Counter petition to the MEGA petition, brainstorming stage

TiredSam

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Pretty much my thoughts but it's my first email from him, perhaps I can impress him with big words at a future date.....
Who else do we know who avoids getting "tied up in the detail" at all costs?

Oh that's right, our old pal Sir Simon, who Holgate asked for advice on appointments. Maybe he'll be asking him for advice on how to avoid details too - who better?
 

TiredSam

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There clearly is a misunderstanding which is always a risk when trying to explain complex reasoning behind experimental design in this hypothesis-free approach to uncovering novel causative pathways in complex diseases.
And who else do we know who writes as if they've swallowed a dictionary in order to mask the fact that their text is completely devoid of content? Ah yes, Peter White, who it is proposed will be joining Sir Simon in that shadowy advisory land behind the scenes.

I wonder if there is much point in trying to clarify a misunderstanding with people whose sole mission seems to be to perpetuate one?

An Esther Crawley fatigue study - no thanks. Now that PACE looks like crumbling, why should these charletans get to arrange a free ride on the coat-tails of real scientists?
 

Aurator

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So, I have good news and bad news
"Hypothesis-free research", eh. Does he really mean that, I wonder, or does he mean research where the hypothesis is not explicitly stated?

Since there is in practice no such thing as hypothesis-free data even, how can there be hypothesis-free research?

Perhaps Professor Holgate could explain what he means.
 

Chrisb

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It is probably best to wait for the substantive response before we get too judgmental. Things don't look promising but this is just one of those messages to adopt a holding position and buy a little time. They can sometimes be expressed in unintentionally unhelpful terms.
 

trishrhymes

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I think we should give him a chance to come up with more detail before we jump to conclusions on the basis of a few words.

Maybe he's only heard about some people's confusion between hypothesis free studies (like Naviaux and Ron Davis are doing where you look for patterns in lots of biological data to try to help understand a disease) and clinical trials of treatments.

He may not be aware (yet) about why we are concerned that they are treating White and Crawley as experts.
 

Simon

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There clearly is a misunderstanding which is always a risk when trying to explain complex reasoning behind experimental design in this hypothesis-free approach to uncovering novel causative pathways in complex diseases.
So, yes, I agree we need a lot more information to remove the problems of misunderstanding - and that's down to MEGA. Clearly they haven't explained adequately to date.

But hypothesis-free does have a clear meaning (Ron Davis talked about at the IiME conference). Normally you have a hypothesis before doing a study eg X causes Y.

With hypothesis-free approaches, such as MEGA plan and Ron Davis used in his OMF study, you just look to see what's there, usually in great detail. What's happening at the metabolic level, what's going on with gene expression, proteins and what genes are linked with a disease. You can still find out a ton of important stuff (and can make unrelated findings in the same study) but you don't really know what you will find before you start.

As Ron Davis said, he hoped the IOM group he served on, that reviewed 9,000 studies, would throw up a lot of useful data that would inform new hypotheses. But he said there was precious little data out there, so he had to generate his own - hence the OMF big data study.

Ron D criticised the NIH for not funding hypothesis-free studies. He said that makes sense when you already know a lot about a disease, but when you know so little, you just need to go out and look in detail to see what's going on, so you can then generate/test new hypotheses eg this pathway came up as really important in our study - lets now zoom in on this in a smaller more focused study to confirm/refute the finding.
 

Simon

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Raising concerns about entrance criteria for this MEGA study, and raising concerns about recruitment is not unreasonable. Dismissing such concerns as "knee jerk" is not helpful, indeed rather insulting to the intelligence of those raising the concerns..
Sorry, that was a bit unfair, and I'd like to withdraw it. 'knee-jerk' was my own knee-jerk reaction to your unsubstantiated comment MEGA would not include anyone with PEM (assertions are my personal bugbear, but still).

