How to get a flawed systematic review and meta-analysis withdrawn from publication: a detailed example

Cochrane normally requires authors to agree to withdraw completed reviews that have been published. This withdrawal in the face of resistance from the authors is extraordinary.

There is a lot to be learned from this letter and the accompanying documents in terms of Courtney calmly and methodically laying out a compelling case for withdrawal of a review with important clinical practice and policy implications.

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Robert Courtney’s wonderfully detailed cover letter probably proved decisive in getting the Cochrane review withdrawn, along with the work of another citizen scientist/patient advocate, Tom Kindlon.

Cochrane normally requires authors to agree to withdraw completed reviews that have been published. This withdrawal in the face of resistance from the authors is extraordinary.

There is a lot to be learned from this letter and the accompanying documents in terms of Courtney calmly and methodically laying out a compelling case for withdrawal of a review with important clinical practice and policy implications.

Especially take a look at the exchanges with the author Lillebeth Larun that are included in the letter.

Excerpt from the cover letter below:

It is my opinion that the published Cochrane review unfortunately fails to meet the standards expected by the public of Cochrane in terms of publishing rigorous, unbiased, transparent and independent analysis; So I would very much appreciate it if you could investigate all of the problems I raised in my submitted comments and ensure that corrections are made or, at the very least, that responses are provided which allow readers to understand exactly why Cochrane believe that no corrections are required, with reference to Cochrane guidelines.

On this occasion, in certain respects, I consider the review to lack rigour, to lack clarity, to be misleading, and to be flawed. I also consider the review (including the discussions, some of the analyses, and unplanned changes to the protocol) to indicate bias in favour of the treatments which it investigates.

robert bob courtneyAnother key excerpt summarized Courtney’s four comments on the Cochrane review that had not yet succeeded in getting the review withdrawn:

In summary, my four submissions focus on, but are not restricted to the following issues:

  • The review authors switched their primary outcomes in the review, and used unplanned analyses, which has had the effect of substantially transforming some of the interpretation and reporting of the primary outcomes of the review;

  • The review fails to prominently explain and describe the primary outcome switching and to provide a prominent sensitivity analysis. In my opinion, the review also fails to justify the primary outcome switching;

  • The review fails to clearly report that there were no significant treatment effects at follow-up for any pooled outcomes in any measures of health (except for sleep, a secondary outcome), but instead the review gives the impression that most follow-up outcomes indicated significant improvements, and that the treatments were largely successful at follow-up;

  • The review uses some unpublished and post-hoc data from external studies, despite the review-authors claiming that they have included only formally published data and pre-specified outcome data. Using post-hoc and unpublished data, which contradicts the review’s protocol and stated methodology, may have had a significant effect on the review outcomes, possibly even changing the review outcomes from non-significant to significant;

  • The main discussion sections in the review include incorrect and misleading reports of the review’s own outcomes, giving a.false overall impression of the efficacy of the reviewed therapies;

  • The review includes an inaccurate assessment of bias (according to the Cochrane guidelines for reporting bias) with respect to some of the studies included in the review’s analyses.

These are all serious issues, that I believe we should not be seeing in a Cochrane review.

Digression: My Correspondence with Tom Kindlon regarding this blog post

James Coyne <jcoynester@gmail.com>

Oct 18, 2018, 12:45 PM (3 days ago)

to Tom

I’m going to be doing a couple of blog posts about Bob, one of them about the details of the lost year of his life (2017) which he shared with me in February 2018, shortly before he died. But the other blog post is going to be basically this long email posted with commentary. I am concerned that you get your proper recognition as fully sharing the honors with him for ultimately forcing the withdrawal of the exercise review. Can you give me some suggestion how that might be assured? references? blogs

Do you know the details of Bob ending his life? I know it was a deliberate decision, but was it an accompanied suicide? More people need to know about his involuntary hospitalization and stupid diagnosis of anorexia.

Kind regards

tom Kindlon
Tom Kindlon

Tom Kindlon’s reply to me

Tom Kindlon

Oct 18, 2018, 1:01 PM (3 days ago)

Hi James/Jim,

It is great you’re going to write on this.

I submitted two long comments on the Cochrane review of exercise therapy for CFS, which can be read here:

<https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003200.pub7/detailed-comment/en?messageId=157054020&gt;

<https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003200.pub7/detailed-comment/en?messageId=157052118&gt;

Robert Courtney then also wrote comments. When he was not satisfied with the responses, he made a complaint.

All the comments can be read on the review here:

<https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003200.pub7/read-comments&gt;

but as I recall the comments by people other than Robert and myself were not substantial.

I will ask what information can be given out about Bob’s death.

Thanks again for your work on this,

Tom

The Cover Letter: Did it break the impasse about withdrawing the review?

from:     Bob <brightonbobbob@yahoo.co.uk>

to:            James Coyne <jcoynester@gmail.com>

date:     Feb 18, 2018, 5:06 PM

subject:                Fw: Formal complaint – Cochrane review CD003200Sun, Feb 18, 1:15 PM

THIS IS A COPY OF A FORMAL COMPLAINT SENT TO DR DAVID TOVEY.

Formal Complaint

12th February 2018

From:

Robert Courtney.

UK

To:

Dr David Tovey

Editor in Chief of the Cochrane Library

Cochrane Editorial Unit

020 7183 7503

dtovey@cochrane.org

Complaint with regards to:

Cochrane Database of Systematic Reviews.

Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2017; CD003200. DOI: 10.1002/14651858.CD003200.pub7

Dear Dr David Tovey,

This is a formal complaint with respect to the current version of “Exercise therapy for chronic fatigue syndrome” by L. Larun et al. (Cochrane Database Syst Rev. 2017; CD003200.)

First of all, I would like to apologise for the length of my submissions relating to this complaint. The issues are technical and complex and I hope that I have made them easy to read and understand despite the length of the text.

I have attached four PDF files to this email which outline the details of my complaint. In 2016, I submitted each of these documents as part of the Cochrane comments facility. They have now been published in the updated version of the review. (For your convenience, the details of these submissions are listed at the end of this email with a weblink to an online copy of each document.)

I have found the responses to my comments, by L. Larun, the lead author of the review, to be inadequate, especially considering the seriousness of some of the issues raised.

It is my opinion that the published Cochrane review unfortunately fails to meet the standards expected by the public of Cochrane in terms of publishing rigorous, unbiased, transparent and independent analysis; So I would very much appreciate it if you could investigate all of the problems I raised in my submitted comments and ensure that corrections are made or, at the very least, that responses are provided which allow readers to understand exactly why Cochrane believe that no corrections are required, with reference to Cochrane guidelines.

On this occasion, in certain respects, I consider the review to lack rigour, to lack clarity, to be misleading, and to be flawed. I also consider the review (including the discussions, some of the analyses, and unplanned changes to the protocol) to indicate bias in favour of the treatments which it investigates.

Exercise as a therapy for chronic fatigue syndrome is a highly controversial subject, and so there may be more of a need for independent oversight and scrutiny of this Cochrane review than might usually be the case.

In addition to the technical/methodological issues raised in my four submitted comments, I would also like you to consider whether there may be a potential lack of independence on the part of the authors of this review.

All of the review authors, bar Price, are currently working in collaboration on another Cochrane project with some of the authors of the studies included in this review. (The project involves co-authoring a protocol for a future Cochrane review) [2]. One of the meetings held to develop the protocol for this new review was funded by Peter White’s academic fund [1]. White is the Primary Investigator for the PACE trial (a study included in this Cochrane review).

It is important that Cochrane is seen to uphold high standards of independence, transparency and rigour.

Please refer to my four separate submissions (attached) for the details of my complaint regarding the contents of the review. As way of an introduction, only, I will also briefly discuss, below, some of the points I have raised in my four documents.

In summary, my four submissions focus on, but are not restricted to the following issues:

  • The review authors switched their primary outcomes in the review, and used unplanned analyses, which has had the effect of substantially transforming some of the interpretation and reporting of the primary outcomes of the review;
  • The review fails to prominently explain and describe the primary outcome switching and to provide a prominent sensitivity analysis. In my opinion, the review also fails to justify the primary outcome switching;
  • The review fails to clearly report that there were no significant treatment effects at follow-up for any pooled outcomes in any measures of health (except for sleep, a secondary outcome), but instead the review gives the impression that most follow-up outcomes indicated significant improvements, and that the treatments were largely successful at follow-up;
  • The review uses some unpublished and post-hoc data from external studies, despite the review-authors claiming that they have included only formally published data and pre-specified outcome data. Using post-hoc and unpublished data, which contradicts the review’s protocol and stated methodology, may have had a significant effect on the review outcomes, possibly even changing the review outcomes from non-significant to significant;
  • The main discussion sections in the review include incorrect and misleading reports of the review’s own outcomes, giving a.false overall impression of the efficacy of the reviewed therapies;
  • The review includes an inaccurate assessment of bias (according to the Cochrane guidelines for reporting bias) with respect to some of the studies included in the review’s analyses.

These are all serious issues, that I believe we should not be seeing in a Cochrane review.

These issues have already caused misunderstanding and misreporting of the review in academic discourse and publishing. (See an example of this below.)

All of the issues listed above are explained in full detail in the four PDF files attached to this email. They should be considered to be the basis of this complaint.

For the purposes of this correspondence, I will illustrate some specific issues in more detail.

In the review, the following health indicators were used as outcomes to assess treatment effects: fatigue, physical function, overall health, pain, quality of life, depression, anxiety, and sleep. All of these health indicators, except uniquely for sleep (a secondary outcome) demonstrated a non-significant outcome for pooled treatment effects at follow-up for exercise therapy versus passive control. But a reader would not be aware of this from reading any of the discussion in the review. I undertook a lengthy and detailed analysis of the data in the review before i could comprehend this. I would like these results to be placed in a prominent position in the review, and reported correctly and with clarity, so that a casual reader can quickly understand these important outcomes. These outcomes cannot be understood from reading the discussion, and some outcomes have been reported incorrectly in the discussion. In my opinion, Cochrane is not maintaining its expected standards.

Unfortunately, there is a prominent and important error in the review, which I believe helps to give the mis-impression that the investigated therapies were broadly effective. Physical function and overall-health (both at follow-up) have been mis-reported in the main discussion as being positive outcomes at follow-up, when in fact they were non-significant outcomes. This seems to be an important failing of the review that I would like to be investigated and corrected.

Regarding one of the points listed above, copied here:

“The review fails to clearly report that there were no significant treatment effects at follow-up for any pooled outcomes in any measures of health (except for sleep, a secondary outcome), but instead the review gives the impression that most follow-up outcomes indicated significant improvements, and that the treatments were largely successful at follow-up”

This is one of the most substantial issues that I have highlighted. This issue is related to the primary outcome switching in the review.

(This relates to assessing fatigue at long-term follow-up for exercise therapy vs passive control.)

An ordinary (i.e. casual) reader of the review may easily be left with the impression that the review demonstrates that the investigated treatment has almost universal beneficial health effects. However there were no significant treatment effects for pooled outcome analyses at follow-up for any health outcomes except for sleep (a secondary outcome ). The lack of universal treatment efficacy at follow-up is not at all clear from a casual read of the review, or even from a thorough read. Instead, a careful analysis of the data is necessary to understand the outcomes. I believe that the review is unhelpful in the way it has presented the outcomes, and lacks clarify.

These follow-up outcomes are a very important issue for medical, patient and research communities, but I believe that they have been presented in a misleading and unhelpful way in the discussions of the review. This issue is discussed mainly in my submission no.4 (see my list of PDF documents at the bottom of this correspondence), and also a little in submission no.3.

I will briefly explain some of the specific details, as way of an introduction, but please refer to my attached documents for the full details.

The pre-specified primary outcomes were pooled treatment effects (i.e. using pooled data from all eligible studies) immediately after treatment and at follow-up.

However, for fatigue, this pre-specified primary outcome (i.e. pooled treatment effects for the combination of data from all eligible studies) was abandoned/switched (for what i consider to be questionable reasons) and replaced with a non-pooled analysis. The new unplanned analysis did not pool the data from all eligible studies but analysed data from studies grouped together by the specific measure used to assess fatigue (i.e. grouped by the various different fatigue questionnaire assessments).

Looking at these post-hoc grouped outcomes, for fatigue at follow-up , two out of the three grouped outcomes had significant treatment effects, and the other outcome was a non-significant effect. This post-hoc analysis indicates that the majority of outcomes ( i.e. two out of three) demonstrated a significant treatment effect , however, this does not mean that the pre-specified pooled analysis of all eligible studies would have demonstrated a positive treatment effect. Therefore switching outcomes, and using a post-hoc analysis, allows for the potential introduction of bias to the review. Indeed, on careful inspection of the minutia of the review, the pre-specified analysis of pooled outcomes demonstrates a non-significant treatment effect, for fatigue at follow-up (exercise therapy versus passive control)

The (non-significant) outcome of this pre-specified pooled analysis of fatigue at follow-up is somewhat buried within the data tables of review, and is very difficult to find; It is not discussed prominently or highlighted. Furthermore, the explanation that the primary outcome was switched, is only briefly mentioned and can easily be missed. Uniquely, for the main outcomes, there is no table outlining the details of the pre-specified pooled analysis of fatigue at follow-up. In contrast, the post-hoc analysis, which has mainly positive outcomes, has been given high prominence throughout the review with little explanation that it is a post-hoc outcome.

So, to reiterate, the (two out of three significant, and one non-significant) post-hoc outcomes for fatigue at follow-up were reported as primary outcomes instead of the (non-significant) pre-specified pooled treatment effect for all eligible studies. Two out of three post-hoc outcomes were significant in effect, however, the pre-specified pooled treatment effect, for the same measures, were not significant (for fatigue at follow-up – exercise therapy versus passive control). Thus, the outcome switching transformed one of the main outcomes of the review, from a non-insignificant effect to a mainly significant effect.

Furthermore, for exercise therapy versus passive control at follow-up, all the other health outcomes were non-significant (except sleep – a secondary outcome), but I believe the casual reader would be unaware of this because it is not explained clearly or prominently in the discussion, and some outcomes have been reported erroneously in the discussion as indicating a significant effect.

