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Tug of War: Epic battle over data in controversial paper on chronic fatigue syndrome

Sopranos_ep211b

James Coyne wrote to me a couple weeks ago:

This time I’m critiquing a horrible mediational analysis. The larger context is that the authors have refused all requests to share data that would be needed to make an independent evaluation of their interpretation. I am now in what will be a highly visible confrontation with them because I’ve asked for related data that they published in PLOS One. PLOS One has strict data sharing policies and we are awaiting a Thursday midnight deadline for a response from their university.

He sent me a copy of the paper (Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial, by Trudie Chalder, Kimberley Goldsmith, Peter White, Michael Sharpe, and Andrew Pickles) that he’d criticized. I glanced at the paper and his comments and wrote back to him:

Maybe it’s worth just ignoring this stuff. There’s so much bad research out there! Or is the topic itself important, and you’re concerned that the bad research will have a malign effect on policy?

Before going on, that you should not consider my above statement as a diss of the Chalder et al. paper, nor, for that matter, should you consider this disclaimer as a statement of support. I looked at the paper only very quickly, and I have a skepticism of pretty much any of these mediation models (as illustrated, for example, by figure 7 from Chalder et al.), so I responded to Coyne with a generic statement that sometimes it’s better just to ignore bad research.

Coyne replied:

I agree it’s an absolute disaster of a paper. It otherwise should not be the object of my attention but there is some nastiness associated with its dissemination. Peter White, one of the authors is paid for working with a group trying to get social welfare payments denied to people with chronic physical illness. He promotes the idea that chronic fatigue syndrome, whatever its origins, is perpetuated by fears of exertion. The deconditioning model that is the basis for these claims has been discredited. So he is forced to rely on dodgy research like this to promote the view that chronic fatigue syndrome is largely “cognitive” and psychosomatic. I’ve seen horrible testimony from him that patients who “appear” to be disabled should be denied handicap parking passes because that will force them to walk more. He has personally testified in a number of hearings where patients with chronic fatigue syndrome have had the benefits revoked.

The Institute of Medicine has recently released an extensive report that takes issue with conceptualization of chronic fatigue syndrome as psychosomatic. It explores a number of physiological bases for what is a very heterogeneous group of conditions. Most importantly, while the report indicates that fatigue is a common symptom, the disabilities are much more extensive and subjective fatigue is not a suitable primary outcome for evaluating interventions.

Here is my [Coyne’s] blogging about a more recent paper from this group.

And then more:

We have come under pressure from a number of sources, including Richard Horton, editor of the Lancet [the journal where the Chalder et al. paper appeared]. Comments on my blog posts were temporarily closed at PLOS’s’ Mind the Brain last Monday. Although I am still blogging there, I have moved my advocacy for releasing the the data from a cost analysis of the PACE trial published in PLOS One to my own blog, Quick Thoughts. This was done to decrease the pressure on PLOS and to ensure there was no appearance of a conflict of interest in my using their blog site. I am not involved in the decision-making at the journal concerning the release of the data and anyone can make a similar request.

But now, Retraction Watch, Dorothy Bishop, and even Richard Smith, former editor of BMJ, have joined me in calling for the release of the PLOS data. PLOS is in contact with lawyers.

Although there is a remarkable lack of transparency and basic data being presented, enough issues can be raised about claims the PACE investigators have made in their articles and to the press. An independent look at the data is needed.

So, this is emerging as a major, maybe historic confrontation between the forces pushing for sharing of data and the British establishment. I think I am going to get the data, but the task remains of degrading this ridiculous mediational analysis paper which is used to deny benefits to patients with chronic fatigue syndrome. One of the authors, Peter White, was testifying before a British government toward to get the handicap parking passes of persons with chronic fatigue, before the data were even analyze. Furthermore, primary outcomes were changed after patients started new crew. It’s an incredible mess.

I haven’t looked into any of this in detail but I’m posting the story here because it illustrates the connections between disputed research claims and policy. Never-back-down, never-admit-error attitudes can have consequences.