I would add that I was the first person on this thread (I believe) to point out that recruiting from the clinics would exclude severely sick housebound and bed bound people who are a significant percentage of the UK ME population (a point that those representing MEGA have not so far considered) …
It's a good point as I said (sorry I credited someone else for that - I have limited energy and haven't been able to keep up with everything on every single thread).

Recruiting from the clinics would also exclude the significant numbers who do not attend the clinics because (as I have already pointed out on this thread) they have been ill a long time, have learned to pace themselves, or seek private treatment as the clinics do not offer any actual treatment, and the clinics can offer them nothing.
We don't have any feel for that. We know that many thousands a year new patients pass through NHS clinics every year - I'm assuming that these are the ones that will be recruited by MEGA since they are already being screened/diagnosed. Some will have been ill for a long time, some for much shorter (I'm sure there's data on this somewhere). The clinics do offer treatment (yes, they may be ineffective, but that information won't have reached many patient and like I said, thousands of new patients attend NHS clinics every year). Pacing isn't a cure, as we all know, so I'm not sure that alone is a reason for patients not to attend.

The second point is that having been referred to a clinic, and found that no actual help was involved, people who had asked for referral saw no point in continuing, so those people no longer attend the clinics.
See above, new patients coming through, not necessarily new cases.

The petition in favour of MEGA comes across as cheerleading, enticing patients to appear to be endorsing the study before they actually know much about it. That comes across as rather manipulative.
I hope MEGA appreciate that now; I assume it wasn't their intention.

Finally, there is no patient consensus that MRC research funding should spent on ‘broad church’ or ‘big umbrella’ studies.
Agreed, and I didn't say there was. My point would be that that's where we are. Stephen Holgate has always advocated for a broad church approach, and always for a huge, omics-based biomedical study focused on understanding the biology. I still think is an incredibly valuable approach, not withstanding that MEGA has communicated poorly with patients so far.
 

slysaint

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you need to be sure that this biomarker, or biomarkers - as with a pattern of metabolic differences that have recently been suggested - is NOT also found in people with chronic undiagnosed fatigue, healthy controls, people with other conditions involving severe fatigue (e.g. multiple sclerosis) and (at some stage) people with psychiatric conditions such as depression.
Isn't this what Dr Naviaux is about to start doing?

So are the MEGA team also going to recruit patients with all of the above to study as well or are they part of the 12000 that will be recruited from NHS clinics?
 

eafw

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His reply was cc'd to Sonya Chowdhury (to be expected I suppose) and to Esther Crawley...
This doesn't bode well. The three most pro-BPS people at the CMRC are the ones making the decisions that will have the worst consequences for us, and are effectively blocking any serious conversation with the proper scientists.

There clearly is a misunderstanding which is always a risk when trying to explain complex reasoning behind experimental design in this hypothesis-free approach to uncovering novel causative pathways in complex diseases.
Well, we do need to wait and see what his follow-up is but, oh dear. Lowly patients failing to understand "complex reasoning" is not what the problem is here.
 

BurnA

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We've had that. It's the answer that gets tied up in the detail that we want.
Maybe he should be reminded that it was the patients who spotted all the flaws in 'the now discredited' PACE trial, long before anyone else, including all the trial designers and peer reviewers.

In fact we would only be too happy to be MEGA advisors if he would like to avoid a repeat of PACE.
 

Aurator

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So, yes, I agree we need a lot more information to remove the problems of misunderstanding - and that's down to MEGA. Clearly they haven't explained adequately to date.

But hypothesis-free does have a clear meaning (Ron Davis talked about at the IiME conference). Normally you have a hypothesis before doing a study eg X causes Y.

With hypothesis-free approaches, such as MEGA plan and Ron Davis used in his OMF study, you just look to see what's there, usually in great detail. What's happening at the metabolic level, what's going on with gene expression, proteins and what genes are linked with a disease. You can still find out a ton of important stuff (and can make unrelated findings in the same study) but you don't really know what you will find before you start.

