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

Here are my two suggestions.

1. Prospective study: infectious mononucleosis (and Covid?)

As suggested above. Think of this as Dubbo 2, recruiting people at the point of diagnosis with glandular fever/infectious mononucleosis. Then follow-up detailed follow-up for two years, checking people's biology activity levels, work status et cetera. As with Dubbo, I'm in favour of collecting both psychological and biological data (bring it on).

Using glandulare fever, which occurs at a consistent background level and doesn't rely on outbreaks and isn't a rural (hard to collect samples: Q fever and Ross River virus) disease.

The ideal methodology is to get people before they are ill so that you have true baseline data. This is the approach taken by Jason and others in their $5 million NIH study at Northwestern University. Unfortunately, it didn't yield many ME/CFS cases and didn't produce good data. I'm not sure why not.

But by using lab diagnosis to pick up people, you can get in at the beginning and watch the illness ME develop – or not. I think it took the Jason study up to 6 weeks from lab diagnosis to recruit new mono cases and it's quite possible that they missed the biological action by then.

Ideally, this study would run in parallel with a similar long Covid study.

Because Covid is far more common than glandular fever, it would probably be possible to arrange this recruit this sample from an existing health cohort that already has baseline/pre-illness data. Hopefully, it's already been done.
 
2. Getting serious about epidemiology

We need to kneel down the epidemiological findings to date on prevalence and incidence (onset).

Personally, I think Norway might be the ideal place for this because of its comprehensive health system and quality of health reporting (many cohorts, e.g. autism, are based in Norway because of this).

The "two age peaks" study was useful and very large but retrospective and the diagnosis was questionable – they simply selected everyone with a G 93.3 diagnostic code. Perhaps we need a rerun of this study, screening likely people with symptom questions and providing a full medical diagnosis by specialists for a random sample. Maybe this could be combined with the creation of a patient registry @Hutan.

This approach would certainly give us onset data. I'm not sure if it would also give us prevalence data.

Prevalence is hard to measure for a relatively rare disease because you have to contact enormous numbers of people to generate the roughly 1 in 400 individuals who have the illness. And how do you get a random sample? Response rates are now so low (online, phone, email) that there is inevitably a high level of bias in the selected sample. Again, maybe Norway, with its rich health data on most of the population, would provide a good place to run this study.

CRG said:
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.
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I agree with most of that, though I'm not sure why the 10M threshold. Norway seems admirably placed, and the Bakkens study had 5.8k cases. That should be plenty.
 
I was thinking more about it, and I feel that funding prevalence, 'how PWME's lives are affected', and other such studies are kind of defeatist: they're assuming that research is not going to crack the mystery any time soon. Being 60+, I personally don't want the target date for funding actual research into a treatment to be set at 50+ years in the future.

I also worry that it could turn ME into just another 'funding is spent to get more funding' business that would not want ME to ever actually be solved. MS seems like a 'funding is spent to get more funding' business. I see "donate for MS research" ads all over. Has anyone done a study on how much of the actually useful research was funded by those MS funding organization?

I'm not saying that prevalence data, biomarkers of common symptoms, and other such studies are worthless. It would be very valuable to have better selection of study subjects via biomarkers, and be able to measure the effects of treatments on those biomarkers. Prevalence data could result in more funding. The question is: what is the return on that investment for 5, 10, 20, etc, years ahead? Would it add billions in 20 years, or just make a difference in a couple of decisions about a million or so?

Funding for treatment trials would be good ... if there were any good candidates. Trials that showed benefits for a few patients, but no benefit for most, don't count. I've had significant benefits from several treatments ... that don't work for anyone else; that's just how this disease is. Since we still don't have any supported theory about the mechanism of ME, the candidate treatments are just guesses. I'd let the proponents of those theories work for the funding themselves. Let them convince the drug manufacturers to fund it.
 
Simon M said:
As suggested above. Think of this as Dubbo 2, recruiting people at the point of diagnosis with glandular fever/infectious mononucleosis. Then follow-up detailed follow-up for two years, checking people's biology activity levels, work status et cetera.
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I'd put this at low priority too. It assumes that ME is due to an infection. Ditto for genetics studies, which assume a genetic cause. ME could turn out to have a developmental cause, such as how blood vessels develop in the brainstem at age 6 due to environmental factors. It could turn out to have an environmental cause, such as accumulation of a certain common toxin in combination with some other chemical (excess or deficiency), or your sleep patterns in adolescence, or something even less likely. I prioritize finding the core mechanism, over finding what people who develop ME might have in common.

We can't find a reliable marker in PWME, so why would you expect studies of people who get mono and then develop ME to show a reliable marker?
 
Trish said:
I would go for longitudinal studies in a cohort chosen as as true as possible a representative sample of all pwME - all severity levels, all ethnicities, genders, ages, duration of disease, variations in which symptoms are most disabling etc.

