How to create good quality research proposals?

I believe the 2-Day CPET test was mentioned at the hearing today. Replicating that and determining how specific that test is to ME would be of great value. The BPS explanation is in doubt. Confirming the diagnostic validity of 2-Day CPET might shovel the deconditioning theory into its grave, while giving other researchers a reason to pursue the physiological roots of those odd results.

 

Just to throw an idea into the ring (which admittedly builds on some suggestions already) - why not identify the top 5 studies to replicate, allocate appropriate levels of funding for each replication effort, and then look to recruit researchers to undertake those replication efforts?

 

The concern for me is that politicians think this is a solution in itself, as may do lots of others. Ring fencing by definition means accepting projects of lower quality or of lower perceived potential. And if that happens then the money disappears immediately into the pockets of opportunists.

 

We have to remember that this is all about real people and real people are imperfect and not always rational. Who removes the inhibitors? We live in a democracy. What seems to have worked recently is making inhibitors feel so uncomfortable in the face of criticism that they have slipped away. But the treacle-like nature of the establishment can be harder to get rid of.

Interested people have been reaching out very effectively but this is a tough nut to crack and my perception is that the number of people who really have a grasp of what sort of synthesis might work can be counted on the fingers of one hand. Moreover, they are not particularly high profile individuals.

And who would I invite to lunch? Stephen Holgate? I think the funders need to be presented with a rigorous analysis of the situation by a group of people seen to have no conflict of interest. Patients are in the best position to do that. Despite the fact that I have no conflict of interest everyone immediately assumes that I do. There is no need for a search committee to have any qualifications. What matters is the quality of the analysis. The patient community have already demonstrated that they are ahead of the game on that score.

I don't think it is actually that difficult. Andy's suggestion is a good start. We flag up a list of things worth replicating and take a careful look at the logistics and who might be able to deliver.

 

I don’t disagree, but the problem is that this has been used as an excuse for not funding anything in the past. If the ring-fenced funds can be carried over and added to the next year’s funds, and the right people are making the decisions, standards do not necessarily need to be lowered. Carrying funds over could potentially send an important message about standards and the MRC’s intentions to fund. Although, getting the right people to make the decisions may be more difficult than attracting the right proposals.

I like the roadshow idea.

 

The Japanese brain inflammation study is important to replicate. Could lead to a diagnostic test and low grade brain inflammation could explain a lot.

Mauren Hanson's recent work on PEM using metabolomics, autonomic testing and CPET (still ongoing, but some preliminary results were published). It's important to understand PEM and because the results showed that PEM subgroups exist (physiologic, anaerobic, autonomic, no PEM).

https://www.youtube.com/watch?v=uWjJMzZTtvI

My feeling is that replication is more valuable when it happens quickly so ideally there would be some funds set aside to immediately begin replicating any interesting findings.

If the Norwegian fecal transplant study reports positive results, it should be replicated immediately.

The OMF should soon start publishing some of their findings and they need to be replicated.

The NIH research centers should also start publishing their findings at some point.

Perhaps a role that we patients can play is facilitating rapid replication work?

 

Let me give you a little background, @NelliePledge,
The idea should make sense but the history is against us.

IiME separated themselves from other groups because they were not prepared to associate with the BPS group. I have a lot of respect for that position. However, I think IiME's reason was that they did not want to be associated with psychiatric research, rather than with bad research. I would have no problem with psychiatric research if it was well founded. For me the reason not to associate with BPS is that it is bad science.

Anyway, we have ended up with a complete polarisation and separation of IiME and CMRC (including AfME and MEA). Around 2014 IiME seemed to be doing well by being more selective about who they invited to their colloquium and generating a genuine sense of research community. I tried to advise on refining that further but my suggestions were not taken up. More recently my impression has been that the mix of scientists has been much less consistent and there has been fragmentation. Indeed IiME's webpage talked of such fragmentation. There seems now to be virtually no interaction between USA and Europe and at the last meeting hardly any UK groups were present.

