Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of PACE trial

[user9876]

Thanks for all of that, user.


Yes, it seems that they have included baseline variable in the analysis, but I don't understand to what purpose they did this.
Partly because I can't see that they've published any results based on different baseline variables.
And I can't see any discussion in relation to which baseline variables had an influence on results, or no influence.

Have you noticed any such results or discussion?

I think the idea is to mitigate any effects of poor randomization leading to groups with a biased randomization group.

 

[Bob]

I think the idea is to mitigate any effects of poor randomization leading to groups with a biased randomization group.

Ah, i see. Yes, that makes sense. Thank you.

 

[anciendaze]

I will have to confess I've stopped trying to read the tea leaves in publications by this bunch to extract useful information. I am still bothered by apparent internal contradictions in arguments presented by the authors. Perhaps those who are still in the trenches of this war can answer one question.

Have any of the people involved yet noticed that PACE totally failed to support the theory that CFS patients primary physical problem is deconditioning? If a year of GET failed to produce any change in actual condition, and merely changed attitudes, either those attitudes remained crippling -- even after touted therapies like CBT -- or physical deconditioning was not the most significant factor at all. Together these implicit admissions amount to total failure of the most favored therapies to produce any significant change in illness.

Simply changing attitudes via CBT produced no change in performance. Claimed changes in performance due to GET were not validated as improvements in physical condition by the step test.

Even if I were to charitably assume that every patient involved in the PACE trial could have benefited as much as those in the best groups, it appears that you get about 8 meters improvement on the walk test in a group of 641 for every one million pounds input. To bring them up by the 200+ meters needed to match performance of the general population would take about 25 million pounds, even with highly optimistic assumptions. Applying this to the entire ME/CFS community would break various national budgets.

I think this demonstrates that this group never had any real intention of actually returning patients to healthy performance, unless you count wishful thinking. As psychiatrists I don't doubt they have had a great deal of experience helping patients adapt to conditions of permanent inferiority which no known treatment is able to cure. This should not be extended to physical illnesses.

 

[Bob]

Have any of the people involved yet noticed that PACE totally failed to support the theory that CFS patients primary physical problem is deconditioning?

They might have noticed but they certainly haven't made a public confession. As you say, this latest paper debunks the deconditioning hypothesis, and it admits as much in the discussion, but still no mea-culpa from the authors, of course.

Extract:

We found that fitness […] did not appear to mediate treatment effects […]. This suggests that increasing tolerance of physical activity might produce benefit without improving physical fitness.

 

[anciendaze]

As I understand this it means "benefit" is not connected with any objective measure, a peculiar idea for a scientific paper. Perhaps they are talking about benefits enjoyed by the authors, not patients.

 

[lansbergen]

Perhaps they are talking about benefits enjoyed by the authors, not patients.

 

[cfsStevew]

I don't know if I will explain it well, seeing as I'm only just getting to grips with it, but here goes...
If the changes in the mediating outcomes (e.g. fear) happened simultaneously to the main trial outcomes (self-report fatigue and physical function), then the investigators haven't demonstrated that one led to the other, but they are just making an assumption that a reduction in fear has led to an improvement in the primary outcomes. But if the changes happened simultaneously, then it could have been the other way around; an improvement in fatigue and physical function could have mediated a reduction in fear (which makes more sense to me.) Or there might not be any direct relationship. In relation to this, they say: "it is possible that the variables were affecting each other reciprocally", which is code for "we really haven't got a clue, and we just made it up".

It's all a load of nonsense, of course, seeing as all they've proven is that CBT and GET are equivalent to homoeopathy or a placebo, with no improvements seen in any objective measures.

Thanks Bob - I think I get what you say and it makes sense. It sort of amazes me when the manipulation of data is revealed...I mean - this entire trial STINKS!

I presume they dress it up the way they have for the benefit of their careers?

 

[Sean]

I presume they dress it up the way they have for the benefit of their careers?

I think sheer desperation and blind panic are starting to set in, as the full horror of what they did and the implications for them professionally and personally become undeniable. They can't win this one in the long run, that possibility is long gone. It is now a matter of them trying to delay the inevitable, until retirement at least.