23 Comments

  1. Carlos says:

    “I have a skepticism of pretty much any of these mediation models”

    Hi Andrew,

    Why are you skeptical about this approach? I like to think of this method as a way to better understand how variables are related to the outcome variable and thinking about the problem more conceptually. Really, I think that this is a good way to build models by starting simple then adding complexity.

    Of course, I wouldn’t make definitive statements based on the results of these methods, but that should be the case for any method used. Maybe I’m wrong, but I’d like to get your thoughts on this.

    Carlos

  2. Z says:

    Is the Sopranos picture a reference to Janice (who is the type of person that Peter White imagines all chronic fatigue syndrome benefit collectors to be)? Or is there another connection I’m missing?

  3. A.M. says:

    The PACE trial mediation analysis in question was exploratory. The strength of the asserted associations appear to have increased significantly after revising the methodology of the analysis (weaker preliminary results were presented at conferences before being published). Does this raise a red flag?

  4. Robin says:

    PACE trial study results are being used worldwide by the medical profession and governments for the treatment of pwME/CFS.
    This is causing great harm to many for whom exertion causes severe amplification of symptoms . Many are devastatingly ill and made worse by PACE -GET and PACE-CBT. It is imperative that the reautks are anysed by others, without links to the insurance industry.

  5. Robert says:

    Hi Andrew,

    Thanks for an interesting blog. Interesting to hear your views on mediation analyses. It seems to me that there is plenty of room for guess-work, false assumptions, error and statistical noise in mediation analyses, perhaps especially in the case of analyses that use self-report questionnaires (that may be vulnerable to response bias, therapist allegiance and other biases).

    A brief note about the particular Secondary Mediation Analysis in question…

    Chalder et al. [1] used the “single mediation model” for their methodology, which is explained in detail in a book by MacKinnon [2]. Explaining the methodology MacKinnon says a temporal separation between variables must be observed (i.e. changes in mediating variable must occur before changes in the mediated variable) for a mediation effect to be empirically and robustly established.

    Chalder et al. were working to this model and acknowledged that they failed to establish a temporal or causal relationship between variables, and therefore did not empirically establish a mediation effect: “Given the pattern of change in the mediators was similar to the pattern of change in the outcomes it is possible that the variables were affecting each other reciprocally”.

    However, despite the lack of empirical evidence to support a mediation effect, the investigators concluded that they had established mediation effects, e.g: “Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET.”

    The study’s conclusion relied upon an assumption that the investigators’ favoured hypothetical model of illness for ME/CFS has a robust empirical evidence base and is applicable to this study. The hypothesis is based upon the idea that symptoms and disability in ME/CFS are perpetuated by false illness beliefs, fear, and an avoidance of activity.

    However, the prestigious National Academy of Medicine (formerly known as the Institute of Medicine) recently released a comprehensive report [3] into ME/CFS that rejected such a hypothetical model of illness, and unambiguously concluded that ME/CFS does not have a psychological or cognitive-behavioural basis, but is an organic illness that requires biomedical research.

    Chalder et al. discussed the possibility that more frequent measurements may have potentially demonstrated a temporal separation between the variables, and therefore a mediation effect. However, this raises the possibility of whether changes in the primary outcome variables (self-report physical function and fatigue) may, in fact, have occurred before changes in the presumed mediator variables. Such an outcome would entirely contradict the investigators’ premature conclusions. According to MacKinnon [2] and Wiedermann et al. [4], unexpected outcomes should not be ruled out.

    Chalder et al. concluded that symptoms and physical impairment, in ME/CFS patients, are mediated by activity avoidance and other factors. However, from a common sense point of view, this seems like rather a convoluted conclusion, and it seems more likely that symptoms would be the direct cause of activity avoidance in any illness. And physical impairment is identical to activity avoidance. To conclude that activity avoidance causes fatigue (rather than fatigue being a direct cause of activity avoidance), is similar to concluding that a person has flu because they’ve taken a day off work, rather than the obvious conclusion that they’ve taken a day off work because they have flu.

