Trial by Error, Continued: More on Graded Exercise from Peter White and The Lancet

By David Tuller, DrPH

[June 30, 2017: This post has been corrected and revised.]

Professor Peter White and colleagues have published yet another study in The Lancet promoting graded exercise as an appropriate intervention for the illness they refer to as “chronic fatigue syndrome” but that is more appropriately called “myalgic encephalomyelitis.” (Two compromise terms, ME/CFS and CFS/ME, satisfy no one.) This new article exhibits the range of problems found repeatedly in this body of research, including the reliance on subjective outcomes for an open-label trial, unusual outcome-switching, and self-serving presentations of data.

In short, this latest study seeks to bolster the crumbling evidence base for the PACE/CBT/GET paradigm by reporting modest benefits for graded exercise. But as with previous research espousing this approach, even the unimpressive results reported here cannot be taken seriously by scientists who understand basic research standards.

The full name of the article is: “Guided graded exercise self-help plus specialist medical care vs. specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial.” It involved 211 patients, split into two groups. Both groups received at least one meeting with a doctor—what the study called “specialist medical care.” The intervention group also received up to 90 minutes of instruction from a physiotherapist on how to pursue a self-guided graded exercise program.

The results presented are short-term–12 weeks after trial entry. The investigators reported very modest benefits for the intervention in scores for self-reported fatigue and non-clinically significant improvements in scores for self-reported physical function. There has already been some terrific analysis of the study’s shortcomings on patient forums, so I’m just going to make a few points here.

The study design itself incorporates a huge and fundamental flaw: The unreliable combination of an open-label study with subjective outcomes. Experts outside the influence of Sir Simon Wessely, most notably Jonathan Edwards, an emeritus professor of medicine from University College London, have repeatedly highlighted this feature as rendering the findings meaningless. As Professor Edwards wrote recently in his commentary for the Journal of Health Psychology, this flaw alone makes the PACE trial “a non-starter in the eyes of any physician or clinical pharmacologist familiar with problems of systemic bias in trial execution.” Studies with this design, he explained, have been abandoned in other fields of medicine.

The difficulty of shielding such trials from systematic bias is the reason that studies are blinded in the first place. It is common sense that if you tell people in one group that the intervention they are getting should help them, and then if you don’t give the intervention to people in another group and do not provide encouragement that they will improve, more people from the first group than the second group are likely to tell you in the short term that they feel a bit better.

It does not mean that they have experienced any objective improvements. It also doesn’t mean that these self-reported benefits of the intervention will be apparent at long-term follow-up. In fact, follow-up studies in this body of research do not provide evidence of long-term differences between study groups.

Unlike in the PACE trial, the investigators chose not to test these subjective findings against objective outcomes. They acknowledge the absence of objective outcomes as a limitation but do not explain why they made the choice to exclude them. Presumably they remembered that PACE’s own objective measures—the six-minute walking test, the step-test for fitness, and whether people got off benefits and back to work—all failed to confirm the trial’s claims of success. In other trials, objective measurements of participants’ movements have also failed to document benefits from the non- interventions tested for the illness.

[Correction/revision: The following three paragraphs replace material included in the original version posted on June 28, 2017]

In this new article, Professor White and his colleagues refer to the GETSET intervention as a “management approach.” The investigators fail to mention that a 2013 paper in Psychological Medicine purported to have proven that people could actually “recover” with GET. They mention patient surveys on reported harms from graded exercise, but they choose to omit the growing peer-reviewed literature on immunological and other dysfunctions of ME/CFS, from leading medical research centers around the world.

They also ignore the major 2015 report from the U.S. Institute of Medicine (now called the Academy of Medicine). This report, which involved an extensive review of the literature, identified “post-exertional malaise” as the cardinal symptom, in the process proposing to rename the illness “systemic exertion intolerance disease.” Other research has also shed light on possible pathophysiological pathways involved in causing the severe relapses that characterize the disease.

If post-exertional malaise or (per the IOM) exertion intolerance is the cardinal symptom, then graded exercise in any form could be contraindicated. Professor White and his colleagues obviously do not have to agree with this interpretation of the recent research and reports. But the failure to mention and discuss these findings in an article investigating a graded exercise intervention demonstrates the investigators’ apparent unwillingness or inability to grapple with the current state of scientific knowledge in the field.

In terms of outcome-switching, the investigators report that they made a confusing (to me) change midway through the trial. Here’s how they explain it:

The original protocol had only one primary outcome measure, the SF-36 PF. However, when some eligible participants were found to have high SF-36 PF scores at randomisation (because of their illness affecting cognitive or social functions but not physical function), we decided to also include fatigue, using the CFQ, as a co-primary outcome. This decision was made mid-way through trial recruitment (on June 20, 2013, after recruitment of 99 [47%] patients), before any outcome data had been examined, and was approved by the Research Ethics Committee, the Data Monitoring and Ethics Committee, and the Trial Steering Committee.

