Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of PACE trial

[Dolphin]

Here are the questions for the Cognitive Behavioural Responses Questionnaire (CBRQ).

The text says:

We measured several of the putative mediators using the Cognitive Behavioural Responses Questionnaire (CBRQ); these were five cognitive measures: catastrophising, fear avoidance beliefs, damage beliefs, symptom focusing, and embarrassment avoidance beliefs, and two behavioural measures: all-or-nothing behaviour and avoidance or resting behaviour.

Appendix says:

Putative mediating variables at 12 weeks (24 weeks for walk test) Cognitive Behavioural Response Questionnaire This is a self-rated questionnaire designed to measure patients’ cognitive and behavioural responses to illness (5, 6). Items are rated on a 5-point Likertscale ranging from ‘strongly disagree’ to ‘strongly agree’. Five cognitive and two behavioural subscales can be derived, with higher scores on each scale indicating greater impairment of the response in question: catastrophising (range 0 to 16), fear avoidance beliefs (0 to 24), damage beliefs (0 to 20), symptom focusing (0 to 24), embarrassment avoidance beliefs (0 to 24), all-or-nothing behaviour (0 to 20) and avoidance/resting behaviour (0 to 32). To clarify, an example of an item from the cognitive subscale fear avoidance is “I am afraid thatI will make my symptoms worse if I exercise”. An example of an item from the behavioural subscale avoidance behaviour is “I tend to avoid activities that make my symptoms worse”.

I'll try to mark the ones that are definitely or possibly part of a scale - the definite ones are underlined. I have a PhD thesis that looked at them but it used four cognitive factors rather than five (it didn't have "damage beliefs). It had the first 11 as fear avoidance when there are only 6 of them (I think many of them are damage beliefs). It also had the next 6 questions [i.e. "I worry that I may become permanently bedridden because of my symptoms" to "I will never feel right again"] as catastrophising while there is only supposed to be 4 (although figures in the Appendix only add to 40 questions while there are 42 questions so the 6 questions may all be catastrophising].

Please indicate how much you agree or disagree with the following statements about your current symptoms by ticking the appropriate box.

Views about your symptoms
STRONGLY DISAGREE

DISAGREE NEITHER

AGREE NOR DISAGREE

AGREE

STRONGLY AGREE

I am afraid that I will make my symptoms worse if I exercise [said to be fear avoidance in Chalder et al. 2015]

My symptoms would be relieved if I were to exercise [I imagine this is fear avoidance]

Avoiding unnecessary activities is the safest thing I can do to prevent my symptoms from worsening [I imagine this is fear avoidance]

The severity of my symptoms must mean there is something serious going on in my body (Damage - from http://bjp.rcpsych.org/content/suppl/2011/08/30/bjp.bp.110.082974.DC1/ds82974.pdf)

Even though I experience symptoms, I don't think they are actually harming me

When l experience symptoms, my body is telling me that there is something seriously wrong

Physical activity makes my symptoms worse

Doing less helps symptoms

Symptoms are a signal that I am damaging myself [said to be damage beliefs in Chalder et al. 2015]

I am afraid l will have more symptoms if I am not careful

I should avoid exercise when l have symptoms [fear avoidance from "Mediators of the Effects on Fatigue of Pragmatic Rehabilitation for CFS" (Wearden & Emsley))]

I worry that I may become permanently bedridden because of my symptoms

lf I push myself too hard I will collapse

My illness is awful and I feel that it overwhelms me

lf I overdo things it will cause a major relapse (catastrophising - from "Mediators of the Effects on Fatigue of Pragmatic Rehabilitation for CFS" (Wearden & Emsley))

I will never feel right again (catastrophising - from http://bjp.rcpsych.org/content/suppl/2011/08/30/bjp.bp.110.082974.DC1/ds82974.pdf

When l experience symptoms, l think about them constantly (this was classed as symptom focusing in a PhD once)

I worry when I am experiencing symptoms (this was classed as symptom focusing in a PhD once)

When I am experiencing symptoms it is difficult for me to think of anything else (symptom focusing - http://bjp.rcpsych.org/content/suppl/2011/08/30/bjp.bp.110.082974.DC1/ds82974.pdf)

