-reported PEM from patients, and also compare with the patterns of sick controls.
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Is this something that the UK MEbiobank could take on IF we could find an interested researcher and funding?
 
obeat said:
Is this something that the UK MEbiobank could take on IF we could find an interested researcher and funding?
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Well, I think the potential is there but as you state it would need an interested, and skilled in the relevant area, researcher with the time and funding. I do know that all in the CureME team are very busy with various projects already.
 
Simon M said:
Objective measures of post exertional malaise

Just wanted to highlight the idea submitted by the famous anonymous author:

The other idea is something that came from a 'citizen scientist' patient. The key clinical problem in ME/CFS is exertion intolerance. I think we need to be able to measure that objectively. I think there is an analogy with the inability to move rapidly and smoothly in Parkinsonism. The neurologists have made progress in documenting this with actimetry - including describing on-off phenomena. Actimetry in ME/CFS has mostly looked at just quantity of activity but I think it needs to be used to look at PATTERNS of impaired activity so that these can be tracked objectively over long periods. The technical term for this is apparently 'motor fatigue'. That is to say not a sense of fatigue but a behavioural pattern that can be studied objectively. Only when we understand these patterns will we know what we are trying to explain. I think it very likely that if we really knew what the activity deficit was we would know we are not looking for a metabolic defect, for instance.​


This is a great idea. The challenge, of course, is to identify the characteristic patterns. It would be necessary to validate the patterns against self-reported PEM from patients, and also compare with the patterns of sick controls.
Click to expand...

I'm having trouble understanding why activity patterns would show what we have is not a metabolic defect. The only analogy that makes some sort of partial sense of my experience of rapid muscle fatiguability and slow recovery (accompanied by other symptoms such as pain that increases as muscles are used) is the faulty battery one - low and faulty energy supply that runs out too quickly and generates pain (chemically?) as a side effect of activity, and takes a longer time than it should to recharge. What could that be if not metabolic?

I agree that long timescale actimetry recorded alongside symptoms including PEM would show something of our pattern of activity and symptoms, but how that can be interpreted biochemically or any other way is puzzling me.
 
Simon M said:
Objective measures of post exertional malaise
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I think both fatiguability and PEM could be measured. IMO it's important to distinguish between the two.

Also it could be helpful to distinguish between studying movement patterns as patterns of 'fatigued'/ specifically altered/ impaired movements on the one hand and behavioral patterns (how people adjust their general activities to impaired movements and/or cognition) on the other hand in order to understand how both relate.

Not able to elaborate on this ATM.

Simon M said:
The challenge, of course, is to identify the characteristic patterns. It would be necessary to validate the patterns against self-reported PEM from patients, and also compare with the patterns of sick controls.
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Yes, e.g. controls with depression or anxiety (again, not only PEM but also fatigabuility) --
perhaps similiar to this kind of assessing motor fatiguability in MS:
https://www.s4me.info/threads/objec...lity-lurija-institute.4241/page-2#post-184072

Edited for clarity.
 
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I'm surprised there were so many comments!

There are a lot of good ones but also some weird ones (about stealth adapted virus, testosterone replacement therapy, the zoonotic nematode Varestrongylus klapowi (Vk), natural, homeoparhic treatment, The Wahls Protocol, Chinese acupuncturists etc.). I got the impression that the vast majority of comments came from patients instead of researchers. Some were quite angry.

I've tried to make some sort of summary as the full documents might be too long for some patients to read. It isn't an exact representation of all what was said and proposed, but I think it gives more or less an impression of the things that were brought up. At the end of each comment, between [] is the question the comment responded to. [EDIT: I've added a short title to each comment to make it easier to read, and larger titles to group the comments selected to make it easier to follow]
 
Funding and NIH organisation

Break the cycle
The most urgent ME/CFS research need is for funding. There is currently a futile cycle of “there is not enough quality research, so there cannot be more funding allotted to it,”and so no more quality research is done due to lack of funding. There is a need for investment on the part of the NIH in order to break this cycle. [The most compelling ME/CFS research needs]

Stability in funding
Stability is needed to grow a field of research. Young researchers need to know that there is a future in this field, that funding will not be pulled away arbitrarily, as has been the case in the past (and, unfortunately, present, barring change). This is entirely a matter of will and leadership, both of which have been thoroughly lacking in handling this disease, not just at NIH but in the whole of medicine. Historically, most research in ME has been hit-and-run, researchers working on individual grants then moving to another subject of study because more funding was never available. The usual approach will not work, stable long-term funding has to be set aside so researchers can feel comfortable establishing themselves in the long term. [The most compelling ME/CFS research needs]