I’m not a statistician or an epidemiologist, but it struck me as unusual that investigators would be allowed to make a change of this magnitude in the middle of a trial. If the specialized treatment centers were following the NICE guidelines and yet diagnosing people having high SF-36 physical function scores, one obvious possible explanation is they could have been misdiagnosing people as having chronic fatigue syndrome even if they were suffering from chronic fatigue for other reasons. In that case, I can understand that adding a fatigue outcome measure might make it easier to demonstrate evidence for improvement. But could this addition be justified from the methodological and statistcal perspective?

For an answer, I turned to Bruce Levin, a professor of biostatistics at Columbia. Since Professor Levin first reviewed the PACE study at my request in 2015, he has been a staunch critic of the trial’s methodological choices and the decision by journals like The Lancet and Psychological Medicine to publish the questionable results. Here’s Professor Levin’s perspective on the choice to add fatigue [July 3, 2017: changed “physical function” to “fatigue”; as previously explained, “physical function” was already the primary outcome] as a co-primary outcome midway through the GETSET trial:

I think the main problem with this follows from the overarching issue of bias in unblinded studies.  Inflation of the type I error rate isn’t a problem because the significance criterion was adjusted to control that.  My concern is what the investigators could have observed and surmised regarding the treatment effect mid-way through the trial, even though they claim not to have looked at any A versus B comparisons.  Even an inkling that the pooled mean physical functioning outcome was too high could suggest a lack of treatment effect.

Obviously they were looking at baseline data in order to notice that “too many” subjects had non-disabled physical functioning.  There should have been no concern about imbalance between the groups in that regard, because they planned to adjust for baseline physical functioning, which would remove any chance imbalance.  [I assume that is the case—I haven’t seen the trial’s SAP.]  No, it seems that (once again) the investigators were second-guessing their own protocol and worrying about having “too little” room for improvement.  If the decision to change the primary endpoint (by adding a co-primary endpoint) was based on what they could see in this unblinded study, that would incur bias.

I find it astonishing that the investigators’ remedy for the perceived problem of “too many” non-disabled subjects was to add a co-primary endpoint.  If one is concerned about low power, the last thing one would ordinarily think of is adding a co-primary endpoint which reduces power, because the adjustment to control type I error makes it less likely to correctly declare statistical significance when the alternative hypothesis is true.

Furthermore, although mid-trial changes in protocol can be implemented without bias in so-called adaptive trial designs, it is important to note that such adaptations are contemplated a priori and built into the design of the study before it begins. This is the so-called “adaptive-by-design” feature.  Other ad hoc or post-hoc adaptations are to be avoided, especially in unblinded studies with self-reported endpoints.

So that’s the blunt assessment from an unimpeachable expert. The statisticians and numbers experts out there will understand the inner details of Professor Levin’s comments much better than me, but the gist is certainly clear. That The Lancet has once again chosen to publish work of this low caliber is sad but predictable, given the journal’s record in this domain. Although the 2011 paper was “fast-tracked” to publication, editor Richard Horton stated in a radio interview not long after the publication of the results that it had undergone “endless rounds” of peer review. He has not explained this apparent contradiction, despite my efforts to extract an answer from him.

This new publication again raises questions about the thoroughness and integrity of The Lancet’s reviewing and editorial processes. And the decision confirms what has been demonstrated repeatedly in this whole saga. Those who have tied their prestige and reputations to the PACE paradigm, like the editors of The Lancet, are willing to make themselves look ridiculous in their misguided and unconvincing efforts to defend this indefensible enterprise.

**********

[June 30, 2017: Explanation for changes]:

In the original version, I quoted the following phrase from the new Lancet article and suggested it represented a change in direction for Professor White and his colleagues: “It is important to note that this trial was not designed to test causative factors in chronic fatigue syndrome, and the relative efficacy of a behavioural intervention does not imply that chronic fatigue syndrome is caused by psychological factors.”

I was wrong. Similar phrasing appeared in the 2011 Lancet article as well as other publications. My mistake was that I forgot to recognize the distinction in the PACE vocabulary between “causative” and “perpetuating” factors of the illness. I have removed the inaccuracy and statements arising from it, and have revised the section to accommodate the correction. For full transparency, I include the original paragraphs below. Of course, I apologize to Professor White and his colleagues for the error.

**********

[Original version}:

In this new article, Professor White appears to be back-pedaling away from a central claim in PACE. GETSET avoids arguing that chronic fatigue syndrome (per the article’s usage) is “reversible” with a graded exercise program. The investigators also fail to mention that a 2013 paper in Psychological Medicine purported to have proven that people could “recover” with GET. Instead, they here refer to the intervention as a “management approach.”

They also insist that any apparent benefit for this management approach would not suggest anything about the cause of the illness. “It is important to note that this trial was not designed to test causative factors in chronic fatigue syndrome, and the relative efficacy of a behavioural intervention does not imply that chronic fatigue syndrome is caused by psychological factors,” they write.

