The P2P Draft report is out

[Jonathan Edwards]

A quick thing for @Bob . I think PEM is probably a very useful and practical feature to select on. It is the oddest feature and the one that ought to be telling us most about an unusual mechanism, I agree. I have no problem selecting on PEM and that was one thing we had agreed on in our local group.

But taking a broader view, there are other issues that need dealing with - which I hope to come to in a post shortly if I can. I am not an expert on these criteria sets but I am still a bit cautious about the ICC proposal - for the reasons I have given before. It seems to confuse agendas. I am not sure what would be wrong with CCC with a stipulation of PEM included and a significant score on a depression scale excluded to try to reduce uncertainties for a study aimed at immune mechanisms - i.e. what we thought might be suitable for local research purposes. For other studies other criteria are likely to be better and for clinical management I am unclear that these criteria are useful and I would tend to think that a clear history of PEM or crash would on its own be enough to guide the clinical approach.

 

[Bob]

Does anyone know of research that compares the disability profile of ME to MS? E.g., % bedbound/housebound?

I'm sure there is stuff, but I can't remember any specific papers. I think even Beth Unger has made that comparison. If I come across anything then i'll post it.

 

[Jonathan Edwards]

I am trying to get back to replying to @Large Donner on those unclear issues. I would like to start with when I might suggest using vague criteria - or perhaps to be more exact 'broad' or 'non-specific' criteria. I think PACE provides a good illustration. Others have touched on this.

Let us assume I am an academic physician, or perhaps psychiatrist, referred large number of patients with fatigue of whom nearly all fit Oxford criteria but only 40% have PEM and fit CCC. In 2005 CBT and GET are popular but unproven therapies for fatigue. What am I duty bound to do as my contribution to research? I think probably I am bound to try to set up a trial of CBT and GET using Oxford criteria. I am aware that there are all sorts of other issues relating to the historical situation but let's just consider the use of Oxford criteria for such a trial. I think I have no alternative.

If I restricted myself to CCC, 60% of my patients would gain no benefit from the trial. Why should I do this? As far as I can see only because I might think this 60% were just boring people with depression or false beliefs about having ME or being fatigued or just lazy, not worth doing research for. But the whole point of PR seems to be to discourage doctors from thinking like that. So I have to assume that nobody on PR would condone using CCC here. And if people who think they have ME start saying that all those other people are just depressed or lazy or have false beliefs but cannot prove they are any different it might look like throwing stones from a glasshouse.

In the event the PACE trial is useless as a demonstration that therapies work because of problems of bias from start to finish. Presumably, anyone with PEM is likely not to have volunteered because they would not want to get allocated to GET. So maybe the entry criteria should have been Oxford positive and CCC/PEM negative but that still does not make Oxford irrelevant. And in fact PACE is probably rather useful in showing that even using Oxford criteria CBT and GET achieve nothing of human significance. I realise that for PWME it seems that this message has not been heard but I talk to lots of researchers who take precisely this message from PACE. The useful work goes on in the shadows very often - by people who do not publish until they have made a quantum step forward.

I do think that the suggestion that Oxford criteria are retired as criteria of ME is useful. But that does not mean the criteria are invalid or should be retired for clinical use. They identify a group and there may be times when that group will need identifying. They are human beings. This is where Emerson's phrase is so important. Consistency is the enemy. Flexibility is everything.

Sasha and others might think that I might be back peddling on welcoming Oxford retirement but in terms of feedback to P2P I would be very upbeat about retiring this as a set of criteria for ME. There needs to be an agreement that PEM is worth treating as a clue to a more specific mechanism. For research PEM would be mandatory for studies related to this idea. For treating real people PEM would not be mandatory because like everything else there may be exceptions.

 

[A.B.]

And in fact PACE is probably rather useful in showing that even using Oxford criteria CBT and GET achieve nothing of human significance. I realise that for PWME it seems that this message has not been heard but I talk to lots of researchers who take precisely this message from PACE. The useful work goes on in the shadows very often - by people who do not publish until they have made a quantum step forward.

It does feel like the world is oblivious to the PACE demonstrating the opposite of what it claims to demonstrate. Are researchers afraid of publicly calling the PACE trial flawed, misleading or dare I say a fraud?

 

[Sasha]

Let us assume I am an academic physician, or perhaps psychiatrist, referred large number of patients with fatigue of whom nearly all fit Oxford criteria but only 40% have PEM and fit CCC.[...]What am I duty bound to do as my contribution to research? I think probably I am bound to try to set up a trial of CBT and GET using Oxford criteria.[...]

