PACE Trial and PACE Trial Protocol

[Dolphin]

I now understand that a score of 65 was an upper bound for entry. This would confine adverse outcomes without dropout, and thus likely to be reported, to approximately the range 55-65. A strong selection effect is possible.

And initially the entry criteria was 60.

And in the final analysis they changed the requirement from what they said in the protocol (one measurement) to two being on two separate occasions:

Serious deterioration in health was
defi ned as any of the following outcomes: a short form-36
physical function score decrease of 20 or more between
baseline and any two consecutive assessment interviews;16

 

[Dolphin]

There were lots of non-serious adverse events

Adaptive pacing therapy (n=159); Cognitive behaviour therapy (n=161) Graded exercise therapy (n=160); Specialist medical care alone (n=160)
Non-serious adverse events 949 848 992 977
Participants with non-serious adverse events 152 (96%) 143 (89%) 149 (93%) 149 (93%)
Non-serious adverse events per 100 person-years 597 (559–636) 527 (492–563) 620 (582–660) 611 (573–650)

It seems to me to be a bit ridiculous at this level. They should probably have divided these up a bit more.

 

[anciendaze]

Re Anciendaze post #195,
...As far as letters go, why not? The more the merrier. There are more than a few people who are more than willing to help proof read etc.

The danger here is that the editors of The Lancet have not behaved like fair arbiters of sober debate in the past. Given a large selection of letters they could easily choose to publish those which might discredit people who believe in an organic cause. British establishment tactics of ridicule based on insider knowledge (of subjects like Latin grammar) is a long tradition.
(If you don't believe the toffs engage in obscure jokes about grim subjects, check on a certain one-word telegram by Sir Charles James Napier.)

 

[Dolphin]

PS: To me, the drop outs don't look bad. I think that they may have toned down their therapies because they knew this study was looking at potential hamr... it would be good if this work did lead to a more cautious approach to CBT/GET being taken at CFS centers across the country.

Yes, I read somebody who was counting 10 minutes of house work as her exercise for the day. I'm not sure I can find a specific reference but the way GET has been described in the past, this wouldn't qualify. It doesn't fit in with what is said in the manuals either.

 

[Dolphin]

The danger here is that the editors of The Lancet have not behaved like fair arbiters of sober debate in the past. Given a large selection of letters they could easily choose to publish those which might discredit people who believe in an organic cause.

Ok, but hopefully one of yours wouldn't be like that. I'm willing to check one of your letters also (and I did over 4 years of Latin).

 

[anciendaze]

Say what?

Dolphin, I've read what you quoted in two posts above about these criteria. The subject has not been clarified in my mind. I hope those more experienced with this protocol will forgive me for thinking this might be deliberate obfuscation.

With reason to believe fatigue has been redefined as a purely subjective experience, I am even more in doubt about how adverse outcomes are defined. We also need to understand the distinction between adverse events, serious adverse events and adverse outcomes, as these represent categories which might contain information we are looking for. Nothing presented so far removes a suspicion that "these things are what we say they are", and nothing else.

As Humpty-Dumpty said, it's a question of who's to be the master, you or the word.

 

[Dolphin]

Firstly, I changed the wording on post #201 in case it was unclear.

With reason to believe fatigue has been redefined as a purely subjective experience, I am even more in doubt about how adverse outcomes are defined. We also need to understand the distinction between adverse events, serious adverse events and adverse outcomes, as these represent categories which might contain information we are looking for.

I agree.

Here's something else from the Appendix for anyone who doesn't have it:

Description (n = 49)
b) Life threatening (1)
Laparotomy for ectopic pregnancy

c) Hospital admission (38)
 Surgery (18)
Arthroscopic subacromial decompression, repair of ankle tendon, total hip replacement, tonsillectomy (2),
septoplasty, sinus wash-out and trimming of turbinates, removal of rectal abscess, abdominal adhesions release,
laparoscopy for adhesions of endometriosis, Herniorrhaphy, stress incontinence repair, urethral dilatation and
hysteroscopy, orchidectomy, prostatectomy, uterine cystectomy, colposcopy, hysteroscopy.

 Inpatient investigation (9)
Investigation of headache and drop attacks, epileptic seizure, polysomnography, chest pain, atrial fibrillation,
abdominal pain (2), kidney pain, Neutropoenia.

