A general thread on the PACE trial!

Kalliope said:
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I wonder if the topic of "not cheating to get the outcome you were seeking" will come up. Or maybe the topic of "our cherry-picked 'evidence' shows the exact opposite of what hundreds of thousands say but we'll stick to our beliefs, thank you very much".

The Replicable part is a bit amusing, since you can evidently replicate fraud many times without being caught. Very relevant to Bastien's post on Cochrane: "I've been doing this wrong for 30 years and by gawd I will continue doing it the same way no matter what because I'm right".

It's getting pretty clear that EBM is a massive failure because it still operates in the echo chamber where patients are irrelevant to the point of being excluded entirely, especially when it contradicts the researchers' beliefs. You can replicate all you want and show the appearance of success if you just cherry-pick what you like. In the end it's all supply-side medicine: by physicians, for physicians.

A whole paradigm shift is needed. What a waste.
 
Jonathan Edwards said:
I think there is a simple sense in which the placebo effect for healing of a broken bone is small and the placebo effect for anything where the ascertainment of outcome is subjective, as for pain, is likely to be larger. ME is bound to fall more in the second category at least in the wider context of a spurious positive result that gets bundled under placebo effect.
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There is some good evidence for this. This study below, from our Science library at this link, was a metanalysis of clinical trials that contained both blinded and non-blinded phases (all kinds of trials). They found that treatment-related self-reported improvements were greatly exaggerated in the non-blinded arms, when compared to the blinded arms. But there was no significant effect of blinding on observer-rated outcomes or objectively measurable outcomes.

This is a very important point, because many psychologists try to claim that the placebo effect is "real", that is, the patient is actually better. The're not. They're just biased in favour of noticing ad remembering things that align with what they know about their treatment. If you treat patients by using a placebo, not only is that dishonest and patronising, but you are writing a cheque you cannot cash. That initial feeling of hope that something might have actually worked eventually gets replaced with the crushing despair of realisation that it didn't.

** Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies.
Hróbjartsson A, Emanuelsson F, Skou Thomsen AS, Hilden J, Brorson S.
International journal of epidemiology. 2014 May 30;43(4):1272-83.
link to article
This study asks the question: "How much of an effect does blinding have on the outcomes of a clinical trial"? The researchers selected all clinical trials they could find that comprised two phases: one where participants were fully aware of what treatment they were getting, and the other where they were fully blinded. The authors found that participants' own ratings of their health/symptoms were powerfully affected by their knowledge of their treatment allocation. Treatment effects were much bigger when participants knew which treatment group they were in. However, objective measures, or ratings of health/symptoms made by a (blinded) observer were not affected in this way. This study shows that when participants have a strong expectation that a treatment will work, their perceptions of its effectiveness are massively inflated; consequently, trials that cannot be blinded (e.g, psychotherapy trials) should avoid outcomes that rely entirely on patients' own self reports.
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Woolie said:
This study below
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Thanks @Woolie. That study is of relevance to my expert testimony to UK NICE. I could have made use of it I guess, although I sort of like the a priori approach to this. That is to say unblinded studies with subjective outcomes are by definition unreliable in the context of human nature. Nevertheless, having formal demonstration is useful to back up arguments if challenged.
 
Jonathan Edwards said:
Thanks @Woolie. That study is of relevance to my expert testimony to UK NICE. I could have made use of it I guess, although I sort of like the a priori approach to this. That is to say unblinded studies with subjective outcomes are by definition unreliable in the context of human nature. Nevertheless, having formal demonstration is useful to back up arguments if challenged.
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I hope you won't be banging your head against a brick wall of people who have decided ME is subjective and that talk of objectivity is irrelevant, or possibly even worse,who accept objective talk for tactical reasons only.
 
richie said:
I hope you won't be banging your head against a brick wall of people who have decided ME is subjective and that talk of objectivity is irrelevant, or possibly even worse,who accept objective talk for tactical reasons only.
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I have pointed out in my testimony, and can reiterate it, that objective endpoints are not in themselves best used as primary endpoints, since subjective symptoms are what actually matter, but as objective corroborators of the subjective outcomes. I have given an example of how that can be done and ha not been done in ME trials.
 
Jonathan Edwards said:
I have pointed out in my testimony, and can reiterate it, that objective endpoints are not in themselves best used as primary endpoints, since subjective symptoms are what actually matter, but as objective corroborators of the subjective outcomes. I have given an example of how that can be done and ha not been done in ME trials.
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Fair enough, I just hope they care.
 
Jonathan Edwards said:
I have pointed out in my testimony, and can reiterate it, that objective endpoints are not in themselves best used as primary endpoints, since subjective symptoms are what actually matter, but as objective corroborators of the subjective outcomes. I have given an example of how that can be done and ha not been done in ME trials.
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That worries me a bit. To me and my wife one of the most crucial measures of her recovery would be to be able to walk 8~10 miles across Dartmoor, or the South Downs, or the Lake District, etc, each day, as she once could. Very objective and very valid surely.
 
Barry said:
That worries me a bit. To me and my wife one of the most crucial measures of her recovery would be to be able to walk 8~10 miles across Dartmoor, or the South Downs, or the Lake District, etc, each day, as she once could. Very objective and very valid surely.
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To be 'able to walk' I would regard as a subjective outcome. To have actually walked would be the objective corroboration.
 