To those who understand the history of this body of research, this statement represents somewhat of a surprising shift. By directly contradicting the description of GET in The Lancet’s 2011 paper, the statement appears to eviscerate the rationale for the graded exercise intervention in the first place. The description in 2011 is very clear. Deconditioning and avoidance of activity are the causes of the continuing symptoms, and the syndrome is “reversible” by addressing these specific problems:

GET was done on the basis of deconditioning and exercise intolerance theories of chronic fatigue syndrome. These theories assume that the syndrome is perpetuated by reversible physiological changes of deconditioning and avoidance of activity. These changes result in the deconditioning being maintained and an increased perception of effort, leading to further inactivity. The aim of treatment was to help the participant gradually return to appropriate physical activities, reverse the deconditioning, and thereby reduce fatigue and disability.

There is no room in this 2011 description of GET for whatever other “causative factors” Professor White now seems to acknowledge could be implicated in the disease. Presumably those possible “causative factors” include ongoing pathological organic processes independent of the “reversible physiological changes” arising from deconditioning. (Professor White has long acknowledged that acute biological illnesses can trigger the onset of chronic fatigue syndrome. This initial illness is then presumed to have launched the downward cycle of deconditioning and fear of activity–the factors seen as responsible for perpetuating the symptoms after the acute illness has been resolved.)

The difficulty for this new study is that GET in PACE is based on the hypothesis that people are experiencing “reversible physiological changes” arising from nothing other than serious deconditioning. Does Professor White still believe in this hypothesis, or not? On the evidence of the current paper, he has disavowed it, without explicitly acknowledging this disavowal.

Since the PACE version of GET was designed to address reversible symptoms occurring in the explicit absence of organic disorders, what is Professor White’s current rationale for recommending a graded exercise approach? And if the underlying rationale for the intervention is no longer the absence of organic disorders, how can PACE itself or the NICE guidelines or Cochrane’s systematic reviews be credibly cited in support of it?

If I interpret the new paper correctly, it appears that Professor White and his team do not believe the PACE hypothesis that deconditioning and avoidance of activity are the sole causes of the perpetuation of the symptoms. They acknowledge that other possible “causative factors” could be involved. Given that change in perspective about the illness itself, I don’t understand the basis on which they are recommending graded exercise. I think they need to provide a new and plausible scientific explanation to support the continued testing of this approach on human subjects diagnosed with this disease.

This is especially so given the wealth of information that has emerged since 2011. The investigators mention patient surveys on reported harms from graded exercise, but they choose to ignore the growing peer-reviewed literature from leading medical research centers around the world. They also ignore the major 2015 report from the U.S. Institute of Medicine (now called the Academy of Medicine), which identified “post-exertional malaise” as the cardinal symptom, in the process renaming it “exertion intolerance.”

If “post-exertional malaise” or “exertion intolerance” is the cardinal symptom, then graded exercise in any form could be contraindicated. Professor White and his colleagues obviously do not have to agree with this reasonable interpretation of the recent research and reports. But the failure to mention and discuss these findings in an article investigating a graded exercise intervention demonstrates the investigators’ apparent unwillingness or inability to grapple with the current state of scientific knowledge in the field.

Comments on this entry are closed.

  • Wendy Boutilier 28 June 2017, 8:13 pm

    The Authors of PACE are something like a Scientology cult. They are trying to position themselves for the funding process. IIME Charity isn’t too impressed abou how this is unfolding so I’m going to post their response. Bear in mind that IiME & Thymes Trust were only given 10 days to respond.

    Invest in ME
    Via: Invest in ME Research

    We do not believe this is quite good enough. So the charity has sent back this reply to NICE –

    “Thank you for the notification.

    However, the two week consultation is only 10 working days and you state that we will be contacted once the consultation has opened.

    Would it not be advisable to give advanced warning of what the consultation process will consist of in order that we may prepare the appropriate information?

    You will be aware, perhaps, that a charity such as Invest in ME Research has many other tasks it is performing at this time and we would wish for NICE to have the fullest possible information available in order to make the very necessary decision that a revision is necessary.

    We would suggest distributing relevant documents already before the consultation opens in order to give more time to those submitting information.”

  • Wendy Boutilier 28 June 2017, 8:22 pm

    This is their revised GetFit Graded Exercise Therapy daily journal. It’s a joke. https://uploads.disquscdn.com/images/1f1b126167c0855fc7c1aec8c7d6d053f512beb00c48e5850fc8debdc9be63ac.jpg

  • Erik Johnson 28 June 2017, 8:30 pm
  • Oldfarticus 28 June 2017, 8:33 pm

    Thanks to David for another important article, and thanks to Dr Levin for taking the time to provide us with expert opinion.

    PS GETSET Julie is pretty close to a hate crime.

  • Alex Young 28 June 2017, 9:10 pm

    I could do two or maybe in some cases three of the things in this chart, per day, and ignoring sleep (which I frequently cannot do anyway). This is the kind of program that might fit with patients so mild they are subclinical. I probably could have done this thirty years ago. In fact much of what is in the chart is what I WAS doing. I used to walk a lot, including to and from work, which was kilometers from where I lived. This did not stop me declining to the point where I was incapable of working even part time.