Establish and fund an Office of ME Research
If NIH continues not to house ME in NINDS, then NIH must implement the necessary organizational structures to ensure progress is effectively achieved within its institute-driven organization. One approach is to establish and fund an Office of ME Research within the Office of the Director to drive the strategic planning, coordination, resource commitment, stakeholder engagement, and monitoring across institutes and with other key stakeholders that are required to get this field moving. Continuing to use part-time staff and the Trans-NIH structure to implement our country’s response to this disease is inadequate and must be urgently revised. [The most compelling ME/CFS research needs]

Establish a ME/CFS research ‘Tsar’ to proactively encourage new researchers to enter the field. Ideally, an established and experienced ME/CFS researcher(s) could be assigned to visit and give talks at many universities in an attempt to attract new researchers to the field. Perhaps set annual targets for the number of new researchers that are to be confirmed as conducting studies in ME/CFS. Give reassurances that the NIH will look very favourably on new entrants to the field in terms of research grants. [Potential research resources, tools, and/or materials that could help advance ME/CFS research or enable early career investigators and senior investigators new to the ME/CFS field to more easily conduct research]

Review the grant review process
Grant Review Processes: Given the challenges that researchers have reported in getting grant applications approved for ME, it is important to assess in what ways these processes may be impeding access to funds. Specific concerns with the review processes include: What is NIH doing to address the dearth of reviewers on the SEP who both: thoroughly understand ME as a disease and have sufficient knowledge and expertise about the given area of science being studied (e.g. immunology, metabolomics, genomics, etc.) and the type of technology being used (e.g. imaging technology, computational modeling)? Is the ad hoc nature of the SEP reviewers resulting in challenges with getting grants approved because the grantee is faced with new reviewers and new concerns if he or she has to resubmit the application? Are applications being scored poorly by SEP reviewers and reviewers of clinical trials because: The reviewer has a personal opinion that the research is unimportant but that personal opinion does not reflect the actual priorities of the field? The reviewer has an expectation for preliminary data, size of supporting studies, etc. that is not realistic given the state of ME research? Are experienced researchers with broad success in getting grants in other fields still having their ME applications scored poorly and if so, why? [The most compelling ME/CFS research needs]

Something to replace CFSAC
With the recent dissolution of CFSAC, no formal venue exists for engagement of ME stakeholders with federal agencies responsible for addressing needs of patient community, research groups and other institutions. In a field where agency-interdependent issues have long been critical bottlenecks to advancement, it is unacceptable that a venue does not exist for the communication and coordination of actions to address interrelated needs. NIH is in a strategic position to rectify this deficiency and should therefore develop a structured, NIHled venue that engages community, academic, federal agency and industry stakeholders in a holistic and comprehensive approach to advancing research [The most compelling ME/CFS research needs]

NIH supporting ME/CFS on social media
I see Francis Collins posting on Twitter frequently about ALS/MS/auto-immune diseases/cancer, yet I never see mentioning of ME/CFS. Public perception is power. I'm of the belief that it can only help researchers apply when they feel there is NIH support and backing. [Strategies for overcoming scientific challenges or barriers to progress in ME/CFS research]

Director Francis Collins should immediately issue a strongly worded statement on multiple platforms with national and international visibility that ME/CFS is an organic disease that affects millions in the US and tens of millions worldwide, that medical education needs to be brought up to date with current research, and that past efforts to psychologize ME/CFS were wrong and a disservice to patients. This statement should be published as a letter to the editor in prominent medical journals, issued to all medical schools in the US, and publicized in the national media. [Strategies for overcoming scientific challenges or barriers to progress in ME/CFS research]

A budget for all underfunded diseases
It would make sense to have a dedicated funding category for all substantially underfunded diseases and conditions. This would help everyone who is behind get a better start in research, and it could not be criticized as benefitting solely a particular group. There would be a standing fund set at some generous amount tied to a relevant index, perhaps 10% (or even 15% or some other percentage, given that it’s for many diseases) of the overall NIH budget. That way there would be a stable funding source that everyone in need could access if for any reason (the disease is too rare; the patients are too ill to advocate for funds; there’s a lack of information; etc.) there isn’t funding for any particular condition, and this way could be easier and simpler than doing it group by group. A fix for everyone in one go. And any group that does catch up to a reasonable funding level phases out of the category, so it is always relevant[Strategies for overcoming scientific challenges or barriers to progress in ME/CFS research]

There is currently no medical specialty that takes ownership of ME/CFS
There is currently no medical specialty that takes ownership of the disease. This breaks the standard approach of GP referrals, when there is no one to refer to and GPs simply cannot have reliable expertise to handle such a complex disease. [Identifying related scientific areas that may be relevant to ME/CFS and strategies for establishing collaborations with experts in those areas to help advance ME/CFS research]
 
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