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PACE Trial and PACE Trial Protocol

Messages
13,774
I just noticed that PACE have released a comprehensive FAQ2 on their website on the 13th December 2011.

http://www.pacetrial.org/faq/faq2.html

LOL at their FAQ. Frequently asked by who?

I love the way that they have conversations with imagined patients who only ever ask questions in a way that they want to answer.

The PACE leaflet with the "How many patients got back to normal?" question to set up their absurd re-defintion of 'normal' is still the classic example.

Why did you omit actigraphy as an outcome measure?

Actigraphy is a measure of physical activity, measured by a wrist watch sized accelerometer, worn around the ankle continuously for a week. Before we started the trial, we were advised that the number and scope of the outcome measures were too great and that it might reduce the proportion of participants making it through to the end of the trial. Actigraphy was the obvious measure to reject because of its burden in time and effort required by participants. The patient charity advising us agreed that this would be sensible.

I'd be interested to know if the researchers were aware of the Bleijenberg results, which showed CBT did not increase the levels of activity in CFS patients, at the time that they decided this would be the obvious measure to reject. Did they communicate this information to the patient charity involved?

The most common complaint I've seen has been about the re-definition of 'normal', in a way that overlaps with their criteria for CFS and severe and disabling fatigue. No response to that.

They describe CBT and GET rather differently here than they did in their paper.

I can't be bothered to go through it... it doesn't seem to say anything interesting.

I had another point I wanted to make about this... but have forgotten it.
 

Sean

Senior Member
Messages
7,378
Actigraphy was the obvious measure to reject because of its burden in time and effort required by participants.

A small waterproof ankle bracelet, weighing no more than about 40 grams (or about 1.5 oz, and some weigh less than half that), deliberately designed to be as unobtrusive as possible and which would have collected invaluable objective data about outcomes was the obvious measure to reject because of its burden in time and effort required by participants?

Bullshit.
 

Sean

Senior Member
Messages
7,378
The most common complaint I've seen has been about the re-definition of 'normal', in a way that overlaps with their criteria for CFS and severe and disabling fatigue.

Many years ago a senior materials scientist said to me that the only important section of any scientific paper is the Methods section. He regarded the rest of a paper as mostly just padding and PR.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
The most common complaint I've seen has been about the re-definition of 'normal', in a way that overlaps with their criteria for CFS and severe and disabling fatigue. No response to that.

In the FAQs, they talk about how many patients were within the 'normal range' in each therapy group at the end of the trial, as if this is relevent.
But seeing as we don't know how many patients were within the 'normal range' at the start of the trial, in each group, then this is meaningless.
Not to mention all the other issues with the 'normal range'.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
I'd be interested to know if the researchers were aware of the Bleijenberg results, which showed CBT did not increase the levels of activity in CFS patients, at the time that they decided this would be the obvious measure to reject. Did they communicate this information to the patient charity involved?

They knew. And they certainly knew after a whole bunch of people mentioned it in letters to the editor of the Lancet. LOL.

If not, then they'll find out when they hear about this thread. :rolleyes:

Many years ago a senior materials scientist said to me that the only important section of any scientific paper is the Methods section. He regarded the rest of a paper as mostly just padding and PR.

That and maybe the results section.

Funny how in Nature journals, the publish the intro, discussion first and the methods at the end.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
I just noticed that PACE have released a comprehensive FAQ2 on their website on the 13th December 2011.

http://www.pacetrial.org/faq/faq2.html

Enjoy / have fun. Haven't looked at it all yet but noticed some of the usual spin, such as Q&A #46 (Some patients didnt improve: was it worth it?):

Thanks for posting the link biophile (I don't think I thanked you earlier)... I don't remember seeing it before...

Unfortunately, there are still a number of untruths in what they have to say, aren't there.

They obviously haven't felt any pressure, as a result of all our activities, to clean up their act yet.

Quite depressing really.



Unhelpful/meaningless reporting:

Approximately 12 out of 20 patients made a clinically useful reduction in fatigue and improvement in functioning with either CBT or GET compared to about 8 out of 20 with APT and 9 out of 20 with SMC.

In truth, it was approx 13% of participants who were shown to benefit from CBT or GET. (Approx 1 in 8 participants.)


Meaningless drivel (corrupt methodology):

Twelve months after starting in the trial, 3 out of 10 participants were within normal population ranges for both fatigue and function, following CBT and GET, which were approximately twice as many participants than after APT and SMC.

In truth, the 'normal range' was a statistically corrupted methodology, and a patient could have been made worse from treatment with GET or CBT and then be declared as being within the 'normal range' (and reported in the media as 'recovered'). Also, we don't know how many were in the 'normal range' in each group at the start of the trial, so a comparison at 52 weeks is meaningless.


