[UK] A proposal for an ME/CFS, Long Covid, and Post-Infectious Disease research platform

Have the MRC never been confronted? People have been complaining forever about their mad decisions and irrational rejections by BPSers, but do you think those complaints weren't necessarily justified?

 

Doesn't being able to find odd bits of money depend on being allied with someone in a senior position who can access those departmental pots and apply for grants, though, which is something that people on research contracts can't do? Unless a researcher can glom onto someone senior with a permanent contract who is willing to support their ME/CFS research, we're going to lose them, surely?

 

The reality is more complex and also more mundane. You survive if you can. A high proportion of good women scientists in particular have held on simply because they were indispensable - they knew what they were doing when nobody else did.

That doesn't really arise. A senior researcher is only going to support what they are interested in.

 

And senior researchers who are interested seem to be pretty good at finding bright minds to work with them, if Chris Ponting is anything to go by.

Whereas the NIH, which had enough money to buy Edinburgh and put a sprig of parsley on top, found Brian Walitt.

 

A lot of the criticism of PACE in the early days was misplaced and in a sense unjustified. The problem with PACE was not the diagnostic criteria or choosing to study a psychological meachniasm. It was the methodology that made it a bad project. I wrote to Fiona Watt to question her continuing support for PACE and she replied in a way that indicated she wasn't the slightest bit interested in quality, just the MRC reputation. Until recently it seems that the MRC has just assumed the critics are irritating activists. That may have changed but I don't have any detailed information. The government working parties provided an opportunity for a frank discussion of what was the real situation but the chair was clearly not interested in annoying the funding bodies so nothing happened. The representatives from the funding bodies didn't really seem to recognise what problem there might be. They just produced the usual statements about having fair rules and being pleased to have good applications.

The whole infrastructure of biomedical science is pretty much a cess pit I am afraid. If general there are far too many people doing science, and for the wrong reasons. Progress up the ladder is much the same as events in Lilliput and Brobdingnag. S4ME is an island of sanity in comparison.

 

And that is exactly the problem.

 

That's my point, though. If a junior researcher can't become a protegee, they've had it.

 

Doesn't that apply in almost every field with tough competition, though? I've never worked in science, but it often did in those I am familiar with.

It's not what you know, it's who you know etc.

 

One thing I was surprised NOT to read about. Having ME/CFS clinics tied to research.

If my reading of @Jonathan Edwards posts about his ground breaking research are right, he had a steady access to patients. How are ME/CFS researchers going to be able to access patients if they need to access fresh blood and process blood immediately to control their experiments. There seem to be no biomedical research clinics especially after funding for Julia Newton's team at Newcastle dried up.

I understand the almost universal plaudits for DecodeME but they "only" needed postal access with samples processed by an experienced team who had processed 100,000's exact same samples before.

Karl Morten was one of the only signatures on the researchers letters. Do people understand how many years and how many hoops he had to go through just to get the Raman Diagnostics papers(s) published. Again and again he had to add more samples due to peer review asking for more. And again and again he had to beg and scrounge to add another batch of patient samples to the pilot study cohort. Even with promising pilot studies there is no access to MRC/NIHR funds to do a proper sized replication study. UK biomedical research has been at a dead end except for the odd project or so.

And the US has funded a significant amount of UK research via LSHTM and now Brunel with Jackie Cliff. More than a dozen years of funding I believe. Without that funding there would have likely been no team to build the CureME biobank initially. The UK has to step up in funding. How is that going to happen if a research network linked to clinical access to patients is not built.

The Netherlands have a plan they are implementing. So is Germany. Please UK, catch up.

In the last CureME webinar they mentioned that samples are aging fast and they have a lot of available samples. Who in the UK is placed to use them for a good quality study that has funding?

 

Structures that can funnel funding and nurture careers could overcome major barriers. From what I can see this is considered best practice. Some money goes into overheads, but the result is greater continuity stability and ability to get things done.

I'd be interested to hear from current researchers on how they see it.

 

One might expect that this is the sort of thing that a well-funded system would fix. The papers suggest that the hub model will be based on a model the UK uses for mental health.