  • Fiona 28 June 2017, 9:11 pm

    David, once again you have articulated thoughts that I’ve been struggling to pull together. The only thing more contorted than the GETSET researchers’ attempts to flog a dead horse, is the state of my brain as I try to follow their endless side-stepping and back-pedalling!

  • Lisa 28 June 2017, 9:25 pm

    It seems like the authors might be anxious to get a study in print that formally states that they accept the possibility of a biological cause. It could also be possible that they wanted the outcomes they got — some very modest improvements, a therapy touted only as a potential management tool, and little evidence of harm. In other words, it looks like an exit strategy. The authors can’t actually be unaware of the biomedical research that’s being done and must know that more and more of it is going to be published. It would make sense to start looking for the door….

  • Erik Johnson 28 June 2017, 10:44 pm
  • IgnorantConservative 29 June 2017, 12:28 am

    Something needs to be done to hit The Lancet.
    Researchers of all colours need to be aware that The Lancet has become a second rate journal, with sloppy standards of peer review & hence to avoid publishing with.

  • Maree 29 June 2017, 1:42 am

    Thanks David.
    Regarding the nature of the ‘specialist medical care’, you say

    ‘Both groups received at least one meeting with a doctor—what the study called “specialist medical care.”’

    But the paper says:

    ‘Participants in the control group were no more likely to receive SMC sessions during the trial than those in the GES group. In the GES group, 28 (26%) of 107 patients attended one session, two (2%) attended two sessions, and none attended three sessions; in the control group, 28 (27%) of 104 patients attended one session, two (2%) attended two sessions, and two (2%) attended three sessions (χ2 2·126; p=0·54).’

    My reading of that (and I may be wrong) is that 72% of the GES group and 69% of the control group didn’t see any specialist at all during the trial. It’s a small point, but I don’t think the authors should be calling the care ‘Specialist Medical Care’ when most of the participants were getting no medical care at all.

    Imagine if, instead of money wasted on CBT and GET, funds were spent on doing prompt comprehensive diagnostic screening of the people turning up at these fatigue clinics. How much public money could be saved and people’s lives improved by identifying treatable conditions in a timely way?

  • A.B. 29 June 2017, 2:17 am

    In my opinion the statement about the study not suggesting that CFS is a psychological condition is nothing more than an attempt to avoid some criticism. They know that this idea has been rejected by the patient community. That they are not presently making the claim does not mean that this isn’t their working model. In their papers they never try to relate biomedical findings by other researchers to their own work. Especially the growing literature on PEM is highly relevant, yet completely ignored. I think this makes it very clear what they really believe. CBT/GET therapist manuals typically recommend avoiding debating with the patient on what causes CFS and whether it’s a physical or psychological condition.

  • Susanna Degaardt 29 June 2017, 2:40 am

    Thank you!

  • A.B. 29 June 2017, 2:57 am

    I would say that the papers by White and colleagues exhibit a strong bias against biomedical research findings, and I cannot avoid the feeling they’re trying to lead readers down the path of concluding that this is a psychological and behavioural condition even if they might not say so openly,

    For example in this review on the role dietary modification in the treatment of ME/CFS [1], the authors refer to the illness as “chronic multisystemic condition that severely affects daily life”. The IOM report is mentioned, as well as the recent findings by Naviaux. The authors are acknowleding recent and important developments concerning the illness. This puts the paper in the proper perspective for readers that may be unfamiliar with the topic.

    In contrast the GETSET paper doesn’t acknowledge any of the recent and important biomedical findings concerning ME/CFS, not even those that are highly relevant in the context of exercise therapy! For example that there is reproduced objective evidence that exertion causes an unusual objectively measured INCREASE in impairment as described in the IOM report. The illness is described as “chronic disabling fatigue in the absence of an alternative diagnosis.” which ignores the many abnormalities that have by now been found in patients (that justify the adjective “systemic”).

    1. Role of dietary modification in alleviating chronic fatigue syndrome symptoms: a systematic review http://onlinelibrary.wiley.com/doi/10.1111/1753-6405.12670/full

  • cinderkeys 29 June 2017, 3:21 am

    They also insist that any apparent benefit for this management approach would not suggest anything about the cause of the illness. “It is important to note that this trial was not designed to test causative factors in chronic fatigue syndrome, and the relative efficacy of a behavioural intervention does not imply that chronic fatigue syndrome is caused by psychological factors,” they write.

    So they’re retreating a few inches. And also gaslighting us.

  • Susanna Degaardt 29 June 2017, 3:33 am

    Agree. I have the same experience. My ME, that I got after infection as a teenager, then improved a lot spontaniously since I was young.

    I then had a mild ME for many years (full time studies and work).

    In my 40s I gradually lost energy, but i did everything I could think of to get more energy. I struggled to keep up my daily walks to and from work and be even more active. But then I got even worse and 2 yrs ago my body suddenly detoriated into severe ME. No work, no social life, mostly need help with cleaning and cooking.

  • Joan Byrne 29 June 2017, 3:43 am

    Sometimes you just don’t know whether to laugh or cry at the utter rubbish this cabal produces, propped up gamely by The Lancet. Their brains must be addled trying, and failing, to keep any consistency in their utterings. In this case I actually laughed out loud.

