Suppose you have €5-10 million for ME/CFS research, what would you spend it on?

Not that I have that much on my bank account, but I wondered what medium-to large scale studies would be most interesting in doing in ME/CFS research.

Many have discussed this on this forum but it is often scattered among different threads and discussions. The James Lind Society helped to set out priorities for ME/CFS research, but these were large topics rather than concrete research proposals.

So if you had the power to decide with a budget of say 5-10 million (a substantial amount but not enormous either) what ME/CFS projects would you spend it on?

 

This question came up during a discussion. Here's how I answered it after only brief thought:

I think a prevalence study (e.g. in Germany) would be useful to get a better overview of severity/disease burden, case definitions, comorbidities (hEDS, POTS, MCAS), prognosis etc. For all these questions one would need a large representative sample of the ME/CFS population. Now we often extrapolate from a study in Chicago in the 1990s that only used the Fukuda criteria. A prevalence study may not be the most exciting project, but it would provide a lot of data that would be useful, regardless of the results.

I also think that a larger longitudinal EBV-study like Dubbo would be helpful. Because you start with people who do not have disease, you can look for factors that increase the risk of ME/CFS. Thus far this hasn’t led to anything useful, but I suspect with much bigger samples and longer follow-up something will show up.

Similarly, there are projects where a representative sample of the population is followed-up over time to test for predictors of all sorts of disease and social outcomes. It would be useful if ME/CFS research could tap into that by asking questions about ME/CFS symptoms as a first selection and a clinical examination to confirm ME/CFS diagnosis in the second round. Then one could look back decades to see if the ME/CFS cases stood out in some sense.

I also think post-mortem studies of ME/CFS patients, and more brain imaging studies (e.g with PET scans) are interesting. There has to be a reason why standard test come back normal while patients are severely ill. So perhaps the explanation is that the abnormalities are in the hardest place to look, the brain.

 

I think we need studies using methods that have so far not been applied or only to a very limited degree. There is a lack of tissue studies.

Post-mortem studies (not just of the brain), muscle biopsies, skin biopsies, growing cells from patient skin and seeing if they're abnormal and stuff like that.

Wearables that track some parameters as they change in daily life for patients could also be useful, if the right things can be measured.

I also think that there must be some forms of ME/CFS where genetics plays a larger role than usual and if we could track these cases down and study them it could be enormously helpful. DecodeME will examine common SNPs, not rare severely damaging mutations.

 

^ absolutely this. Without understanding who is ill, how they are ill, when they became ill, the context of their becoming ill, and how long they have been ill, everything else (other than GWAS) is simply sticking pins in a biological map and having a poke around in those random locations in the hope of finding treasure.

It requires a major epidemiological study to be done in a country where there is consistent developed world level health delivery across its regions and socioeconomic groups, where ME/CFS diagnosis is broadly consistent, where the demographic structures of the country are well characterised and with a minimum population of 10 million.

Previous epidemiology has been valuable but neither large enough nor extensive enough:

• Bakken, Tveito, Gunnes, Ghaderi, Stoltenberg, Trogstad, Håberg & Magnus 01 October 2014. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012 https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-014-0167-5
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• Nacul, Lacerda, Pheby, Campion, Molokhia, Fayyaz, Leite, Poland, Howe, & Drachler. Published: 28 July 2011. Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care. https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-91
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• Reyes, Nisenbaum & Hoaglin, July 14, 2003. Prevalence and Incidence of Chronic Fatigue Syndrome in Wichita, Kansas https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/215827
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• Jason, Richman & Rademaker October 11, 1999. A Community-Based Study of Chronic Fatigue Syndrome https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/415556
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• Steele, Dobbins, Fukuda, Reyes, Randall, Koppelman & Reeves 1998 Sep 28 The epidemiology of chronic fatigue in San Francisco https://www.ncbi.nlm.nih.gov/pubmed/9790487

 

DecodeME is banking half of every DNA sample so that a future whole genome sequencing study can be done that will pick up these rare mutations. And I agree, spending some of the hypothetical buddies on this would be a smart move.

I agree and include prospective studies of glandular fever etc in that.

What do we really know about this illness? Many thousands of research studies have come up with next to nothing, but I suggest we do know (with a high degree of confidence) the following:
1. About three-quarters of cases have a suspected-infectious onset. There is a proven link with EBV/glandular fever. Links with other infections are less conclusive (due to doubts over accuracy of diagnosis of the initial infection or the ME.)
2. At least 80% of cases are female.
3. Onset there are two age peaks for onset: from puberty to early 20s and 30s-to-early 40s.
4. Prevalence is between 0.1% and 0.8%.

It's not much, is it? And it all epidemiological research. Perhaps what we need to do is really nail down these findings.

 

I too would like more brain imaging studies. Ones sufficiently robust enough to garner attention. We have smaller studies showing brain abnormalities. It would be good to see larger studies.

As well, additional studies on the blood of pwME.

 

Need clinical trials, so people can get better!

1) cyclophosphamide—Phase 3 is needed with either blinding or a dose response study.

2) Dopamine stabilizer drugs either Aripiprazole (Abilify), Brexpiprazole (Rexulti), cariprazine (Vraylar) or OSU 6162 or all/crossover. Ron Davis estimated this study to cost about $10 million.

You can spend 10 million trying to elucidate mechanisms—but how did that work out for Alzheimer’s where billions has been spent and they have nothing.

 

Speaking of the devil…

https://twitter.com/user/status/1589628272811593729

 

I'd also like to see research that somehow got to grips with whether pwME have an active, ongoing viral infection or not.

Agreed, epidemiogical studies are required to fill in the blanks of what we already have. Both counting and causes are very lacking.