All of the above is outlined in my four PDF submissions, with detailed reference to specific sections of the review and specific tables etc.

I believe that the actual treatment effects at follow-up are different to the impression gained from a casual read of the review, or even a careful read of the review. It’s only by an in-depth analysis of the entire review that these issues would be noticed.

In what i believe to be a reasonable request in my submissions, i asked the reviewers to: “Clearly and unambiguously explain that all but one health indicator (i.e. fatigue, physical function, overall health, pain, quality of life, depression, and anxiety, but not sleep) demonstrated a non-significant outcome for pooled treatment effects at follow-up for exercise therapy versus passive control”. My request was not acted upon.

The Cochrane reviewers did provide a reason for the change to the protocol, from a pooled analysis to analyses of groups of mean difference values: “We realise that the standardised mean difference (SMD) is much more difficult to conceptualise and interpret than the normal mean difference (MD) […]”.

However, this is a questionable and unsubstantiated claim, and in my opinion isn’t an adequate explanation or justification for changing the primary outcomes; personally, I find it easier to interpret a single pooled analysis than a group of different analyses with each analysis using a different non-standardised scale to measure fatigue.

Using a SMD is standard practice for Cochrane reviews; Cochrane’s guidance recommends using pooled analyses when the outcomes use different measures, which was the case in this review; Thus i struggle to understand why (in an unplanned change to methodology) using a SMD was considered unhelpful by the reviewers in this case. My PDF document no.4 challenges the reviewers’ reason, with reference to the official Cochrane reviewers’ guidelines.

This review has already led to an academic misunderstanding and mis-reporting of its outcomes, which is demonstrated in the following published letter from one of the co-authors of the IPD protocol……

CMAJ (Canada) recommends exercise for CFS [http://www.cmaj.ca/content/188/7/510/tab-e-letters ]

The letter claims: “We based the recommendations on the Cochrane systematic review which looked at 8 randomised trials of exercise for chronic fatigue, and together showed a consistent modest benefit of exercise across the different patient groups included. The clear and consistent benefit suggests indication rather than contraindication of exercise.”

However, there was not a “consistent modest benefit of exercise” and there was not a “clear and consistent benefit” considering that there were no significant treatment effects for any pre-specified (pooled) health outcomes at follow-up, except for sleep. The actual outcomes of the review seem to contradict the interpretation expressed in the letter.

Even if we include the unplanned analyses in our considerations, then it would still be the case that most outcomes did not indicate a beneficial treatment effect at follow-up for exercise therapy versus passive control. Furthermore, one of the most important outcomes, physical function, did not indicate a significant improvement at follow up (despite the discussion erroneously stating that it was a significant effect).

Two of my submissions discuss other issues, which I will outline below.

My first submission is in relation to the following…

The review states that all the analysed data had previously been formally published and was pre-specified in the relevant published studies. However, the review includes an analysis of external data that had not been formally published and is post-hoc in nature, despite alternative data being available that has been formally published and had been pre-specified in the relevant study. The post-hoc data relates to the FINE trial (Wearden 2010). The use of this data was not in accordance with the Cochrane review’s protocol and also contradicts the review’s stated methodology and the discussion of the review.

Specifically, the fatigue data taken from the FINE trial was not pre-specified for the trial and was not included in the original FINE trial literature. Instead, the data had been informally posted on a BMJ rapid response by the FINE trial investigators[3].

The review analyses post-hoc fatigue data from the FINE trial which is based on the Likert scoring system for the Chalder fatigue questionnaire, whereas the formally published FINE trial literature uses the same Chalder fatigue questionnaires but uses the biomodal scoring system, giving different outcomes for the same patient questionnaires. The FINE trial’s post-hoc Likert fatigue data (used in the review) was initially published by the FINE authors only in a BMJ rapid response post [3], apparently as an after-thought.

This is the response to my first letter…

Larun
Larun said she was “extremely concerned and disappointed” with the Cochrane editors’ actions. “I disagree with the decision and consider it to be disproportionate and poorly justified,” she said.

———————-

Larun said:

Dear Robert Courtney

Thank you for your detailed comments on the Cochrane review ‘Exercise Therapy for Chronic Fatigue Syndrome’. We have the greatest respect for your right to comment on and disagree with our work. We take our work as researchers extremely seriously and publish reports that have been subject to rigorous internal and external peer review. In the spirit of openness, transparency and mutual respect we must politely agree to disagree.

The Chalder Fatigue Scale was used to measure fatigue. The results from the Wearden 2010 trial show a statistically significant difference in favour of pragmatic rehabilitation at 20 weeks, regardless whether the results were scored bi-modally or on a scale from 0-3. The effect estimate for the 70 week comparison with the scale scored bi-modally was -1.00 (CI-2.10 to +0.11; p =.076) and -2.55 (-4.99 to -0.11; p=.040) for 0123 scoring. The FINE data measured on the 33-point scale was published in an online rapid response after a reader requested it. We therefore knew that the data existed, and requested clarifying details from the authors to be able to use the estimates in our meta-analysis. In our unadjusted analysis the results were similar for the scale scored bi-modally and the scale scored from 0 to 3, i.e. a statistically significant difference in favour of rehabilitation at 20 weeks and a trend that does not reach statistical significance in favour of pragmatic rehabilitation at 70 weeks. The decision to use the 0123 scoring did does not affect the conclusion of the review.

Regards,

Lillebeth Larun

——————

In her response, above, Larun discusses the FINE trial and quotes an effect size for post-hoc outcome data (fatigue at follow-up) from the FINE trial that is included in the review. Her quoted figures accurately reflect the data quoted by the FINE authors in their BMJ rapid-response comment [3] but, confusingly, these are slightly different from the data in the Cochrane review. In her response, Larun states that the FINE trial effect size for fatigue at 70 weeks using Likert data is -2.55 (-4.99 to -0.11; p=.040), whereas the Cochrane Review states that it is -2.12 [-4.49, 0.25].

This inconsistency makes this discussion confusing. Unfortunately there is no authoritative source for the data because it had not been formally published when the Cochrane review was published.

It seems that, in her response, Larun has quoted the BMJ rapid response data by Wearden et al.[3], rather than her own review’s data. Referring to her review’s data, Larun says that in “our unadjusted analysis the results were similar for the scale scored bi-modally and the scale scored from 0 to 3, i.e. a statistically significant difference in favour of rehabilitation at 20 weeks and a trend that does not reach statistical significance in favour of pragmatic rehabilitation at 70 weeks”.

It is not clear exactly why there are now two different Likert effect sizes, for fatigue at 70 weeks, but we can be sure that the use of this data undermines the review’s claim that “for this updated review, we have not collected unpublished data for our outcomes…”

This confusion, perhaps, demonstrates one of the pitfalls of using unpublished data. The difference between the data published in the review and the data quoted by Larun in her response (which are both supposedly the same unpublished data from the FINE trial) raises the question of exactly what data has been analysed in the review, and what exactly is the source . If it is unpublished data, and seemingly variable in nature, how are readers expected to scrutinise or trust the Cochrane analysis?

With respect to the FINE trial outcomes (fatigue at 70 week follow-up), Larun has provided the mean differences (effect size) for the (pre-specified) bimodal data and for (post-hoc) Likert data. These two different scoring methods (bimodel and Likert), are used for identical patient Chalder fatigue questionnaires, and provide different effect sizes, so switching the fatigue scoring methods may possibly have had an impact on the review’s primary outcomes for fatigue.

Larun hasn’t provided the effect estimates for fatigue at end-of-treatment, but these would also demonstrate variance between bimodal and Likert scoring, so switching the outcomes might have had a significant impact on the primary outcome of the Cochrane review at end-of-treatment, as well as at follow-up.

Note that the effect estimates outlined in this correspondence, for the FINE trial, are mean differences (this is the data taken from the FINE trial), rather than standardised mean differences (which are sometimes used in the meta-analyses in the Cochrane review); It is important not to get confused between the two different statistical analyses.

Larun said: “The decision to use the 0123 [i.e. Likert] scoring did does [sic] not affect the conclusion of the review.”

But it is not possible for a reader to verify that because Larun has not provided any evidence to demonstrate that switching outcomes has had no effect on the conclusion of the review. i.e. There is no sensitivity analysis, despite the review switching outcomes and using unpublished post-hoc data instead of published pre-specified data. This change in methodology means that the review does not conform to its own protocol and stated methodology. This seems like a significant issue.

Are we supposed to accept the word of the author, rather than review the evidence for ourselves? This is a Cochrane review – renowned for rigour and impartiality.

Note that Larun has acknowledged that I am correct with respect to the FINE trial data used in the review (i.e. that the data was unpublished and not part of the formally published FINE trial study, but was simply posted informally in a BMJ rapid response). Larun confirms that: “…the 33-point scale was published in an online rapid response after a reader requested it. We therefore knew that the data existed, and requested clarifying details from the authors…” But then Larun confusingly (for me) says we must “agree to disagree”.

Larun has not amended her literature to resolve the situation; Larun has not changed her unplanned analysis back to her planned analyses (i.e. to use published pre-specified data as per the review protocol, rather than unpublished post-hoc data); nor has she amended the text of the review so that it clearly and prominently indicates that the primary outcomes were switched. Neither has a sensitivity analysis been published using the FINE trial’s published pre-specified data.

Note the difference in the effect estimates at 70 weeks for bimodal scoring [-1.00 (CI -2.10 to +0.11; p =.076)] vs Likert scoring [-2.55 (-4.99 to -0.11; p=.040)] (as per the Cochrane analysis) or -2.12 [-4.49, 0.25] (also Likert scoring) as per Larun’s response and the BMJ rapid response where the data was initially presented to the public.

Confusingly, there are two different effect sizes for the same (Likert) data; one shows a significant treatment effect and the other shows a non-significant treatment effect. This seems like a rather chaotic situation for a Cochrane review . The data is neither consistent nor transparent. The unplanned Cochrane analysis uses data which has not been published and cannot be scrutinised.

Furthermore, we now have three sets of data for the same outcomes. Because an unplanned analysis was used in the review, it is nearly impossible to work out what is what.

In her response, above, Larun says that both fatigue outcomes (i.e. bimodal & Likert scoring systems) at 70 weeks are non-significant. This is true of the data published in the Cochrane review but, confusingly, this isn’t true if we consider the data that Larun has provided in her response, above. The bimodal and Likert data (fatigue at 70 weeks) presented in the review both have a non-significant effect, however, the Likert data quoted in Larun’s correspondence (which reflects the data in the FINE trial authors’ BMJ rapid response) shows a significant outcome. This may reflect the use of adjusted vs unadjusted data, but it isn’t clear.

Using post-hoc data may allow bias to creep into the review; For example, the Cochrane reviewers might have seen the post hoc data for the FINE trial , because it was posted in an open-access BMJ rapid response [3] prior to the Cochrane review publication date. I am not accusing the authors of conscious bias but Cochrane guidelines are put in place to avoid doubt and to maintain rigour and transparency. Hypothetically, a biased author may have seen that a post-hoc Likert analysis allowed for better outcomes to be reported for the FINE trial. The Cochrane guidelines are established in order to avoid such potential pitfalls and bias, and to avoid the confusion that is inherent in this review.

Note that the review still incorrectly says that all the data is previously published data – even though Larun admits in the letter that it isn’t. (i.e. the data are not formally published in a peer-reviewed journal; i assume that the review wasn’t referring to data that might be informally published in blogs or magazines etc, because the review pretends to analyse formally published data only.)

The authors have practically dismissed my concerns and have not amended anything in the review, despite admitting in the response that they’ve used post-hoc data.

The fact that this is all highly confusing, even after I have studied it in detail, demonstrates that these issues need to be straightened out and fixed.

It surely shouldn’t be the case, in a Cochrane review, that we ( for the same outcomes ) have three sets of results being bandied about, and the data used in a post hoc analysis seems to vary over time, and change from a non-significant treatment effect to a significance treatment effect, depending on where it is quoted. Because it is unpublished, independent scrutiny is made more difficult.

For your information, the BMJ rapid response (Wearden et al.) includes the following data : “Effect estimates [95% confidence intervals] for 20 week comparisons are: PR versus GPTAU -3.84 [-6.17, -1.52], SE 1.18, P=0.001; SL versus GPTAU +0.30 [-1.73, +2.33], SE 1.03, P=0.772. Effect estimates [95% confidence intervals] for 70 week comparisons are: PR versus GPTAU -2.55 [-4.99,-0.11], SE 1.24, P=0.040; SL versus GPTAU +0.36 [-1.90, 2.63], SE 1.15, P=0.752.”

My second submission was in relation to the following…

I believe that properly applying the official Cochrane guidelines would require the review to categorise the PACE trial (White 2011) data as ‘unplanned’ rather than ‘pre-specified’, and would require the risk of bias in relation to ‘selective reporting’ to be categorised accordingly. The Cochrane review currently categorises the risk of ‘selective reporting’ bias for the PACE trial as “low”, whereas the official Cochrane guidelines indicate (unambiguously) that the risk of bias for the PACE data should be “high”. I believe that my argument is fairly robust and water-tight.

This is the response to my second letter…

———————–

Larun said:

Dear Robert Courtney

Thank you for your detailed comments on the Cochrane review ‘Exercise Therapy for Chronic Fatigue Syndrome’. We have the greatest respect for your right to comment on and disagree with our work. We take our work as researchers extremely seriously and publish reports that have been subject to rigorous internal and external peer review. In the spirit of openness, transparency and mutual respect we must politely agree to disagree.

Cochrane reviews aim to report the review process in a transparent way, for example, are reasons for the risk of bias stated. We do not agree that Risk of Bias for the Pace trial (White 2011) should be changed, but have presented it in a way so it is possible to see our reasoning. We find that we have been quite careful in stating the effect estimates and the certainty of the documentation. We note that you read this differently.