Some truth at last:

Outcome measurement bias: This might have occurred because the research assessors knew which treatment each participant had received.


Info they say they are still to release:

Do the treatments give value for money?
Our health economic analysis will be reported in a separate paper.

Do the effects of these treatments last?
We will have followed up participants long-term (for 2.5 years) and therefore will be able to make a better assessment of whether the positive effects shown in the trial are long-lasting. Previous studies have shown that the effects of both CBT and GET do last.

Recovery:
we are analysing separately the numbers of patients who recovered after treatment.

Why havent you reported all the outcome data from the trial?
We plan to publish all the outcome data from the trial, but could not fit this all in to the main paper.


(If they are planning to release all the data, then I don't know why they've refused to release it in a FOI request, on grounds of privacy for the participants.)
 

oceanblue

Guest
Messages
1,383
Location
UK
Correlation between 6MWT and actometer readings

The 6MWT and it's meaningulness has been discussed on another thread. Thought this would be useful info re PACE:

Correlates of Physical Activity in Chronic Obstructive Pulmonary Disease

Abstract

Background: Physical activity is a key dimension of functional status in people with chronic obstructive pulmonary disease (COPD), and the central target of interventions in this group.

Objectives: To determine the relationships among functional performance measured as physical activity, functional capacity, symptom experiences, and health-related quality of life in people with COPD.

Method: Cross-sectional, descriptive study. Convenience sample of 63 outpatients with COPD studied prior to entry into a pulmonary rehabilitation program.

Results: Daily physical activity, as measured by an accelerometer, was strongly associated with maximal distance walked during a 6-minute walk test (r = .60, p < .00), level of airway obstruction (r = .37, p < .01), walking self-efficacy (r = .27, p < .05), and physical health status (r = .40, p < .01). Physical activity was not correlated with self-report of functional status. The only predictor of physical activity was the 6-minute walk test.

Conclusions: Accelerometer measurement of functional performance was most significantly related to walking abilities. This methodology represents a novel approach to measuring an important dimension of functional status not previously well quantified.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi oceanblue, yes its the benchmark of the 6MWD - that it gives reliable findings. This is why I made so much of the importance of repeatability in another thread. In every other disease the results one day are more or less the same as the results next day - but not with post exertional issues. In most cases I think they are confusing exercise induced fatigue or exercise intollerance with PEM/PENE. They are not the same. We can have all three. Bye, Alex
 

oceanblue

Guest
Messages
1,383
Location
UK
Hi oceanblue, yes its the benchmark of the 6MWD - that it gives reliable findings. This is why I made so much of the importance of repeatability in another thread. In every other disease the results one day are more or less the same as the results next day - but not with post exertional issues. In most cases I think they are confusing exercise induced fatigue or exercise intollerance with PEM/PENE. They are not the same. We can have all three. Bye, Alex
Hi alex
As I said on the other thread:

1) 6MWT is self-paced so patients have the opportunity to adjust there walking pace to the task (they are all ambulatory and travelled to the assessment centre so probably have a feel for how far they can walk and at what pace). To some extent the issue of repeatability/PEM is taken into account in the pace patients walk at - and probably explains the rather short distances.
2) the mean baseline SF-36 score of around 40 would tie in with walking 100m OK amd walking 300m limited a little/not limited at all for many (lmited a lot for some, almost certainly, though without the raw data we can't know for sure).
3) I'm not sure CPOD could repeat quite as easily as you suggest and certainly not with chronic pain and MS where there is a lot of variability day to day.

You seem to be implying that the PACE authors were right to ignore these inconvenient results. The 6MWT is far from ideal for ME patients, but it is not meaningless, in my opinion. If you really think otherwise I'd appreciate you addressing the points above.
thanks
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi oceanblue, 1. self-paced is irrelevant. Many of us go at our own pace and cross the limit - its what we do. When they are encouraged, expected and trained to push - what do you expect? Self paced under those conditions makes it very likely they are pushing too hard, especially on the test after their training.

2. I am not sure of the relevance of this. Why do you think its relevant? The SF-36 is not validated by studies looking at post exercise repeatability in ME. They might claim relevance of course.

3. I am going on the Pacific Labs research and commentaries for this. They cite that every other disease they have looked at - and there is a list somewhere - the results one day to the next were very similar, within I think about 7%. They do not see this in ME, the drop in capacity is sometimes 30%. I am aware, as you stated in another thread, that the Pacific Labs testing is more intense, but I think this is enough to show the 6MWT has to be revalidated to show it works on those with PEM before any results can be considered reliable. In fact the lack of intensity in the 6MWT is another count against its validity. That intensity is critical to appropriately investigate those with PEM.