ETA: doubtless in many countries we need ME coding for physicians' consults. I understand the US just added this in October. I don't know if we have this yet in Canada.

 

I'm curious what a study would find that counted rare variants in genes that could be relevant to ME/CFS. The genes where patients in comparison to controls have a larger number of rare variants could be the ones that are causally involved. The genes could be selected by using the existing metabolomic studies as reference to help decide what is potentially relevant or not.

The disadvantage is that one would need to a lot of whole exome or whole genome data for patients, which is expensive.

 

As always my initial response is perhaps something of a tangent. My lottery fantasy is to fund two?three projects:

• I would love to see a well written popular book out lining the more scandalous aspects of the BPS hijacking of ME. A book that clearly sets out the flawed research and the lies about the evil ME activists, a book that calls out particularly the culprits in the UK but also the ongoing LP saga with such as Recovery Norge. Ideally a book that would be accessible to the general reader and that would spawn various newspaper articles, a TV documentary and perhaps even inspire some writers of drama and/or fiction.
• Funding of an academic chair in the biomedical basis of ME, helping raise the profile of ME research and provide at potential home for a range of PhD studentships. Ideally even stimulate the creation of a specific university department. I am not sure of the best setting in terms of a medical school or a broader biological science context, or which individual university or even which country. Now would the time to do something like this while Long Covid is an obvious but under recognised priority.
• The third could be part of the second, a good general academic text book that provides an overview of our current understanding of ME with all the hints provided on the nature/aetiology so far and an outline of the research required to answer definitively the many possibilities incompletely address by research so far. I would ideally want such a text to make it clear that ME unambiguous involves a range of physiological anomalies despite current uncertainty about its aetiology.

added - I would hope the result of such projects would make it clear that the functional/somatic obsessives were in fact the ones on the fringes of science, not the established experts.

 

That's my belief about ME too: that it's a subtle dysfunction in possibly just a few brain cells, which affects various other brain cells in other parts of the brain, varying with the individual. Given the difficulty of that, I think a better approach might be to test a large number of brain-cell-influencing chemicals, and hope that one or more produce a reliable effect (positive or negative) on ME symptoms. I managed to snap out of the ME state several times, from three unrelated chemicals, so it does seem possible to affect that core dysfunction.

If they aren't willing to try that approach, then I'd put the resources into functional brain scans and post-mortem studies of the brain.

If the core dysfunction is in a small portion of the brain, I doubt that it will show signs in blood or even CSF. Some signalling molecules only travel a few cell widths. Blood studies would probably only show some signs of downstream symptoms. While treating those symptoms would be worthwhile, it would still leave the other symptoms--and the core dysfunction--untreated, so I feel that the brain has higher priority for research resources.

 

Yes, I've been saying for some time, well, over 3 decades that the brain should be researched much more. It seems logical that with so many neurological and cognitive symptoms the brain should be comprehensively studied.

Regarding blood studies, those with far and away more scientific knowledge than me have delved into this area.

 

@Peter Trewhitt

I like your book, and academic ideas.

The way to get knowledge of this scandal out to a very large audience is via "entertainment" of a sort.

 

Develop the nanoneedle into a commercially available test for ME or prove conclusively it doesn't work. If we succeed, we'd make ME easily diagnosable and prove it's physical. We'd also have a platform for in vitro research--we could try different drugs on the blood of pwME and see if it makes the tests normal. Ron Davis did some of this, but at a very small scale, and without the test being validated.

 

Full trials for any of the existing potential biomarkers. Trials to ensure its accurate and correlates well to disease severity and distinguishes from conditions with somewhat similar symptoms but not in the same cluster of disease. We don't need perfect we need obviously wrong and with the right symptoms presented a test that shows its ME/CFS with reasonable certainty and the extent. Maybe that is the Nanoneedle, maybe its one of the combined blood markers, maybe its the cerebral blood flow test. We should probably try to get the top candidates today in to the next stages of trial as some might not make it and ideally to a decent sized trial with healthy and other disease control to show effectiveness. This will bring world wide acceptance and I think that in itself will drive research funding faster.

 

Agreed.

Can you say how that would work? I've been tracking this in studies for decades and have never seen good evidence for anything much below 80%.

Could you explain more? I think the Bakkens study had over 5,800 cases, taken from a retrospective analysis of the entire Norwegian health system across many years. Also, the anaecdotal evidence from PwME has always pointed to the same two age peaks (that was my impression long before I saw the Bakkens study).

I would say all those are likely, but we 'know' it with lesser degrees of confidence than with GF. Most Q-fever studies lack proper diagnosis (questionnaire only), though I agree it's likely it's some kind of post-viral thing. Dubbo (Q fever, RRV) was quite small. I've read SARS-1 and Ebola studies - they do not sound to me like ME, do not properly apply ME /CFS criteria and ignore other possible causes of fatigue etc. such as organ damage. The link with Long Covid remains unproven: most researchers seem to think ME is probably a subset of LC.

 

As for any other rare variant whole genome/exome study, the aim is to find mutations with a big effect, usually affecting the protein normally made by the gene. That then provides a massive clue as to the underlying biology:
1. It could point to the biology in rare cases, tiny sub-groups of ME.
2. Or, it could be more general. Almost all DNA differences from GWAS affect gene control, so small changes in timing, quantity or location of protein production. Rare variants hitting the protein function are like a flashing beacon compared with a dim glow of various (more common) gene-control variants.

Yes, it's expensive. You probably need to study at least a thousand patients, and costs are not much under thousand dollars per individual. All in, that's going to cost at least £1 million. A bigger study would be better, so if you million pounds/euros.