As Ron Davis said, he hoped the IOM group he served on, that reviewed 9,000 studies, would throw up a lot of useful data that would inform new hypotheses. But he said there was precious little data out there, so he had to generate his own - hence the OMF big data study.

Ron D criticised the NIH for not funding hypothesis-free studies. He said that makes sense when you already know a lot about a disease, but when you know so little, you just need to go out and look in detail to see what's going on, so you can then generate/test new hypotheses eg this pathway came up as really important in our study - lets now zoom in on this in a smaller more focused study to confirm/refute the finding.
Thanks for putting some flesh on the bones. Helpful.
Stephen Holgate has always advocated for a broad church approach, and always for a huge, omics-based biomedical study focused on understanding the biology. I still think is an incredibly valuable approach, not withstanding that MEGA has communicated poorly with patients so far.
Let's hope then that the money available will be enough to produce meaningful data obtained on a broad enough front to exclude even the possibility that hypothesis-driven bias may have operated. It's one thing having raw data: it's another matter entirely what that data consists of and what conclusions you're entitled to draw from it.

Did someone say there was going to be £250 per patient? Or was it £25? If it's the latter, it may not be hypothesis-free research we end up getting, but rather research-free hypothesis, which PACE has given us so much of already, at significant cost, and I don't just mean economic.
 

Simon

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Let's hope then that the money available will be enough to produce meaningful data obtained on a broad enough front to exclude even the possibility that hypothesis-driven bias may have operated. It's one thing having raw data: it's another matter entirely what that data consists of and what conclusions you're entitled to draw from it.
That's important - with a warehouse full of data there will inevitably be loads of false positives. But that's a well-known issue in omics research now (George Davey Smith was one of those who highlighted the problem) and a lot of work goes into dealing with this. Basically you don't use p<0.05, but p<0.0000x, though there's more to it than that - eg you look for eg findings of the same pathways to be flagged up by eg genomics and metabolomics, which you wouldn't expect to happen by chance.

Did someone say there was going to be £250 per patient? Or was it £25? If it's the latter, it may not be hypothesis-free research we end up getting, but rather research-free hypothesis, which PACE has given us so much of already, at significant cost, and I don't just mean economic.
I don't know where the budget figures come from, but the CMRC have already said (minutes) that first stage is to get the funds for sample collection. The second stage is the omics work. So I don't think we know the budget. But a bunch of omics researchers won't be signing up for a study with no chance of gettingi the money to do omics.
 

A.B.

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I don't know where the budget figures come from, but the CMRC have already said (minutes) that first stage is to get the funds for sample collection. The second stage is the omics work. So I don't think we know the budget. But a bunch of omics researchers won't be signing up for a study with no chance of gettingi the money to do omics.
Okay, this sounds more reasonable now. A study of this kind is going to need in depth testing or it will find nothing that could really distinguish between subgroups.
 

BurnA

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So, I have good news and bad news


Thank you for your email. There clearly is a misunderstanding which is always a risk when trying to explain complex reasoning behind experimental design in this hypothesis-free approach to uncovering novel causative pathways in complex diseases. I am consulting my colleagues at the CMRC to try to offer the best answer without getting too tied up with detail.

His reply was cc'd to Sonya Chowdhury (to be expected I suppose) and to Esther Crawley.....

I'll leave it to you guys to analyse it, I don't have time at the minute.
Didn't White once complain about patients obsessing over detail ? ( cant remember when and where but i think it was in relation to the PACE data release)
Maybe we could remind the CMRC about that and suggest they let us at it ?
Seeing as their esteemed advisor recognises how good we are at it.
 

AndyPR

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Hang on a minute, you tell him the ME community has serious concerns, shouldn't his answer have been 'what are the concerns'?
Nope, apparently he knows what THE concern is and they will get back to us and explain it in small, easy to understand words that thicky patients like us will be able to comprehend.