And I would like it to focus on as many biological factors that can be monitored continuously using wearables as possible, not just step counts, plus a manageable way of recording symptoms and treatments daily, with more detailed questionnnaires on symptoms etc monthly, and regular home testing of biological factors that can't be done with continuous wearables, say by monthly visits to take blood and other samples. And perhaps at the beginning and every 6 months, using portable equipment brought to the patient's home to mimic what a CPET does, but during normal daily activities.

I'd like to see it run continously for a couple of years at least, with data analysis and publication after a year, and repeated after the second year.
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I think Jonas Bergquist has monitored the Swedish population fairly intensively.
 
I have mentioned before biopsy studies would be interesting to me, and I was optimistic for the Harvard OMF's study before Tompkins passing. As he was uniquely qualified I don't know what will happen there.

There have been quite a few studies imaging the brain, and many of them have been abnormal. The problem is more "what does it mean?" which is way beyond me. I have no idea how to interpret, for example, most of what Zinn's papers show or Barndens'. They are usually on the small side, but I wonder if there has been some consistency there anyway.

Maybe this is a bit divergent, but I feel like long epidemiological studies might not be as useful, and are problematic when me/cfs is a diagnosis of exclusion. I suspect you might find very generic things that apply broadly to illness, predisposition to illness and other factors.
 
Epidemiological studies are indeed paramount to better understanding ME/CFS and emphasizing its scale at a societal level.

However, once the results are in, they must be acted on and this requires the involvement of politicians. It would seem wise to set aside some money for political lobbying.

Revitalizing the UK ME/CFS biobank also seems important.
 
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dreampop said:
I have mentioned before biopsy studies would be interesting to me, and I was optimistic for the Harvard OMF's study before Tompkins passing. As he was uniquely qualified I don't know what will happen there.

There have been quite a few studies imaging the brain, and many of them have been abnormal. The problem is more "what does it mean?" which is way beyond me. I have no idea how to interpret, for example, most of what Zinn's papers show or Barndens'. They are usually on the small side, but I wonder if there has been some consistency there anyway.
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I tried to chase down with the OMF, NIH and British Brain bank to see if I could register my body for use in ME/CFS research, I spent weeks trying to find anyone interested in a body. If I die I would really like my body to be sliced every which way to work out what the heck went wrong and hopefully to inform ME/CFS research. But as is none of the ME/CFS donations to the NIH brain bank nor the Uk one have been used, the one full body that was donated also went unused. I couldn't find anyone interested when I researched this. I can't support biopsies of live people when we wont test tissue of dead people who have donated their entire bodies to ME/CFS research and its been wasted. There must be people dying with this every year and its just an untapped resource, its definitely one I think there ought to be a drive to investigate but as it stands I couldn't not find a researcher interested, I think it ought to be pursued too. Its not my top priority because I think identification drives funding and recognition and root cause or other unknown dysfunctions can come later with better funding but there is a problem with this aspect of research currently.
 
I agree @BrightCandle. New Zealand has a brilliant brain bank service, and potentially a lot of people dying soon who got ME/CFS during the Tapanui flu outbreak of the mid 1980s. I'd love to see funding put to developing an ME/CFS brain bank as part of the NZ brain bank.

I think it could be done. It's on my (long) list of things I would like to do. If anyone has a spare $1 million or two to put towards it, I'd throw myself into making it happen.
Edit - I've sent the Brain Bank an email.
 
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Simon M said:
I agree with most of that, though I'm not sure why the 10M threshold. Norway seems admirably placed, and the Bakkens study had 5.8k cases. That should be plenty.
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Not casting aspersions on Norway but a couple of considerations that may to a greater or lesser extent apply other smaller countries.

Although now broadly similar to the European average Norway (at 12%) has historically had a low immigrant population, and with just a single mostly sparsely populated open border with another country it is reasonable to suggest that Norway has a fairly strongly conserved genetic profile which might produce a patient population that is untypical in presentation of ME/CFS - so for example Bakken's twin peaks might be a local artifact.

Norway also has some unique demographic features, it has a very particular population distribution, it has extremely high socio economic standing, and it has a climate which is atypical for most human populations. A further oddity is that Norway's population has slightly more males than females - perhaps due to immigration related to the oil industry.

It may be that all these characteristics could be controlled for when extrapolating to larger populations but on balance I'd prefer to see a much larger population, representative of cosmopolitanism of the last 100 years and located closer to the median line of the northern temperate zone - Germany is probably the best fit.
 
Creekside said:
I'd put ..genetics studies [as a low priority], which assume a genetic cause. ME could turn out to have a developmental cause, such as how blood vessels develop in the brainstem at age 6 due to environmental factors. It could turn out to have an environmental cause, such as accumulation of a certain common toxin in combination with some other chemical (excess or deficiency), or your sleep patterns in adolescence, or something even less likely. I prioritize finding the core mechanism, over finding what people who develop ME might have in common.
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I agree that the priority is finding core mechanisms and I understand the scepticism over genetic studies But people have been following hypotheses for mechanisms for decades and we've got nowhere. Genetic studies are different because any DNA differences are causal, so provide better clues. Though it isn't always obvious how they do help.