    #GetSetJulie has become an Internet meme among people with M.E. and I suspect will be the ‘go to’ lens through which any of their future utterances will be viewed. This paper, and it’s publishers, are trolling this very sick and neglected community. Shameful behaviour on their behalf.

    Thanks again to your good self and to Dr. Levin for your expert analysis.

  • Olivia Beatty 29 June 2017, 5:01 am

    Can we raise all the shortcomings of this trial at the NICE review? The statisticians commentary is very important. Maybe this time the GET lobby have shot themselves in the foot with such a poor study

  • Diane Kirk 29 June 2017, 5:03 am

    Another well written, well researched post David. Thank you again.
    Their criteria for participants is so lax that (apart from all the other problems) this type of ‘research’ is irrelevant for most sufferers.

  • Jo Best 29 June 2017, 5:05 am

    They’ve been saying for years that their trials aren’t investigating causes, as they’re in the business of rehab, and that CBT and GET don’t imply psychological cause, usually citing that these therapies are used for various physical illnesses, but failing to note the important difference that they’re only adjunctive therapies for those other diseases, not first line treatments as recommended by NICE for ‘CFS/ME’. This line is also trotted out routinely by government/establishment sources, which of course, are all either run or advised by the PACE-stable researchers / ‘Wessely school’.

  • Lady Shambles 29 June 2017, 5:14 am

    Excellent. Sentence on sentence of slam-dunk take-downs. The one that made me laugh the most I have to say was Prof Levin’s observation “Obviously they were looking at baseline data in order to notice that “too many” subjects had non-disabled physical functioning” which is so simple and yet so simultaneously damning. Get out of that one Peter White! 😉

  • Lady Shambles 29 June 2017, 5:16 am

    #GETSetJulie has the stamina of a triathlete. The memes are hilarious.

  • Jo Best 29 June 2017, 6:30 am

    “In short, this latest study seeks to bolster the crumbling evidence base for the PACE/CBT/GET paradigm by reporting modest benefits for graded exercise. But as with previous research espousing this approach, even the unimpressive results reported here cannot be taken seriously by scientists who understand basic research standards.”
    You hit the nail on the head, as NICE is about to decide whether to review the guideline for this disease and while they’re still defending the PACE trial, they also need more recent evidence in the bank, supported by a long list of ‘expert opinion’ provided by the UK Science Media Centre.
    http://www.sciencemediacentre.org/expert-reaction-to-study-on-guided-self-help-graded-exercise-therapy-as-a-treatment-for-chronic-fatigue-syndrome-cfs/

  • Magapanthus Smith 29 June 2017, 6:55 am

    Many Thanks David. You are indefatigable indeed. This is a bit of a side issue, but it struck me that there must be a lot of data out there on the physiological and biochemical changes associated with deconditioning in normal healthy individuals (if there is such a thing) and how their bodies respond to exercise which could be compared with similar markers in people (carefully diagnosed) with ME as an avenue of research to prove or more likely to disprove the ME deconditioning theory once and for all. Clearly something the UK shrinks have no interest in.

  • Cathrine engsig 29 June 2017, 8:40 am

    The Danish ME Association does not support Peter White and his CBT/GET paradigm. Every day we see how this harms ME patients. The Lancet should consider how this paper is “good medicine” and be aware of the life quality of ME patients are low ;http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132421
    Thank you to Levin and Tuller for insigth and independent analysis. Your work is of great importance and is followed here in Denmark.

  • Brenda Vreeswijk 29 June 2017, 9:18 am

    Well…what could be expected of them…real science?? They still keep wiggling their butts to make their research look good…but it still doesn’t. Don’t have a good word for The Lancet as well…they still allow deeply flawed trials to enter their pages.
    Thanks again for your work David and prof. Bruce Levin… it’s time this kind of papers should be appointed to the right area….the toilet that is.

  • Rob Wijbenga 29 June 2017, 9:57 am

    “Professor White and his team do not believe the PACE hypothesis that
    deconditioning and avoidance of activity are the sole causes of the
    perpetuation of the symptoms. They acknowledge that other possible
    “causative factors” could be involved.”

    You touch the core. They will never confirm this openly and will never pin down themselves on statements which they pretend to agree with, just like they will never openly declare ME isn’t a psychogenic disease. For the simple reason that it leaves them with the option that those ‘other possible causative factors’ after all have a psychogenic cause.

    they are eels.

  • Scott Simpson 29 June 2017, 10:31 am

    David, you are worth every penny and more in donations in your efforts to right this egregious wrong. Keep piling on the sticks, and break those psychobabblers’ backs. The millions of people with ME around the world will not be subjected to iatrogenic harm from contraindicated ‘treatment’ and trauma-inducing experiences with ill-informed physicians. You give us hope and your tenacity is inspiring – thank you.

  • N. 29 June 2017, 11:03 am

    I am 37 now and will have been ill with severe ME for 10 years this fall. I’m starting to think we will battle the horrible influence of the psychosocial cabal until the end of our lives. They are like onlookers after an accident keeping the paramedics from reaching the injured victims. And robbing them while they’re at it.