Regards,

Lillebeth

————————-

I do not understand what is meant by: “We do not agree that Risk of Bias for the Pace trial (White 2011) should be changed, but have presented it in a way so it is possible to see our reasoning.” …

The review does not discuss the issue of the PACE data being unplanned and I, for one, do not understand the reasoning for not correcting the category for the risk of selective reporting bias. The response to my submission fails to engage with the substantive and serious issues that I raised.

To date, nearly all the issues raised in my letters have been entirely dismissed by Larun. I find this surprising, especially considering that some of the points that I have made were factual (i.e. not particularly open to interpretation) and difficult to dispute. Indeed, Larun’s response even accepts the factual point that I made, in relation to the FINE data, but then confusingly dismisses my request for the issue to be remedied.

There is more detail in the four PDF submissions which are attached to this email, and which have now been published in the latest version of the Cochrane review. I will stop this email now so as not to overwhelm you, and so I don’t repeat myself .

Again, I apologise for the complexity. My four submissions , attached to this email as PDF files, form the basis of my complaint so I ask you to consider them to be the central basis of my complaint . I hope that they will be sufficiently clear.

I trust that you will wish to investigate these issues, with a view to upholding the high standards expected from a Cochrane review.

I look forward to hearing from you in due course. Please feel free to email me at any time with any questions, of if you believe it would be helpful to discuss any of the issues raised.

Regards,

Robert Courtney.

My ‘comments’ (submitted to the Cochrane review authors):

Please note that the four attached PDF documents form the basis of this complaint.

For your convenience, I have included a weblink to a downloadable online copy of each document, and I have attached copies to this email as PDF files, and the comments have now been published in the latest updated version of the review.

The dates refer to the date the comments were submitted to Cochrane.

  1. Query re use of post-hoc unpublished outcome data: Scoring system for the Chalder fatigue scale, Wearden 2010.

Robert Courtney

16th April 2016

https://sites.google.com/site/mecfsnotes/submissions-to-the-cochrane-review-of-exercise-therapy-for-chronic-fatigue-syndrome/fine-trial-unpublished-data

  1. Assessment of Selective Reporting Bias in White 2011.

Robert Courtney

1st May 2016

https://sites.google.com/site/mecfsnotes/submissions-to-the-cochrane-review-of-exercise-therapy-for-chronic-fatigue-syndrome/pace-trial-selective-reporting-bias

  1. A query regarding the way outcomes for physical function and overall health have been described in the abstract, conclusion and discussions of the review.

Robert Courtney

12th May 2016

[ https://sites.google.com/site/mecfsnotes/submissions-to-the-cochrane-review-of-exercise-therapy-for-chronic-fatigue-syndrome/misreporting-of-outcomes-for-physical-function ]

  1. Concerns regarding the use of unplanned primary outcomes in the Cochrane review.

Robert Courtney

3rd June 2016

https://sites.google.com/site/mecfsnotes/submissions-to-the-cochrane-review-of-exercise-therapy-for-chronic-fatigue-syndrome/primary-outcome-switching

References:

  1. Quote from Cochrane reference CD011040:

“Acknowledgements[…]The author team held three meetings in 2011, 2012 and 2013 which were funded as follows: […]2013 via Peter D White’s academic fund (Professor of Psychological Medicine, Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London).”

  1. Larun L, Odgaard-Jensen J, Brurberg KG, Chalder T, Dybwad M, Moss-Morris RE, Sharpe M, Wallman K, Wearden A, White PD, Glasziou PP. Exercise therapy for chronic fatigue syndrome (individual patient data) (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD011040.

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011040/abstract

http://www.cochrane.org/CD011040/DEPRESSN_exercise-therapy-for-chronic-fatigue-syndrome-individual-patient-data

 

  1. Wearden AJ, Dowrick C, Chew-Graham C, et al. Fatigue scale. BMJ Rapid Response. 2010.

http://www.bmj.com/rapid-response/2011/11/02/fatigue-scale-0 (accessed Feb 21, 2016).

End.

Cochrane complaints procedure:

http://www.cochranelibrary.com/help/the-cochrane-library-complaints-procedure.html

The lost last year of one of the key two people in getting the Cochrane review of exercise withdrawn

Did the struggle to get the Cochrane review withdrawn kill Robert Courtney? Or the denial of his basic human rights by the medical system?

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An incomplete  story that urgently needs to be told. We need to get some conversations going.

Did the struggle to get the Cochrane review withdrawn kill Robert Courtney? Or did the denial of his basic human rights by the medical system?

LONDON, Oct 17 (Reuters) – A respected science journal is to withdraw a much-cited review of evidence on an illness known as chronic fatigue syndrome (CFS) amid fierce criticism and pressure from activists and patients.

robert courtney
Robert Courtney from https://www.meaction.net/2018/03/19/a-tribute-to-robert-courtney/

Citizen scientists and patient advocates Tom Kindlon and Robert Courtney played a decisive role in getting the Cochrane review withdrawn.

In the next few days, I will provide the cover letter email sent by Robert Courtney to Senior Cochrane Editor David Tovey that accompanied his last decisive contribution.  Robert is now deceased.

I will also provide links to Tom Kindlon’s contributions that are just as important.

Readers will be able to see from what David Tuller calls their cogent, persuasive and unassailable submissions that the designation of these two as citizen scientists is well-deserved.

Background

Since 2015, I have kept in touch with an advisory group of about a dozen patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs). I send emails to myself with this group blind copied. The rationale was that any one of them could respond to me and not have the response revealed to anyone else. A number of patients requested that kind of confidentiality, given the divisions within the patient community.

Robert Courtney was a valued, active member of that group, but then he mysteriously disappeared in January 2017. Patients have their own reasons for entering and withdrawing from social engagement. Sometimes they announce taking leave, sometimes not. I’ve learned to respect absences without challenge, but  I sometimes ask around. In the case of Robert, I could learn nothing from the community except he was not well.

Then in February 2018, Robert reemerged with the email message below. I had assumed his recovery would continue and he would participate in telling his story. Obviously there were a lot more details to tell, but he died by suicide a few weeks later.

Long, unbroken periods of being housebound and often bedridden is one of the curses of having  severe ME/cfs. Able-bodied persons need to understand the reluctance of patients to invite them into their homes.  Even able-bodied persons who believe that they have forged strong bonds with patients on social media.

I nonetheless occasionally make such offers to meet, as I travel through Europe.  I’m typically told things like “sorry, I only leave my house for medical appointments and a twice a year holiday with my family.”

We have to learn not to be offended.

Consequently, few  people who were touched by Robert Courtney and his efforts have ever met him. Most know little about him beyond his strong presence in social media.

From MEpedia, a crowd-sourced encyclopedia of ME and CFS science and history:

Robert Courtney (d. March 7, 2018) was a patient advocate for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and an outspoken critic of the PACE trial and the biopsychosocial model of chronic fatigue syndrome. He authored numerous published letters in medical journals regarding the PACE trial and, also, filed freedom of information requests in an attempt to get the authors of the PACE trial to release the full trial data to the public for scrutiny.

The day after I received the email below, Robert Courtney sent off to  David Tovey of the Senior Editor Cochrane his final comments.

The email describes the horrible conditions of his last year and his mistreatment and the denial of basic human rights by the medical system. I think airing his story as a wake up call can become another of his contributions to the struggle for the dignity and rights of the patient community.

An excerpt from the email, repeated below.

It seems that this type of mistreatment is all too typical for ME patients. Since I’ve been out of hospital, many patients have told me that they have similar nutritional difficulties, and that they are too scared to seek medical assistance, and that quite a lot of them have been threatened with detention or indeed have been detained under the mental health act. It is a much worse situation than I ever realised.-Robert “Bob” Courtney

We can never know whether Bob’ determined effort to get the review withdrawn led to his medical collapse. The speculation is not just a mindless invoking of “stress kills.” One of the cardinal, defining symptoms of myalgic encephalomyelitis is post exertion malaise.

We usually think of the “exertion” as being physical, but patients with severe form of the illness learn to anticipate that sustained emotional arousal can, within 48 hours or so, put them in their beds for weeks. That applies to positive emotion, like a birthday party, and certainly to negative emotion. Aside from the stress, frustration, and uncertainty of trying to get bad science out of the literature, Bob and other members of the patient community had to contend with enormous vilification and gaslighting, which  still continues today.

After the anorexia diagnosis, they rediagnosed my ME symptoms as being part of a somatoform disorder, and placed me on an eating disorders unit. .-Robert “Bob” Courtney

On Sat, Feb 17, 2018 at 2:44 PM, Bob <brightonbobbob@yahoo.co.uk> wrote:

Hi James,

I don’t know if you’ll remember me. I am an ME patient who was in regular contact with you in 2016. Unfortunately I had a health crisis in early 2017 and I was hospitalised for most of the year. I had developed severe food intolerances and associated difficulties with eating and nutrition. When I admitted myself to hospital they quickly decided there was nothing medically wrong with me and then diagnosed me with anorexia ( to my shock and bewilderment ), and subsequently detained me under the mental health act. I’m not anorexic. The level of ignorance, mistreatment, neglect, abuse, and miscommunication was staggering. After the anorexia diagnosis, they rediagnosed my ME symptoms as being part of a somatoform disorder, and placed me on an eating disorders unit. Then they force-fed me.  It is a very long and troubling story and I’ll spare you the details. I’d quite like a journalist to write up my story but that will have to wait while I address my ongoing health issues.

Unfortunately, it seems that this type of mistreatment is all too typical for ME patients. Since I’ve been out of hospital, many patients have told me that they have similar nutritional difficulties, and that they are too scared to seek medical assistance, and that quite a lot of them have been threatened with detention or indeed have been detained under the mental health act. It is a much worse situation than I ever realised. It is only by sharing my story that people have approached me and been able to tell me what had happened to them. It is such an embarrassing situation both to have eating difficulties and to be detained. The detention is humiliating and the eating difficulties are also excruciatingly embarrassing. Having difficulties with food makes one feel subhuman. So I have discovered that many patients keep their stories to themselves.

You might remember that in 2016 I submitted four lengthy comments to Cochrane with respect to the exercise therapy for chronic fatigue syndrome review. . Before hospital, I had also written an incomplete draft complaint to follow up my submitted comments, but my health crisis interrupted the process and so I haven’t yet sent it .

I am out of hospital now and have finished editing the complaint and I am about to send it. I am going to blind copy you into the complaint so this email is just to let you know to expect it. I’ll probably send it within the next 24 hours. The complaint isn’t as concise or carefully formatted as it could be because I’m still unwell and I have limited capacity.

Anyway this is just to give you some advance notice. I hope this email finds you in good spirits. I haven’t been keeping up to date with the news and activities, while I’ve been away, but I see there’s been a lot of activity. Thanks so much your ongoing efforts.

Best wishes,

Bob (Robert Courtney)

My replies

James Coyne <jcoynester@gmail.com>

Feb 17, 2018, 2:50 PM

to Bob

Bob, I remember you well as one of the heroes of the patient movement, and a particularly exemplary hero because you so captured my idea or of the citizen scientist gathering the data and the sense of methodology to understand the illness and battle the PACE people. I’m so excited to see your reemergence. I look forward to what you send.

Warmest regards

Jim

James Coyne <jcoynester@gmail.com>

Feb 17, 2018, 3:11 PM

to Bob

Your first goal must be to look after yourself and keep yourself as active and well as possible. You know, the patient conception of pacing. You are an important model and resource for lots of people

But when you are ready, I look forward to your telling your story and how it fits with others.

Warmest of regards

Jim

When psychotherapy trials have multiple flaws…

Multiple flaws pose more threats to the validity of psychotherapy studies than would be inferred when the individual flaws are considered independently.

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Multiple flaws pose more threats to the validity of psychotherapy studies than would be inferred when the individual flaws are considered independently.

We can learn to spot features of psychotherapy trials that are likely to lead to exaggerated claims of efficacy for treatments or claims that will not generalize beyond the sample that is being studied in a particular clinical trial. We can look to the adequacy of sample size, and spot what Cochrane collaboration has defined as risk of bias in their handy assessment tool.

We can look at the case-mix in the particular sites where patients were recruited.  We can examine the adequacy of diagnostic criteria that were used for entering patients to a trial. We can examine how blinded the trial was in terms of whoever assigned patients to particular conditions, but also what the patients, the treatment providers, and their evaluaters knew which condition to which particular patients were assigned.

And so on. But what about combinations of these factors?

We typically do not pay enough attention multiple flaws in the same trial. I include myself among the guilty. We may suspect that flaws are seldom simply additive in their effect, but we don’t consider whether they may be even synergism in the negative effects on the validity of a trial. As we will see in this analysis of a clinical trial, multiple flaws can provide more threats to the validity trial than what we might infer when the individual flaws are considered independently.

The particular paper we are probing is described in its discussion section as the “largest RCT to date testing the efficacy of group CBT for patients with CFS.” It also takes on added importance because two of the authors, Gijs Bleijenberg and Hans Knoop, are considered leading experts in the Netherlands. The treatment protocol was developed over time by the Dutch Expert Centre for Chronic Fatigue (NKCV, http://www.nkcv.nl; Knoop and Bleijenberg, 2010). Moreover, these senior authors dismiss any criticism and even ridicule critics. This study is cited as support for their overall assessment of their own work.  Gijs Bleijenberg claims:

Cognitive behavioural therapy is still an effective treatment, even the preferential treatment for chronic fatigue syndrome.

But

Not everybody endorses these conclusions, however their objections are mostly baseless.

Spoiler alert

This is a long read blog post. I will offer a summary for those who don’t want to read through it, but who still want the gist of what I will be saying. However, as always, I encourage readers to be skeptical of what I say and to look to my evidence and arguments and decide for themselves.

Authors of this trial stacked the deck to demonstrate that their treatment is effective. They are striving to support the extraordinary claim that group cognitive behavior therapy fosters not only better adaptation, but actually recovery from what is internationally considered a physical condition.

There are some obvious features of the study that contribute to the likelihood of a positive effect, but these features need to be considered collectively, in combination, to appreciate the strength of this effort to guarantee positive results.

This study represents the perfect storm of design features that operate synergistically:

perfect storm

 Referral bias – Trial conducted in a single specialized treatment setting known for advocating psychological factors maintaining physical illness.

