A general thread on the PACE trial!

[Esther12]

Just saw this reply from the Department for Business, Energy & Industrial Strategy to @Paul Watton linked to on social media, which includes bits on PACE: https://app.box.com/s/wr8rzkaeulprkki2y213yinmqtpoh0vu

eg:

The Minister is sorry that you were not satisfied with his response to Lee Rowley MP, dated 5 April. Whilst we are aware of the concer ns raised about the PACE trial’s methodology, there has been no suggestion of fabrication or falsification of the data, or of plagiarism. We do not believe it is fair to characterise the researchers as determined wrong - doers.

The Government strongly supports the drive towards transparency and ensuring the results of all trials are published. Withdrawing the paper from the literature goes against transparency requirements, and controversy over the methodology is not appropriate grounds for retraction. The right place for debate about the quality of the evidence , from this and other trials , is in the scientific literature and amongst those responsible for developing or updating clinical practice guidelines.

I'm sure I saw an earlier part of this correspondance elsewhere. @Paul Watton - is there anywhere that all the letters are linked from, for people to follow them through?
https://twitter.com/sjblakemore

 

[Sean]

The Government strongly supports the drive towards transparency and ensuring the results of all trials are published. Withdrawing the paper from the literature goes against transparency requirements, and controversy over the methodology is not appropriate grounds for retraction. The right place for debate about the quality of the evidence , from this and other trials , is in the scientific literature and amongst those responsible for developing or updating clinical practice guidelines.

Which, among other things, would require access to the full (anonymised) data set.

So PACE will be releasing that without delay?

Just asking for a dead friend.

 

[Sly Saint]

Lancet TV

this was the Trudie Chalder one from the same time:


the PACE press conference:


and an interview with Chalder on how to 'deal' with CFS patients:



not recommended if you're feeling queasy; and if you are not then you will be afterwards....

 

[Dolphin]

(Probably not very important)
Not to be confused with Richard Horton of the Lancet

---------- Forwarded message ----------
From: 'Dr. Marc-Alexander Fluks' fluks@combidom.com [LocalME]
Richard Holton's 3rd Uehiro Lecture: PACE





Source: Practical Etics
Date: May 28, 2018
URL:
http://blog.practicalethics.ox.ac.u...-attitude-richard-holtons-3rd-uehiro-lecture/

Illness and Attitude – Richard Holton's 3rd Uehiro Lecture
----------------------------------------------------------
Jonathan Pugh

In the final lecture of the 2018 Uehiro lecture series, Richard Holton
concluded his reflections on the theme of 'illness and the social self'
by turning to questions about how attitudes can play a role in the onset
of medical disorders, with a particular focus on psycho-somatic
disorders.

Self Conception and Psycho-Somatic Disorders

(...)

Psycho-somatic illness is of course a hugely contested area, as
evidenced by the hotly contested PACE trial into myalgic
encephalomyelitis/chronic fatigue syndrome in 2011, and the nosological
boundaries remain sketchy in this area.

(...)

--------
(c) 2018 University of Oxford

 

[Hutan]

(Probably not very important)

but it's an interesting quick read.
Of psychosomatic illness:

Moreover, attempts to define it negatively (the approach taken by DSM IV) as ‘disease which isn’t physiologically explained’ are too broad; according to the negative approach AIDs should have been classified as a psychosomatic illness prior to the discovery of the HIV virus.

Well, yes.

It seems the best theory of psychosomatic illness that Holton could come up with is this:

Holton suggests that patients presenting with psycho-somatic disorders may genuinely believe (in a non-motivated sense) that they have a disorder (based on evidence of their own symptoms), and that this belief leads them to manifest the symptoms more strongly. It is essentially a self-re-inforcing loop; to put it crudely, the symptoms cause the belief, and the belief causes further manifestations of those symptoms. Holton claims that the picture here looks simplistic, but we do not yet have evidence that would give us sufficient reason to abandon it.

I'm going off topic, but while you are at that Oxford University Ethics site, this article is worth reading after the Holton one. It is ironic that there is such outrage about the possibility of demonic possession while psychosomatic illness, which has a similar evidence base, is seen as mainstream.

http://blog.practicalethics.ox.ac.u...ics-really-are-possessed-by-demons-after-all/

Irmak concludes that ‘it is time for medical professions to consider the possibility of demonic possession in the etiology of schizophrenia’ and that ‘it would be useful for medical professions to work together with faith healers to define better treatment pathways for schizophrenia’ (p. 776).