If I restricted myself to CCC, 60% of my patients would gain no benefit from the trial. Why should I do this? As far as I can see only because I might think this 60% were just boring people with depression or false beliefs about having ME or being fatigued or just lazy, not worth doing research for.

I don't think that you would be morally obliged to set up a trial for all your Oxford patients. Oxford is essentially chronic and severe fatigue with the odd knob on. PEM is something very unusual and has been known for decades as an ME symptom. Just because patients are very tired, it doesn't mean that they have much in common with people with a PEM-causing disease. If you had a clinic full of the chronically fatigued and 40% of them had cancer, surely you'd separate the cancer ones out and run separate trials?

I wouldn't accuse these poor 60% of patients of being deluded - I'd assume they had something organically wrong and that they too had had the misfortune of being thrown in the Oxford binbag. Fatigue is such a common symptom that it just doesn't seem to make sense to throw everyone in together in the same trial, especially when money is scarce. A trial restricted to your PEM patients, who you can be fairly sure have the same PEM-producing disease, is going to cost 40% of what a trial on all your patients would cost. There are probably things that would allow you to subgroup the remaining 60% into useful groups and each group deserves an adequately-powered trial. You might find six groups among them so you're looking at six lots of 10%. If they all get lumped into the big trial, things will be statistically underpowered for their subgroups.

This seems to me like saying, 'Fatigue in MS and ME and cancer and RA might all benefit from Intervention X. Let's do a big trial of all of them together.' It seems more sensible to me to do separate trials.

What am I missing?

Sasha and others might think that I might be back peddling on welcoming Oxford retirement but in terms of feedback to P2P I would be very upbeat about retiring this as a set of criteria for ME. There needs to be an agreement that PEM is worth treating as a clue to a more specific mechanism. For research PEM would be mandatory for studies related to this idea. For treating real people PEM would not be mandatory because like everything else there may be exceptions.

I never said a word! But it's helpful to know your view on this in relation to P2P.

 

[Sasha]

I've just reread the report looking for a statement about funding. All I can find are suggestions about piggybacking onto existing infrastructure for efficiency. I'm surprised not to see a flat-out call for more funding. Bit of a shocker.

 

[Bob]

OK, I've flicked through the suggestions that have been made re the cost-to-society papers, and I'm going to attempt to summarise the details below...

The best papers for us to cite are the following two...



The Economic impact of ME/CFS: Individual and societal costs.
Jason LA, Benton MC, Valentine L, Johnson A, Torres-Harding S.
2008
Dyn Med. 7:6.
http://www.dynamic-med.com/content/7/1/6

Jason et al. (2008) place a cost-to-society value of roughly between $19b to $24b.

"...the direct and indirect cost of ME/CFS to society was estimated to be $18,677,912,000 for the community sample and $23,972,300,000 for the tertiary sample"

@catly helpfully summarised it:

To summarize, the paper estimates the economic cost to be 19-24 billion per year, in the US based on an estimated 800K people with the disease, published in 2008 and including direct ( doctors visits, hospital, medical testing and medications) and indirect (lost productivity, disablity, inablity to perform duties at home e.g.) costs.

Since that was published in 2008 on data from the 1990's I think it would be safe to assume these costs would be higher now--unless the incidence and prevelance of MECFS has declined since then. (Not hoping to open the can of worms on that one).

The economic impact of chronic fatigue syndrome in Georgia: direct and indirect costs
Lin JM, Resch SC, Brimmer DJ, Johnson A, Kennedy S, Burstein N, Simon CJ.
2011
Cost Eff Resour Alloc. 9:1
http://www.resource-allocation.com/content/9/1/1

The other study, by Lin et al. (2011), is a CDC study. They place a cost-to-society value of roughly $51 billion.

The paper says:
"This study is a first step in using cost-effectiveness analyses to identify the economic impact of CFS and may assist in future research by directing policy in research and education. For example, extrapolating our data to the U.S. population ages 18-59, CFS could account for as much as (or as little as) $14 billion in healthcare expenditures and $37 billion in lost productivity. However, this estimate should be interpreted with caution given that our data stem from a population-based study in Georgia. A previous CFS study11 in Wichita, Kansas estimated a national economic burden of $9.1 billion per year in productivity; about 3-fold less than the current study."

Note that @Sasha says that this paper is problematic, because it estimates that 4 million people in the US have CFS, probably based on some dodgy broad criteria, such as Reeves:

The CDC paper is problematic because it gives an estimated 4 million PWCFS in the US ... - I think it must have been Reeves CFS or something.