    In the case of fatigue, it seems reasonable to consider the possibility that, as the symptom of fatigue fluctuates, patients may intuitively or rationally adapt their activity levels according to what is comfortable and safe. i.e. patients reduce activity levels because they are fatigued. The investigators have concluded that patients are fatigued because they have reduced activity levels.

    Perhaps patients’ perspectives and insights would help clarify the issues but, unfortunately, patients were not consulted for this study.

    References:

    1. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry 2015; 2: 141–52.

    2. MacKinnon DP. Introduction to Statistical Mediation Analysis. Taylor and Francis: New York 2008.

    3. http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx

    4. Wiedermann W, von Eye A. Direction of Effects in Mediation Analysis. Psychol Methods 2015; 20: 221-44.

  6. Not The Science Police says:

    The bigger issue for me is how Coyne or other “critics” select their targets when, as Gelman notes, there’s so much bad science out there. My fear is that Coyne, like Lior Pachter, picks his targets for personal, and not truly scientific, reasons. I’ve not once personally known of a “scientific” disagreement that wasn’t at least partially a personal one. We aren’t involved in a science with certain truths or without uncertainty. This makes poking holes in research like shooting fish in a barrel. Name a paper and I can critique it. But I don’t because I recognize the uncertainty in what we do and recognize the scientific method and process. Bad science won’t replicate. Unless, of course, there is clear evidence of fraud, data dredging, etc then why is all of this drama necessary. It certainly feeds the minds of the anti-science crowd. Maybe Coyne would’ve been better served working as a physical scientists where truths are provable. Otherwise I think Dr Coyne doth protest too much.

    • Andrew says:

      Not:

      1. I have no idea about this particular case but I can assure you that I’m aware of many many scientific disagreements that have no personal dimension. Most of the papers I’ve criticized are by authors whom I’ve never met and know nothing about personally, indeed typically I’ve never even heard of these people until their papers have been pointed out to me.

      2. You write, “Bad science won’t replicate. Unless, of course, there is clear evidence of fraud, data dredging, etc then why is all of this drama necessary.” Unfortunately, bad science does replicate, in the sense that internal standards of replication are low enough that it is indeed possible to replicate via various selection mechanisms such as the garden of forking paths. Recall that Bem claimed that his ESP study replicated.

      As to “why is all this drama necessary,” see the above post: According to Coyne and others, flawed work has malign real-world effects on treatments for chronic fatigue syndrome. If this work is not flawed, fine, go make the case for that. But if it’s flawed and bad treatments are being recommended, that’s a real problem—and it’s a problem whether or not “fraud, data dredging, etc.” are involved.

      3. You write, “Dr Coyne doth protest too much.” What does that mean? If he sees flaws in a study and, in his view, this is leading to bad outcomes for sick people, why shouldn’t he make this view known? His behavior doesn’t in any way seem like protesting too much.

    • Martha says:

      @Not The Science Police,

      You said, “Unless, of course, there is clear evidence of fraud, data dredging, etc …”

      Robert’s comments above (see especially the paragraphs starting with “However, despite the lack of empirical evidence to support a mediation effect, the investigators concluded that they had established mediation effects”) seem to fit well in the “etc” category — that is, Chalder et al stated a conclusion despite lack of empirical evidence to support it. That’s not scientific.

    • Andrew [not Gelman] says:

      There are a lot of flawed studies out there that don’t receive high profile criticism. Why? Because most readers already know they are flawed. Such studies are not spun in the media etc.

      It is those flawed studies which are heavily spun in the media which are most deserving of criticism.

      • Martha says:

        I’m not convince that “most readers already know [that flawed studies] are flawed, but I agree that “It is those flawed studies which are heavily spun in the media which are most deserving of criticism.”

    • Fiona says:

      Bad science very much does replicate. This one trial has caused so much damage to M.E sufferers. There are 250,000 of them in the UK alone. The treatments recommended by the paper in question aren’t just unhelpful, they can actually exacerbate symptoms, sometimes catastrophically. A person with moderate M.E might be pushed into having severe M.E. Most people are unaware of the nature of this illness: it can involve severe pain and fatigue, not being able to tolerate light or sound, being unable to walk or talk or be touched. Some sufferers live in darkened rooms for years at a time. The PACE trial has very much affected what treatment options are available and also how those with M.E are regarded by their friends and families and by society in general. It has been hugely destructive.