This is a dumbfounding argument, and it is shocking to find it published in a post-mediaeval peer-reviewed journal. Lest anyone suspect me of being unfairly prejudiced against the possibility of demons, let me point out that even those who subscribe to a demonic metaphysics should not be persuaded by Irmak’s argument. His observation that ‘there exist similarities between the clinical symptoms of schizophrenia and demonic possession’ is no more surprising than the observation that there exist similarities between financial compensation for childhood tooth loss and visits by the tooth fairy: in each case, the latter is a hypothesis motivated by a desire to explain the former. ... But, even so, in the words of the comedian Dara Ó Briain, ‘just because science doesn’t know everything doesn’t mean you can fill in the gaps with whatever fairy tale most appeals to you’.

What is most concerning about this argument is not that Irmak believes demonic possession to be worthy of serious consideration in explaining schizophrenia. People hold bizarre beliefs all the time, and it may be that Irmak is well-intentioned; ... What I find more disturbing is that the editorial board and peer reviewers of a scholarly publication, in 2014, find this view of mental illness worthy of dissemination.

It was strangely comforting to see that the first comment under that article was a strenuous defence of the existence of demons. When the bar is so low for published theories on the cause of poorly understood illnesses, it's not surprising that the PACE trial results were published uncritically.

 

[Jonathan Edwards]

Holton claims that the picture here looks simplistic, but we do not yet have evidence that would give us sufficient reason to abandon it.

Or to even take it seriously?

The more I think about these things the more it all seems similar to homeopathy. The idea of treating like with like, although triggered in 1810 by Jenner's vaccination, probably draws on a deep belief in this principle in all of us. The exorcist treats the violent devilish possession with even more violent shaking of the subject's head and body. The GET therapist treats suffering caused by exercise with exercise. The homeopath treats fever with a fever-inducing agent.

Science, as Lewis Wolpert pointed out, is about replacing intuitive ideas that don't actually work very well when tested with counter-intuitive ideas that do. The idea of a vicious circle of belief and symptoms is what anybody's grandma can think up. Science is not about giving grandma's prejudices fancy names, it is about seeing the emptiness of the popular view and replacing it with something else.

 

[alex3619]

"Whilst we are aware of the concer ns raised about the PACE trial’s methodology, there has been no suggestion of fabrication or falsification of the data, or of plagiarism. We do not believe it is fair to characterise the researchers as determined wrong - doers. "

There is however deliberate and inappropriate manipulation of that data with respect to SF36PF data. How should we consider that? I don't think anyone is claiming they falsified data, the issues are in methodology, analysis, and claims based upon extreme interpretations.

 

[alex3619]

The more I think about these things the more it all seems similar to homeopathy.

The problem is large areas of psychiatry, though not everything, are about as substantive as homeopathy. Imagine homeopathy became taught in medical schools around the world ... psychiatry is about that bad for the most part, with respect to hypotheses, evidence, and methodology. At least biopsych studies in drugs can be double blinded, though the area has big credibility issues especially with the claim, which persists, that depression is due to serotonin deficiency.

 

[Woolie]

Science, as Lewis Wolpert pointed out, is about replacing intuitive ideas that don't actually work very well when tested with counter-intuitive ideas that do. The idea of a vicious circle of belief and symptoms is what anybody's grandma can think up. Science is not about giving grandma's prejudices fancy names, it is about seeing the emptiness of the popular view and replacing it with something else.

Interesting. This touches on the notion of folk psychology, which I have recently been discussing with some colleagues.

Folk psychology refers to explanations of people's behaviour that draw on universally understood vocabulary and concepts. So for example, saying someone did something "on impulse", or "to seek attention", or "out of anger" are all folk psychological explanations. They are the sort of hypotheses we all make every day to explain other people's actions.

Folk psychology changes as our culture changes, and there's some trickle down effect from disciplines like psychiatry and psychology. So for example, 150 years ago, you might not hear ordinary people talking about "pent up anger", or a person entreating a grieving friend to "have a good cry, let it all out". The idea that strong emotions can do harm, if left unexpressed, is a relatively new folk psychological concept.

The problem arises when you use folk psychological concepts as the basis for a research hypothesis. This is because the terms are fairly loose and amorphous. They can mean whatever you want them to mean on the day. So claims can't ever really be disproved - any potentially challenging evidence can addressed by just saying, "I didn't mean it in that sense".

The other problem is that folk psychological constructs. appear to have a self-evident "truth" about them, making them seem logical and uncontentious. But they're not. Are we really sure that "letting it all out" is a good thing? I suspect it probably isn't a good thing in some situations, and there is some evidence from anger management studies to suggest that expressing anger can sometimes enhance it, not reduce it (think angry mobs and there you have it).

