UK CMRC Nov Board meeting - Grand Challenge confirmed, Davey Smith keen

[Dolphin]

If the study uses the UK's biobank, then I won't have any problems with the patient cohort. If I remember correctly, the biobank patients are diagnosed using CDC and CCC. The biobank patients would be a heterogeneous group, but if the researchers recognise this and are aiming to distinguish subsets (which they are) then this isn't a problem.

I'm pretty sure that the number of samples the biobank has is less than 1000 and they have no plans to collect anything close to 10,000.

Funding from the NIH:
The grant from the NIH will enable important research on the immunology and genetics of ME/CFS, which may lead to the discovery of much needed disease biomarkers. It will also help to expand the Biobank to store samples from over 500 participants, including almost 300 patients and over 200 controls (comprising healthy controls and people with multiple sclerosis), which will be made available to medical researchers internationally.

http://blogs.lshtm.ac.uk/news/2013/...awarded-1-million-grant/#sthash.bIA6U1hm.dpuf

Charity money may have allowed them to collect more than 300 patients but I imagine the total is still going to be less than 1000 given the NIH grant is bigger than what the charities have put in.

 

[SOC]

What I could see happening is that a lot of cheap data will be collected from questionnaires and not much biomedical will be measured.

Oh lord, no! Please not questionnaires!


I agree, with almost no money per patient, they can't do anything of real substance. The money they're allocating per patient will barely cover the most basic blood testing once you take out the overhead of researcher pay, office space, statistical analysis, costs to produce papers (admin people, editors), and so on. I don't see how they can do any sophisticated testing like proper immune tests, or cutting edge testing like the most modern pathogen tests. Seriously, what can you do with $600 per patient after you pay overheads? I doubt they'd have enough to do even one CPET, much less any immune labs.

OMF's Severely Ill Big Data study costs $25,000 per patient for "logistics and supplies". Why the huge difference? Because OMF is actually going to do serious objective testing in areas where abnormalities are likely to be found. At less than 3% of that cost per patient, what can this CMRC study do other than the same old terrible questionnaires that cost nearly nothing to administer and the same routine blood tests we've all already had?

More smoke and mirrors to give the impression they're doing real science and "prove" there's no biomedical abnormalities in ME/CFS.

It would be SO much better if the $6,000,000 was spent on having another 240 patients tested in the OMF Severely Ill Big Data Study. But no, that's not going to happen. Instead we are going to get more expensive low-quality, large-volume, high-impact kick-us-in-the-head BS passed off as research.

$600 per patient. We are SO screwed.

 

[Snow Leopard]

Yes, sounds great on paper. My concern would be, given the involvement of certain usual suspects, whether these 10,000 patients are actually going to have ME or some kind of ill-defined unexplained fatigue and depression. I actually think small but extremely well characterised patient cohorts are a better starting point which is what Ron Davis is doing.

Right, quality not quantity.

I mean 10,000 participants filling out questionnaires, and a 23andme style genotyping will be very unlikely to find anything of value that we don't already know.

 

[worldbackwards]

The first principle is that this is a very high-level science-led endeavour.

It is striking that you would have to emphasise this. Imagine the reverse: "The first principle is that this is a very low level endeavour, led by bias and opinion." One wonders if they protest a bit too much.

 

[Marco]

Yes, sounds great on paper. My concern would be, given the involvement of certain usual suspects, whether these 10,000 patients are actually going to have ME or some kind of ill-defined unexplained fatigue and depression. I actually think small but extremely well characterised patient cohorts are a better starting point which is what Ron Davis is doing.

On the other hand if done properly* this could be the very approach needed if biomarkers actually produce more coherent sub-groups than arbitrary symptom based diagnoses.

Thanks to @ggingues for posting on this :

Biomarkers outperform symptoms in parsing psychosis subgroups

http://www.nih.gov/news-events/news...tperform-symptoms-parsing-psychosis-subgroups

* Obviously £400 per head isn't going to cover fMRI; ERP studies; Genomics; gene expression; cytokine studies; 'exercise' challenge etc that might identify distinct biological pathways.

What really bothers me about this collaborative is an apparent lack of transparency. It would be nice if they could tell us exactly who they're recruiting, from where and what testing will be done (and what working models they have in mind otherwise they're just collecting clumps of posssibly unrelated data).

 

[Simon]

Then my concern is that he doesn't know much about ME, and is going to be getting the wrong impression from the wrong people. There's still a lot of ways this can all go very wrong.