I think a great deal about my symptoms [symptom focusing from "Mediators of the Effects on Fatigue of Pragmatic Rehabilitation for CFS" (Wearden & Emsley))]

My symptoms are always at the back of my mind (this was classed as symptom focusing in a PhD once)

I spend a lot of time thinking about my illness (this was classed as symptom focusing in a PhD once)

I am embarrassed about my symptoms (this was classed as embarrassment avoidance beliefs in a PhD once)

I worry that people will think badly of me because of my symptoms [embarrassment from "Mediators of the Effects on Fatigue of Pragmatic Rehabilitation for CFS" (Wearden & Emsley))]

The embarrassing nature of my symptoms prevents me from doing things (embarrassment from http://bjp.rcpsych.org/content/suppl/2011/08/30/bjp.bp.110.082974.DC1/ds82974.pdf)

I avoid social situations because I am scared my symptoms will get out of control (this was classed as embarrassment avoidance beliefs in a PhD once)

I am ashamed of my symptoms (this was classed as embarrassment avoidance beliefs in a PhD once)

My symptoms have the potential to make me look foolish in front of other people (this was classed as embarrassment avoidance beliefs in a PhD once)

--------------
Two behavioural measures: all-or-nothing behaviour and avoidance or resting behaviour. I believe these last 13 questions are them

I stay in bed to control my symptoms (avoidance http://bjp.rcpsych.org/content/suppl/2011/08/30/bjp.bp.110.082974.DC1/ds82974.pdf)

When I experience symptoms, I rest [avoidance or resting behaviour from "Mediators of the Effects on Fatigue of Pragmatic Rehabilitation for CFS" (Wearden & Emsley))]

I tend to avoid activities that make my symptoms worse [avoidance or resting behaviour (Chalder et al. 2015 appendix)]

I tend to nap during the day to control my symptoms (this was classed as avoidance or resting behaviour in a PhD once)

I tend to overdo things when I feel energetic (this was classed as all-or-nothing behaviour in a PhD once)

| find myself rushing to get things done before I crash (this was classed as all-or-nothing behaviour in a PhD once)

I tend to overdo things and then rest up for a while (this was classed as all-or-nothing behaviour in a PhD once)

I tend to do a lot on a good day and rest on a bad day [all-or-nothing behaviour from "Mediators of the Effects on Fatigue of Pragmatic Rehabilitation for CFS" (Wearden & Emsley))]

I sleep when I'm tired in order to control my symptoms (this was classed as avoidance or resting behaviour in a PhD once)

l avoid making social arrangements in case I'm not up to it. (this was classed as avoidance or resting behaviour in a PhD once)

I avoid exerting myself in order to control my symptoms (this was classed as avoidance or resting behaviour in a PhD once)

I'm a bit all or nothing when it comes to doing things (this was classed as all-or-nothing behaviour in a PhD once)

I avoid stress situations (this was classed as avoidance or resting behaviour in a PhD once)

 

[Dolphin]

If anyone has more info on the Cognitive Behavioural Responses Questionnaire (CBRQ), it'd be appreciated.

 

[Dolphin]

If anyone had the time/energy, it could be fruitful to compare the paper with earlier abstracts the PACE Trial team have published on mediators e.g. there are a few in this thread: http://forums.phoenixrising.me/inde...-to-free-txt-help-sought-to-explain-it.13888/

 

[WillowJ]

"Most objective measures showed no difference in the PACE Trial."

I think we can safely say something much more definitive and punchy:

No objective measure showed any clinically significant improvement.



I don't know if that dropout rate is normal, let alone acceptable, for clinical studies. But given the very meagre 6MWT 'gains', presumably it could easily confound that result.