Strong self-selection bias of a minority of patients enrolling in the trial seeking a treatment they otherwise cannot get.

Broad, overinclusive diagnostic criteria for entry into the trial.

Active treatment condition carry strong message how patients should respond to outcome assessment with improvement.

An unblinded trial with a waitlist control lacking the nonspecific elements (placebo) that confound the active treatment.

Subjective self-report outcomes.

Specifying a clinically significant improvement that required only that a primary outcome be less than needed for entry into the trial

Deliberate exclusion of relevant objective outcomes.

Avoidance of any recording of negative effects.

Despite the prestige attached to this trial in Europe, the US Agency for Healthcare Research and Quality (AHRQ) excludes this trial from providing evidence for its database of treatments for chronic fatigue syndrome/myalgic encephalomyelitis. We will see why in this post.

factsThe take away message: Although not many psychotherapy trials incorporate all of these factors, most trials have some. We should be more sensitive to when multiple factors occur in the same trial, like bias in the site for patient recruitment; lacking of blinding; lack of balance between active treatment and control condition in terms of nonspecific factors, and subjective self-report measures.

The article reporting the trial is

Wiborg JF, van Bussel J, van Dijk A, Bleijenberg G, Knoop H. Randomised controlled trial of cognitive behaviour therapy delivered in groups of patients with chronic fatigue syndrome. Psychotherapy and Psychosomatics. 2015;84(6):368-76.

Unfortunately, the article is currently behind a pay wall. Perhaps readers could contact the corresponding author Hans.knoop@radboudumc.nl  and request a PDF.

The abstract

Background: Meta-analyses have been inconclusive about the efficacy of cognitive behaviour therapies (CBTs) delivered in groups of patients with chronic fatigue syndrome (CFS) due to a lack of adequate studies. Methods: We conducted a pragmatic randomised controlled trial with 204 adult CFS patients from our routine clinical practice who were willing to receive group therapy. Patients were equally allocated to therapy groups of 8 patients and 2 therapists, 4 patients and 1 therapist or a waiting list control condition. Primary analysis was based on the intention-to-treat principle and compared the intervention group (n = 136) with the waiting list condition (n = 68). The study was open label. Results: Thirty-four (17%) patients were lost to follow-up during the course of the trial. Missing data were imputed using mean proportions of improvement based on the outcome scores of similar patients with a second assessment. Large and significant improvement in favour of the intervention group was found on fatigue severity (effect size = 1.1) and overall impairment (effect size = 0.9) at the second assessment. Physical functioning and psychological distress improved moderately (effect size = 0.5). Treatment effects remained significant in sensitivity and per-protocol analyses. Subgroup analysis revealed that the effects of the intervention also remained significant when both group sizes (i.e. 4 and 8 patients) were compared separately with the waiting list condition. Conclusions: CBT can be effectively delivered in groups of CFS patients. Group size does not seem to affect the general efficacy of the intervention which is of importance for settings in which large treatment groups are not feasible due to limited referral

The trial registration

http://www.isrctn.com/ISRCTN15823716

Who was enrolled into the trial?

Who gets into a psychotherapy trial is a function of the particular treatment setting of the study, the diagnostic criteria for entry, and patient preferences for getting their care through a trial, rather than what is being routinely provided in that setting.

 We need to pay particular attention to when patients enter psychotherapy trials hoping they will receive a treatment they prefer and not to be assigned to the other condition. Patients may be in a clinical trial for the betterment of science, but in some settings, they are willing to enroll because of a probability of getting treatment they otherwise could not get. This in turn also affects the evaluation of both the condition in which they get the preferred treatment, but also their evaluation of the condition in which they are denied it. Simply put, they register being pleased with what they wanted or not being pleased if they did not get what they wanted.

The setting is relevant to evaluating who was enrolled in a trial.

The authors’ own outpatient clinic at the Radboud University Medical Center was the site of the study. The group has an international reputation for promoting the biopsychosocial model, in which psychological factors are assumed to be the decisive factor in maintaining somatic complaints.

All patients were referred to our outpatient clinic for the management of chronic fatigue.

There is thus a clear referral bias  or case-mix bias but we are not provided a ready basis for quantifying it or even estimating its effects.

The diagnostic criteria.

The article states:

In accordance with the US Center for Disease Control [9], CFS was defined as severe and unexplained fatigue which lasts for at least 6 months and which is accompanied by substantial impairment in functioning and 4 or more additional complaints such as pain or concentration problems.

Actually, the US Center for Disease Control would now reject this trial because these entry criteria are considered obsolete, overinclusive, and not sufficiently exclusive of other conditions that might be associated with chronic fatigue.*

There is a real paradigm shift happening in America. Both the 2015 IOM Report and the Centers for Disease Control and Prevention (CDC) website emphasize Post Exertional Malaise and getting more ill after any effort with M.E. CBT is no longer recommended by the CDC as treatment.

cdc criteriaThe only mandatory symptom for inclusion in this study is fatigue lasting 6 months. Most properly, this trial targets chronic fatigue [period] and not the condition, chronic fatigue syndrome.

Current US CDC recommendations  (See box  7-1 from the IoM document, above) for diagnosis require postexertional malaise for a diagnosis of myalgic encephalomyelitis (ME). See below.

pemPatients meeting the current American criteria for ME would be eligible for enrollment in this trial, but it’s unclear what proportion of the patients enrolled actually met the American criteria. Because of the over-inclusiveness of the entry diagnostic criteria, it is doubtful whether the results would generalize to American sample. A look at patient flow into the study will be informative.

Patient flow

Let’s look at what is said in the text, but also in the chart depicting patient flow into the trial for any self-selection that might be revealed.

In total, 485 adult patients were diagnosed with CFS during the inclusion period at our clinic (fig. 1). One hundred and fifty-seven patients were excluded from the trial because they declined treatment at our clinic, were already asked to participate in research incompatible with inclusion (e.g. research focusing on individual CBT for CFS) or had a clinical reason for exclusion (i.e. they received specifically tailored interventions because they were already unsuccessfully treated with individual CBT for CFS outside our clinic or were between 18 and 21 years of age and the family had to be involved in the therapy). Of the 328 patients who were asked to engage in group therapy, 99 (30%) patients indicated that they were unwilling to receive group therapy. In 25 patients, the reason for refusal was not recorded. Two hundred and four patients were randomly allocated to one of the three trial conditions. Baseline characteristics of the study sample are presented in table 1. In total, 34 (17%) patients were lost to follow-up. Of the remaining 170 patients, 1 patient had incomplete primary outcome data and 6 patients had incomplete secondary outcome data.

flow chart

We see that the investigators invited two thirds of patients attending the clinic to enroll in the trial. Of these, 41% refused. We don’t know the reason for some of the refusals, but almost a third of the patients approached declined because they did not want group therapy. The authors left being able to randomize 42% of patients coming to the clinic or less than two thirds of patients they actually asked. Of these patients, a little more than two thirds received the treatment to which were randomized and were available for follow-up.

These patients receiving treatment to which they were randomized and who were available for follow-up are self-selected minority of the patients coming to the clinic. This self-selection process likely reduced the proportion of patients with myalgic encephalomyelitis. It is estimated that 25% of patients meeting the American criteria a housebound and 75% are unable to work. It’s reasonably to infer that patients being the full criteria would opt out of a treatment that require regular attendance of a group session.

The trial is biased to ambulatory patients with fatigue and not ME. Their fatigue is likely due to some combinations of factors such as multiple co-morbidities, as-yet-undiagnosed medical conditions, drug interactions, and the common mild and subsyndromal  anxiety and depressive symptoms that characterize primary care populations.

The treatment being evaluated

Group cognitive behavior therapy for chronic fatigue syndrome, either delivered in a small (4 patients and 1 therapist) or larger (8 patients and 2 therapists) group format.

The intervention consisted of 14 group sessions of 2 h within a period of 6 months followed by a second assessment. Before the intervention started, patients were introduced to their group therapist in an individual session. The intervention was based on previous work of our research group [4,13] and included personal goal setting, fixing sleep-wake cycles, reducing the focus on bodily symptoms, a systematic challenge of fatigue-related beliefs, regulation and gradual increase in activities, and accomplishment of personal goals. A formal exercise programme was not part of the intervention.

Patients received a workbook with the content of the therapy. During sessions, patients were explicitly invited to give feedback about fatigue-related cognitions and behaviours to fellow patients. This aspect was introduced to facilitate a pro-active attitude and to avoid misperceptions of the sessions as support group meetings which have been shown to be insufficient for the treatment of CFS.

And note:

In contrast to our previous work [4], we communicated recovery in terms of fatigue and disabilities as general goal of the intervention.

Some impressions of the intensity of this treatment. This is a rather intensive treatment with patients having considerable opportunities for interactions with providers. This factor alone distinguishes being assigned to the intervention group versus being left in the wait list control group and could prove powerful. It will be difficult to distinguish intensity of contact from any content or active ingredients of the therapy.

I’ll leave for another time a fuller discussion of the extent to which what was labeled as cognitive behavior therapy in this study is consistent with cognitive therapy as practiced by Aaron Beck and other leaders of the field. However, a few comments are warranted. What is offered in this trial does not sound like cognitive therapy as Americans practice it. What is often in this trial seems emphasize challenging beliefs, pushing patients to get more active, along with psychoeducational activities. I don’t see indications of the supportive, collaborative relationship in which patients are encouraged to work on what they want to work on, engage in outside activities (homework assignments) and get feedback.

What is missing in this treatment is what Beck calls collaborative empiricism, “a systemic process of therapist and patient working together to establish common goals in treatment, has been found to be one of the primary change agents in cognitive-behavioral therapy (CBT).”

Importantly, in Beck’s approach, the therapist does not assume cognitive distortions on the part of the patient. Rather, in collaboration with the patient, the therapist introduces alternatives to the interpretations that the patient has been making and encourages the patient to consider the difference. In contrast, rather than eliciting goal statements from patients, therapist in this study imposes the goal of increased activity. Therapists in this study also seem ready to impose their views that the patients’ fatigue-related beliefs are maladaptive.

The treatment offered in this trial is complex, with multiple components making multiple assumptions that seem quite different from what is called cognitive therapy or cognitive behavioral therapy in the US.

The authors’ communication of recovery from fatigue and disability seems a radical departure not only from cognitive behavior therapy for anxiety and depression and pain, but for cognitive behavior therapy offered for adaptation to acute and chronic physical illnesses. We will return to this “communication” later.

The control group

Patients not randomized to group CBT were placed on a waiting list.

Think about it! What do patients think about having gotten involved in all the inconvenience and burden of a clinical trial in hope that they would get treatment and then being assigned to the control group with just waiting? Not only are they going to be disappointed and register that in their subjective evaluations of the outcome assessments patients may worry about jeopardizing the right to the treatment they are waiting for if they overly endorse positive outcomes. There is a potential for  nocebo effect , compounding the placebo effect of assignment to the CBT active treatment groups.

What are informative comparisons between active treatments and  control conditions?

We need to ask more often what inclusion of a control group accomplishes for the evaluation of a psychotherapy. In doing so, we need to keep in mind that psychotherapies do not have effect sizes, only comparisons of psychotherapies and control condition have effect sizes.

A pre-post evaluation of psychotherapy from baseline to follow-up includes the effects of any active ingredient in the psychotherapy, a host of nonspecific (placebo) factors, and any changes that would’ve occurred in the absence of the intervention. These include regression to the mean– patients are more likely to enter a clinical trial now, rather than later or previously, if there has been exacerbation of their symptoms.

So, a proper comparison/control condition includes everything that the patients randomized to the intervention group get except for the active treatment. Ideally, the intervention and the comparison/control group are equivalent on all these factors, except the active ingredient of the intervention.

That is clearly not what is happening in this trial. Patients randomized to the intervention group get the intervention, the added intensity and frequency of contact with professionals that the intervention provides, and all the support that goes with it; and the positive expectations that come with getting a therapy that they wanted.

Attempts to evaluate the group CBT versus the wait-list control group involved confounding the active ingredients of the CBT and all these nonspecific effects. The deck is clearly being stacked in favor of CBT.

This may be a randomized trial, but properly speaking, this is not a randomized controlled trial, because the comparison group does not control for nonspecific factors, which are imbalanced.

The unblinded nature of the trial

In RCTs of psychotropic drugs, the ideal is to compare the psychotropic drug to an inert pill placebo with providers, patients, and evaluate being blinded as to whether the patients received psychotropic drug or the comparison pill.

While it is difficult to achieve a comparable level of blindness and a psychotherapy trial, more of an effort to achieve blindness is desirable. For instance, in this trial, the authors took pains to distinguish the CBT from what would’ve happened in a support group. A much more adequate comparison would therefore be CBT versus either a professional or peer-led support group with equivalent amounts of contact time. Further blinding would be possible if patients were told only two forms of group therapy were being compared. If that was the information available to patients contemplating consenting to the trial, it wouldn’t have been so obvious from the outset to the patients being randomly assigned that one group was preferable to the other.

Subjective self-report outcomes.

The primary outcomes for the trial were the fatigue subscale of the Checklist Individual Strength;  the physical functioning subscale of the Short Health Survey 36 (SF-36); and overall impairment as measured by the Sickness Impact Profile (SIP).

Realistically, self-report outcomes are often all that is available in many psychotherapy trials. Commonly these are self-report assessments of anxiety and depressive symptoms, although these may be supplemented by interviewer-based assessments. We don’t have objective biomarkers with which to evaluate psychotherapy.

These three self-report measures are relatively nonspecific, particularly in a population that is not characterized by ME. Self-reported fatigue in a primary care population lacks discriminative validity with respect to pain, anxiety and depressive symptoms, and general demoralization.  The measures are susceptible to receipt of support and re-moralization, as well as gratitude for obtaining a treatment that was sought.

Self-report entry criteria include a score 35 or higher on the fatigue severity subscale. Yet, a score of less than 35 on this scale at follow up is part of what is defined as a clinically significant improvement with a composite score from combined self-report measures.