      See here for example:
      http://www.telegraph.co.uk/news/health/11959193/Chronic-Fatigue-Syndrome-sufferers-can-overcome-symptoms-of-ME-with-positive-thinking-and-exercise.html

      I think the fact that a trial of this scale, where such basic mistakes were made, hasn’t been demolished sooner is far more in danger of feeding the anti-science crowd. Why has the Lancet not retracted the paper? Why didn’t the peer review process highlight the many flaws? It makes scientists look untrustworthy and more people should recognise this and speak out against it. There is masses of fantastic research being done on M.E – credible, trustworthy biomedical research which deserves more of the spotlight.

    • Arnold says:

      I think you’ve missed the point completely.
      For a start, whether there is a personal reasons or not doesn’t take away from the facts so this cannot be an argument.
      The point is if there is bad science that is influencing medical policy then everyone should be objecting. Those who are aware of bad science and do nothing are not only doing the scienctific community a disservice but are complicit in the bad science.

      There are sick people involved here who have no medical treatment due to lack of research directly because of this bad science and you think that it is ok to stand by and say nothing ? You think this isn’t worth protesting over ?

  7. John says:

    Below is a progression of previous iterations of this publication and here’s a link to a thread about this paper on a ME/CFS patient forum-

    http://forums.phoenixrising.me/index.php?threads/rehabilitative-therapies-for-chronic-fatigue-syndrome-a-secondary-mediation-analysis-of-pace-trial.34927/

    ————————————-

    http://www.trialsjournal.com/content/12/S1/A144

    Clinical Trials Methodology Conference 2011
    Oral presentation

    How do treatments for chronic fatigue syndrome work? Exploration of instrumental variable methods for mediation analysis in PACE – a randomised controlled trial of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care
    Kimberley Goldsmith, Trudie Chalder, Peter White, Michael Sharpe and Andrew Pickles

    Objectives

    Background: Chronic fatigue syndrome (CFS) is characterised by chronic disabling fatigue. The PACE trial compared four treatments for CFS and found that for therapies added to specialist medical care (SMC), cognitive behaviour therapy (CBT) and graded exercise therapy (GET) were more effective than adaptive pacing therapy (APT) and SMC alone in improving physical function and fatigue. What are the mechanisms of these treatments? CBT and GET may affect outcomes through thought processes and behaviours (mediators). Traditional Baron, Judd and Kenny (BJK) methods for estimating mediation effects can be subject to bias; instrumental variable methods (IV) can address this problem. The aims were:

    – To explore potential IVs for causal analysis of mediation in PACE.
    – To compare IV estimates to those obtained using BJK methods, which are unbiased only under restrictive assumptions such as no unmeasured confounding.

    Methods: Two treatment arms were compared at a time. BJK methods were applied using three ordinary least squares (OLS) regression models. IV methods were applied by compiling a list of baseline variables that could act as IVs in interaction terms with treatment arm and then assessing these using OLS with the mid-treatment measurement of the putative mediator as the outcome. Instrument strength was assessed using the R2 change between models with main effects only and with the interaction term. Two-stages least squares regression (2SLS) was used to estimate effects in the presence of IVs. Collective instrument strength was assessed using an F test and partial R2.

    Results: The IVs were weak, with a maximum R2 change of 0.03. The five strongest IVs were therefore used in the 2SLS in each case. There was modest mediation of CBT and GET effects (approximately 20% of the total effect). The IV-derived estimators were somewhat different in magnitude than the BJK estimators and were less precise. There is scope for modelling a common effect of mediators on outcomes across trial arms.

    Conclusions: There was evidence for modest mediation of CBT and GET effects. Potential IVs for the study of PACE treatment mechanisms can be found, however, these were weak. Combining trial arms may allow for more efficient analysis using IVs.