  • Trish Davis 29 June 2017, 11:34 am

    Excellent article, David. Thank you.
    I haven’t read all the comments yet, so someone else might have already pointed this out – just before you quote Levin, you say ‘to add physical function as co-primary outcome…’ I think you meant ‘to add Chalder Fatigue score…’

  • Sean 29 June 2017, 11:48 am
  • Karen Kirke 29 June 2017, 12:01 pm

    Thank you Dr Tuller and Prof Levin. I don’t think there is a shift in rationale or hypothesis between PACE and GETSET, there is just a shift in where that rationale or hypothesis is explicitly stated, from the published paper and trial manuals to trial manuals only. This shift could reduce readership of that rationale or hypothesis and therefore reduce criticism of the trial. The GETSET trial therapist manual and patient booklet make it very clear that the rationale and theoretical model for GES in GETSET is the same as that for GET in the PACE trial (see below).

    The therapist manual was authored by Clark, Tims and White and can be read here: http://www.wolfson.qmul.ac.uk/images/pdfs/getset/GETSET%20therapists%20manual%20with%20appendices.pdf:

    The patient booklet was written by 9 NHS GET therapists, edited by Clark with thanks to White, Cunningham and Bavinton, and can be read here: http://www.wolfson.qmul.ac.uk/images/pdfs/getset/GET%20guide%20booklet%20version%201%2022062010.pdf

    The patient booklet sticks with the PACE rationale for graded exercise:
    “After a period of illness…we tend to avoid physical activity and rest more than usual. When we do less each day our body loses fitness and strength in a physical process called deconditioning…The inability to function as before leads to frustration and an eventual lack of motivation for any physical activity. This starts a vicious cycle of avoiding activity and increased fatigue which then results in further deconditioning. The aim of GET is to break this cycle.” (p.4)

    Patients are also reassured that no harm will come to them:
    “Will GET do me harm? You may be worried that any increase in exercise or physical activity could make your condition worse. Be reassured – research has shown that a guided, gradual exercise programme can help people who suffer from CFS/ME without causing ill effects.” (GETSET patient booklet p.2)

    Patient surveys famously contradict this claim of no harm – see figure 1 and table 1 of this article for an overview of UK survey data: http://journals.sagepub.com/doi/full/10.1177/1359105317703787.

    A more nuanced explanation is given to the therapists. On p.7 of the GETSET therapist manual, Clark
    et al state:
    “It is not fully understood why GET helps many people with CFS/ME…One theory which can be used to explain GET, as outlined in the GET booklet is based on deconditioning…Another theory points to an altered perception of effort (this may be more significant than deconditioning) [NB Patient booklet does not refer to this more significant effort perception theory.] Participants are encouraged to see symptoms
    as temporary and reversible, as a result of their current physical inactivity, and not as signs of progressive pathology.”

    Mechanisms are discussed here:

    “Apart from the behavioural and perceptual effects of graded exposure to previously avoided physical activities, there may be other mechanisms involved in the success of GET such as reversing deconditioning, including elements of habituation, and positive effects of re-engagement with important activities” (p.7-8, GETSET therapist manual).

    “Preliminary research suggests that reduced symptoms (including fatigue) are related to simply participating in a GET programme, rather than necessarily getting fitter, whereas improved functioning is related to getting fitter and stronger” (p.7, GETSET therapist manual).

    Therapists are told that “It is important to explain that although [patients] have an increase in symptoms, ‘hurt does not equal harm’ (GETSET therapist manual p.26). Patients are told “Remember that although you may not feel like exercising during a CFS/ME related setback, by resting too much you can quickly lose the physical gains you have made” (GETSET patient booklet p.20).

    While Clark et al tell the GES therapists that the effort perception theory may be more significant, they tell therapists:
    “The rating of perceived exertion…is not discussed in the GET booklet [for patients] and therefore is not something you need to discuss with the participant unless they mention it.” (p.49)

    They go on to explain to the GES therapists that:
    “[rating of perceived exertion] is a concept that is important to the participant in their overall success with GES because it is usual for CFS/ME patients to have higher Rating of Perceived Exertion (RPE) than those who do not have CFS.”

    While some might think this is because the key feature of ME/CFS is exertion intolerance, to the extent that the Institute of Medicine suggested renaming it “Systemic Exertion Intolerance Disease” https://www.ncbi.nlm.nih.gov/books/NBK274235/pdf/Bookshelf_NBK274235.pdf, Clark et al explain to the GES therapists in their manual that:

    “[CFS patients’ higher Ratings of Perceived Exertion] may be related to sleep disturbance, deconditioning, enhanced interoception (increased awareness of body sensations), or mood disturbance among other reasons.”

    They then clarify for the GES therapists that:
    “The RPE cannot therefore be used as an objective measure of intensity for this patient group…After an exercise programme, research has shown that the RPE in CFS patients is normalised, and can at that stage usually be reliable as a measure of intensity.”