Folk psychology is a huge problem in cognitive neuroscience, because people try to go and look for the area of the brain that supports "desire" (probably not a thing!), or "guilt" (probably also not a thing!). Constructs like guilt and desire probably reflect complex combinations of motivations and affective states, with a good dose of normative values added in.

Sorry, bit of a digression from the main topic, but I thought someone here might have useful thoughts on all this.

 

[alex3619]

This is because the terms are fairly loose and amorphous. They can mean whatever you want them to mean on the day.

This is where the term psychobabble comes in. Anything that vague and ill-defined is not subject to quality scientific investigation. It is however subject to persuasive rhetoric instead of evidence and reason.

We even see that in regard to ME and CFS with respect to fatigue. Even though we have enough physiological evidence of fatigue related processes in ME to engage in science, fatigue as a concept and used in psychobabble is still vague. Indeed even PEM is problematic, despite that we can physiologically demonstrate PEM, as such tests are not fully validated as diagnostic of PEM, and nearly always not used. It seems we prefer vague and ill-defined over concrete and physically demonstrable, at least in general. This is why I have been pointing out we need to work on not just ME definitions, but PEM definitions, backed by validated biomarkers.

Most discussions of depression run into the same issue.

Indeed I suspect the big three vague symptoms all have this issue ... pain, fatigue and depression. They aren't a "thing", an entity, a discrete category, they are a hodge-podge of related things, with most or all insufficiently defined.

Can you imagine how PACE would have gone if they had used repeat CPET to validate PEM in every single patient in the study?

 

[janice]

Reply from Prof Walport re questions raised by Carol Monoghan about the lost data of PACE trial......whooopee it's NOT lost.

Does anyone know if any who are interested in this issue have been able to access the data they need?

This was dated 8th May 2018 and I hope I'm not wasting anyone's time. Might already have been aired and discussed?

Here is part of what I received from my MPs senior advisor............so my meeting with MP maybe wasn't a total waste of energy and nudged a little speck?

"The session was part of the Committee’s ongoing Inquiry on research integrity. I include an excerpt from the transcript where this issue was raised:

Carol Monaghan: Another study that was done—and one I have spoken about in this place—was the PACE trial for ME. One of the issues with that is that we are still struggling to get the data released. If we are talking about research integrity, do you think that, as a rule, all data should be made available to all people who need to see them?

Professor Walport: Open science, which we strongly support, requires that data are made available. Therefore, we expect data to be made available.

Q564 Carol Monaghan: This is another case where The Lancet has not withdrawn the paper, but the researchers are refusing to release data. In fact, I think that they have said that a lot of the data have been lost. Do you agree that that does not do UK research integrity any good?

Professor Walport: We will be happy to write to you about the PACE trial, if you would like something more specific. I have some briefing on it. I am aware that a number of aspects of the trial have been criticised, including methodology. The trial team made it clear that there were some changes in the statistical analysis plan, but that decision was taken before data were examined. This was rectified by the trial steering committee.

Q565 Carol Monaghan: If you are happy to write to me or to the Committee, the information I am looking for is about release of data from the team.

Professor Walport: I am afraid that I will need to write to you about that.

Chair: We would appreciate it if you wrote to us specifically addressing the issue of transparency.

Professor Walport: Okay.[4]

The Science and Technology Committee has not received this information from Professor Walport yet. It will be published on the Committee website when it has been received. "

The bit in Prof Walport's reply about PACE is here:-

"The PACE clinical trial


The PACE clinical trial was a randomised, controlled trial of cognitive behavioural therapy, graded exercise, adaptive pacing and usual medical care for Chronic Fatigue Syndrome, also known as Myalgic Encephalomyelitis (CFS/ME). It aimed to inform the evidence base to determine which existing treatments were most effective for patients with CFS/ME. Funded by an MRC grant to Queen Mary University London (QMUL) the study ran from 2004 to 2011, with co-principal investigators based at QMUL, King’s College London and the University of Oxford.


Since the end of the study, its authors have received a number of requests from researchers to access the study data. Fifteen requests were approved by QMUL and data was shared as part of research collaborations and two requests were refused. Freedom of Information Act requests have also been received seeking the public release of individual participant level data, and anonymised individual-level data was released as a result of one such request.


Following my evidence to the Committee, the MRC sought clarification from QMUL concerning MsCarol Monaghan’s comment that she thought the research team had said a lot of data had been lost. We have been assured that this is not the case, and access to the data may be requested by contacting the co-principal investigators. To support data sharing, the investigators have published guidance on the study webpage for researchers requesting access to the study data.