@Hope123 helpfully summarised, as follows (I've modified it slightly):

Another source of economic impact is this CDC article about direct (e.g. medical care) and indirect costs (e.g. lost productivity, taxes, etc.) in Georgia. In the conclusions, they take the numbers from Georgia, extrapolate it to the entire US, and come up with $54 $51 [Bob's correction] billion a year.

"Georgia has roughly 5.5 million people [24] age 18-59, if the similar patterns prevail CFS could account for $452 million in healthcare expenditures and $1.2 billion of lost productivity for the state."

"For example, extrapolating our data to the U.S. population ages 18-59, CFS could account for as much as (or as little as) $14 billion in healthcare expenditures and $37 billion in lost productivity."

Anyone, please copy and paste any of my text for your own purposes.

 

[Sasha]

Actually, @Jonathan Edwards, one issue that I have with Oxford is that I'm concerned that many non-CCC Oxford patients have been on the receiving end of a premature failure to diagnose. NICE advises against all sorts of tests for PWME. I'm concerned that they have something treatable but undiscovered and that's another reason why I don't think (for their sake) that they should be bundled with us into trials. If they have Oxford CFS but not ME they're being treated like the bits of pastry left over when someone has gone over with the cookie-cutter and I don't think it's fair on them.

I know that some patients may just be baffling but I don't know that you can generalise from one baffling patient to another (that is from a trial of baffling patients to baffling patients in the clinic) when all that connects them is severe fatigue.

You've commented before on how the NHS ought to ditch GPs and just have specialists and I find that persuasive. But Oxford patients are being diagnosed by GPs and then by a random specialist. Presumably an infectious diseases consultant might miss a diagnosis that an endocrinologist might make? I wonder if these are just often patients who were unlucky enough to see the wrong specialist.

 

[Sasha]

OK, I've flicked through the suggestions that have been made re the cost-to-society papers, and I'm going to attempt to summarise the details below...

The best papers for us to cite are the following two...

@Bob, I thought I was doing that one! I posted my summary here:

http://forums.phoenixrising.me/inde...draft-report-is-out.34480/page-19#post-538266

I've used that Jason paper and as I mentioned, the other is problematic.

Have we ended up at cross-purposes? Sorry if I have been confusing somewhere!

 

[user9876]

And in fact PACE is probably rather useful in showing that even using Oxford criteria CBT and GET achieve nothing of human significance. I realise that for PWME it seems that this message has not been heard but I talk to lots of researchers who take precisely this message from PACE.

I think several of us believe that the PACE results were very poor for CBT and GET but they rewrote the protocol at the end of the trial and have been refusing to release results that would allow us to properly understand what was happening. The way I would describe PACE was they took a group of patients and asked them how ill they were, told half of them if they ignored their symptoms they would get better and half that managing their illness better may help. They then re-asked patients how ill they were and the half told that they will get better if they ignored their symptoms answered a couple of questions in questionnaires i a slightly more positive way.

I tend to think the criteria used were almost irrelevant to the result apart from the Oxford criteria allow more co-existing mental health issues.

Its good to hear a lot of researchers take the PACE results as a lack of success. The worrying thing for patients is White gives talks pushing PACE as a success with a message that people with CFS should push themselves to improve.

There needs to be an agreement that PEM is worth treating as a clue to a more specific mechanism. For research PEM would be mandatory for studies related to this idea. For treating real people PEM would not be mandatory because like everything else there may be exceptions.

Would it be worth having a study comparing groups with and without PEM? At times I worry that PWME without PEM may be less severe and it takes more to trigger the PEM or that some people with poor memory are just not as observant (like my child!).

 

[Sasha]

At times I worry that PWME without PEM may be less severe and it takes more to trigger the PEM or that some people with poor memory are just not as observant (like my child!).

Good point - I had been very ill (bedbound) for a number of years before my late father pointed out that I was worse the day or two after activity than on the day itself. I hadn't noticed - and then read some years later that other patients were finding the same thing.

 

[Valentijn]

My comments were only on points 3 & 4. I took the kill-PACE approach.

 

[Bob]

@Bob, I thought I was doing that one! I posted my summary here:

http://forums.phoenixrising.me/inde...draft-report-is-out.34480/page-19#post-538266

I've used that Jason paper and as I mentioned, the other is problematic.

Have we ended up at cross-purposes? Sorry if I have been confusing somewhere!

I didn't say that I wasn't going to comment on any other aspects of the paper... I just said that my main focus would be on CBT etc.
But apart from that, no, we're not a cross-purposes... I had been flicking through the papers that were posted, and just thought I'd post my summary for anyone to use...

Why is the CDC paper is problematic? Is it because of the cohort?