The PACE authors stacked the deck when they dropped the actometers or decided not to use them in final assessment. They also knew, if they were following the literature, from about 2006, that repeatability was potentially an issue. They stacked the deck again by mostly including mild patients, which is an intrinsic flaw to using the Oxford definition, though I think it likely there were some moderate patients. Severe patients? Doubtfull. Very severe - impossible in my view, by definition - such patients could not participate.

Every single study using actometers has found either no improvement or a worsening of function - the 6MWT has to be interpreted in light of that. A Spanish study showing this came out just two months prior to the PACE study. I can push myself too, it doesn't mean I don't have payback and have to cut on my activity in other ways.

Similarly they want to imply it shows functional capacity. Yet the Belgians found that in 862 patients there were no cures and a worsening in function. This does not match the 6MWT implication. NO objective evidence matches the 6MWT findings. If they were serious they could have used gold standard exercise testing. They chose the lead standard instead. Its cheap, its easy, and its widely thought to be reliable without justification in this case.

Now, as an aside, I think if they recruited a whole lot of Oxford defined CFS patients to validated the test they would in all likelihood validate it - provided they ignored the test-retest requirement with full gas analysis etc. However if they tried it with CCC ME/CFS then I think they would fail to validate it. If they had managed to validate it for Oxford CFS patients, then at least we would know it was more or less reliable for this heterogenous cohort as a group, even if it were invalid for subgroups.

One of the things they would have to do is, with different definitions of ME and CFS, compare test-retest gold standard exercise testing versus the 6MWT. If they could pull that off, and show reliable results, then I would consider it validated.

One of the things an RCT is supposed to do, properly designed, is help guard against bias and confounding factors. However when this many confounding and potentially biasing factors are included, especially subjective measures and psychological intervention, a really large effect size would be necessary to get beyond the range of potential bias and confounding factors. They got a small effect size. They cite it as a great result purely on statistical significance - however bias and confounds can give you a very significant result and still be wrong, and the risk of this rises inversely to the effect size.

Variability of disease is another and very different factor - but it rarely matters in a large group as the average effect will still be reliable - if you don't have ME. We have variability too, like in MS. However post exertional declines are not VARIABLE they are DEPENDENT. An entirely different issue.

Bye, Alex
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Perhaps it would make my point clear if I clarified a few things. I think the 6MWT is invalid in that it is biased to give results more favourable to the PACE trial than is actually the case. This means that the lack of decent results, of an effect size that mattered, is even more damning than we have been discussing. It does not invalidate the claim that they have failed to show a substantive effect - it reinforces it. Bye, Alex
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
Messages
13,774
Let me guess:
Have they released the data for 'recovery' and 'positive outcome' as was laid out in the protocol, and included other missing data, like hours worked? Have they? Have they?
Oh... I see what they've done... how useful...
 

PoetInSF

Senior Member
Messages
167
Location
SF
Perhaps it would make my point clear if I clarified a few things. I think the 6MWT is invalid in that it is biased to give results more favourable to the PACE trial than is actually the case.

Far from being irrelevant or invalid, I think 6mwt is the most important measure in PACE. Any CFSer who has been "training" could tell you how hypersensitive we are to the walking speed. I for one am keenly aware how fast/far I can walk without triggering PEM. The GET program for PACE appears to be carefully monitored and negotiated according to their manual, so, if they stuck to the manual, I'm sure the patients knew what their pace should be at any given moment.

What I'm really interested to know is if the patients continue to improve vis-a-vis the control, or if they plateaued out. The former would validate GET, while the latter would only mean that the improvement was from the initial reconditioning within the limit imposed by CFS rather than from fundamental change to the underlying condition. Does anybody know if/when PACE is releasing their next results?
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
Far from being irrelevant or invalid, I think 6mwt is the most important measure in PACE. Any CFSer who has been "training" could tell you how hypersensitive we are to the walking speed. I for one am keenly aware how fast/far I can walk without triggering PEM. The GET program for PACE appears to be carefully monitored and negotiated according to their manual, so, if they stuck to the manual, I'm sure the patients knew what their pace should be at any given moment.

I remember reading somewhere that good practise for the 6MWDT was to have one or two practise runs before measuring the results. (I can't remember the details, or where I read it.) They didn't do this in the PACE Trial, as far as I am aware.

Also, there were a large number of non-participants in the 6MWDT. Again, I can't remember the details, without looking it up in the paper, but there were quite a number. I don't think we have been told why there are so many non-participants, but obviously, if we aren't given the reason, then we are left thinking that maybe they weren't well enough to participate, thus making the recorded results skewed.

But even so, CBT still managed to fail to improve disability, and GET made a minimal/marginal difference.

What I'm really interested to know is if the patients continue to improve vis-a-vis the control, or if they plateaued out. The former would validate GET, while the latter would only mean that the improvement was from the initial reconditioning within the limit imposed by CFS rather than from fundamental change to the underlying condition.