    ———————————————-

    http://kivik.no/ISCB/wordpress/wp-content/uploads/2012/08/iscb33_2012_abstractbook_web.pdf

    33rd Annual Conference of the International Society for Clinical Biostatistics
    19-23 August 2012 – Bergen, Norway

    Exploration of instrumental variable methods for estimation of causal mediation effects in the PACE trial of complex treatments for chronic fatigue syndrome
    Kimberley Goldsmith, Trudie Chalder, Peter White, Michael Sharpe, Andrew Pickles

    Background: Chronic fatigue syndrome (CFS) is characterised by chronic disabling fatigue. The PACE trial compared four treatments for CFS and found cognitive behaviour therapy (plus specialist medical care, CBT+SMC) and graded exercise therapy (GET+SMC) to be more effective than adaptive pacing therapy (APT+SMC) and SMC alone in improving physical function and fatigue. Estimates of causal mediation effects are of interest, for example, fear avoidance and activity avoidance as mediators of the effect of CBT and GET respectively. Traditional Baron, Judd and Kenny (BJK) methods can be subject to bias; instrumental variable methods (IV) can address this problem. The aims were to explore causal analyses using IVs in PACE and to compare IV and BJK estimates.

    Methods: BJK methods were applied using ordinary least squares regressions. IV methods were applied by assessing several baseline variables in interaction terms with treatment arm. Instrument strength was assessed using the R2 change between models with main effects only and with the interaction term. Different IV estimators were compared. Collective instrument strength was assessed using an F test and partial R2.

    Results: The IVs were weak, with small R2 changes. The IV-derived estimators were different in magnitude and less precise than the BJK estimators. The relative precision of different IV estimators varied 10-18%. There is scope for modelling a common effect of mediators on outcomes across trial arms.

    Conclusions: Potential IVs for the study of PACE treatment mechanisms can be found, however, these were weak. Combining trial arms may allow for more efficient IV analysis.

    ————————————————-

    http://www.da.ugent.be/cvs/pages/en/final_program.pdf

    Causal Mediation Analysis.
    Symposium Organized by the Center for Statistics
    Ghent University
    Ghent January 28 and 29, 2013

    Exploration of instrumental variable methods for estimation of causal mediation effects in the PACE trial of complex treatments for chronic fatigue syndrome
    Kimberley Goldsmith, T. Chalder, P. White, M. Sharpe, A. Pickles

    Background: Chronic fatigue syndrome (CFS) is characterised by chronic disabling fatigue. The PACE trial compared four treatments for CFS and found cognitive behaviour therapy (CBT) and graded exercise therapy (GET) to be more effective in improving physical function and fatigue than two other treatments. It is of interest to study whether the effects of CBT and GET are mediated through cognitive measures such as fear avoidance and activity avoidance. The traditional Baron, Judd and Kenny (BJK) methods for studying mediation do not account for unmeasured confounders and so may provide incorrect mediation effects; instrumental variable methods (IV) from economics can address this problem.

    Aim: to explore mediation in PACE using BJK and IV estimates.

    Methods: BJK and IV methods were applied using linear regression models. IV methods require instrumental variables – variables not in the postulated mediation model. Several interaction terms between baseline variables and treatment were assessed as instruments using the R2 change between models with main effects only and with the interaction term. Different IV estimators were compared. Collective instrument strength was assessed using recommended measures.

    Results: Tests of instrument strength indicated these were weak (ie. poor predictors of the mediator). The IV estimators were different in magnitude and less precise than the BJK estimators. The relative precision of different IV estimators varied 10-18%. There is scope for modelling a common effect of the mediators across different treatments.

    Conclusions: Interaction term IVs in PACE were found to be weak. Combining trial arms may allow for more efficient analysis.