Well, anything can go wrong, for sure, and so can this. But I've been ill for over two decades now, and for me this is the most exciting development so far in UK research - by a country mile.

Perhaps more to the point, Davey Smith is a very smart guy: he knows a huge amount about how to use big data intelligently to get the right answer, and is critical of bunk. Not surprised he follows Coyne. Perhaps most encouragingly of all, he's very upfront he knows nothing about mecfs - here's his opening slide from his CMRC talk

I'm sure he'll make up his own mind as he learns.

What really bothers me about this collaborative is an apparent lack of transparency. It would be nice if they could tell us exactly who they're recruiting, from where and what testing will be done (and what working models they have in mind otherwise they're just collecting clumps of posssibly unrelated data).

I'm sure they will be clearer, once they've decided. They are currently assembling the team and are having a big meet in April which will thrash out a lot of the basic priniciples, before work on a full grant starts in earnest. Until that meeting, hopefully most things will still be up in the air. I think the Wellcome Trust grant they have in mind requires seven major investigators from different disciplines; those investigators will no doubt have a big say in how the project will look.

Meanwhile, here's a Stephen Holgate presentation (to patients in Edinburgh) which gives the priniciples of the Grand Challenge. It's very firmly biomedical.
New Inroads into Understanding the Mechanisms of CFS and ME

Btw, at the CMRC conference, he was lauding both the IOM and NIH/P2P studies, which of course emphasised the need for more biomedical research.

One thing that stands out to me is that £4,000,000/10,000 patients = £400 per patient. And drawing blood (and probably often transporting it somewhere), collecting questionnaire data, etc. costs money. So one wonders how much will be left for biomedical tests. What I could see happening is that a lot of cheap data will be collected from questionnaires and not much biomedical will be measured. As @user9876 mentioned, symptoms are often not very stable.

I agree the budget looks too small, but they have the option of going to the MRC too, and the MRC have been making encouraging noises. But if you read the Holgate presentation above it's clear this is a big primarily biomedical project. I'm sure the issue of getting enough funding for the necessary biological sampling and analysis will be raised when the project is discussed in detail next April.

 

[Sean]

Hope you're right, Simon. All very nerve-wracking, this waiting to see the quantity of research funds and where it gets spent, in both the UK and the USA.

 

[user9876]

I agree the budget looks too small, but they have the option of going to the MRC too, and the MRC have been making encouraging noises. But if you read the Holgate presentation above it's clear this is a big primarily biomedical project. I'm sure the issue of getting enough funding for the necessary biological sampling and analysis will be raised when the project is discussed in detail next April.

I'm assuming they would need to stage it and funding it might be easier to get funding for a relatively small number and then increase that later once they have processes etc in place.

Do you know if they intend to collect samples from healthy people and those with other chronic illnesses as controls?

 

[Simon]

I'm assuming they would need to stage it and funding it might be easier to get funding for a relatively small number and then increase that later once they have processes etc in place.

Do you know if they intend to collect samples from healthy people and those with other chronic illnesses as controls?

Not sure about staged funding - I think scale is a core part of the project. It's almost impossible to get meaningful genomic data from small samples, for instance.

And I'm sure they will incllude sick and healthy controls. Whether that's new subjects, or whether they can use existing data is another question. One of the good thing about many omics is that there are vast data depositories covering healthy and diseaase groups, which may or many not be suitable. Some research fields are built on open data .

 

[duncan]

I just finished reviewing the slides for the SH presentation "New Inroads into Understanding the Mechanisms of CFS and ME".

I am unclear on how it demonstrates a very firm biomedical approach to ME/CFS. It speaks to results of a patient questionnaire. Then it goes on an entertaining narrative (strangely reminiscent of a Disney Pavilion ride) about how the nature of medicine is evolving.

Not quite sure it took a definitive stand on what biomedical steps would be undertaken specific to ME/CFS.

 

[Bob]

My guess is that they will collect public health and survey data (e.g. symptoms, length of illness, diagnostic criteria, age, gender, age of onset, level of disability, etc) on 10,000 patients, and carry out biomedical investigations on a proportion i.e. 500-1,000. The proposals are to carry out a range of biomedical investigations (e.g. proteomics, metabolomics, genes, etc) so £4m wouldn't pay to do that for all 10,000 participants.