    To be clear, they have stated that a rating of a patient’s perception of how effortful things are relative to other things is an objective measure in some patient groups, but is not objective in CFS, because CFS patients differ from other patient groups in that they have skewed perceptions, perceiving things to be more effortful than they actually are. This skewed perception is fixed, according to the authors, by exercise programmes.

    Perception rating scales are, objectively speaking, not objective; they are and will be subjective for every patient group that exists now and may exist in the future. All outcome measures in GETSET were subjective.

    Thankfully other researchers are seeking to understand what ongoing pathophysiological process might be behind exertion intolerance in ME/CFS, taking patients’ experience/perceptions as their starting point, and using objective as well as subjective outcome measures.

  • Karen Kirke 29 June 2017, 12:55 pm

    The therapist manual link in original post does not seem to be working, here is the link:
    http://www.wolfson.qmul.ac.uk/images/pdfs/getset/GETSET%20therapists%20manual%20with%20appendices.pdf
    If that doesn’t work, try navigating to both therapist manual and patient booklet from here:
    http://www.wolfson.qmul.ac.uk/current-projects/getset-trial#links
    or here
    http://www.wolfson.qmul.ac.uk/current-projects/getset-trial#trial-information

  • Wolfita 29 June 2017, 2:27 pm

    Well, they’ve always been very careful to distinguish between “causation” and “perpetuation”. PACE itself says
    “The effectiveness of behavioural treatments does not imply that the condition is psychological in nature.”

  • Steve Hawkins 29 June 2017, 4:31 pm

    Same here. These researchers think they are the only people capable of logical thought. We all tried exercising ourselves better and willing ourselves to keep going–some of us from before these people even got qualified. These patronising fools think they just invented the wheel, and want the rest of us to go back to using horses and carts to try it out!

  • Steve Hawkins 29 June 2017, 4:54 pm

    I really can’t fathom Horton’s unshakeable support of this poor science. In other fields he writes strongly on the need for scientific integrity, evidence-based medicine, and sharing of data, yet anything that comes out of the ‘Wessely school’ seems to be accepted without question. Whatever their fascination to him is, he better be aware and ready when they take him down with their sinking ship.

    As for this latest ‘trial’, whatever its other failings, it’s obvious that it doesn’t include anyone with M.E, so why is it allowed to be reported as if it did? While the people in this study were, apparently, living relatively normal lives, with normal physical capacity, and only rare need for making use of the health services, a large number of us are lying in bed with nobody from anywhere ever interested in finding out what is keeping us this way. We live on painkillers and hope, while the Lancet’s favoured researchers go on and on chasing after column inches devoted to people who are not ill and who we never see in any of these columns or fora devoted to the illness they are supposed to be suffering from!

    How much longer are the UK establishment science community and the MRC going to go on both tolerating and sponsoring this absurd charade? They’re bringing UK medical research into disrepute across the world, and they don’t seem to care.

    It’s just plain weird.

  • Alex Young 29 June 2017, 8:46 pm

    “As for this latest ‘trial’, whatever its other failings, it’s obvious that it doesn’t include anyone with M.E, so why is it allowed to be reported as if it did?” In the minds of most people ME is still just CFS, and CFS is just CF. They do not know enough about the topic to realize their mistake.

  • Steve Hawkins 29 June 2017, 10:49 pm

    There is no excuse for that among editorial staff of top medical journals for whom it is very easy to check the real state of the science. Both Lancet and BMJ are diligent at tracking down and exposing other fakers, when it suits them, and they often do a very good job of it. Why they are so free and easy when it comes to going along with psychobabble from a widely discredited source, is quite baffling, if it is not actually dishonest.

  • Alex Young 29 June 2017, 10:53 pm

    There is a lot of blind faith in evidence based medicine, as opposed to evidence based practice, which is not the same thing and emphasizes more autonomy to doctors. I do wonder if we should however be talking about biased based medicine. A study which is a kludge of biases all moving in one direction, even if it were statistically significant at followup (unlike PACE), would only be statistically significant bias. A meta-analysis based on such studies would just be reinforcing the bias.

  • Barry 30 June 2017, 4:20 am

    A nicely measured and very effective article David – excellent. The authors’ greatest skill seems to be in shooting themselves in the foot over and over again. I suspect from what you write that this paper effectively provides evidence of what a scientific disaster PACE is, maybe along with everything else they touch. Huge thanks as always for helping expose all this, your work is one of the cornerstones of advocacy for us.

  • Barry 30 June 2017, 4:24 am

    Except they invented a square wheel.

  • Barry 30 June 2017, 4:28 am

    Not yet, but further down the line once other higher priority issues have been fully sorted, an investigation into The Lancet might itself be worthwhile.

  • Noreen Murphy 30 June 2017, 12:57 pm

    Steve, I totally agree on all points.

    I have been wondering (and trying to find out) what is the connection between the “Wessely school” and Richard Horton? There must be one, he seems to be inextricably linked with/to them. The PACE trial was ‘fast-tracked’ and yet Horton said it went through “endless” rounds of peer-reviews Well, I think it can be only one or the other.