I thought this would be beyond the figure where data would be beyond analysis (can't recall the exact figure I was taught, though), but I did find a presentation on accounting for dropouts. This one says they should be modeled. Maybe someone who has current capacity for maths would like to have a look.
http://www.amstat.org/chapters/northeasternillinois/pastevents/presentations/fall08_Thisted_R.pdf

There are some non-math bits in there, too, like:

Reasons For Dropout

• Cannot tolerate treatment (side effects)
• Got better; discontinued to avoid tolerable side effects
• Did not get better; gave up
• Injury required discontinuation
• Lost job, moved from study area
• Study requirements too onerous; withdrew
• Unrelated illness required treatment with contraindicated med

- NOTE: These can affect active and placebo groups differently.
- Should any or all of these affect what we mean by "effective"?

 

[WillowJ]

So, "I tend to overdo things when I feel energetic" is bad but "I sleep when I'm tired in order to control my symptoms" is also bad?

Can't win for losing.

 

[biophile]

 

[Snow Leopard]

By the way, since they have now found a mediator, doesn't this mean that now they can just provide a questionnaire before delivering the intervention and only provide the intervention to those who meet the criteria (eg high fearfulness about their symptoms)? (the question is how they would define that in a population that is ill...)

 

[biophile]

By the way, since they have now found a mediator, doesn't this mean that now they can just provide a questionnaire before delivering the intervention and only provide the intervention to those who meet the criteria (eg high fearfulness about their symptoms)? (the question is how they would define that in a population that is ill...)

Good point, but after seeing how poorly they redefined the recovery thresholds, would you trust them to accurately define "high fearfulness about their symptoms" when they don't accept that post-exertional symptoms have any significant pathophysiological basis beyond stress and deconditioning etc (despite the evidence)?

 

[Valentijn]

So, "I tend to overdo things when I feel energetic" is bad but "I sleep when I'm tired in order to control my symptoms" is also bad?

Symptoms are irrelevant! Everyone (not just ME patients) should use a clock to determine when they should be sleeping, exercising, or emptying their bowels (and calling it a research paper)!

God only knows how mankind managed to survive for so long without schedules and quacks telling us what to do.

 

[charles shepherd]

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These articles, along with other UK media coverage, are all available on the MEA Facebook page: https://www.facebook.com/pages/ME-Association/171411469583186

 

[Simon]

But 60 per cent of the benefit gained was reducing people’s concerns that exercise or activity would worsen symptoms.

Read more: http://www.dailymail.co.uk/health/a...vities-aggravate-condition.html#ixzz3On0QchuH
Follow us: @MailOnline on Twitter | DailyMail on Facebook

I've not started reading the paper yet, but anyone know if this is right? Or was it 60% of the benefit they could account for with their model (it's usual for there to be a lot of change that mediation models can''t account for, the 'error' term).

 

[Sidereal]

I've not started reading the paper yet, but anyone know if this is right? Or was it 60% of the benefit they could account for with their model (it's usual for there to be a lot of change that mediation models can''t account for, the 'error' term).

The latter.

 

[Dolphin]

By the way, since they have now found a mediator, doesn't this mean that now they can just provide a questionnaire before delivering the intervention and only provide the intervention to those who meet the criteria (eg high fearfulness about their symptoms)? (the question is how they would define that in a population that is ill...)

This is a paper on mediators (scores at 12 weeks). I think we will also be getting a paper on predictors (baseline values).

 

[Dolphin]

I just noticed that the step test/fitness test results for 12 weeks, 24 weeks and 52 weeks are all in Figure 2. By 52 weeks, GET and CBT have the worst results (numerically).

 

[user9876]

I just noticed that the step test/fitness test results for 12 weeks, 24 weeks and 52 weeks are all in Figure 2. By 52 weeks, GET and CBT have the worst results (numerically).

In case you missed it the formula for fitness is given in the appendix

The self-paced step test of fitness involves timing participants while they do 20 step-ups and step-downs (of two steps each), as well as gathering resting and post-exercise heart rates (10). A measure of fitness was calculated as [Body Mass (in kilograms) x 9.81 x total step height (in metres) x 20] / time(in seconds) / %HRR, where %HRR = [(highest measured HR - resting HR) / (predicted max HR -resting HR)] x 100 (11)

 

[Artstu]

Worth noting that the best case walking speed in the trial was just under 2.4 mph (if my maths is correct) I didn't do the maths on the slowest, but imagine it's below 2 mph.
The average walking speed of someone the age of those in the trial is 3.37 mph.