We know from medical trials that differences can be observed with subjective self-report measures that will not be found with objective measures. Thus, mildly asthmatic patients will fail to distinguish in their subjective self-reports between [  between the effective inhalant albuterol, an inert inhalant, and sham acupuncture, but will rate improvement better than getting no intervention.  However,  there will be a strong advantage over the other three conditions with an objective measure, maximum forced expiratory volume in 1 second (FEV1) as assessed  with spirometry.

The suppression of objective outcome measures

We cannot let these the authors of this trial off the hook in their dependence on subjective self-report outcomes. They are instructing patients that recovery is the goal, which implies that it is an attainable goal. We can reasonably be skeptical about acclaim of recovery based on changes in self-report measures. Were the patients actually able to exercise? What was their exercise capacity, as objectively measured? Did they return to work?

These authors have included such objective measurements in past studies, but not included them as primary outcomes, nor, even in some cases, reported them in the main paper reporting the trial.

Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Jan 5:1

The senior authors’ review fails to mention their three studies using actigraphy that did not find effects for CBT. I am unaware of any studies that did find enduring effects.

Perhaps this is what they mean when they say the protocol has been developed over time – they removed what they found to be threats to the findings that they wanted to claim.

Dismissing of any need to consider negative effects of treatment

Most psychotherapy fail to assess any adverse effects of treatment, but this is usually done discretely, without mention. In contrast, this article states

Potential harms of the intervention were not assessed. Previous research has shown that cognitive behavioural interventions for CFS are safe and unlikely to produce detrimental effects.

Patients who meet stringent criteria for ME would be put at risk for pressure to exert themselves. By definition they are vulnerable to postexertional malaise (PEM). Any trail of this nature needs to assess that risk. Maybe no adverse effects would be found. If that were so, it would strongly indicate the absence of patients with appropriate diagnoses.

Timing of assessment of outcomes varied between intervention and control group.

I at first did not believe what I was reading when I encountered this statement in the results section.

The mean time between baseline and second assessment was 6.2 months (SD = 0.9) in the control condition and 12.0 months (SD = 2.4) in the intervention group. This difference in assessment duration was significant (p < 0.001) and was mainly due to the fact that the start of the therapy groups had to be frequently postponed because of an irregular patient flow and limited treatment capacities for group therapy at our clinic. In accordance with the treatment manual, the second assessment was postponed until the fourteenth group session was accomplished. The mean time between the last group session and the second assessment was 3.3 weeks (SD = 3.5).

So, outcomes were assessed for the intervention group shortly after completion of therapy, when nonspecific (placebo) effects would be stronger, but a mean of six months later than for patients assigned to the control condition.

Post-hoc statistical controls are not sufficient to rescue the study from this important group difference, and it compounds other problems in the study.

Take away lessons

Pay more attention to how limitations any clinical trial may compound each other in terms of the trial provide exaggerated estimates of the effects of treatment or the generalizability of the results to other settings.

Be careful of loose diagnostic criteria because a trial may not generalize to the same criteria being applied in settings that are different either in terms of patient population of the availability of different treatments. This is particularly important when a treatment setting has a bias in referrals and only a minority of patients being invited to participate in the trial actually agree and are enrolled.

Ask questions about just what information is obtained in comparing active treatment group and the study to its control/comparison. For start, just what is being controlled and how might that affect the estimates of the effectiveness of the active treatment?

Pay particular attention to the potent combination of the trial being unblinded, a weak comparision/control, and an active treatment that is not otherwise available to patients.

Note

*The means of determining whether the six months of fatigue might be accounted for by other medical factors was specific to the setting. Note that a review of medical records for sufficient for an unknown proportion of patients, with no further examination or medical tests.

The Department of Internal Medicine at the Radboud University Medical Center assessed the medical examination status of all patients and decided whether patients had been sufficiently examined by a medical doctor to rule out relevant medical explanations for the complaints. If patients had not been sufficiently examined, they were seen for standard medical tests at the Department of Internal Medicine prior to referral to our outpatient clinic. In accordance with recommendations by the Centers for Disease Control, sufficient medical examination included evaluation of somatic parameters that may provide evidence for a plausible somatic explanation for prolonged fatigue [for a list, see [9]. When abnormalities were detected in these tests, additional tests were made based on the judgement of the clinician of the Department of Internal Medicine who ultimately decided about the appropriateness of referral to our clinic. Trained therapists at our clinic ruled out psychiatric comorbidity as potential explanation for the complaints in unstructured clinical interviews.

workup

Accompanied suicide: A Swedish woman with myalgic encephalomyelitis/chronic fatigue syndrome chooses death over further suffering

“I felt it was important to write it and have it published to explain why I personally had to take this step, and hopefully illuminate why so many ME/CFS patients consider or commit suicide.”

Anne-ÖrtegrenAnne Örtegren has circulating  in the patient community a farewell post to follow her recent death, which she chose over further suffering.

“As you understand, this blog post has taken me many months to put together. It is a long text to read too, I know. But I felt it was important to write it and have it published to explain why I personally had to take this step, and hopefully illuminate why so many ME/CFS patients consider or commit suicide.

“And most importantly: to elucidate that this circumstance can be changed! But that will take devoted, resolute, real action from all of those responsible for the state of ME/CFS care, ME/CFS research and dissemination of information about the disease. Sadly, this responsibility has been mishandled for decades. To allow ME/CFS patients some hope on the horizon, key people in all countries must step up and act.”

Her last message is well worth the long read. I just want to start by dispelling a few issues with excerpts from Anne’s post.

Anne’s choice was not a matter of being clinically depressed.

As for most other ME/CFS patients who have chosen suicide, depression is not the cause of my choice. Though I have been suffering massively for many years, I am not depressed. I still have all my will and my motivation. I still laugh and see the funny side of things, I still enjoy doing whatever small activities I can manage. I am still hugely interested in the world around me – my loved ones and all that goes on in their lives, the society, the world (what is happening in human rights issues? how can we solve the climate change crisis?) During these 16 years, I have never felt any lack of motivation. On the contrary, I have consistently fought for solutions with the goal to get myself better and help all ME/CFS patients get better. There are so many things I want to do, I have a lot to live for. If I could only regain some functioning, quieten down the torture a bit and be able to tolerate clothes and a normal environment, I have such a long list of things I would love to do with my life!

Anne’s choice was not hasty, but occurred after much deliberation and a consultation.

This is not a rash decision. It has been processed for many years, in my head, in conversations with family and friends, in discussion with one of my doctors, and a few years ago in the long procedure of requesting accompanied suicide. The clinic in Switzerland requires an extensive process to ensure that the patient is chronically ill, lives with unendurable pain or suffering, and has no realistic hope of relief. They require a number of medical records as well as consultations with specialized doctors.

For me, and I believe for many other ME/CFS patients, this end is obviously not what we wanted, but it was the best solution to an extremely difficult situation and preferable to even more suffering. It was not hasty choice, but one that matured over a long period of time.

a remarkable life
Anne had a remarkable life ahead of her – until ME/CFS hit

The three main reasons Anne cites for her decision (elaborated below in in her post).

  1. Unbearable suffering
  2. No realistic way out of the suffering
  3. The lack of a safety net, meaning potential colossal increase in suffering when the next setback or medical incident occurs

Farewell – A Last Post from Anne Örtegren

Nobody can say that I didn’t put up enough of a fight.

For 16 years I have battled increasingly severe ME/CFS. My condition has steadily deteriorated and new additional medical problems have regularly appeared, making it ever more difficult to endure and make it through the day (and night).

Throughout this time, I have invested almost every bit of my tiny energy in the fight for treatment for us ME/CFS patients. Severely ill, I have advocated from my bedroom for research and establishment of biomedical ME/CFS clinics to get us proper health care. All the while, I have worked hard to find something which would improve my own health. I have researched all possible treatment options, got in contact with international experts and methodically tried out every medication, supplement and regimen suggested.

Sadly, for all the work done, we still don’t have adequately sized specialized biomedical care for ME/CFS patients here in Stockholm, Sweden – or hardly anywhere on the planet. We still don’t have in-patient hospital units adapted to the needs of the severely ill ME/CFS patients. Funding levels for biomedical ME/CFS research remain ridiculously low in all countries and the erroneous psychosocial model which has caused me and others so much harm is still making headway.

And sadly, for me personally things have gone from bad to worse to unbearable. I am now mostly bedbound and constantly tortured by ME/CFS symptoms. I also suffer greatly from a number of additional medical problems, the most severe being a systematic hyper-reactivity in the form of burning skin combined with an immunological/allergic reaction. This is triggered by so many things that it has become impossible to create an adapted environment. Some of you have followed my struggle to find clothes and bed linen I can tolerate. Lately, I am simply running out. I no longer have clothes I can wear without my skin “burning up” and my body going into an allergic state.

This means I no longer see a way out from this solitary ME/CFS prison and its constant torture. I can no longer even do damage control, and my body is at the end of its rope. Therefore, I have gone through a long and thorough process involving several medical assessments to be able to choose a peaceful way out: I have received a preliminary green light for accompanied suicide through a clinic in Switzerland.

When you read this I am at rest, free from suffering at last. I have written this post to explain why I had to take this drastic step. Many ME/CFS patients have found it necessary to make the same decision, and I want to speak up for us, as I think my reasons may be similar to those of many others with the same sad destiny.

These reasons can be summed up in three headers: unbearable suffering; no realistic way out of the suffering; and the lack of a safety net, meaning potential colossal increase in suffering when the next setback or medical incident occurs.

Important note

Before I write more about these reasons, I want to stress something important. As for most other ME/CFS patients who have chosen suicide, depression is not the cause of my choice. Though I have been suffering massively for many years, I am not depressed. I still have all my will and my motivation. I still laugh and see the funny side of things, I still enjoy doing whatever small activities I can manage. I am still hugely interested in the world around me – my loved ones and all that goes on in their lives, the society, the world (what is happening in human rights issues? how can we solve the climate change crisis?) During these 16 years, I have never felt any lack of motivation. On the contrary, I have consistently fought for solutions with the goal to get myself better and help all ME/CFS patients get better. There are so many things I want to do, I have a lot to live for. If I could only regain some functioning, quieten down the torture a bit and be able to tolerate clothes and a normal environment, I have such a long list of things I would love to do with my life!

Three main reasons

So depression is not the reason for my decision to terminate my life. The reasons are the following:

  1. Unbearable suffering

Many of us severely ill ME/CFS patients are hovering at the border of unbearable suffering. We are constantly plagued by intense symptoms, we endure high-impact every-minute physical suffering 24 hours a day, year after year. I see it as a prison sentence with torture. I am homebound and mostly bedbound – there is the prison. I constantly suffer from excruciating symptoms: The worst flu you ever had. Sore throat, bronchi hurting with every breath. Complete exhaustion, almost zero energy, a body that weighs a tonne and sometimes won’t even move. Muscle weakness, dizziness, great difficulties standing up. Sensory overload causing severe suffering from the brain and nervous system. Massive pain in muscles, painful inflammations in muscle attachments. Intensely burning skin. A feeling of having been run over by a bus, twice, with every cell screaming. This has got to be called torture.

It would be easier to handle if there were breaks, breathing spaces. But with severe ME/CFS there is no minute during the day when one is comfortable. My body is a war zone with constant firing attacks. There is no rest, no respite. Every move of every day is a mountain-climb. Every night is a challenge, since there is no easy sleep to rescue me from the torture. I always just have to try to get through the night. And then get through the next day.

It would also be easier if there were distractions. Like many patients with severe ME/CFS I am unable to listen to music, radio, podcasts or audio books, or to watch TV. I can only read for short bouts of time, and use the computer for even shorter moments. I am too ill to manage more than rare visits or phone calls from my family and friends, and sadly unable to live with someone. This solitary confinement aspect of ME/CFS is devastating and it is understandable that ME/CFS has been described as the “living death disease”.

For me personally, the situation has turned into an emergency not least due to my horrific symptom of burning skin linked to immunological/allergic reactions. This appeared six years into my ME/CFS, when I was struck by what seemed like a complete collapse of the bodily systems controlling immune system, allergic pathways, temperature control, skin and peripheral nerves. I had long had trouble with urticaria, hyperreactive skin and allergies, but at this point a violent reaction occurred and my skin completely lost tolerance. I started having massively burning skin, severe urticaria and constant cold sweats and shivers (these reactions reminded me of the first stages of the anaphylactic shock I once had, then due to heat allergy).

Since then, for ten long years, my skin has been burning. It is an intense pain. I have been unable to tolerate almost all kinds of clothes and bed linen as well as heat, sun, chemicals and other everyday things. These all trigger the burning skin and the freezing/shivering reaction into a state of extreme pain and suffering. Imagine being badly sunburnt and then being forced to live under a constant scalding sun – no relief in sight.

At first I managed to find a certain textile fabric which I could tolerate, but then this went out of production, and in spite of years of negotiations with the textile industry it has, strangely, proven impossible to recreate that specific weave. This has meant that as my clothes have been wearing out, I have been approaching the point where I will no longer have clothes and bed linen that are tolerable to my skin. It has also become increasingly difficult to adapt the rest of my living environment so as to not trigger the reaction and worsen the symptoms. Now that I am running out of clothes and sheets, ahead of me has lain a situation with constant burning skin and an allergic state of shivering/cold sweats and massive suffering. This would have been absolutely unbearable.

For 16 years I have had to manage an ever-increasing load of suffering and problems. They now add up to a situation which is simply no longer sustainable.

  1. No realistic way out of the suffering

A very important factor is the lack of realistic hope for relief in the future. It is possible for a person to bear a lot of suffering, as long as it is time-limited. But the combination of massive suffering and a lack of rational hope for remission or recovery is devastating.

Think about the temporary agony of a violent case of gastric flu. Picture how you are feeling those horrible days when you are lying on the bathroom floor between attacks of diarrhoea and vomiting. This is something we all have to live through at times, but we know it will be over in a few days. If someone told you at that point: “you will have to live with this for the rest of your life”, I am sure you would agree that it wouldn’t feel feasible. It is unimaginable to cope with a whole life with the body in that insufferable state every day, year after year. The level of unbearableness in severe ME/CFS is the same.

