CORRESPONDENCE The PACE trial of treatments for chronic fatigue syndrome: a response to WILSHIRE et al (2019) Sharpe, Goldsmith & Chalder

[rvallee]

The question should be asked further and aiming to justify the £5M price tag. There is no reasonable justification for the price tag other than creating sunk cost momentum. It's no more sophisticated or developed than the SMILE trial with its LP BS or the 3-needle acupuncture trial we saw recently.

The cost justifications are over specialist training and weekly therapy sessions, which is labor intensive. But that's just describing what was done, not a proper justification. There is no reason why PACE couldn't have been done for 1/10th the price tag, there is no specialist knowledge involved or innovative techniques. It was big for the sake of being big, not because anything they did warranted it. There is no costly equipment or process, the training is dubious at best and they even recognize it can't be scaled to a large population, meaning it's all for show.

The only reason PACE stands is precisely because of the price tag. It justifies itself by having been so costly. The 4-day intensive thing that was done (in Norway?) was no more or less advanced or technical or any of that. This is no different than slapping a $40 price tag on a $.2 chocolate with fancy $1 decorations and getting people impressed because it's so luxurious. No one who paid $40 for that would comment it tasted like $.2 chocolate, even though that's exactly what it is.

 

[Jonathan Edwards]

I don't see what the authors could have done to make it fair. The right thing would have been not to do this sort of trial, or use objective outcomes measures.

The comparison of CBT and GET was a good thing to do. Unfortunately, there was not much difference between the two so no conclusion about efficacy or otherwise of either can be drawn. If one had been much better than the other it would have been a useful result. As it is the default assumption is that 'modality does not matter'. Or in other words there is no special skill needed in persuading people to fill in forms more positively.

 

[Dolphin]

While also admitting that they do not know what recovery means or how to define it. But this changes nothing to their assertions that participants met a "strict criterion" for recovery.

Did they use this term? I know Bleijenberg and Knoop did in a Lancet editorial in 2011.

 

[Jonathan Edwards]

You would understand reviewer code better than I would, but I read that differently. I read it as an endorsement of the discussion, that he is saying the debate about the trial is providing a necessary and interesting review of the PACE papers and there's really no need for him to say anything more.

You might be right but if I was reviewing I would not raise all this fluff about not giving an opinion. If the referee thought the letter was cogent all he has to say is that it is a well written reply, or maybe point out some language issues.

 

[rvallee]

For posterity's sake:

Sharpe was one of the people responsible for creating CFS as a replacement for ME. He invented the Oxford criteria that underlie his idea of a syndrome of chronic fatigue (read that again: a syndrome, by definition a presentation of multiple symptoms, made-up and focused entirely on one symptom that isn't even a main symptom of the disease he equates with chronic fatigue).

Sharpe published several papers arguing they are the same and that ultimately they are the same as neurasthenia or somatisation. His like-minded colleagues did as well.

Sharpe repeated this claim in several newspaper articles that covered PACE and his work in general. The media's confusion is entirely his and come from his own words, not taken out of context.

Authorities officially use CFS because of Sharpe's work promoting his (and colleagues') idea of a replacement for ME that reduces it to chronic fatigue, for which he invented the made-up diagnosis of CFS.

And while we're here, Sharpe is not a "top researcher" in the field and especially not "one of a few". His ideas still have no objective evidence and are a fringe and otherwise inconsequential oddity in the overall field of medical research on ME.

Sharpe deserves all the criticism he gets for these and many more reasons. His work has all the academic substance and real-world value of an inkblot.

 

[dave30th]

You would understand reviewer code better than I would, but I read that differently. I read it as an endorsement of the discussion, that he is saying the debate about the trial is providing a necessary and interesting review of the PACE papers and there's really no need for him to say anything more.

I also read it this way.

 

[rvallee]

"[Use of CBT/GET] they imply that CFS or ME is psychiatric or psychological in nature"

I know others have pointed out the many reasons why this is not the argument, but while doing a transcript of Trudie Chalders recent lecture (long way off finished), right at the beginning she says



as opposed to 'based on the idea' that it is a psychological one?