    I’d love to know the connection. Normally, I say “Follow The Money” but I’m not sure that’s correct in this instance. So, what could it be?

  • barrydavies 30 June 2017, 4:06 pm

    I have been in contact with several physiotherapists, mainly because they wanted to learn from someone with M.E. about how it affects you, I was actually needing physic to rebuild the muscles in my lower leg after a break, they were amazed at how I could be variable in fiction when doing the exercises, and wanted to learn about it. As I was effectively teaching them, for free, how can the GET supporters claim it works when the physic’s are not actually trained to do it.

  • Steve Hawkins 30 June 2017, 9:17 pm

    I really don’t understand it Noreen. Horton writes some excellent campaigning editorials, and I have shared several and even written to congratulate him on some. But, when it comes to the ‘Wessely school’ all objectivity seems to go out of the window.

    Science will win out in the end. I hope he sees the writing on the wall, and snaps out of it before then.

    :/

  • Noreen Murphy 1 July 2017, 6:20 am

    Methinks he should have seen the writing on the wall by now, Steve.

    Until the PACE trial is retracted, it can and is being quoted. So, he is also harming patients, just like the “Wessely school”.

    Allowing the publication of yet another farce GET trail shows he intends to continue in the ‘collusion’ (for want of a better word, as words are muddled in my head at the moment). Yes, I also believe science will prevail but he is certainly not helping matters.

  • Jo Best 1 July 2017, 7:29 am

    I don’t read as much about or by him as you do Steve, but I get the impression it’s about casting doubt on medicine in order to promote non-pharmacological therapies and if so then that fits with his unwavering support of the ‘Wessely school’.

  • Jo Best 1 July 2017, 8:06 am

    Fortunately, it’s not the case that “nobody from anywhere ever interested in finding out what is keeping us this way.” For example, a translational biomedical research programme is underway in UK as an intergral part of the Centre of Excellence for ME projects instigated by UK charity Invest in ME Research in cooperation with researchers leading in their respective fields in UK and other countries. Patient samples have been taken from 2014 (including home or bedbound).

    The hub is at Norwich Research Park, where the work moves into the Quadram Institute when the new building opens in 2018, and there are a few pages on the research on the QI website: https://quadram.ac.uk/targets/me-cfs/

    The international collaboration has been supported and developed through an annual international conference and colloquium and formation of a European ME Research Group.

    So, while the PACE stable researchers are bringing UK medical research into disrepute, there are also serious scientists bringing research into this disease to the cutting edge.

    Of course, this has all been made possible by charity fundraising/crowdfunding, and with the solid foundations laid, we’ll have to see if government funding follows in support.

  • Steve Hawkins 1 July 2017, 4:11 pm

    But look at this brilliant piece he wrote on April 8: It’s so good I wrote and congratulated him on it: yet he does the opposite when it comes to the Wessely school. It’s like two completely different people: is he himself mentally ill, or what? Weird. :/

    “The most important idea that science stands for is its willingness to be wrong. Science gains its strength from error. The quantification of its own uncertainty is a mathematical way of asking: how can we be so sure? The gathering and reporting of new scientific evidence is part of a negotiation about the truth of a particular claim. The scientist engages in attack and defence. The important word is “engage”. Science (and its journals) create a habit of debate—an institutional scaffold in which exchange and disagreement, error and uncertainty, can be transformed into a common pursuit for truth. Science welcomes disagreement, provided that one can turn disagreement into constructive debate. What saves us is our commitment to value truth more than victory. Science provides one means to get closer to that truth. But the strength of science is its original position—that one can never be certain, that our theories and interpretations are open to revision in the light of new and better evidence. Scientific journals matter because they enable the free expression of evidence, ideas, and arguments—the tools of truth seeking. In a world that is divided by fear, a space for discovering, participating, creating, experiencing, learning, meeting, inspiring, and performing matters deeply. This kind of exchange can enrich lives. Journals are places where you can belong, somewhere that is open to everybody for collaboration and partnership, guidance and purpose, in an age of information excess. Journals are a hinge in our communities, connecting specialists with publics, offering moments for extraordinary dialogue and cooperation. * And yet at this moment of urgent need, scientific publishers may be turning away from their critical social role. I recently attended a conference of publishers. The future of scientific publishing was the urgent issue at hand. The conclusion? That publishers no longer wish to be publishers. Instead of creating places for reporting, reflecting, and engaging in a habit of debate and a common pursuit of truth, publishers now prefer to think of themselves as vast data repositories, their task being to sell services to customers. These services might well have value. But eyeing the revenues of Google, Amazon, and Apple, publishers hope to shed their historic role, revoke their vital social purpose, and reinvent themselves as technology companies. Instead of actively defending science and society, they wish to evolve into neutral Uber-like platforms, selling what they call digital solutions. Some label this new era Content 2.0. Publishing? “We don’t use that language”, said one speaker. As the savagery and violence of exclusive nationalism become normalised in our brittle and fearful communities, the prospects for science and its journals to be healers in this conflicted world may be diminishing. That cannot be allowed to happen”