 

[biophile]

Apart from the highly questionable and suspiciously timed dropping of follow up actigraphy (which according to the results of previous trials would have been a null result and further discredited the deconditioning hypothesis), I would guess that their intentions and expectations were relatively optimistic towards the start of the trial. They expected good results and the definition of clinical improvement and recovery were generally much stricter back then compared to what it became.

Since then they have made big changes to the individual-level definitions of clinical improvement and recovery, seemingly well after the trial was already over and after they had already become very familiar with the outcomes data. Even the changing of the primary end point (to continuous scores instead of categorical outcomes), which we were told happened after the collection of data was over but before the unblinding of data, coincided with the FINE Trial failure which used the same or very similar outcomes as PACE originally planned. The PACE Trial was open label so it's not like general impressions about how the trial was going while it was still running were adequately suppressed either.

But the imbalanced politics of ME/CFS are such that, while it is widely acknowledged outside our community that changing protocol after seeing data is an obvious source of potential bias, it is politically incorrect to remotely suggest that the PACE authors, after having largely built their reputations on the success of CBT/GET and with a clear stake in the controversy, could possibly have been influenced by the poor trial results (subconsciously or otherwise) when drastically lowering the thresholds for success. There are not just one or two minor infractions which could have happened by chance, but a long list of questionable changes, poor justifications, published errors, weak dismissals for the lack of objective improvements, spin doctoring, and media hype or misinterpretation: *all* of which just happened to coincide in their favour.

Despite all the spin and posturing, there should be no doubt that the PACE Trial has ironically dealt a massive blow to the cognitive behavioural model of CFS. Even after 80% of ME/CFS candidates were excluded from participation leaving an Oxford criteria cohort, there was only modest self-reported improvements for a small fraction of remaining participants but no relevant objective improvements on average. The results are consistent with the placebo response and response biases in an open label trial which aimed to change participants' perceptions about their illness. The "recovery" criteria was so poor that the results for this outcome can basically be ignored. The "mediators" paper actually admits that the direction of causation is uncertain! If there is anything at all to CBT/GET, they should be finding out what that is, and who it specifically applies to, without subjecting all patients by default to a non-representative model promoted beyond its worth.

 

[Sean]

Yes. With all of the lavish advantages they enjoyed in running this trial, many of them less than legit, all they still managed was a small, clinically meaningless, and methodologically dubious shift in subjective scores, and what real evidence they did produce from the trial points in every direction except the one they claim it does.

The magic of propaganda.

 

[Tom Kindlon]

A BMJ e-letter of mine that was posted on the site today:

Objective measures found a lack of improvement for CBT & GET in the PACE Trial: subjective improvements may simply represent response biases or placebo effects in this non-blinded trial
http://www.bmj.com/content/350/bmj.h227/rr-10

 

[Tom Kindlon]

I thought this BMJ e-letter was very good.

And great to see a new name writing:

http://www.bmj.com/content/350/bmj.h227/rr-7

From: Carolyn E Wilshire
Senior Lecturer
School of Psychology, Victoria University of Wellington, New Zealand PO Box 600 Wellington, New Zealand

Subject: Re: Tackling fears about exercise is important for ME treatment, analysis indicates

 

[cfsStevew]

I thought this BMJ e-letter was very good.

And great to see a new name writing:

http://www.bmj.com/content/350/bmj.h227/rr-7

From: Carolyn E Wilshire
Senior Lecturer
School of Psychology, Victoria University of Wellington, New Zealand PO Box 600 Wellington, New Zealand

Subject: Re: Tackling fears about exercise is important for ME treatment, analysis indicates

wow that really was top notch.

Did the wessely school at some point claim the 'ME activists' were unscientific? It seems to me ironic that people fighting for justice for ME sufferers are using far superior science to dismantle their work. What concerns me is that status, power and connections corrupt good science which has enabled such poor science to thrive and create the damage in the first place....

 

[Gijs]

Chalder and White are quackers. There 'science' is based on ideas, no objectivity, selecty bias and argumentum ad verecundiam There ideas are very welcome for disability companies. It is a scam and a shame for real scientists.

 

[Sean]

What concerns me is that status, power and connections corrupt good science which has enabled such poor science to thrive and create the damage in the first place....

Quite shocking, isn't it, that such obviously poor quality science has been allowed to become so influential and immune to legit criticism.

 

[Bob]

Just spotted this:
"We did not find evidence of differing b paths (relations between the mediators and outcomes) by treatment group, but we might have had limited power to test for these interactions."