I note that the National Institute for Clinical Evidence is currently seeking to update its guidance onthe diagnosis and management of CFS/ME. The review will take all relevant research into accountand provide an opportunity for stakeholders to contribute evidence.



[4] Science and Technology Committee Oral evidence: Research integrity, HC 350 Tuesday 6 March 2018"

I'm going back to my relaxation/deep breathing, etc. since I'm trying hard not to spend too much of my time in "angry outraged mode" since it's wastes far too much of my energy

Enjoy hopefully.?

 

[Jonathan Edwards]

I remember watching the video of that oral session. It is interesting to see Walport's subsequent written statement.

Monaghan was only asking about data availability here and so Walport could produce an answer without saying anything about the quality of PACE. He makes a statement about queries having been addressed by the authors but in the video it looks very much as if he is just reading a briefing.

At some time it would be useful to find an opportunity to get Walport to give his opinion on the quality of the trial. He has to say it is hopelessly bad because he cannot maintain his intellectual reputation if he does. Maybe this was a missed opportunity for Monaghan but maybe it was a way of bringing PACE to Walport's attention without making a reply so difficult that he just avoided it altogether.

This needs another go, in due course.

 

[Andy]

Professor Walport: Open science, which we strongly support, requires that data are made available. Therefore, we expect data to be made available.

Can this response not be followed up in some way. Especially when this response skirts around the issue of fully releasing the data, which Professor Walport apparently would support.

Since the end of the study, its authors have received a number of requests from researchers to access the study data. Fifteen requests were approved by QMUL and data was shared as part of research collaborations and two requests were refused. Freedom of Information Act requests have also been received seeking the public release of individual participant level data, and anonymised individual-level data was released as a result of one such request.


Following my evidence to the Committee, the MRC sought clarification from QMUL concerning MsCarol Monaghan’s comment that she thought the research team had said a lot of data had been lost. We have been assured that this is not the case, and access to the data may be requested by contacting the co-principal investigators. To support data sharing, the investigators have published guidance on the study webpage for researchers requesting access to the study data.

It's almost admirable how their refusals to release data are actually spun so well as to then sound, to someone who doesn't know the background, as if they have reasonably responded to the requests for data.

 

[Trish]

Fifteen requests were approved by QMUL and data was shared as part of research collaborations

Disingenuous. Releasing to their friends doesn't count. True release would be public release of all anonymised data, or at least release to truly independent researchers.

 

[Sean]

The PACE clinical trial was a randomised, controlled trial...

No, PACE was not controlled. It was described as 'controlled' in the PACE protocol paper (2007), but not in the main paper (2011). Which means that either the PACE authors decided not to claim controlled status, or it was denied to them by the reviewers or journal editors.

The word 'controlled' is mentioned only once in the main text, in relation to the PACE team's search strategy for pre-existing literature, and a handful of times in the reference section in the titles of some of the studies they used as citations.

PACE was not controlled.

How many times do we have to go through this charade? Why are people in the most senior of positions, as is Prof Walport, still making this basic mistake? It does not fill me with confidence about his understanding of this problem.

 

[JohnTheJack]

Reply from Prof Walport re questions raised by Carol Monoghan about the lost data of PACE trial......whooopee it's NOT lost.

Does anyone know if any who are interested in this issue have been able to access the data they need?

This was dated 8th May 2018 and I hope I'm not wasting anyone's time. Might already have been aired and discussed?

Here is part of what I received from my MPs senior advisor............so my meeting with MP maybe wasn't a total waste of energy and nudged a little speck?

"The session was part of the Committee’s ongoing Inquiry on research integrity. I include an excerpt from the transcript where this issue was raised:

Carol Monaghan: Another study that was done—and one I have spoken about in this place—was the PACE trial for ME. One of the issues with that is that we are still struggling to get the data released. If we are talking about research integrity, do you think that, as a rule, all data should be made available to all people who need to see them?

Professor Walport: Open science, which we strongly support, requires that data are made available. Therefore, we expect data to be made available.

Q564 Carol Monaghan: This is another case where The Lancet has not withdrawn the paper, but the researchers are refusing to release data. In fact, I think that they have said that a lot of the data have been lost. Do you agree that that does not do UK research integrity any good?

Professor Walport: We will be happy to write to you about the PACE trial, if you would like something more specific. I have some briefing on it. I am aware that a number of aspects of the trial have been criticised, including methodology. The trial team made it clear that there were some changes in the statistical analysis plan, but that decision was taken before data were examined. This was rectified by the trial steering committee.