    —————————————————–

    http://www.babcpconference.com/archive/london2013/programme/Abstract%20Book_2013.pdf

    2013 British Association for Behavioural & Cognitive Psychotherapies(BABCP) conference abstracts
    41st Annual Conference
    17th-19th July 2013 | Imperial College London

    Mediation effects in the PACE trial of complex treatments for chronic fatigue syndrome
    Trudie Chalder, King’s College London, Kim Goldsmith, King’s College London; Peter White, Queen Mary’s London; Michael Sharpe, Oxford University

    Background: We have previously shown that both cognitive behaviour therapy (CBT) and graded exercise therapy (GET) are superior to adaptive pacing therapy (APT) and specialist medical care (SMC) in reducing fatigue and physical functioning in people with chronic fatigue syndrome (White et al 2011). The aim of this study was to investigate potential mechanisms of change underlying the efficacy of these treatments

    Method: We examined a number of cognitive and behavioural mediators such as fearful cognitions, avoidance behaviour and walking. Mediation was assessed using Baron-Judd-Kenny, or BJK methods fitting a series of regression models.

    Results: Cognitive and behavioural mediating variables generally showed similar patterns, with the majority of change in the mediators occurring during the treatment phase. There was no change in the mediators between the end of treatment at 24 weeks and follow up at 52 weeks. Beliefs had the largest mediated effect on both fatigue and physical functioning for both CBT and GET. However the effect of these mediators on outcomes in GET was stronger than for CBT.

    Conclusion: Both CBT and GET were mediated primarily by beliefs. Both CBT and GET should target specific beliefs through behaviour change in order to change fatigue and disability.

    ——————————————

    http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366%2814%2900069-8/abstract

    Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial
    Trudie Chalder†, Kimberley A Goldsmith†, Peter D White, Michael Sharpe, Andrew R Pickles
    †Contributed equally
    Published Online: 13 January 2015

    Summary

    Background: Cognitive behaviour therapy (CBT) added to specialist medical care (SMC), or graded exercise therapy (GET) added to SMC, are more effective in reducing fatigue and improving physical function than both adaptive pacing therapy (APT) plus SMC and SMC alone for chronic fatigue syndrome. We investigate putative treatment mechanisms.

    Methods: We did a planned secondary mediation analysis of the PACE trial comparing SMC alone or SMC plus APT with SMC plus CBT and SMC plus GET for patients with chronic fatigue syndrome. 641 participants were recruited from six specialist chronic fatigue syndrome clinics in the UK National Health Service between March 18, 2005, and Nov 28, 2008. We assessed mediation using the product of coefficients method with the 12 week measure of the mediators and the 52 week measure of the outcomes. The primary outcomes were fatigue measured by the Chalder fatigue scale and physical function measured by the physical function subscale of the SF-36. We included confounder covariates and used treatment by mediator interaction terms to examine differences in mediator–outcome relations by treatment group.

    Findings: The largest mediated effect for both CBT and GET and both primary outcomes was through fear avoidance beliefs with an effect of larger magnitude for GET (standardised effects ×10, CBT vs APT, fatigue −1·22, 95% CI −0·52 to −1·97, physical function 1·54, 0·86 to 2·31; GET vs APT, fatigue −1·86, −0·80 to −2·89, physical function 2·35, 1·35 to 3·39). Increase in exercise tolerance (6 min walk distance) was a potent mediator of the effect of GET (vs APT, fatigue −1·37, 95% CI −0·76 to −2·21, physical function 1·90, 1·10 to 2·91), but not CBT.

    Interpretation: Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET. Changes in both beliefs and behaviour mediated the effects of both CBT and GET, but more so for GET. The results support a treatment model in which both beliefs and behaviour play a part in perpetuating fatigue and disability in chronic fatigue syndrome.

    Funding: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions, National Institute for Health Research (NIHR), NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, and Institute of Psychiatry, Psychology, and Neuroscience, King’s College London.

    • JohnCB says:

      What is APT? Am I right in thinking that this did not exist as a recognised therapy prior to the PACE trial?

      It was invented as an Aunt Sally, I think, supposedly based on anecdotal patient claims that loosely defined pacing was more useful to them than CBT/GET. APT has little in common with pacing as understood by the lay patient community, where it means a subjective accommodation to the rigours of the illness based upon the personal discovery that fighting the illness results in worsening health, just as trying to exercise yourself out of influenza is equally ineffective.