 

[Simon]

My guess is that they will collect public health and survey data (e.g. symptoms, length of illness, diagnostic criteria, age, gender, age of onset, level of disability, etc) on 10,000 patients, and carry out biomedical investigations on a proportion i.e. 500-1,000. The proposals are to carry out a range of biomedical investigations (e.g. proteomics, metabolomics, genes, etc) so £4m wouldn't pay to do that for all 10,000 participants.

500-1,000 is nowhere near enough for a robust Genome Wide Association Study, so I don't think that would be the plan at all. If you are going to diagnose and phenotype a lot of patients, that's very expensive: taking a load of blood samples at the same time from those patients adds minimal cost and they'd be mad not too. But I agree, £4m won't get a decent 'omics study done on those numbers, which is why I'd be amazed if they didn't look for more funds from elsewhere.

 

[SOC]

Looks like we have a lot of "I'm sure that..." wishful thinking, hopeful guesswork, and nightmarish thinking, none of which has much to do with any solid knowledge of what's going to happen. For a project that's already funded (It is, isn't it? ), there is a lot of ambiguity about what's actually going to take place in this research. Lots of high-flown language, but as usual with these people, no substance. We'll just have to wait and see how it pans out and roll with it when it comes.

As for Davey Smith admitting loudly and clearly to CMRC that he knows nothing about ME -- I don't see that as a positive. That looks more to me like Little Red Riding Hood entering Grandma's house. I can see EC's eyes gleaming from here. I'm sure she'll make sure he's all up-to-date about ME before much time passes.

 

[Bob]

For a project that's already funded (It is, isn't it? ), there is a lot of ambiguity about what's actually going to take place in this research. Lots of high-flown language, but as usual with these people, no substance. We'll just have to wait and see how it pans out and roll with it when it comes.

No, it's not funded. They're just discussing funding ideas. And there's no methodology yet. It's still early days. Holgate is putting the pieces into place.

 

[SOC]

No, it's not funded. They're just discussing funding ideas. And there's no methodology yet. It's still early days. Holgate is putting the pieces into place.

Ah, thank you. That explains a lot.

In that case, there may be time to put a stop to this, or at least alter the approach so that it makes sense as a biomedical study instead of a sociological/psychological study based primarily on questionnaires and minimal objective testing.

I'm relying on our UK cohort to stay on top of this and make sure your taxpayer funds are not once again going towards screwing the ME population worldwide. The UK medical world has made it very, very clear they're not in the least interested in what the rest of the world has to say about ME, although they continue to shove their garbage down our throats. So it's up to you to ride herd on this project and demand that it be something UK ME patients can be proud of. Wishful thinking is not going to accomplish that. Determined active involvement might, although I don't know how easy that's going to be when they're already painting patient groups and their concerns as dangerous and hostile... not a good sign.

 

[Snow Leopard]

500-1,000 is nowhere near enough for a robust Genome Wide Association Study.

What are the hypothetical expectations of a large GWAS for ME & CFS? Given that the epidemiological data so far doesn't really fit the pattern of a genetic disease (eg age of onset, no difference between identical twins vs non identical, no clear ethnic component, nothing worthwhile found in genomic studies so far.)

If the study doesn't find any clear patterns on a pilot study, of say, 100 patients, why do 10,000?

 

[Valentijn]

If the study doesn't find any clear patterns on a pilot study, of say, 100 patients, why do 10,000?

The problem isn't replication, but rather it's arising because a ton of comparisons are being made (hundreds, thousands, or millions of SNPs). A very large sample of patients is needed to help prevent false positives while allowing the trial to still have the power to find a statistically significant correlation.

 

[Bob]

In that case, there may be time to put a stop to this, or at least alter the approach so that it makes sense as a biomedical study instead of a sociological/psychological study based primarily on questionnaires and minimal objective testing.

The whole point of the study is that it is intended to be a deep biomedical investigation in an attempt to objectively identify disease mechanisms and subsets. I don't have any objections to the stated aims. And Holgate really does know what he's doing in terms of the science. The only worry I have is recruitment i.e. if patients are selected from cognitive-behavioural clinics, then that may bias the recruitment process. I received the Action for ME magazine today and it says that Holgate expects the patient charities to be involved in recruitment, which is somewhat reassuring.

 

[Bob]

I'm relying on our UK cohort to stay on top of this and make sure your taxpayer funds are not once again going towards screwing the ME population worldwide.

That makes it sound like you are blaming the UK patient community, SOC. I know you're not, but we don't need that sort of guilt/blame laid upon us! We have enough to deal with already.

 

[Sean]

I don't have any infections to the stated aims.