If we knew there were relief on the horizon, it would be possible to endure severe ME/CFS and all the additional medical problems, even for a long time, I think. The point is that there has to be a limit, the suffering must not feel endless.

One vital aspect here is of course that patients need to feel that the ME/CFS field is being taken forward. Sadly, we haven’t been granted this feeling – see my previous blogs relating to this here and here.

Another imperative issue is the drug intolerance that I and many others with ME/CFS suffer from. I have tried every possible treatment, but most of them have just given me side-effects, many of which have been irreversible. My stomach has become increasingly dysfunctional, so for the past few years any new drugs have caused immediate diarrhoea. One supplement triggered massive inflammation in my entire urinary tract, which has since persisted. The list of such occurrences of major deterioration caused by different drugs/treatments is long, and with time my reactions have become increasingly violent. I now have to conclude that my sensitivity to medication is so severe that realistically it is very hard for me to tolerate drugs or supplements.

This has two crucial meanings for many of us severely ill ME/CFS patients: There is no way of relieving our symptoms. And even if treatments appear in the future, with our sensitivity of medication any drug will carry a great risk of irreversible side-effects producing even more suffering. This means that even in the case of a real effort finally being made to bring biomedical research into ME/CFS up to levels on par with that of other diseases, and possible treatments being made accessible, for some of us it is unlikely that we would be able to benefit. Considering our extreme sensitivity to medication, one could say it’s hard to have realistic hope of recovery or relief for us.

In the past couple of years I, being desperate, have challenged the massive side-effect risk and tried one of the treatments being researched in regards to ME/CFS. But I received it late in the disease process, and it was a gamble. I needed it to have an almost miraculous effect: a quick positive response which eliminated many symptoms – most of all I needed it to stop my skin from burning and reacting, so I could tolerate the clothes and bed linen produced today. I have been quickly running out of clothes and sheets, so I was gambling with high odds for a quick and extensive response. Sadly, I wasn’t a responder. I have also tried medication for Mast Cell Activation Disorder and a low-histamine diet, but my burning skin hasn’t abated. Since I am now running out of clothes and sheets, all that was before me was constant burning hell.

  1. The lack of a safety net, meaning potential colossal increase in suffering when the next setback or medical incident occurs

The third factor is the insight that the risk for further deterioration and increased suffering is high.

Many of us severely ill ME/CFS patients are already in a situation which is unbearable. On top of this, it is very likely that in the future things will get even worse. If we look at some of our symptoms in isolation, examples in my case could be my back and neck pain, we would need to strengthen muscles to prevent them from getting worse. But for all ME/CFS patients, the characteristic symptom of Post-Exertional Malaise (PEM) with flare-ups of our disease when we attempt even small activities, is hugely problematic. Whenever we try to ignore the PEM issue and push through, we immediately crash and become much sicker. We might go from being able to at least get up and eat, to being completely bedbound, until the PEM has subsided. Sometimes, it doesn’t subside, and we find ourselves irreversibly deteriorated, at a new, even lower baseline level, with no way of improving.

PEM is not something that you can work around.

For me, new medical complications also continue to arise, and I have no way of amending them. I already need surgery for one existing problem, and it is likely that it will be needed for other issues in the future, but surgery or hospital care is not feasible for several reasons:

One is that my body seems to lack repairing mechanisms. Previous biopsies have not healed properly, so my doctor is doubtful about my ability to recover after surgery.

Another, more general and hugely critical, is that with severe ME/CFS it is impossible to tolerate normal hospital care. For ME/CFS patients the sensory overload problem and the extremely low energy levels mean that a normal hospital environment causes major deterioration. The sensory input that comes with shared rooms, people coming and going, bright lights, noise, etc, escalates our disease. We are already in such fragile states that a push in the wrong direction is catastrophic. For me, with my burning skin issue, there is also the issue of not tolerating the mattresses, pillows, textile fabrics, etc used in a hospital.

Just imagine the effects of a hospital stay for me: It would trigger my already severe ME/CFS into new depths – likely I would become completely bedbound and unable to tolerate any light or noise. The skin hyperreactivity would, within a few hours, trigger my body into an insufferable state of burning skin and agonizing immune-allergic reactions, which would then be impossible to reverse. My family, my doctor and I agree: I must never be admitted to a hospital, since there is no end to how much worse that would ma

Many ME/CFS patients have experienced irreversible deterioration due to hospitalization. We also know that the understanding of ME/CFS is extremely low or non-existent in most hospitals, and we hear about ME/CFS patients being forced into environments or activities which make them much worse. I am aware of only two places in the world with specially adjusted hospital units for severe ME/CFS, Oslo, Norway, and Gold Coast, Australia. We would need such units in every city around the

It is extreme to be this severely ill, have so many medical complications arise continually and know this: There is no feasible access to hospital care for me. There are no tolerable medications to use when things get worse or other medical problems set in. As a severely ill ME/CFS patient I have no safety net at all. There is simply no end to how bad things can get with severe ME/CFS.

Coping skills – important but not enough

I realize that when people hear about my decision to terminate my life, they will wonder about my coping skills. I have written about this before and I want to mention the issue here too:

While it was extremely hard at the beginning to accept chronic illness, I have over the years developed a large degree of acceptance and pretty good coping skills. I have learnt to accept tight limits and appreciate small qualities of life. I have learnt to cope with massive amounts of pain and suffering and still find bright spots. With the level of acceptance I have come to now, I would have been content even with relatively small improvements and a very limited life. If, hypothetically, the physical suffering could be taken out of the equation, I would have been able to live contentedly even though my life continued to be restricted to my small apartment and include very little activity. Unlike most people I could find such a tiny life bearable and even happy. But I am not able to cope with these high levels of constant physical suffering.

In short, to sum up my level of acceptance as well as my limit: I can take the prison and the extreme limitations – but I can no longer take the torture. And I cannot live with clothes that constantly trigger my burning skin.

Not alone – and not a rash decision

In spite of being unable to see friends or family for more than rare and brief visits, and in spite of having limited capacity for phone conversations, I still have a circle of loved ones. My friends and family all understand my current situation and they accept and support my choice. While they do not want me to leave, they also do not want me to suffer anymore.

This is not a rash decision. It has been processed for many years, in my head, in conversations with family and friends, in discussion with one of my doctors, and a few years ago in the long procedure of requesting accompanied suicide. The clinic in Switzerland requires an extensive process to ensure that the patient is chronically ill, lives with unendurable pain or suffering, and has no realistic hope of relief. They require a number of medical records as well as consultations with specialized doctors.

For me, and I believe for many other ME/CFS patients, this end is obviously not what we wanted, but it was the best solution to an extremely difficult situation and preferable to even more suffering. It was not hasty choice, but one that matured over a long period of time.

A plea to decision makers – Give ME/CFS patients a future!

As you understand, this blog post has taken me many months to put together. It is a long text to read too, I know. But I felt it was important to write it and have it published to explain why I personally had to take this step, and hopefully illuminate why so many ME/CFS patients consider or commit suicide.

And most importantly: to elucidate that this circumstance can be changed! But that will take devoted, resolute, real action from all of those responsible for the state of ME/CFS care, ME/CFS research and dissemination of information about the disease. Sadly, this responsibility has been mishandled for decades. To allow ME/CFS patients some hope on the horizon, key people in all countries must step up and act.

If you are a decision maker, here is what you urgently need to do: You need to bring funding for biomedical ME/CFS research up so it’s on par with comparable diseases (as an example, in the US that would mean $188 million per year). You need to make sure there are dedicated hospital care units for ME/CFS inpatients in every city around the world. You need to establish specialist biomedical care available to all ME/CFS patients; it should be as natural as RA patients having access to a rheumatologist or cancer patients to an oncologist. You need to give ME/CFS patients a future.

Please listen to these words of Jen Brea, which sum up the situation in the US, but are applicable to almost every country:

“The NIH says it won’t fund ME research because no one wants to study it. Yet they reject the applications of the world class scientists who are committed to advancing the field. Meanwhile, HHS has an advisory committee whose sole purpose seems to be making recommendations that are rarely adopted. There are no drugs in the pipeline at the FDA yet the FDA won’t approve the one drug, Ampligen, that can have Lazarus-like effects in some patients. Meanwhile, the CDC continues to educate doctors using information that we (patients) all know is inaccurate or incomplete.”

Like Jen Brea, I want a number of people from these agencies, and equivalent agencies in Sweden and all other countries, to stand up and take responsibility. To say: “ME! I am going to change things because that is my job.”

And lastly

Lastly, I would like to end this by linking to this public comment from a US agency meeting (CFSAC). It seems to have been taken off the HHS site, but I found it in the Google Read version of the book “Lighting Up a Hidden World: CFS and ME” by Valerie Free. It includes testimony from two very eloquent ME patients and it says it all. I thank these ME patients for expressing so well what we are experiencing.

PS.

My previous blog posts:

From International Traveler to 43 Square Meters: An ME/CFS Story From Sweden

Coping With ME/CFS Will Always Be Hard – But There are Ways of Making It A Little Easier

The Underfinanced ME/CFS Research Field Pt I: The Facts – Plus “What Can We Do?

The Underfinanced ME/CFS Research Field Pt II: Why it Takes 20 Years to Get 1 Year’s Research Done

My Swedish ME/CFS newsletters, distributed via e-mail to 2700 physicians, researchers, CMOs, politicians and medical journalists:

https://mecfsnyheter.se/

Take care of each other.

Love, Anne

 

low level funding
Relative to other diseases the NIH has provided pennies for ME/CFS research …but that does not mean progress is not being made

 

Photos are from Anne’s blog posts which are linked above.

Better days: When PLOS Blogs honored my post about fatal flaws in the PACE chronic fatigue syndrome follow-up study (2015)

The back story on my receiving this honor was that PLOS Blogs only days before had shut down the blog site because of complaints from someone associated with the PACE trial. I was asked to resign. I refused. PLOS Blogs relented when I said it would be a publicity disaster for PLOS Blogs.

mind the brain logoThe back story on my receiving this honor was that PLOS Blogs only days before had shut down the blog site because of complaints from someone associated with the PACE trial. I was asked to resign. I refused. PLOS Blogs relented when I said it would be a publicity disaster for PLOS Blogs.

screen shot 11th most accessedA Facebook memory of what I was posting two years ago reminded me of better days when PLOS Blogs honored my post about the PACE trial.

Your Top 15 in ’15: Most popular on PLOS BLOGS Network

I was included in a list of the most popular blog posts in a network that received over 2.3 million visitors reading more than 600 new posts. [It is curious that the sixth and seventh most popular posts were omitted from this list, but that’s another story]

I was mentioned for number 11:

11) Uninterpretable: Fatal flaws in PACE Chronic Fatigue Syndrome follow-up study Mind the Brain 10/29/15

Investigating and sharing potential errors in scientific methods and findings, particularly involving psychological research, is the primary reason Clinical Health Psychologist (and PLOS ONE AE) Jim Coyne blogs on Mind the Brain and elsewhere. This closely followed post is one such example.

Earlier decisions by the investigator group preclude valid long-term follow-up evaluation of CBT for chronic fatigue syndrome (CFS). At the outset, let me say that I’m skeptical whether we can hold the PACE investigators responsible… Read more

The back story was that only days before, I had gotten complaints from readers of Mind the Brain who found they were blocked from leaving comments at my blog site. I checked and found that I couldn’t even access the blog as an author.

I immediately emailed Victoria Costello and asked her what it happened. We agreed to talk by telephone, even though it was already late night where I was in Philadelphia. She was in the San Francisco PLOS office.

In the telephone conversation,  I was reminded me that there were some topics about which was not supposed to blog. Senior management at PLOS found me in violation of that prohibition and wanted me to stop blogging.

As is often the case with communication with the senior management of PLOS, no specifics had been given.  There was no formal notice or disclosure about what topics I couldn’t blog or who had complained. And there had been no warning when my access to the blog site was cut. Anything that I might say publicly could be met with a plausible denial.

I reminded Victoria that I had never received any formal specification about what I could blog nor from whom the complaint hand come. There had been a vague communication from her about not blogging about certain topics. I knew that complaints from either Gabrielle Oettingen or her family members had led to request the blog about the flaws in her book,  Rethinking Positive Thinking . That was easy to do because I was not planning another post about that dreadful self-help book.  Any other prohibition was left so vague that had no idea that I couldn’t blog about the PACE trial. I had known that the authors of the British Psychological Society’s Understanding Psychosis were quite upset with what I had said in heavily accessed blog posts. Maybe that was the source of the other prohibition, but no one made that clear. And I wasn’t sure I wanted to honor it, anyway.

I pressed Victoria Costello for details. She said an editor had complained. When I asked if it was Richard Horton, she paused and mumbled something that I took as an affirmative. Victoria then suggested that  it would be best for the blog network and myself if we had a mutually agreed-upon parting of ways. I told her that I would probably publicly comment that the breakup was not mutual and it would be a publicity disaster for the blog.

igagged_jpg-scaled500Why I was even blogging for PLOS Blogs? Victoria Costello had recruited me over after I expressed discontent with the censorship that I was receiving at Psychology Today. The PT editors there had complained that some of my blogging about antidepressants might discourage ads from pharmaceutical companies for which they depended for revenue. The editors had insisted on  the right to approve my posts before I uploaded them. In inviting me to PLOS Blogs, Victoria told me that she too was a refugee from blogging at Psychology Today.  I wouldn’t have to worry about restrictions on what I could say at Mind the Brain, beyond avoiding libel.

I ended the conversation accepting the prohibition about blogging about the PACE trial. This is was despite disagreeing with the rationale that it would be a conflict of interest for me to blog about it after requesting the data from the PLOS One paper.

Since then, I repeatedly requested that the PLOS management acknowledge the prohibition on my blogging or at least put it in writing. My request was met with repeated refusals from Managing Editor Iratxe Puebla, who always cited my conflict of interest.