This is an excerpt from the Brain and genomics Hub of that mental health model and it shows that one of their roles is finding patients to study

 

What I'm catching is that funding and coordinating structures are good, actually?

Is there some other subterranean power struggle going on in the UK

 

I would like to Know how much funding is being asked for over the 5 year period, this type of £20m or would that just be the set up starting costs?

 

Funding individuals who have the talent to make a big impact is clearly good. Such individuals now exist in the UK and they deserve funding.

But I am sceptical that trying to build 'co-ordinating structures' makes any sense. Biomedical science moves by unpredictable shifts in one direction and then another. You cannot build ME/CFS units to cover all the sub disciplines staffed by people with talent. My experience has been that new collaborations form and dissolve along the way.

If you ask a group of researchers what plan they recommend, they will of course suggest a multi-hub model, in the hope that none of them will lose out. Each of them might prefer to say 'just give me all the money' but that tends not to get you anywhere. We have had people saying something like that but they don't seem to be part of the proposal.

I don't think we have evidence that planning co-ordinated superstructure is a good model in medical science. We have no controlled experiments so what evidence we have is as anecdotal as the argument for GET. It suits people to say so.

So, yes, but it isn't subterranean. It is on the table. But much more importantly it seems that the real problem is that the medical profession not only do to believe in ME/CFS but are now deliberately airbrushing it out. As someone has pointed out, there is no mention of a clinical service in the proposal and there is no way forward without doctors and patients. None of the people involved in the proposal as far as I can see are physicians actually providing an ME/CFS service.

What that means is that, much as one would like a fairy godmother to decide who should be funded, we are stuck with a system that will need referee reports from 'experts'. Just as we have had 'experts' from BACME settle back in to running the service side, as soon as experts are called in on the medical academic side the default will be to have advice from people who don't believe there is anything to study.

The situation has been desperate, as we all know. But I am pretty sure it is going to change very soon. Maybe the data from Zhang et al. proves nothing. I would still like to nail that. But if they have genuinely identified genetic risk factors for ME/CFS we now have a real biological process to study. There are several other groups whose work I think will fall into place but is not as yet published, or has to be taken as circumstantial evidence only as yet because it does not have the causal certainty of genetic data. I think it will come together and at that point things should change completely, because academic physicians will be interested and suddenly forget that they did not believe in ME/CFS.

I may be wrong, and there is definitely another lap of the 10,000 metre tack to cover, but I think things are going to change. It would be nice if one could bend the ear of the head of MRC and have them say 'Oh gosh, yes, we really should have been funding these projects' but I don't have that privilege and I have no idea what the reply would be today.

 

It is not so much that the studies in the meta-analysis are duds but rather that a meta-analysis on this topic a priori is a dud (the meta-analysis we are talking about here is also a methodological dud with many errors but that doesn’t matter for the below discussion).

Long-Covid is very roughly defined as "anything new happening for at least 4 (sometimes 12) weeks in a 3 month timeframe following a likely Covid infection". ME/CFS is very roughly defined as "a disabling presence of certain symptoms for 6 months". So by definition there isn't really a canonical notion of ME/CFS prevalence in LC. Suppose you have one fixed cohort of LC patients that you're tracking. At 3 months everyone has LC, nobody has ME/CFS, at 6 months the amount of pwLC decreases but ME/CFS joins the picture, at much later time points the amount of pwLC decrease but the rate of ME/CFS amongst those that still have LC likely increases but that itself will depend on the cohort you’re looking at (it likely won’t increase if you’re only looking at hospitalised people who suffer from permanten damage or PICS). So in that sense there is no "fixed prevalence" and things depend on your study setup. Now this whole problem is complicated by your choice of cohort, are you looking at hospitalized people or different severities in the acute infection (then PICS and other things like a lower rate of onset of ME/CFS in elderly people joins the picture etc), how were they recruited, how does diagnoses look, how do you look at testing and asymptomatic infections, you will definitely need a control cohort, your cohort might consist of severe acute infections from the beginning of the pandemic but those have become rare now, how do you control for loss at follow-up (you'll likely loose people that recover but also some that become too severe) etc etc etc.