(nothing we didn't know already I know but again shows how they twist things to obscure the truth).

Back in the summer of '89.....The mainstay of treatment was rest and it was based on the idea that the illness was a physical one.

I mean... how do you even go from there? Rest is as much a treatment of ME as avoiding an allergen is a treatment for allergies. It's not, it's simply avoiding conditions that make them worse. No patient has ever labeled rest or pacing as treatment. It's rest, which is something sick people naturally do, like when they have the flu.

They've been at it for decades and still talk all sorts of nonsense about the most basic things. And they dare call themselves "top researchers". What hubris.

 

[dave30th]

Did they use this term? I know Bleijenberg and Knoop did in a Lancet editorial in 2011.

I haven't seen the PACE authors use it. Except they read the editorial before publication so they essentially endorsed the language.

 

[rvallee]

Did they use this term? I know Bleijenberg and Knoop did in a Lancet editorial in 2011.

I think I remember Sharpe saying so. Looking. It seems to have been in the registered protocol (and I don't think it was removed) but omitted from the papers and that would be why Knoop and his colleague used that term. So basically they sold a strict criterion when registering protocol and just quietly dropped it when they could not meet it.

There's an article from Tuller on the topic: http://www.virology.ws/2015/11/04/t...really-adopt-a-strict-criterion-for-recovery/.

Compounding the confusion, the Press Complaints Commission decision noted that the Lancet comment had been discussed with the PACE investigators prior to publication. Since the phrase “strict criterion for recovery” had thus apparently been vetted by the PACE team itself, it remained unclear why the commission determined that Bleijenberg and Knoop were only expressing their own opinion.

 

[Barry]

I do think there is a huge statistical naivety around the use of the mean and SD with the sf36 as I see no way that the scores would be equidistant on a definition of physical function. I do think this is an important issue and one that needs to be aired as it seems such a common issue in so much research.

I suspect that even if you tried to plot the SF36 PF scores against perceived PF, there would probably be some pretty horrible looking non-linearity. And if you tried to plot perceived PF against true PF, that also would be a pretty quirky characteristic I imagine. So any attempt to plot SF36 PF against true PF would, I think, be horribly non-linear. The likelihood of stats on SF36 PF scores having much useful meaning regards true PF is pretty remote I think.

But you are right in terms of the biggest issue being that the outcome measures are not robust as for example sf36 is a measure of perception of physical function not physical function itself therefore you can't test if function or perception has changed and interventions are aimed at changing perception hence the experiment is not worth doing.

Absolutely. Although the Lancet never published a letter I wrote regarding this relating to GETSET, I did make it available in S4ME after it was rejected, https://www.s4me.info/threads/my-letter-to-the-lancet-in-response-to-the-getset-publication.1528/. (I realised later I should probably have used the word 'imply' rather than 'infer' in it, but never mind).

 

[Lucibee]

Here's the extract from the Bleijenberg and Knoop editorial (Lancet 2011):

Graded exercise therapy and cognitive behavioural therapy might assume that recovery from chronic fatigue syndrome is possible, but have patients recovered after treatment? The answer depends on one’s definition of recovery.3 PACE used a strict criterion for recovery: a score on both fatigue and physical function within the range of the mean plus (or minus) one standard deviation of a healthy person’s score. In accordance with this criterion, the recovery rate of cognitive behavioural and graded exercise therapy was about 30%—although not very high, the rate is significantly higher than that with both other interventions.

3 Knoop H, Bleijenberg G, Gielissen MFM, van der Meer JWM, White PD.
Is a full recovery possible after cognitive behavioural therapy for chronic fatigue syndrome? Psychother Psychosom 2007; 76: 171–76.

Interestingly, this is the only paper I can find on which White collaborated with Knoop and Bleijenberg.

Given that recovery was not mentioned in the PACE trial paper published in The Lancet in 2011, I think I'm probably correct on my hunch that either Knoop or Bleijenberg were the most likely peer reviewers of PACE. That they had insider knowledge is not a good look.