Jonathan Edwards said:
To be 'able to walk' I would regard as a subjective outcome. To have actually walked would be the objective corroboration.
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So long as those you need to convince are indeed convinced by this very fine-lined distinction, then hopefully OK. I'm finding it hard to see how being able to walk is itself a subjective outcome.
 
Barry said:
I'm finding it hard to see how being able to walk is itself a subjective outcome.
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Being 'able to walk' is a a potential capacity that you judge and report - presumably self-report. Things like Chalder fatigue score include judged abilities like this. I probably was not that clear originally. Subjective outcomes are not only symptoms like pain, they are often things reported rather than measured. Of course there are further layers to subjectivity if there is an effect of motivation on actual execution of the walking, which is why we can expect a 6 minute walking time to be influenced by unblinding to test/control a bit. But a Fitbit that shows regular long periods of walking would be pretty objective evidence that the report reflected real improvement.
 
Barry said:
That worries me a bit. To me and my wife one of the most crucial measures of her recovery would be to be able to walk 8~10 miles across Dartmoor, or the South Downs, or the Lake District, etc, each day, as she once could. Very objective and very valid surely.
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Yes, but not enough on its own. If she then reported that she had to spend the rest of the week in bed, it wouldn't exactly be considered a success.
 
Jonathan Edwards said:
Being 'able to walk' is a a potential capacity that you judge and report - presumably self-report. Things like Chalder fatigue score include judged abilities like this. I probably was not that clear originally. Subjective outcomes are not only symptoms like pain, they are often things reported rather than measured. Of course there are further layers to subjectivity if there is an effect of motivation on actual execution of the walking, which is why we can expect a 6 minute walking time to be influenced by unblinding to test/control a bit. But a Fitbit that shows regular long periods of walking would be pretty objective evidence that the report reflected real improvement.
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My experience is that increased walking over years did not lead to a maintained improvement, and in that sense the "improvement" I showed over several years was not "real". Nor did execution of this competence abolish intervening hours of fatigue, generalised fatigue or neuromuscular symptoms, feelings of being on a"waking coma", foggy-flu etc. The self reported and hard to quantify remained largely the same but was/is real and confounding despite apparent "real" improvement over several years, which has not lasted.

Corroboration of self reported general improvement by an unintimidated/unpropagandised patient is fine. Use by authorities of fulfilment of certain competences to impute general improvement is quite different, especially if the patient is under pressure to concur that they have generally improved The corroborators can only suggest. They do not necessarily imply recovery and recovery must not be inferred on their basis, or be assumed to be lasting.

How any of this stuff plays out in terms of NHS provision can be so dependent on the benevolence/malevolence/honesty/budget of those involved. "You wanted emphasis on objectivity, fine. You walked X distance, there's OUR objective corroboration, YOU can't have ME if you did that, especially since we have just defined ME as an illness where you can't do that, but you may haver CFS............"

Dangers lurk. Whatever sword we may take up, there are still those who will point it back at us.
 
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Jonathan Edwards said:
I have pointed out in my testimony, and can reiterate it, that objective endpoints are not in themselves best used as primary endpoints, since subjective symptoms are what actually matter, but as objective corroborators of the subjective outcomes. I have given an example of how that can be done and ha not been done in ME trials.
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What is now clear to me is that I was insufficiently precise in my original post #650, and so things have veered away from what I was trying to get at with my original statement. So to step back and correct that, am repeating it here, but rephrased to avoid the ambiguity I inadvertently introduced ...

That worries me a bit. To me and my wife one of the most crucial measures of her recovery would be if, at the end of a holiday, she had been able to walk 8~10 miles a day across Dartmoor for a good few of the days we stayed there, with no more than normal recovery needed. Very objective and very valid surely as an outcome in itself.
 
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richie said:
Good point and one of the problems is that people do not see us when we are in rest-recovery or relapse.
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To be fair, it does take years to acquire object permanence.

It's a tough requirement, perhaps, but I really would like research into my disease to take into account object permanence. I guess it's just too darn much to ask of some people, but I will keep on insisting for that requirement until it is actually taken into account. One day, perhaps.
 
Jonathan Edwards said:
Being 'able to walk' is a a potential capacity that you judge and report
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Agreed my terminology was ambiguous. I was meaning it in the other well accepted sense - actually able to walk albeit only proven once successfully undertaken; not a preemptive perception. I didn't realise the ambiguity when I wrote it, hence my correction in earlier post.
 
rvallee said:
To be fair, it does take years to acquire object permanence.

It's a tough requirement, perhaps, but I really would like research into my disease to take into account object permanence. I guess it's just too darn much to ask of some people, but I will keep on insisting for that requirement until it is actually taken into account. One day, perhaps.
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I had to look the term OP up! Sorry for ignorance. I suppose all chronic, fluctuating conditions present this problem.
Another complicating factor for ME/CFS is that some do recover, but the pathways to recovery are unclear and exactly when/how/why a recovery has occurred is not usually clear. It would be interesting in pedeatric cohorts, where recovery is not unknown to do e.g. the 2 day CPET in illness, repeat in self reported recovery/remission, check in relapse etc. (Though I don't know whether 2 day CPETS are generally abnormal in kids to start with). This might also be a possible more robust test for CPET, to determine whether/to what degree a normal result in remission might predict stable recovery or whether relapse might occur.
 
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