In short: If you look at everyone that has had LC (which includes people that are recovered after 6 weeks) at some point in time the number might be below 1% (just a rough guess), but if you look at young people with severe cases that actually influence quality of life and do a study with patients of longer symptom duration that number will likely start creeping up. With how bad LC research has been you’ll probably never get any of these questions answered well because the statistics are build on useless cohorts which people are now forced to work with.

So the question is more so: What would even be a meaningful question to ask?

To bring the discussion back on topic. It might not necessarily inspire confidence that this 50% was quoted in the letter, but people tend to write all sorts of nonsense in letters and proposals to make them more prominent, so I'm happy to ignore it. The question is much rather what does any of this mean in a slightly more concrete sense? Similar to @wigglethemouse I’d like to know what this means in terms of clinical services which seems like a thing that needs urgent addressing both from an ethical and humanitarian standpoint as well as for research.

 

Anecdotally I am in an international long covid support group because my ME got much worse from covid and I would say that a huge proportion, almost certainly a majority of the participants report PEM.

But of course these are the more severe and chronic illness aware people. People who have 6 months of fatigue and POTS generally won't join or leave quickly.

I think it would be a mistake to blindly include long covid but studying the subcategory of long covid with PEM alongside ME could be hugely valuble.

 

With the utmost of respect for your immense contribution then, the research world itself has changed considerably since then. It is itself much more bureaucratic. There is more red tape and there are far fewer resources to go around.

Also more than one approach can be successful to solve a problem at any given point in time. It being a different proposal does not inherently doom it to failure.

The researcher who is currently making the greatest difference to ME is behind this, which counts for a lot in my eyes.

 

It is only more bureaucratic if you feed that though. And there are still people setting up new ventures on the fly under the cover of funding for other things, as we have seen in recent papers. I am fairly sure that there are a lot more resources to go around than when I started!!

But that was my whole point, I think. Rather than try to tie everything into some unwieldy co-ordinated multi-hub 'strategic' centre, why not just fund people when they come up with good ideas, as in the past? I agree that we need a resource base in terms of clinical expertise and patient cohorts but that is the one bit that seems not to be included.

I am not sure researchers have an option not to be behind this, that is my problem. All researchers have to be behind it so that if it is approved they are on board ship. Also, what I get in private conversations isn't quite what presents itself in public!!

 

Unfortunately, but not entirely unreasonable. We operate in a context in which even when we are perfect and our detractors don't even bother, they not only win 9/10, but sometimes even manage to push everything back significantly.

The patient community has been correct in predicting most of what happened with LC, and it changed nothing at all. Being right is almost irrelevant when there is a cultural force against it. Even the rise in disability, for which governments are directly responsible for, has so far only led to crackdowns on disability, instead of a rational response. Basically, there is nothing rational about the context in which we try to make things happen.

This makes any proposal face a lot of heightened criticism, rightly or not, from the knowledge that out of all proposals going on, only one is likely to go through, and we will likely lose control of most of its operation the second it becomes bureaucratized, so it really has to be perfect, and then some.

I don't know how we can work things out any better than this. We truly have to be perfect, but the main lesson out of it is probably that it doesn't matter, our detractors will do and say their thing regardless of anything we put forward. The problem is the reality that we get only one chance per 20 years or so. We can't miss, and yet all the odds are stacked against us, the systems explicitly work against us and want nothing to do with helping us. We have to make them do things they explicitly don't ever want to do. Even though we are right and they are wrong, it literally doesn't matter.

 

Wouldn't that always be the case, though? That any subject that attracts interest will attract more bottom-feeders since by definition most researchers are bottom-rate academics? Something universal to all industries, this is not anything unique to it. Attracting a crowd of top people has to come with a mass of low quality work, since the equation is a simple mass equation: the only way to get more quality work is to get more work done, and since most work is poor then this also means a higher number of low quality work. Can't have a BBQ without flies. Where there's meat, there will be flies.

Which still remains more useful than a mass made up of 100% garbage tier work, from our psychobehavioral overlords.