The basic problem as I perceive it is that IiME, having no expertise of their own in science, tend to bring together people working on projects that sound good to them, without any real understanding of the competence of the scientists involved. That is of no use to us if we want to find the best way forward. Projects may sound great to lay people but be based on nothing of any substance.

I have not been to CMRC since 2014 and it may be that it is doing better in bringing UK scientists together. However, I am not over impressed by what I have heard.

One point I might interject here is that at the Parliamentary debate at least two MPs made a comment about US research being better than here. I do not see that. A lot of the stuff going on in the US looks unlikely to be productive to me. There are a lot of prima donnas but maybe not much more. And in this regard the CMRC looks to be almost as unselective as IiME. The people who have done really useful work in ME tend hardly ever to get mentioned.

So I agree that we seem to need a melting pot forum, but I am not sure either iiME or CMRC are able to deliver. I don't actually think this should be a big summit or have anyone high profile involved. Good scientific meetings tend to be workshops held in some quiet backwater place where people can get on with the work without anyone making great speeches.

 

I agree that the Japanese PET study should be replicated.

A number of people have tried to replicate NK cell findings and I think we may have got to the point where we can agree that there is actually nothing consistent to find but that ought to be thrashed out.

I agree that if major groups come up with published findings they should be looked at but let's wait until we have some firm data!

The T cell clonality finding from Mark Davis should be replicated and Chris Ponting is looking at this. I gather that Ponting has £15k a year for a PhD student for this. I don't really understand why it does not merit a £300K grant and a more senior person (or two).

A Genome wide risk analysis is clearly something that needs attention. It looks as if the UK Biobank have some data, based on the UK ME/CFS Biobank suggestions of trawling for patients by questionnaire.

Perhaps the most obvious development that I see is for the UK ME/CFS Biobank and the UK Biobank to be funded to work as complementary resources for replication efforts. It is crazy to me that the ME/CFS Biobank is still hopping along with shoestring infrastructural funding.

I think Julia Newton's physiological studies should be replicated and further work funded.

I think the autoantibody studies from Germany should be replicated.

I would also like to see a verdict on the vascular response data generated by Belch's group some time ago and followed up by Fluge.

So actually it is not that hard to find a shopping list that would require maybe £10M funding. One has to wonder why the CMRC has not organised this. I strongly suspect that personal interests have got in the way.

 

I was thinking of some sort of mobile colloquium/workshop/mini-conference - something taking just a day or an afternoon, maybe - that would travel to UK locations likely to have a lot of scientists of the sort who might be useful.

Ron Davis goes to conferences/meetings and gives a big talk that gets the audience of scientists all excited and enthused and hanging around for ages afterwards asking questions, such as this latest one. I'm not sure if that's the right format for what we want, but I wonder if having an easy-to-get-to event with a key speaker or two (such as you, Jo) on the science in the major research centres such as London, Cambridge, Edinburgh, etc., might be a way to pull people in.

If this version of a roadshow doesn't seem likely to deliver, can you think of a version that would? I think the key thing is to have a local and short thing that could attract the scientists we want, that would be easy and rewarding for them to attend.

 

Do you have specific people in mind? Can we get them?

Is the paper published in Fatigue that you co-wrote with patients out of date now? That contained some suggestions.

 

Me neither. I put that question forward for the S4ME Q&A with him (don't know if it made the cut). It seems a high and urgent priority to me.

What do we need to do to take this forward?

Not just this, but getting the involvement of the scientists we need?

If charities aren't doing this, and government isn't and can't, we need to take action. Now that we have a science forum (glad I lost the debate about the name!), perhaps we're well placed to do this.

 

The people who understand are already on board and doing their best, often quite low profile. I do not want to keep naming specific names on an open forum.

The Fatigue paper still stands as a broad brush analysis but there have been specific developments - like the T cell story.

 

It would be hard to work on this in open forum I think. But maybe a private working group could be set up.

 

That's good news, and I'm happy not to have people named if they'd rather be working quietly in the background for now.

But do we need more people?

 

Are we at a stage now where we should set one up? Keen for things to get moving.