Not sure of its significance yet.

 

[Esther12]

I find this quite an odd/revealing finding. They looked at all sorts of measures incl. 5 subscales on the participants' beliefs. You'd expect the physical fitness result would be one of the best if not the best mediator.

It suggests to me it's quite likely what people are reporting as their physical functioning in the SF-36 PF questionnaire is influenced by other factors along with their actual level of physical functioning.

Yeah - it does seem to highlight that the SF36-PF does not measure patient's physical function, but their cognitions about their physical functioning.

From the abstract of the PACE Trial protocol: http://www.biomedcentral.com/1471-2377/7/6


There was no sign of the sample being split in two.

It's not 100% clear from the text whether the random split was just for predictors (baseline variables) or also process variables.

I guess that following their protocol and splitting their sample have meant that they'd have found it harder to reach statistical significance? As their initial reports on mediators all indicated that they didn't come up with much, I doubt that they'd have been keen on that.

It would be good to have more information on how they did their initial analyses, and then sexed it up for this paper.

This description of GET sounds a lot less insane and nothing like what early GET programmes were like in the 1990s. Those programmes were regimented and were truly based on the belief (of psychiatrists) that symptom exacerbations didn't matter since they did not reflect underlying damage so the activity was supposed to be increased on a schedule regardless of symptoms. Needless to say that kind of GET had excellent efficacy at turning mild patients into housebound/bedridden ones. Nice move to completely change the nature of the therapy and still call it the same thing.

PACE was much more rigorous than most GET trials at measuring harms. I wonder if that led to a more careful approach?

Some notes.

CBTvsAPT and GETvsAPT - valid comparison?
APT, was a previously untested novel therapy designed especially for the PACE trial, which caused a reduction in physical function (but not fatigue) when compared with SMC-alone. i.e. it had a negative effect for physical function when compared with the SMC control group.
So, considering that APT impaired improvements, a comparison with CBT or GET will place CBT/GET in a favourable light.
As an extreme example, it's a bit like giving patients arsenic, and then declaring that CBT/GET were successful because the outcomes were better!
So APT was an active intervention, and not a placebo control, and shouldn't be used as a control against which to compare CBT or GET.
A comparison with APT doesn't indicate the benefits of CBT or GET, but it illustrates the harm associated with their novel therapy, APT.

Emphasising the APT comparison seems dodgy to me too.

 

[Dolphin]

PACE was much more rigorous than most GET trials at measuring harms. I wonder if that led to a more careful approach?

Yes, I think so. I came across one person in the GET arm who was told by her physio she could count house work as her exercise. This is against what is supposed to be done where people are supposed to exercise at a certain intensity: housework would have lots of intensities, would be stop-start, etc.

 

[Dolphin]

Lancet Psychiatry tweeted https://twitter.com/TheLancetPsych/status/555344559035908096:

Happy to receive 500w/5 reference letters on this at

Note the 5 references part which are not in their guidelines.

I had a look at the correspondence section. They publish more letters than a lot of journals: 30 in 8 issues (I didn't count the first edition as there was nothing to reply to) (the 30 do include letters from the authors replying to letters).

I had a look and most are 5 references or fewer (there were quite a lot at 5 which makes me think 5 is what authors are encouraged to aim for).

There were a few with over 5 references:
6: http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)70296-2/fulltext

6: http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)70352-9/fulltext

6: http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00007-8/fulltext

6 (2 of refs were letters replying to): http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00067-4/fulltext - authors' reply

7: http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00064-9/fulltext

6: http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00066-2/fulltext

As most people here don't have fancy academic titles, I'd aim for letters with 5 or fewer references.

I do know one person who has submitted a letter and it has been accepted.

 

[Dolphin]

(I also posted this on another thread)
(This may have been discussed before)

Whilst some correspondents have complained that the primary outcomes of the trial were self-rated, we argue that these are the most appropriate measures to judge improvement in an illness that is currently defined by symptoms.

Note that the Mediators paper revolved about two outcome measures: a fatigue scale (the chalder fatigue questionnaire) and a questionnaire that asks about physical functioning (the SF-36 physical functioning subscale).

The point they raise about symptoms only applies to one (fatigue). It doesn't explain why a subjective measure of physical functioning would be better than a more objective one.