According to the data already available, when comparing primary outcome results for 12 weeks, 24 weeks and 52 weeks, the improvements almost completely plateau out at 52 weeks.

This is for the data for CBT+SMC and GET+SMC. From memory, I don't think we are able to separate out the improvements attributable to only GET and CBT at 12 weeks and 24 weeks, because they haven't given us the adjusted figures. But for CBT+SMC and GET+SMC, the results almost completely plateau. I've got a graph somewhere, so I might be able to upload it if you want to see it.

Does anybody know if/when PACE is releasing their next results?

They've been promising to release the rest of the data ever since publication. But we've not been given a date. On their FAQs2, they say that they will publish all their data. I'm not sure what they mean by that.
 

Graham

Senior Moment
Messages
5,188
Location
Sussex, UK
I think only fatigue and physical function were given at 12 and 24 weeks, and they were flattening out in a classic exponential decay: probably already at 80% or so of their eventual limit (after a large number of years). The SMC only group flattened out very quickly, but it would be fascinating to know when the SMC sessions stopped. Did they all take place in the first 12 weeks? If so what caused the further progress? If they were spread out over the first six months, then it was the first session that was the main cause of improvement (all the therapies were spread over 6 months: the 52 week measure was a follow-up). If so, then there is a case for suspecting that much of the improvement was just down to familiarisation with the testing and procedures.

Yes, they do recommend several practice walks first, for patients to get an idea of what is expected. PACE of course didn't do that. Only 110 to 123 out of the 160 in each group took part. (This geek has the study printed out and stored in his bedside cabinet!)

Actually they have released all the data. It was a hot, sunny day, so they opened up the doors and windows, and all the data went outside to play, and they haven't been able to round them all up and box them up again. The data clearly had got fed up of being mistreated.
 

oceanblue

Guest
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1,383
Location
UK
Have you seen the latest "PACE" report?
It has only just come out. One of our project survey members gave me this link. Don't look at it if it will make you anxious or depressed though.;)
I dared to look. Is this the same one they published a conference report about earlier?

As e12 implied, it's odd they've found time to do all this analysis yet not done anything with the recovery data. "We spent £5m on a trial to assess the effectiveness of CBT/GET, but more than a year after the inital paper we're still to busy to say how many patients recovered".

Any volunteers to get hold of and trudge through the full text?:
Psychol Med. 2012 May 9:1-6. [Epub ahead of print]
Cognitions, behaviours and co-morbid psychiatric diagnoses in patients with chronic fatigue syndrome.
Cella M, White PD, Sharpe M, Chalder T.
Institute of Psychiatry, King's College London, UK.

Abstract

BACKGROUND: Specific cognitions and behaviours are hypothesized to be important in maintaining chronic fatigue syndrome (CFS). Previous research has shown that a substantial proportion of CFS patients have co-morbid anxiety and/or depression. This study aims to measure the prevalence of specific cognitions and behaviours in patients with CFS and to determine their association with co-morbid anxiety or depression disorders.MethodA total of 640 patients meeting Oxford criteria for CFS were recruited into a treatment trial (i.e. the PACE trial). Measures analysed were: the Cognitive Behavioural Response Questionnaire, the Chalder Fatigue Scale and the Work and Social Adjustment Scale. Anxiety and depression diagnoses were from the Structured Clinical Interview for DSM-IV. Multivariate analysis of variance was used to explore the associations between cognitive-behavioural factors in patients with and without co-morbid anxiety and/or depression.

RESULTS: Of the total sample, 54% had a diagnosis of CFS and no depression or anxiety disorder, 14% had CFS and one anxiety disorder, 14% had CFS and depressive disorder and 18% had CFS and both depression and anxiety disorders. Cognitive and behavioural factors were associated with co-morbid diagnoses; however, some of the mean differences between groups were small. Beliefs about damage and symptom focussing were more frequent in patients with anxiety disorders while embarrassment and behavioural avoidance were more common in patients with depressive disorder.

CONCLUSIONS: Cognitions and behaviours hypothesized to perpetuate CFS differed in patients with concomitant depression and anxiety. Cognitive behavioural treatments should be tailored appropriately.
 

Enid

Senior Member
Messages
3,309
Location
UK
This is devastating - co-morbid psychiatric diagnoses - by who's measures - don't believe a word of it. Depression as I recall was clinical depression when it struck (all bodily systems slowed to a point of barely existing) and anxiety was more related to my Docs baffled by the symptoms when it struck too. CBT tailored or not would obviously have been useless.

(Do we know anything about their measures for "psychiatric" depression and anxiety).
 

PoetInSF

Senior Member
Messages
167
Location
SF
But for CBT+SMC and GET+SMC, the results almost completely plateau. I've got a graph somewhere, so I might be able to upload it if you want to see it.
Thanks Bob, I must've missed that. I'll dig up the data and graph it myself.