 

[Dolphin]

Here's the extract from the Bleijenberg and Knoop editorial (Lancet 2011):



Interestingly, this is the only paper I can find on which White collaborated with Knoop and Bleijenberg.

Given that recovery was not mentioned in the PACE trial paper published in The Lancet in 2011, I think I'm probably correct on my hunch that either Knoop or Bleijenberg were the most likely peer reviewers of PACE. That they had insider knowledge is not a good look.

Yes, I read before that reviewers often then write editorials accompanying articles.
And particularly in this case where the peer review of the paper was fast-tracked, non-reviewers would have had little time to be asked to look over the paper and then write a review of it.

It's also interesting as the authors claimed it was a reviewer who suggested the normal range analysis.

 

[Lucibee]

It's also interesting as the authors claimed it was a reviewer who suggested the normal range analysis.

Really? Where did they say that?

 

[Barry]

I'm not sure that anything is valid for the CFQ tbh!

I think there's a lot of truth in that. In engineering if you have something with a non-linear characteristic, you will typically deal with the non-linearity before trying to do anything else with it. e.g. A thermocouple, which provides changing voltage (albeit very small) with changing temperature, but the plot of T against V is very non-linear. So having read in the voltage it then needs to be "linearised" to arrive at the temperature. But thermocouple characteristics are (mostly) pretty sane, whereas the CFQ I think is pretty insane.

 

[Dolphin]

Really? Where did they say that?

Normal ranges - The primary analysis compared the mean differences in the primary outcome scores across treatment arms, which are in the paper. The normal range analysis was plainly stated as post hoc, given in response to a reviewer’s request. We give the results of the proportions with both primary outcomes within normal ranges, described a priori, using population derived anchors.

 

[rvallee]

Really? Where did they say that?

I seem to remember Ellen Goudsmit mentioning it was her recommendation but I don't remember anyone saying more about it. I found that odd but no one really picked it up so I ignored it but that's weird.

IIRC it was as a comment to Hilda Bastian's PLOS blog post or something like that.

Found it. Don't know if it's really her but this is the comment on Bastian's post (bold mine):

Many fair points but also some b…t. AFME’s description of pacing is a nice way of describing GET. It’s not pacing as promoted by all other groups. And are they suggesting one can recover from ME? Perhaps only 6%. As for the change of scoring the Chalder Fatigue Score, I was partly responsible for that. It was good science to change to the Likert method. Nothing odd at all.

Perhaps one day soon, people will venture outside of group think and check that what they write is accurate. AFME supported the PACE trial and are hopeless when it comes to pacing. Which is sad as I helped them in the early days.

The criticisms re the PACE trial began in 2004. Kindlon and others came much later.

As a referee, I’ve seen the ‘son of PACE’. You have some time to recheck info and not blame White and colleagues for following evidence-based advice from two scientists\patients.

 

[Dolphin]

There was a “booster” session at 36 weeks so the gap to outcomes at 52 weeks is less than the 6 months gap they claim.

 

[Graham]

Once again, a collection of generalized statements and a repeat that "the big boys told us we could do it sir!"

I have yet to see a proper explanation of how scores of 65 or less on the sf-36 at the start of the trial selected those patients diagnosed with CFS who were more badly affected, but scores of 60 or more contributed towards a definition of recovery. Even worse, a score of 70 would override any doctor's diagnosis that the patient still had CFS, despite the fact that, at the start of the trial, there were many patients diagnosed with CFS whose scores were 70 or more (these were excluded from the trial).

Remember, initially they were going to take folk with scores of 60 or less, but upped it to 65 to increase numbers.

 

[Lucibee]

@Dolphin - the normal range analysis they are referring to there is about improvement, not recovery. [ETA - sorry - yes, that was recovery - wow! - so he even forgot he was an author on that paper by Bleijenberg and had to be reminded of it - oops!]

@rvallee - I think Ellen made comments on the Protocol?

 

[Trish]

I don't usually bother with Sharpe on Twitter any more. I decided to have another go.