 Respiratory (5)
Asthma attack (2), pneumonia, chest infection, bronchitis.

 Pregnancy complications (2)
Ectopic pregnancy, post-operative infection.

 Accident (2)
Accidental head injury (2)

 Other (2)
Anorexia nervosa, allergic reaction to bites.
d) Increase in severe and persistent significant disability/incapacity (10)
Breast cancer, cerebrovascular accident, prolapsed intervertebral discs, assault leading to disability, multiple life events leading to disability, upper respiratory infection leading to disability, acutely unwell, acute allergic reaction, blackout (2).

*SAE categories: a) Death; b) Life-threatening event; c) Hospitalisation (hospitalisation for elective treatment of a pre-existing condition is not included), d) Increased severe and persistent disability, defined as a significant deterioration in the participant’s ability to carry out their important activities of daily living of at least four weeks continuous duration; e) Any other important medical condition which may require medical or surgical intervention to prevent one of the other categories listed; f) Any episode of deliberate self-harm.

Web Appendix Table D: Description of Serious Adverse Events

Also:

Web Appendix Table C: Description of Serious Adverse Reactions
Description Relationship to treatment SAR category*

Adaptive pacing therapy (2)
1. Suicidal thoughts possibly related e
2. Worsened depression possibly related e

Cognitive behaviour therapy (4)
1. Episode of self harm possibly related f
2. Low mood and episode of self harm possibly related e & f
3. Worsened mood and CFS symptoms possibly related d
4. Threatened self harm possibly related e

Graded exercise therapy (2)
1. Deterioration in mobility and self-care possibly related d
2. Worse CFS symptoms and function possibly related d

Specialist medical care alone (2)
1. Worse CFS symptoms and function probably related d
2. Increased depression and incapacity possibly related d

*SAR categories: a) Death; b) Life-threatening event; c) Hospitalisation (hospitalisation for elective treatment of
a pre-existing condition is not included), d) Increased severe and persistent disability, defined as a significant
deterioration in the participant’s ability to carry out their important activities of daily living of at least four weeks
continuous duration; e) Any other important medical condition which may require medical or surgical intervention
to prevent one of the other categories listed; f) Any episode of deliberate self-harm.

Some sort of definitions should be in the protocol:
http://www.biomedcentral.com/1471-2377/7/6

Then more detailed information e.g. the actual forms used, may be in the full protocol manual:
https://www.yousendit.com/download/T2pGd0VBaFI4NVh2Wmc9PQ

Unfortunately I've a pile of messages in my inbox I should attend to.

 

[anciendaze]

Ok, but hopefully one of yours wouldn't be like that. I'm willing to check one of your letters also (and I did over 4 years of Latin).

Do you ever have nightmares in which you are about to be called upon to construe a line of Virgil combining obscure fourth-declension nouns and gerundives derived from defective verbs?

 

[Dolphin]

Way off-topic

Do you ever have nightmares in which you are about to be called upon to construe a line of Virgil combining obscure fourth-declension nouns and gerundives derived from defective verbs?

Actually, Latin was second best subject (after mathematics). We did it at a fairly easy pace from age 12/13. I did a term of Latin which involved Virgil and it was a lot less straightforward then the Latin in the normal textbooks. Indeed, we did GCSE Latin (as a sort of aside) and it was easier again than the textbooks - we joked how many translated words you were given down the bottom (around 30 when the piece might only use 50 different words). Can't remember the details but think words might have been left out as well in Virgil? Anyway, I tranferred out as felt Applied Maths would help me more e.g. with my physics which I was already doing - I was undiagnosed with M.E. for a year at that stage and was trying to "consolidate" (Latin teacher told class he didn't know why I did this as he thought I'd get an A in the final exam). You should try reading some of the Irish/Gaelic set novels we had to read (rather than simply the 600 lines of Virgil that was the Latin course) which also used obscure grammar we hadn't touched on despite learning the language since aged 4 - the syllabus was designed to stretch native speakers not those of us trying to learn it as a foreign language. I know some people used to learn off the English translations of the Latin like a poem as they would have been lost trying to translate them.