 

[Sasha]

I didn't say that I wasn't going to comment on any other aspects of the paper... I just said that my main focus would be on CBT etc.
But apart from that, no, we're not a cross-purposes... I had been flicking through the papers that were posted, and just thought I'd post my summary for anyone to use...

Why is the CDC paper is problematic? Is it because of the cohort?

OK - glad I didn't mislead you!

The CDC paper is problematic because it gives an estimated 4 million PWCFS in the US, which is clearly nuts - I think it must have been Reeves CFS or something.

 

[Valentijn]

Does anyone know of research that compares the disability profile of ME to MS? E.g., % bedbound/housebound?

I'm looking at reasons to argue for funding parity.

www.amjmed.com/article/S0002-9343(96)00174-X/pdf (free full text pdf)

It's using the SF-36, and the biggest difference between ME and MS is on Role-Physical and Bodily Pain. It also shows some clear differences between a depression group and ME on emotional scales. Other comparison groups are general population, hypertension, congestive heart failure, Type II Diabetes, and acute myocardial infarction (heart attack) patients.

 

[Valentijn]

I've just reread the report looking for a statement about funding. All I can find are suggestions about piggybacking onto existing infrastructure for efficiency. I'm surprised not to see a flat-out call for more funding. Bit of a shocker.

One of the presenters was suggesting that all of our current funding should go into his MAPP (or whatever) project when someone asked him how it would be funded. It was pretty ridiculous.

 

[worldbackwards]

It does feel like the world is oblivious to the PACE demonstrating the opposite of what it claims to demonstrate. Are researchers afraid of publicly calling the PACE trial flawed, misleading or dare I say a fraud?

I remember Lady Mar bringing up PACE in the Lords and being patronised by pillar of the medical establishment Robert Winston, who referred to it thus:

I commend this study. It is an example of really excellent research done in a very difficult phenotype and done very well indeed. The authors are to be congratulated on demonstrating clearly that cognitive behavioural therapy and, to a certain extent, some exercise in addition, is a real improvement on what has happened for these patients before.

http://www.meassociation.org.uk/201...-verbatim-report-and-youtube-6-february-2013/
Winston doesn't sound afraid, he sounds deluded. He also sounds like he's completely ignored what he's just been told, on the basis of who's said it, whilst being far more interested in his "colleagues" being "vilified".

I think ultimately this is the problem - we're automatically wrong because we're the patients. They are automatically right, because they're the doctors, establishment doctors at that. Our objections are not investigated, they simply aren't heard. After all, as Winston says:

these vague conditions appear almost certainly to have a psychiatric basis

Or: who'd believe a bunch of loonies?

 

[Jonathan Edwards]

It does feel like the world is oblivious to the PACE demonstrating the opposite of what it claims to demonstrate. Are researchers afraid of publicly calling the PACE trial flawed, misleading or dare I say a fraud?

Researchers stick to doing what they need to do and in general do not criticise. Bad science fades out rather than being revealed as bad. That is a pity, since it can take a long time, but it is the tradition.

 

[Jonathan Edwards]

I don't think that you would be morally obliged to set up a trial for all your Oxford patients. Oxford is essentially chronic and severe fatigue with the odd knob on. PEM is something very unusual and has been known for decades as an ME symptom. Just because patients are very tired, it doesn't mean that they have much in common with people with a PEM-causing disease. If you had a clinic full of the chronically fatigued and 40% of them had cancer, surely you'd separate the cancer ones out and run separate trials?

But, as you say later, these 60% deserve a trial just as much. If 60% had ME and 40% cancer which would you go for? Why would people with ME have more right to a trial than people with nonCCC Oxford fatigue?

A trial of just the 40% ME would not be cheaper because the power calculation on the number needed to recruit would be similar. And binbags are often very useful in medicine. A 'joint pain' binbag is fine for testing analgesics. A 'very short of breath' binbag can be good for studying the need for home oxygen. There is no point in sorting asthma from emphysema. If most of your patients do not have PEM then there is no a priori reason to study them alone. I agree that trying out GET on people with PEM seems a poor idea and I have never understood what CBT really is but I can see there being situations where Oxford categorisation is entirely reasonable.

The basic point for me is that PACE is bad for other reasons. It should not be used as a reason to bin the Oxford criteria as a clinical grouping for chronic fatigue. So the suggestion that research has been held up by bad criteria does not work for me. Research has been slow for other reasons as far as I can see.

 

[Ember]

Neuroimmune exhaustion implies that there is something neuroimmune about the exhaustion and the only thing that would make sense is what the definition says - that it the underlying mechanism or cause that is neuroimmune.

Contrary to your interpretation, the definition says: “The cardinal feature [PENE] is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions.”