      The comparison of CBT/GET against APT is not a comparison against a known or established method, neither does it have an established background in science or medicine. Pacing is a lay approach after doctors have shaken their collective heads and said “I don’t know what to do.” APT is something different. It is a prescriptive approach whereas pacing is a subjective approach. The problem for PACE is that patient surveys consistently show that pacing is found to be more effective by patients that either CBT or GET or the combination.

      I think that it may be best to think of pacing as a general advice to avoid doing the things that you know make you ill. Sadly this sensible advice has been twisted and presented as a fear of activity. In any illness you learn to avoid the things that exacerbate the problems, whether you learn from your pain not to walk on a broken leg or are trained by the doctor to avoid sugary foods with diabetes.

      Pacing is a method recommended by one person with ME to another and it has survived in the collective consciousness as it is perceived to work. But there are many different definitions of pacing – in fact there are almost as many definitions of pacing as there are definitions of CFS and ME. The advocates of PACE and CBT/GET dreamt up their own definition of CFS which bears no relation to ME as experienced in the community, so why not dream up their own definition of pacing too? The primary definition of CFS originated with the Centers for Disease Control. In case you are in any doubt, this is not the primary definition used for the PACE study.

  8. Erik Johnson says:

    The moment anyone tries to say CFS is a psychiatric disease, they are ruling out that whatever they are talking about is actually “CFS”
    That ESPECIALLY applies to misguided authorities who dare to contrive new CFS definitions which are in flagrant opposition to the original.

    The 1988 Holmes Definition for CFS
    Chronic Fatigue Syndrome: A Working Case Definition
    Ann Intern Med. 1988; 108:387-389

    Other clinical conditions that may produce similar symptoms must be excluded by thorough evaluation, based on history, physical examination, and appropriate laboratory findings. These conditions include

    chronic psychiatric disease, either newly diagnosed or by history (such as endogenous depression; hysterical personality disorder; anxiety neurosis; schizophrenia; or chronic use of major tranquilizers, lithium, or antidepressive medications); .

  9. Adrian says:

    I think there are serious problems with the scales they use in the trial and the properties that they assume for them in further analysis including the mediation analysis. They use the Chadler fatigue scale (CFQ) which is a series of 11 questions some about physical fatigue and slightly fewer about mental fatigue. They use two different scoring systems in different parts of the trial and switched them in the protocol. What is perhaps interesting is that the different scoring systems do not preserve an ordering between patients. That is patient A can be more fatigued than patient B in one scoring system but the other way around in the alternative system. How can both scoring systems be used as a suitable proxy for fatigue and the way they quote results (mean, SD, mean differences) suggests that the assume the scale is an interval scale but to my mind (and I’m not a statistician) the ordering issues suggest one or the other or both of the marking schemes cannot even be an ordinal scale. There was a nice example in the data released in a recent paper on the FINE trial (a similar trial) published in PLOS One (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144623) where one patient improved on one marking scheme and got worse using the different scheme.

    I don’t really understand mediation analysis but I would assume that the techniques make certain assumptions about the different input variables. I would be concerned that these are not valid for the type of data used here.

    As a more general comment it would be nice if stats packages would produce warnings about the underlying preconditions being assumed for data sources so that it was clear to data analysts. Too often people have not read the detailed maths behind techniques and they can easily apply inappropriate methods.

    • Martha says:

      Adrian said: “They use two different scoring systems in different parts of the trial and switched them in the protocol. What is perhaps interesting is that the different scoring systems do not preserve an ordering between patients. That is patient A can be more fatigued than patient B in one scoring system but the other way around in the alternative system. How can both scoring systems be used as a suitable proxy for fatigue”

      Good point. Measures can make a difference in results!

  10. jeremy says:

    the damage that these wessely school psychiatrists have done, with their abominable ‘research’, has been immense the harm to patients has been incalculable. there is absolutely no doubt about the propriety of releasing any study data, which will allow scientists that have the true respect of patients, to review the findings and methodology

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