 

[anciendaze]

Still Way Off-Topic

...Can't remember the details but think words might have been left out as well in Virgil?

Almost always.

Anyway, I tranferred out as felt Applied Maths would help me more e.g. with my physics which I was already doing - I was undiagnosed with M.E. for a year at that stage and was trying to "consolidate" .

This sounds relevant to my state of mind in the aforementioned nightmares. Were I sure of the declension and conjugation, things would be straight-forward. Uncertainty leaves me in a quantum superposition of states from which my wave function will collapse as soon as I open my mouth. This is painful even in dreams.

You should try reading some of the Irish/Gaelic set novels we had to read (rather than simply the 600 lines of Virgil that was the Latin course) which also used obscure grammar we hadn't touched on despite learning the language since aged 4 - the syllabus was designed to stretch native speakers not those of us trying to learn it as a foreign language.

Afraid I've always had the suspicion Irish/Gaelic pronunciation was designed to prevent invaders from finding anything local, as Brits did with Cholmondeley castle. Beyond phonetics it is worse than Greek to me.

The only relevance this has to the topic comes from British interpretations of class, education, etc. based on language. As a child of parents from different sections of America, my language reveals I have no class.

Who I am, and what authority I might possess, should never become an issue. This leads to misdirection away from the central subject of the research in question.

 

[Dolphin]

Aside

Who I am, and what authority I might possess, should never become an issue. This leads to misdirection away from the central subject of the research in question.

One advantage of internet discussions perhaps? i.e. one can't judge people on how they speak, their appearance, etc.

 

[Dolphin]

Just sort of repeating what people have said before.

With a GET program, one is not supposed to reduce the length or intensity of sessions based on one's symptoms. Basically you're supposed to do the same amount and intensity of exercise or increase.

In this trial, the GET group went from a speed of 312m in 6 minutes to 379m over the course of 12 months. This program seemed to have a relatively low amount of harms associated with it.

In the real world, it's hard to see that most exercise programs would be this slow. So they haven't really proven much about "real world" exercise programs.

They also don't have data on everyone:
111 (70%) 123 (76%) 110 (69%) 118 (74%)
If they used last value carried forward, which sometimes is used, the change might be smaller. It'd be interesting to find out why people didn't do the second assessments.

 

[Esther12]

One advantage of internet discussions perhaps? i.e. one can't judge people on how they speak, their appearance, etc.

Or a disadvantage for us well spoken beauties.

 

[Esther12]

In the real world, it's hard to see that most exercise programs would be this slow. So they haven't really proven much about "real world" exercise programs.

I think that this is another real concern about the media coverage. There's a real danger that GP's are going to be pushing CFS patients in to the gym, believing Pace has shown it's perfectly safe to do so (I was offered gym membership a few years in to my illness... it was a three mile walk there and back!).

 

[Dolphin]

Or a disadvantage for us well spoken beauties.

:Sign giggle:
Don't we all look like the guy in the photo with the PACE Trial piece on the front page of the Lancet http://www.lancet.com/ (also attached)?

 

[anciendaze]

Or a disadvantage for us well spoken beauties.

I don't claim to be hot, only bothered.

Concerning exercise:

The disconnect between research results and headlines is so bad in the present instance we see talking heads assuring viewers the illness we suffer can be cured through means which these results completely fail to support. Researchers can honestly say they never made such a claim, but their role in this mess will not look so harmless once data from laboratory benches replaces self-evaluation questionnaires. I believe I already see them taking steps to cover their *ahem* flanks.

This flap is a predictable result of people reporting what viewers want to believe. My earlier reference to mile Cou demonstrates that willingness to believe in autosuggestion has been widespread for ages. Curiously, current exponents do not reference his work. They did not even attempt to measure the effectiveness of chanting "Every day, in every way, I am becoming better and better."

Take a look at popular dramas. Over and over again you will see the message reinforced that you can achieve whatever you want if you just try harder. This has reached such a level in cinema that young people accept cartoons about superheroes as a minor embroidery on fact. Emergency rooms are familiar with results of putting these beliefs into practice. Random daily example

Expecting carefully measured advice on exercise to result from those press releases would be absurd. Of course, once research data are injected into a world in video feedback, no one can be held responsible for the resulting body count. Past errors will be acknowledged only as "mistakes were made", if at all.