The first step is actually having genetic causal factors. The evidence from various studies (esp the Utah one) is that ME has a modest heritable element – much like many chronic illnesses. This isn't the same as having a "broken" gene, such as in cystic fibrosis and sickle cell disease. instead, the DNA difference leads to a small increase in risk, typically no more than 10%. This is because in most cases the DNA difference only affects gene expression, but doesn't lead to production of a protein that doesn't function properly.

So how can such a weak signal help? Here are two examples:
1. In rheumatoid arthritis and other autoimmune, GWAS identified various genes involved in the interleukin-10 pathway. This led to development of effective drugs that target this pathway, as well as repurchasing existing drugs to other autoimmune diseases that had similar genetic signature.
see my correction https://www.s4me.info/threads/suppo...ould-you-spend-it-on.30357/page-3#post-446241
2. In an indirect way, migraine studies also show how weak signals can point to effective drugs.

Recently, there been a wave of monoclonal antibodies that target a particular neuropeptide — CGRP — and its receptor. Typically, these help half of all treatment-resistant patients who have at least 15 migraine days a month, leading to a reduction of at least 50% in the number of their migraines. It's a breakthrough in migraine treatment (though I wish I were one of the 50%).

Although the breakthrough came from traditional biomedical research, the target neuropeptide — CGRP — was recently highlighted in a big DNA study meta-analysis. So, even if researchers had known nothing else about migraine (this is where we are with ME), they would still have a good clue pointing to the most effective migraine drug ever created. I'd be happy to take something similar for ME.

Creekside said:
We can't find a reliable marker in PWME, so why would you expect studies of people who get mono and then develop ME to show a reliable marker?
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Because of the huge heterogeneity in symptoms and findings, most researchers think MEcfs is likely many diseases or one disease with many subgroups (this is true even for better defined diseases such as asthma and breast cancer). Focusng on a single known cause (mono - well, it's a trigger) increases the chance of finding a 'clean' scientific signal. Findings might just apply to mono cases, but some findings might apply to infectious causes more genrally. Also, with mon, you can see the disease as it develops, not after years of illnesss when there might be lots of confounding signals.
 
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CRG said:
Not casting aspersions on Norway but a couple of considerations that may to a greater or lesser extent apply other smaller countries.
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those are all good points. I'm not at all wedded to Norway or any particular country. The big advantage Norway does have is a well respected health and health data collection system. This would make it faster and cheaper to set up any study, but the most important thing is to get reliable data out of it.
 
I don't have enough scientific knowledge to make more than a vague suggestion.

1) I'd like cellular respiration to be studied in people with ME to see if the energy producing functions of the cell are working correctly. This may already have been done and discarded as an idea.

2) Another related target for study might be the functioning of the Kreb's Cycle/Citric Acid Cycle to see if that is working correctly in people with ME. This may already have been done and discarded as an idea.
 
in response to the OP...

Goodness i dont know. I think i'd want to see some of the 'interestin'g small studies replcated.

What i'd actually do in the situation of a lottery win, (which i have oft fantasised about) is that i'd ask @Jonathan Edwards what research he would spend it on & then fund that :)

Id be interested inhis reply to the OP
 
Simon M said:
1. In rheumatoid arthritis and other autoimmune, GWAS identified various genes involved in the interleukin-10 pathway. This led to development of effective drugs that target this pathway, as well as repurchasing existing drugs to other autoimmune diseases that had similar genetic signature.
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Is this the case, Simon?

I have not heard of new drugs targeting an IL-10 pathway although I may be out of date. IL-10 itself was tried many years ago and failed.

If I remember rightly IL-10 levels are up in RA but IL-10 reduces inflammation in other contexts, so an interesting example of how complicated rationales for treatments can be.
 
Simon refers to a large GWAS study (migraine) think this is it 100K cases* - and I suspect migraine is easier to characterise/has larger subgroup(s) than ME/CFS.
I support GWAS, by the way, but I do wonder if we may need bigger studies - particularly if ME/CFS is heterogenous.

*Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles
https://www.nature.com/articles/s41588-021-00990-0
 
One other test I thought of but haven't heard of being used yet is to collect EEG data from different parts of the brain, vagus nerves, and any other nerves that might be involved in ME symptoms. Then apply the magic of computer processing and see whether there are differences between PWME (mild, moderate and severe) and suitable controls (people with similarly limited lifestyles). Pre and post-PEM would be good too. I think this is a relatively inexpensive study to do, at least compared to PET scans and fMRIs. I think this is a fairly poorly-explored area, so there might be some surprises. What if, for example, only in PWME, the brainstem periodically sent a burst of pulses to the gut, which then--after a multi-hour delay dependent on PEM--sent an inverse response?
 
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