 

[Dolphin]

All of the mediators with the exception of the physical fitness measure were associated with physical function; and similar to fatigue, these were in the directions expected.

I find this quite an odd/revealing finding. They looked at all sorts of measures incl. 5 subscales on the participants' beliefs. You'd expect the physical fitness result would be one of the best if not the best mediator.

It suggests to me it's quite likely what people are reporting as their physical functioning in the SF-36 PF questionnaire is influenced by other factors along with their actual level of physical functioning.

 

[Dolphin]

What fun: another mediation paper to look forward to.

Finally, in this analysis we focused on single mediators and the effects of some of these variables are not likely to be independent. Our forthcoming analysis of multiple mediator effects will provide more information on this issue.

 

[Dolphin]

Lancet Psychiatry tweeted https://twitter.com/TheLancetPsych/status/555344559035908096:

Happy to receive 500w/5 reference letters on this at

Note the 5 references part which are not in their guidelines.

 

[Simon]

Been a bit rough today but will post a few thoughts on the paper

1. Cause or effect?
I think the biggest issue is whether they are measuring true mediators or just a lot of things that improve together. I dopily posted this on the wrong thread this morning:

Cause or effect?

At the heart of the mediation approach is showing a sequence of events, where the treatment afffects the mediator first, then the mediator affects the outcome. This appearst to be the case in this study, where mediators change first (12 weeks, or 24 for 6MWT) followed by an improved outcome at 52 weeks.

Treatment => Mediator => Outcome

Except, the outcomes improve at 12 and 24 weeks too. In other words, judging by figure 3 in this paper and the outcomes in the original PACE trial, 'mediators' and outcomes improve together. It may be that as people become less fatigued/able to do more, the 'mediator beliefs' change as a consequence. I'm not sure this study is able to show which happens first: the outcomes of fatigue and function may be changing the 'beliefs', not the other way around. Or the two may happen in tandem.

Added to this, the study says that the relationship between meditiators and outcomes were the same in all treatment groups, ie including APT and SMC, where beliefs and behaviours were not challenged.

The authors did briefly mention this in their discussion:

Given the pattern of change in the mediators was similar to the pattern of change in the outcomes it is possible that the variables were affecting each other reciprocally and more measures might have helped clarify this. However, this was prohibitive in this trial because of cost and possible measurement fatigue on the patients’ part.

That seems a bit cursory. As far as I can tell, you could have decided fatigue and function were mediators, depression etc were outcomes, rerun the analysis and found that fatigue mediates changes in depression: 'as patients become less fatigued their mood improves', which seems plausible enough. It appears that the data they have doesn't allow them to untangle the direction of these relationships.

That's pretty important, because they are suggesting changing the therapy on the basis of this study.

A small effect?
Most of the effects of individual 'mediators' on the outcome are pretty small. They use effect sizes, the change in the mean divided by the SD, which is a useful way to compare change for different scales (eg in physical function and fatigue).

To be of any interest, effect sizes usually need to be around 0.3, and anything over 0.5 is considered impressive. The effects of the individual mediators varied, but compared with SMC (data in appendix) they were

• Fear avoidance on fatigue: 0.09 (CBT) and 0.15 (GET)
• Fear avoidance on physical function: 0.11 (CBT) and 0.19 (GET)

And these were about the largest effects - though results for multple mediators combined might have been more impressive.

vs APT skewed due to 70% rule?
Surprsingly, the study focused on results vs APT, the pacing group, not SMC the 'standardised' medical care group

It's possible that they did this because results for 'fear avoidance' in particular were more impressive v APT. That's because APT showed no change in fear avoidance while there was a modest drop in SMC.

Perhaps this was the results of APT's bizarre 70% rule, a form of pacing where patients are encouraged not to go over 70% of their limits. Soundsl like it's designed to encourage avoidance. I'd never heard of this approach til the PACE trial and suspect it's not what most patients who pace do. It's probably an unrealistic comparison group.

More another day