Q565 Carol Monaghan: If you are happy to write to me or to the Committee, the information I am looking for is about release of data from the team.

Professor Walport: I am afraid that I will need to write to you about that.

Chair: We would appreciate it if you wrote to us specifically addressing the issue of transparency.

Professor Walport: Okay.[4]

The Science and Technology Committee has not received this information from Professor Walport yet. It will be published on the Committee website when it has been received. "

The bit in Prof Walport's reply about PACE is here:-

"The PACE clinical trial


The PACE clinical trial was a randomised, controlled trial of cognitive behavioural therapy, graded exercise, adaptive pacing and usual medical care for Chronic Fatigue Syndrome, also known as Myalgic Encephalomyelitis (CFS/ME). It aimed to inform the evidence base to determine which existing treatments were most effective for patients with CFS/ME. Funded by an MRC grant to Queen Mary University London (QMUL) the study ran from 2004 to 2011, with co-principal investigators based at QMUL, King’s College London and the University of Oxford.


Since the end of the study, its authors have received a number of requests from researchers to access the study data. Fifteen requests were approved by QMUL and data was shared as part of research collaborations and two requests were refused. Freedom of Information Act requests have also been received seeking the public release of individual participant level data, and anonymised individual-level data was released as a result of one such request.


Following my evidence to the Committee, the MRC sought clarification from QMUL concerning MsCarol Monaghan’s comment that she thought the research team had said a lot of data had been lost. We have been assured that this is not the case, and access to the data may be requested by contacting the co-principal investigators. To support data sharing, the investigators have published guidance on the study webpage for researchers requesting access to the study data.


I note that the National Institute for Clinical Evidence is currently seeking to update its guidance onthe diagnosis and management of CFS/ME. The review will take all relevant research into accountand provide an opportunity for stakeholders to contribute evidence.



[4] Science and Technology Committee Oral evidence: Research integrity, HC 350 Tuesday 6 March 2018"

I'm going back to my relaxation/deep breathing, etc. since I'm trying hard not to spend too much of my time in "angry outraged mode" since it's wastes far too much of my energy

Enjoy hopefully.?

It's good that Carol is raising the issues about PACE, but the data have never been lost. No one disputes the raw data are locked securely in filing cabinets in a QMUL-operated building at St. Bartholomew’s Hospital.

The question raised by my FOIA request is whether QMUL has the means to extract patient-level results from the raw data now that White has retired. If they do not, then in terms of the FOIA, QMUL would not 'hold' the information. That has no bearing on whether they continue to hold the raw data.

 

[Esther12]

It's good that Carol is raising the issues about PACE, but the data have never been lost. No one disputes the raw data are locked securely in filing cabinets in a QMUL-operated building at St. Bartholomew’s Hospital.

The question raised by my FOIA request is whether QMUL has the means to extract patient-level results from the raw data now that White has retired. If they do not, then in terms of the FOIA, QMUL would not 'hold' the information. That has no bearing on whether they continue to hold the raw data.

Yes, it was a misphrasing by Carol which meant that the reply failed to address the real concern. It shows how important it is to get the details of the language exactly right.

I hope that anyone advising her is being careful with that.

 

[Barry]

It's good that Carol is raising the issues about PACE, but the data have never been lost. No one disputes the raw data are locked securely in filing cabinets in a QMUL-operated building at St. Bartholomew’s Hospital.

The question raised by my FOIA request is whether QMUL has the means to extract patient-level results from the raw data now that White has retired. If they do not, then in terms of the FOIA, QMUL would not 'hold' the information. That has no bearing on whether they continue to hold the raw data.

If not lost, it sounds remarkably like it's at least been mislaid.

 

[Barry]

Yes, it was a misphrasing by Carol which meant that the reply failed to address the real concern. It shows how important it is to get the details of the language exactly right.

I hope that anyone advising her is being careful with that.

I think the political arena is very different, and I'm not sure linguistic perfection is quite so important as getting broad messages across. The BPS crew have been controlling the narrative for so long, with their manipulation of the science/medical debate via their SMC lapdog. But the SMC has negligible sway in the political arena that I'm aware of. SW is a very political animal I think, and it will be interesting to see how he plans to try and retain favour with his funny-handshake chums I don't doubt he nurtures behind the scenes.

 

[large donner]

There was some data that was previously claimed by the holder to have been lost from a filing cabinet of some sort.

I am 100% sure of that.

It has been discussed on the forums about how bad it was that they failed to secure the said files effectively. Not sure if it was QMUL but I am pretty sure some kind of files were either claimed to have disappeared or lost and I remember Peter White being at the centre of it.