In early 2017, I began publicly tweeting about the issue, stimulating some curiosity others about whether there was a prohibition. InJuly 2017, the entire Mind the Brain site, not just my blog, was shut.

In early 2018, I will provide more backstory on that shutdown and dispute what was said in the blog post below. And more about the collusion between PLOS One senior management and the PACE investigators in the data not being available 2 years after I requested it.

Message for Mind the Brain readers from PLOSBLOGS

blank plos blogs thumb nail
This strange thumbnail is the default for when no preferred image is provided. It could indicate the haste with which this blog was posted.

Posted July 31, 2017 by Victoria Costello in Uncategorized

After five years and over a hundred posts, PLOSBLOGS is retiring its psychology blog, Mind the Brain, from our PLOS-hosted blog network. By mutual agreement with the primary Mind the Brain blogger, James Coyne, Professor Coyne will retain the name of this blog and will take his archive of posts for reuse on his independent website, http://www.coyneoftherealm.com.

According to PLOSBLOGS’ policy for all our retired (inactive) blogs, any and all original posts published on Mind the Brain will retain their PLOS web addresses as intact urls, so links made previously from other sites will not be broken. In addition, PLOS will supply the archive of his posts directly to Prof Coyne so that he may repost them anywhere he may wish.

PLOS honors James Coyne’s voice as an important one in peer-to-peer scientific criticism. As discussed with Professor Coyne in recent days, after careful consideration PLOSBLOGS has concluded that it does not have the staff resources required to vet the sources, claims and tone contained in his posts, to assure they are aligned with our PLOSBLOGS Community Guidelines. This has lead us to the conclusion that Professor Coyne and his content would be better served on his own independent blog platform. We wish James Coyne the best with his future blogging.

—Victoria Costello, Senior Editor, PLOSBLOGS & Communities

Bollocks!

Stop using the Adverse Childhood Experiences Checklist to make claims about trauma causing physical and mental health problems

Scores on the adverse childhood experiences (ACE) checklist (or ACC) are widely used in making claims about the causal influence of childhood trauma on mental and physical health problems. Does anyone making these claims bother to look at how the checklist is put together and consider what a summary score might mean?

 

mind the brain logo

Scores on the adverse childhood experiences (ACE) checklist (or ACC) are widely used in making claims about the causal influence of childhood trauma on mental and physical health problems. Does anyone making these claims bother to look at how the checklist is put together and consider what a summary score might mean?

In this issue of Mind the Brain, we begin taking a skeptical look at the ACE checklist. We ponder some of the assumptions implicit in what items were included and how summary scores of the number of items checked are interpreted. Readers will be left with profound doubts that the ACE is suitable for making claims about trauma.

This blog will eventually be followed by another that presents the case that scores on the ACC do not represent a risk factor for health problems, only a relatively uninformative risk marker. In contrast to potentially modifiable risk factors, risk markers are best interpreted as calling attention to the influence of some combination of other risk factors, many of as yet unspecified, but undoubtedly of an entirely different nature than what is being studied. What?!! You will have to stay tuned, but I’ll give some hints about what I am talking about in the current blog post.

Summary of key points

 The ACE checklist is a collection of very diverse and ambiguous items that cannot be presumed to necessarily represent traumatic experiences.

Items variously

  • Represent circumstances that are not typically traumatic.
  • Reflect the respondent’s past or current psychopathology.
  • Make equivalent and traumatic vastly different experiences, many neutral and some that are positive.
  • Reinterpret a personal vulnerability due to familial transmission of psychopathology, either direct or indirect, rather than simply an exposure to events.
  • Ignore crucial contextual information, including timing of events.

There is reason not to assume that higher summed scores for the ACE represent more exposure to trauma than lower scores.

Are professionals misinterpreting the ACE checklist just careless or are they ideologues selectively identifying “evidence” for their positions which don’t depend on evidence at all?

ace-7Witness claims based on research with the ACE that migraines are caused by sexual abuse   and that psychotherapy addressing that abuse should be first line treatment. Or claims that childhood trauma is as strong a risk factor for psychosis and schizophrenia as smoking is for lung cancer [* ] and so psychotherapy is equivalent to medication in its effects. Or claims that myalgic encephalomyelitis, formerly known as chronic fatigue syndrome, is caused by childhood trauma and the psychological treatments can be recommended as the treatment of choice. These claims share a speculative, vague neo-cryptic pseudopsychoanalytic set of assumptions that is seldom articulated or explicitly confronted with evidence. Authors typically leap from claims about childhood trauma causing later problems to non sequitur claims about the efficacy of psychological intervention in treating these problems by addressing trauma. These claims about efficacy of trauma-focused treatment are not borne out in actually examining effects observed in randomized controlled trials.

Rather than attempting to address a provocative question about investigator motivation without a ready way of answering it, I will show most claims about trauma causing mental and physical health problems are, at best, based on very weak evidence, if they depend solely on the ACE checklist.

I will leave for my readers to decide if some authors who make such a fuss about the ACE have bothered to look at the instrument or care that is so inappropriate for the purposes to which they put it.

The ACE is reproduced at the bottom of this post and it is a good idea to compare what I’m saying about it to the actual checklist.

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What “science” is behind such speculations?

The ACE was originally intended for educational purposes, not as a scientific instrument. Perhaps that explains its gross deficiencies as a key measure of psychological and epidemiological constructs.

The ACE checklist is a collection of very different and ambiguous items that cannot be presumed to represent traumatic experiences.

The ACE consists of ten dichotomous items for which the respondent is asked to indicate no/yes whether an experience occurred before the age of 18.  However, for six of the 10 items, the respondent is given further choices  that often differ greatly in the kind of experience to which the items refer. Scoring of the instrument does not take which of these experiences is the basis of a response. For example,

5. Did you often feel that … You didn’t have enough to eat, had to wear dirty clothes, and had no one to protect you? or

Your parents were too drunk or high to take care of you or take you to the doctor if you needed it?

Yes   No     If yes enter 1     ________

This item treats some very different circumstances as equivalent. The first half is complex, but largely covers the experience of living in poverty, but combines that with “having no one to protect you.” In contrast, the second half refers to substance abuse on the part of parents. In neither case, is there any room for interpreting what mitigating circumstances in the respondent’s life might have influenced effects of exposure. Presumably, the timing of this exposure would be important. If the exposure only occurred at the end of the 18 year period covered by the checklist, effects could be mitigated by other individual and social resources the respondent had.

Single items that are added together in a summary score.  We have to ask whether there is an equivalency between the two halves of the item that will be treated as the same. This will be an accumulating concern as we go through the 10 item questionnaire

The items vary greatly in the likelihood that they refer to an experience that was traumatic. Seldom do any of the researchers who use the ACE explain what they mean by trauma. If they did, I doubt that they could make a good argument that in endorsing many of these items would indicate that a respondent had faced a trauma.

From the third edition of the American Psychiatric Association Diagnostic and Statistical Manual (DSM-III) onward to DSM-5, the assumption has been that a traumatic event is a catastrophic stressor outside the range of usual human experience.

With that criteria in mind we have to ask if items are likely to represent a traumatic experience for most people. In answering this question, we also have to ask how we willing to consider a particular item is equivalent to other items in arriving at an overall score reflecting exposure to trauma before age 18. Yet, if summary scores are to be meaningful, assumption has to be made that items contribute equally if they are endorsed

6. Were your parents ever separated or divorced?

Yes   No     If yes enter 1     ________

The item refers to a highly prevalent and complex event, the nature and consequences of which are likely to unfold over time. Importantly, we need a sense of context to judge whether the event is traumatic and, if so how severe. Presumably, it would matter greatly when, across the 18 year span, the event that occurred. No timing or other information is asked of the respondent, only whether or not this event occurred. Neither the respondent nor anyone interpreting a score on the inventory has further information as to what is meant.

Other problems with ambiguous items.

Questions can be raised about the validity of all the individual items and the wisdom of combining them as equivalent in creating a summary score.

Items 1 and 2: Items raise questions about what role the respondent played eliciting the event.

 Did an event simply befall a respondent? Was it related to some pre-existing characteristic of the respondent? Or did the respondent have an active role in generating the event?

Did a parent or other adult member of the household often…

Swear at you, insult you, put you down, or humiliate you?

or

Act in a way that made you afraid that you might be physically hurt?

Yes   No     If yes enter 1     ________

And

Did a parent or other adult in the household often …

Push, grab, slap, or throw something at you?

or

Ever hit you so hard that you had marks or were injured?

Yes   No     If yes enter 1     ________

 Here, as throughout the rest of the checklist, questions can be raised about whether these items refer simply to an environmental exposure in epidemiological terms, say, equivalent to asbestos or tobacco. We don’t know the frequency, intensity or context of a the behavior in question, all of which may be crucial in evaluating whether a trauma occurred. For instance, it matters greatly if the behavior happened frequently when the respondent as a toddler or was limited to a struggle that occurred when the respondent was a teen high on drugs  attempting to take the car keys and go for a after midnight drive.

Like most of the rest of the questionnaire, there is the question of timing.

Item 3: There is so much ambiguity in endorsments of (ostensible) sexual abuse. Maybe it was a positive, liberating experience.

This is a crucial item and discussions of the ACE often assume that it is endorsed and represents a traumatic experience:

Did an adult or person at least 5 years older than you ever…

Touch or fondle you or have you touch their body in a sexual way?

or

Try to or actually have oral, anal, or vaginal sex with you?

Note that this is a complex item for which endorsement could be on the basis of a single instance of a person at least 5 years older touching or fondling the respondent. What if the presumed “perpetrator” is the 20 year old boyfriend or girlfriend of a 14 year old?

Are we willing to treat as equivalent “touch” or ‘fondle you” and “having anal sex” in all instances?

Arguably, the event which construed as trauma could actually be quite positive, as in the respondent  forming a secure attachment with a somewhat older, but nonetheless appropriate partner. All that is unconventional is not traumatic. What if the respondent and  alleged “perpetrator” were in a deeply intimate relationship or already married?

The research that attempts to link endorsement of such an item to lasting mental and physical health problems is remarkably contradictory and inconsistent 

Item 4:  Does this  item reflect the respondent’s serious clinical depression or other mental disorder before age 18 or currently, when the checklist is being completed?

Did you often feel that …  No one in your family loved you or thought you were important or special?    or

Your family didn’t look out for each other, feel close to each other, or support each other?

Yes   No     If yes enter 1     ________

As elsewhere in the checklist, there is no place for the respondent or someone interpreting a “yes” response for taking into account timing or contextual factors that might mitigate or compound effects of this “exposure.”

Item 5: Is this a  traumatic exposure or an enduring set of circumstances conferring multiple known risks to mental and physical health?

Did you often feel that …

You didn’t have enough to eat, had to wear dirty clothes, and had no one to protect you?

or

Your parents were too drunk or high to take care of you or take you to the doctor if you needed it?

Yes   No     If yes enter 1     ________

This item has already been discussed above, but is worth revisiting in terms of raising issues whether particular items refer either directly or indirectly to enduring sets of circumstances that pose their own enduring threat. The relevant question is whether items which ostensibly represent “traumatic events” and risk for subsequent problems are not risk factors, but only risk indicators, and not particularly informative ones.

Item 7: Could an ostensibly a traumatic exposure actually be no actual exposure?

Was your mother or stepmother:

Often pushed, grabbed, slapped, or had something thrown at her?    or

Sometimes or often kicked, bitten, hit with a fist, or hit with something hard?    or

Ever repeatedly hit over at least a few minutes or threatened with a gun or knife?

Yes   No     If yes enter 1     ________

Like item four, which refers to ostensible sexual abuse, this item seems to be one of the least ambiguous in terms of representing exposure to risk. But does it? We don’t know the timing, duration, or context. For instance, the mother might no longer be in the home and the respondent might not have known what happened at the time. There is even the possibility that the respondent was the “perpetrator” of such violence against the mother.

Items 8 and 9: Are traumatic exposures or indications of familial transmission of psychopathology?

Did you live with anyone who was a problem drinker or alcoholic or who used street drugs?

Yes   No

If yes enter 1     ________

And

Was a household member depressed or mentally ill or did a household member attempt suicide?    Yes   No     If yes enter 1     ________

These items are highly ambiguous. They don’t take in consideration whether the person was a biological relative, or whether they were a parent, sibling, or someone not biologically related. They don’t take into account timing. There may not have even been any direct exposure to the substance misuse or the attempted suicide, but the respondent only later learned of something that was closeted.

Item 10: traumatic exposure or relief from exposure?

Did a household member go to prison?

Yes   No

If yes enter 1     ________

The implications of endorsement of this item depend greatly on whom the household member was and the circumstances of them going to prison.

There may be a familial relationship with this person, but it could have been an abusive stepparents or stepsiblings, with the incarceration representing a lasting relief from some impressive situations. Or the person who became incarcerated was not an immediate family member, but somewhat more transient, maybe someone who was just renting a room or given a place to stay. We just don’t know.

Does adding up all these endorsements in a summary score clarify or confuse further?

Now add up your “Yes” answers:   _______   This is your ACE Score

 It would be useful to briefly review the assumptions involved in summing across items of a checklist and entering the summary score as a continuous variable in statistical analyses.

Classical test theory recognizes that the individual items may imperfectly reflect the underlying construct, in this case, traumatic exposure. However, in constructing a sum, the expectation is that the imperfections or errors of measurement in particular items cancel each other out. The summed score becomes a purer a representation of the underlying construct than any of the original items. Thus, the summary score will be more reliable and valid than any of the individual items would be.

There are a number of problems in applying this assumption to a summary ACE score. The items are quite heterogeneous, i.e., they vary wildly in whether they are likely to represent a traumatic exposure, and if so, the severity of that exposure. More importantly, there is a huge amount of variation in what these brief items would represent for particular individuals in the contexts they found themselves in the first 18 years of their lives. Undoubtedly, most endorsements of these items would represent false positives, if we hold ourselves to any strict definitions of trauma. If we don’t do so, we risk equating the only normative experiences that may have neutral or even positive effects on the respondent with serious exposures to traumatic events with lasting consequences

We are not in a position to know whether a score of five or even eight necessarily represents more traumatic exposure than a score of one.