Don't expect authority and responsibility to be connected. Hierarchies exist to separate the two. We face an immediate problem in dealing with this disease. For some this will consume the remainder of our lives. The bigger problem of correcting the dysfunctional organizations which brought this about is currently outside our scope.

 

[Dolphin]

Hope123 introduced me to the term, acquiescence bias http://en.wikipedia.org/wiki/Acquiescence_bias, which might be another term to throw in to a letter.

 

[anciendaze]

:Sign giggle:
Don't we all look like the guy in the photo with the PACE Trial piece on the front page of the Lancet ...?

Speak for yourself. My navel remains private, and I have better taste in footgear. (Say. Didn't he escape from one of the Monty Python skits?)

 

[Mark]

Re: Bad Science (off-topic)

Off topic - sorry - but oceanblue's post in this thread has got me back up on another hobby-horse...

I also think this would be great material for Ben Goldacre's Bad Science blog and Guardian column (as opposed to the Bad Science forums). If he ran the story it would make quite an impact - and I believe the column is well-read within the scientific community too.

That would be perfect, please somebody do give this a go and send him our best analysis, but I hold out no hope at all there myself.

It sounds like a pipe-dream to me. It really, really would be the impact we're looking for. It is exactly the place where the story should appear. It is exactly the newspaper that should be 'guarding' us. Goldacre's purported agenda of exposing bad science is exactly where we would expect to turn for support here.

Unfortunately, it's not about that at all, as far as I can see. He seems more interested in attacking those things against which he's prejudiced and defending the scientific status quo from anything "a bit weird". He seems to have the same agenda about neuroscience, mind/body etc as the Wessely crowd. He seems to me to be a part of the same mob. They seem to all be joined at the hip.

This is near enough the epicentre of the problem for us in the UK IMO. Who would we expect to defend us if not the Guardian? That's exactly where I expect to find our support - but instead I find this man, who looks to me like nothing but a wolf in sheep's clothing who is busy pulling the wool over everyone's eyes and merely pretending to be the very thing we so desperately need.

What hope for us, and what place in the Guardian, for a man who hosts an online forum (don't buy into the line of 'nothing to do with me guv, I just host it under the name of my book') with a main section dedicated to:

"The Great British Sport of moron-baiting"

Is this Guardian journalist morality in the post-modern era? Should it have been renamed "New Guardian" when it got its makeover, perhaps?

From everything I've seen, Goldacre and his army go after whatever they deem 'bad science' with aggression, rudeness, disrespect and a massive dose of swearing to make everybody laugh and switch off their brains. I'm judging mainly by the BS forum, some Goldacre videos, and Martin J. Walker, so my sources are limited I admit, but from everything I've seen and heard on the forum especially, they determine what is 'bad science' primarily in accordance with their prejudices, their assumptions, and what they 'just know' to be absolute rubbish. The confirmation bias in their way of thinking is enormous; their arrogance breathtaking; their rudeness and disrespect disgusting to me. I see almost no genuine critical thinking, thoughtful or sober scientific critique in the movement - just a crusade for the concept of science as they understand it, and violently against any other way of looking at the world. And the movement is so easily exploited by vested interests that even the really good science, emerging science, and human-focused science gets trampled underfoot. That's the way the movement he's part of looks to me.

BUT: LET HIM PROVE ME WRONG!

If Goldacre's column - or any other Guardian journalist indeed - addresses the PACE trial and rips it to shreds, exposes how CBT/GET is a con, how any attempt at biomedical research into ME/CFS has been suppressed, and how a group of severely ill people have been brushed under the carpet to save money, for decades....well I'll believe it when I see it...and I'll be delighted to have been proved wrong and made to look foolish. And I'll celebrate with the loudest whoops and cheers of delight - because we will finally be cooking with gas.

I might even start buying and reading the thing again; until then, I simply don't trust it any more.

If there really still was a 'Guardian', would we still be in the mess we're in now?

http://www.scribd.com/doc/8401751/C...n-Goldacre-Quackbusting-and-Corporate-Science

 

[Dolphin]

J Psychosom Res. 1998 Jul;45(1 Spec No):53-65.