Moreover, there is important empirical research of the clustering of events. We certainly cannot consider them random and unrelated. One classic study found 

In our data, total CCA was related to depressive symptoms, drug use, and antisocial behavior in a quadratic manner. Without further elucidation, this higher order relationship could have been interpreted as support for a sensitization process in which the long-term impact of each additional adversity on mental health compounds as childhood adversity accumulates. However, further analysis revealed that this acceleration effect was an artifact of the confounding of high cumulative adversity scores with the experience of more severe events. Thus, respondents with higher total CCA had disproportionately poorer emotional and behavioral functioning because of both the number and severity of the adversities they were exposed to, not the cumulative number of different types of adversities experienced.

And

Because low-impact adversities did not present a cumulative hazard to young adult mental health, they functioned as suppressor events in the total sum score, consistent with Turner and Wheaton’s (1997) expectation. Their inclusion increased the “noise” in the score and greatly watered down the influence of high-impact events. Thus, in addition to decreasing efficiency, total scores may seriously underestimate the cumulative effects of severe forms of childhood adversity, such as abuse and serious neglect.

But what if many or most of the high scores in a particular sample represent only a clustering of low- or no-impact adversities?

Another large-sample, key study cautioned:

Significant effects of parental separation}divorce in predicting subsequent mood disorders and addictive disorders are powerfully affected by whether or not there was parental violence and psychopathology in the household prior to the break-up and whether exposure to these adversities was reduced as a result of the separation (Kessler et al. 1997a). There are some situations – such as one in which the father was a violent alcoholic – where our data suggest that parental divorce and subsequent removal of the respondent from exposure to the father might actually be associated with a significant improvement in the respondent’s subsequent disorder risk profile, a possibility that has important social policy implications.

Finding Your ACE Score-page-0

NOTE

*Richard Bentall commonly interprets summed ACE scores in peer reviewed articles  as having a traditional dose-response association with mental health outcomes, and therefore as representing a modifiable causal factor in psychosis. In books and in social media, his claims become simply absurd.

bentall

I don’t think his interpretations withstand a scrutiny of the items and what a summed score might conceivably represent.

eBook_Mindfulness_345x550Preorders are being accepted for e-books providing skeptical looks at mindfulness and positive psychology, and arming citizen scientists with critical thinking skills. 

I will also be offering scientific writing courses on the web as I have been doing face-to-face for almost a decade. I want to give researchers the tools to get into the journals where their work will get the attention it deserves.

Sign up at my website to get advance notice of the forthcoming e-books and web courses, as well as upcoming blog posts at this and other blog sites. Get advance notice of forthcoming e-books and web courses. Lots to see at CoyneoftheRealm.com.
 

 

 

The SMILE Trial Lightning Process for Children with CFS: Results too good to be true?

The SMILE trial holds many anomalies and leaves us with more questions than answers.

keith'ds pouting girl

A guest post by Dr. Keith Geraghty

Honorary Research Fellow at the University of Manchester, Centre for Primary Care, Division of Population Health and Health Services Research

censored
ASA ruling left some awkward moments in Phil Parker’s videos promoting his Lightning Process.

The Advertising Standards Authority previously ruled that the Lightning Process (LP) should not be advertised as a treatment for CFS/ME. So how then, did LP end up getting tested as a treatment in a clinical trial involving adolescents with CFS/ME? Publication of the trial sparked controversy after it was claimed that LP, in addition to specialist medical care, out-performed specialist medical care alone. This blog attempts to shed light on just how a quack alternative online teaching programme, ended up in a costly clinical trial and discusses how the SMILE trial exemplifies all that is wrong with contemporary psycho-behavioural trials; that are clearly vulnerable to bias and spin.

The SMILE trial compared LP plus specialist medical care (SMC) to SMC alone (commonly a mix of cognitive behavioural therapy and graded exercise therapy). LP is a trademarked training programme created by Phil Parker from osteopathy, life coaching and neuro-linguistic programming. It costs over £600 and after assessment and telephone briefings, clients attend group sessions over three days. While there is much secrecy about what exactly these sessions involve, a cursory search online shows us that past clients were told to ‘block out all negative thoughts’ and to consider themselves well, not sick. A person with an illness is said to be ‘doing illness’ (LP spells doing as duing, to signify LP means more than just doing). LP appears to attempt to get a participant to ‘stop doing’ by blocking negative thoughts and making positive affirmations.

Leading psychologists have raised concerns. Professor James Coyne called LP “quackery” and said neuro-linguistic programming “…has been thoroughly debunked for its pseudoscience”. In an expert reaction to the SMILE trial for the Science Media Centre, Professor Dorothy Bishop of Oxford University stated: “the intervention that was assessed is commercial and associated with a number of warning signs. The Lightning Process appears based on neuro-linguistic programming, which, despite its scientific-sounding name, has long been recognised as pseudoscience“.

The first and most obvious question is why did the SMILE trial take place? Trial lead Professor Esther Crawley, who runs an NHS paediatric CFS/ME clinic, says she undertook the trial after many of her patients and their parents asked about LP. Patients with CFS/ME often report a lack of support from doctors and health care providers and some turn to the internet seeking help; some are drawn to try alternative approaches, such as LP. But is that justification enough for spending over £160,000 on testing LP on children? I think not. Should we test every quack approach peddled online: herbs, crystals, spiritual healing – particularly when funding in CFS/ME research is so limited currently? There must also be a compelling scientific plausibility to justify a trial. Simply wanting to see if something helps, does not merit adequate justification.

The SMILE trial has a fundamental design flaw. The trial compared specialist medical care alone (SMC) against SMC plus LP (SMC&LP). To the novice observer this may appear acceptable, but clinical trials are used to test item x against item y. For example, imagine trying to see which drug works better, drug A or drug B, you would not give drug A to one group and both drugs A and B to another group – yet this is exactly what happened in SMILE. In seeking to test LP, Prof. Crawley gave LP&SMC together – rendering any findings from this trial arm as pretty meaningless. The proper controls were missing. In addition, a trial of this magnitude would normally have a third arm, a do-nothing or usual care group, or another talk therapy control – yet such controls were missing.

Next we turn to the trial’s primary outcome measures. These were subjective self-reports of changes in physical function (using SF-36). Secondary outcomes were quality of life, anxiety and school attendance. These outcomes were assessed at 6 months with a follow-up at 12 months. It is reported that SMC+LP outperformed SMC alone on these measures at 6 and maintained at 12 months. However, there is no way to determine whether any claimed improvements came from LP alone, given LP was mixed with SMC. We could assume that LP+SMC meant more support, positive expectations and increased contact time. Here we see how farcical SMILE is as a trial. We have one group getting two treatments (possible double help) and one group getting one treatment (possible half help).

Of particular concern is how few of the available patients enrolled in and completed the trial: 637 children aged 12-18 attended screening or appointment at a specialist CFS/ME clinic; fewer than half (310) were deemed eligible; just 136 consented to receiving trial information and then only 100 were randomised (less than 1/3 of the eligible group). 49 had SMC and 51 had SMC+LP. Overall 207 patients either declined to participate or were not sufficiently interested to return the consent form. Were patients self-selecting? Were those less likely to respond to nonspecific factors choosing not to participate, and were we left with a group interested in LP – give Prof. Crawley said many patients asked about LP?

As the trial progressed, patients dropped out: of the 51 participants allocated to SMC+LP, only 39 received full SMC+LP. At 6-month assessment just 38 of the 48 allocated to SMC and 46 of the 51 in SMC+LP are fully recorded. At 12 months there are further losses to follow-up in both cohorts: 14% in LP and 24% in SMC.  The reasons for participant loss are not fully clear, though the paper reports 5 adverse events (3 in the SMC+LP arm). It is worth noting that physical function at 6 months deteriorated in 9 participants (roughly 10% overall), 8 in the SMC arm, with 5 participants having a fall of ≤10 on the SF-36 physical function subscale (deemed not clinically important). Again questions are raised as to whether some degree of self-selection took place? The fact 3 of the participants assigned to SMC alone appear to have received LP reflects possible contamination of research cohorts that are meant to be kept apart.

 Seven problems stand out in SMILE:

  1. The use of the SF-36 physical function test was questionable. This self-report instrument is not designed or adequately validated for use in children.
  2. Many of the participants appear to have had symptoms of anxiety and depression at the start of the trial. SMILE defined anxiety and depression as a score of ≥12 out of 22 on the self-report HADS. Usually a score of 8 or above is considered positive for mild anxiety and depression, and of above 12 for moderate anxiety and depression[1]. The average mean HADS score at trial entry was 9.6 (meaning using standard cut-offs, most participants met a criteria for anxiety and depression). On the Spence Anxiety Scale (SCAS) the average entry score was 35, with above 33 indicative of anxiety in this age group. Such mild to moderate elevations in depression and anxiety symptoms are very responsive to nonspecific support.
  3. There is an anomaly in the data on improvement: in the physical function test, the average base level of the children at entry into the trial was 54.5 (n=99), considered severely physically impaired. Only 52.5% of participants had been able to attend at least 3 days of school in the week prior to their entry into the study. Yet those assigned to SMC+LP were well enough to attend 3 consecutive days of sessions lasting 4 hours. The reports of severe physical disablement do not match the capabilities of those who participated in the course. Were the children’s self-reported poor physical abilities exaggerated to justify enrolment in the trial? Were the children’s elevated depression and anxiety symptoms responsive to the nonspecific elements in extra time of being assigned to LP plus standard care?
  4. If the subjective self-report is accepted as a recovery criterion, in LP, just 12 hours of talk therapy, added to SMC would cure the majority of children with CFS. Such an effect would be astonishing, if true. In randomized controlled trials in adults with CFS/ME, such dramatic restoration of physical function (a wholesale return to near normal) is universally not seen. The SMILE Trial is clearly unbelievable.
  5. SMILE’s reliance on the broad NICE criteria means there is a clear risk patients were included in the trial who would not have met stricter definitions of the illness. There is a growing concern that loose entry criteria in clinical trials in ME/CFS allow enrolments of many participants who do not in fact have ME/CFS. A detailed study of CFS prevalence found many children are wrongly diagnosed with CFS, when they may just be suffering from general fatigue and/or mental health complaints (Jones et al., 2004). SMILE uses NICE guidelines to diagnose CFS: fatigue must be present for at least 3 months with one or more of four other symptoms, which can be as general as sleep disturbance[2]. In contrast, Jones et al. showed that using the Centre for Disease Control criteria of at least four specific symptoms alongside detailed clinical examination, many children believed to have CFS are diagnosed with other exclusionary disorders, often general fatigue, mental health complaints, drug and alcohol abuse or eating disorders (that are often not readily disclosed to parents or doctors)[3].
  6. LP involves attempting to coerce clients into thinking that they have control over their symptoms and to block out symptoms. This alone would distort any response by a participant in a follow-on questionnaire about symptoms.
  7. LP was delivered by people from the Lightning Process Company. Phil Parker and his employees held a clear financial interest in a positive outcome in SMILE. Such an obvious conflict of interest is hard to disentangle and totally nullifies any outcomes from this trial.

Final Thoughts

The SMILE trial holds many anomalies and leaves us with more questions than answers.

It is not clear whether the children enrolled in the trial, diagnosed with CFS using NICE criteria, might of been deemed non-CFS using more stringent clinical screening (e.g. CDC or IOM Criteria).

There is no way of determining whether any effect following SMC+LP was anything more than the result of non-specific factors, psychological tricks and persuasion.

The fact LP+SMC appears to have cured the majority of participants with as little as 12 hours talk therapy is a big flashing red light that this trial is clearly fundamentally flawed.

There is a very real danger of promoting LP as a treatment for CFS/ME: The UK ME Association conducted a survey of members (4,217 members) and found that 20% of those who tried LP reported feeling worse (7.9% slightly worse,12.9% much worse). SMILE cannot be, and should not be, used to justify LP as a treatment for CFS/ME.

The Lightning Process has no scientific credibility and this trial highlights a fundamental flaw in contemporary clinical trials: they are susceptible to suggestion, bias and spin. The SMILE trial appears to draw paediatric CFS/ME clinical care for children into a swamp of pseudoscience and mysticism. This is a clear step backward. There is little to smile about after reviewing the SMILE trial.

Dr. Geraghty is currently an Honorary Research Fellow within the Centre for Primary Care, Division of Population Health and Health Services Research at the University of Manchester. He previously worked as a research associate at Cardiff University and Imperial College London. He left a career in clinical medicine after becoming ill with ME/CFS. The main themes of his work are doctor-patient relationships, medically unexplained symptoms, quality and safety in health care delivery, physician well-being and evidence-based medicine. He has a special interest in medically unexplained symptoms (MUS), and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. 

Although only recently published, his recent ‘PACE-Gate’: When clinical trial evidence meets open data access is already ranked #2 out of 1,350 papers in altmetics in Journal of Health Psychology.

A recent Times article cited Dr Geraghty on reasons why NICE need to update their recommendations for ME/CFS

Special thanks to John Peters and David Marks for their feedback.

References:
Coyne, J. (2017) Mind the Brain Blog, https://www.coyneoftherealm.com/blogs/mind-the-brain/embargo-broken-bristol-university-professor-to-discuss-trial-of-quack-chronic-fatigue-syndrome-treatment
Dorothy Bishop andExpert Commentary to the SMC (2017) http://www.sciencemediacentre.org/expert-reaction-to-controversial-treatment-for-cfsme/

1. Crawley, E., et al., Chronic disabling fatigue at age 13 and association with family adversity. Pediatrics, 2012. 130(1): p. e71-e79.
2. Crawley, E.M., et al., Clinical and cost-effectiveness of the Lightning Process in addition to specialist medical care for paediatric chronic fatigue syndrome: randomised controlled trial. Archives of Disease in Childhood, 2017.
3. Jones, J.F., et al., Chronic fatigue syndrome and other fatiguing illnesses in adolescents: a population-based study. Journal of Adolescent Health, 2004. 35(1): p. 34-40.