Fatigue in the general Norwegian population: normative data and associations.
Loge JH, Ekeberg O, Kaasa S.

Department of Behavioural Sciences in Medicine, University of Oslo, Norway. j.h.loge@medisin.uio.no

Abstract
Population norms for interpretation of fatigue measurements have been lacking, and the sociodemographic associations of fatigue are poorly documented. A random sample of 3500 Norwegians, aged 19-80 years, was therefore investigated. A mailed questionnaire included the fatigue questionnaire (11 items) in which the sum score of the responses (each scored 0, 1, 2, 3) is designated as total fatigue (TF). Sixty-seven percent of those receiving the questionnaire responded. Women (TF mean=12.6) were more fatigued than men (TF mean=11.9), and 11.4% reported substantial fatigue lasting 6 months or longer. TF and age were weakly correlated (men: r=0.17; women: r=0.09). No firm associations between fatigue and social variables were found. Disabled and subjects reporting health problems were more fatigued than subjects at work or in good health. Fatigue is highly prevalent in somatic and psychiatric disorders, but is often neglected. This national representative sample provides age- and gender-specific norms that will allow for comparisons and interpretations of fatigue scores in future studies.PMID: 9720855 [PubMed - indexed for MEDLINE]

Somebody sent me the full text (actually more than one person did. ).

The average for the whole group was 12.2 (SD: 4.0). So that would give a threshold of 16 not 18 if it was bluntly used.
However, the group included people over the age of 60, people off sick due to illness, etc.

If one breaks it down the figures are:

Health condition TFa
No disease/current health problem 11.2
Past or current disease 12.1
Current health problem 12.5
Disease and current health problem 14.2

(Unfortunately they don't give SDs - I plan to write).

Remember that a neutral value is 11 - that's if one answered “same as usual” to each of the 11 questions.

Explaination:

The questionnaire further included items about past or current diseases (five items)
and current health problems (nine items). Past or current diseases included hypertension, myocardial infarction,
heart failure, cancer, and diabetes. Current health problems included chronic allergy, low back
pain, visual impairments, chronic skin problems, chronic lung problems, deafness or hearing problems,
functional impairment in leg or arm and other chronic health problems. Based on the responses to these
14 items, the sample was divided into four (1: no disease or current health problem; 2: disease but no
current health problem; 3: no disease but current health problem; 4: disease and current health problem).

The highest scores were for the following group:

Disablement benefit
Women (Raw score) 14.6
(adjusted for age) 14.7

Men (Raw score) 15.7
Men (adjusted for age) 15.5

They use the same definition of caseness as the protocol paper (but not the final paper): >3 on the bimodal scale (a "neutral" score on this is 0). (They make an error in one place and say >4 but say >3 in two places which is the normal way).

They explain where the caseness definition came from:

The cut-off (4 or higher) is
based on a validation study in which the FQ was compared with the question on fatigue
in the Revised Clinical Interview Schedule (CIS-R) [20].

20. Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, Wallace EP. Development of a fatigue scale. J Psychosom Res 1993;37:147–153.

So Trudie Chalder, one of the principal investigators of the PACE Trial, decided in the final paper to not use the definition of caseness she herself had "validated" and which they had also set in the protocol paper.

Instead this paper was used:

Measuring fatigue in clinical and community settings.

J Psychosom Res. 2010 Jul;69(1):17-22. Epub 2009 Dec 11.

Cella M, Chalder T.

Institute of Psychiatry, King's College London, London, United Kingdom. matteo.cella@kcl.ac.uk

Abstract

OBJECTIVE: The Chalder Fatigue Scale (CFQ) is a widely used instrument to assess fatigue in both clinical and nonclinical settings. Psychometric properties of the scale and discriminative abilities were examined.

METHODS: A total of 361 patients with CFS and 1615 individuals in the community were assessed with the CFQ. Principal component analysis (PCA) was used to explore the structure of the scale. Receiver-operating characteristic curve (ROC) was used to investigate the discriminative properties.

RESULTS: Two components, physical and mental fatigue, were identified in the CFS patient group and in the general population samples. Area under the curve for ROC was .91. The fatigue scale effectively discriminates, at high scores, between CFS patients and the general population.

CONCLUSION: Physical and mental fatigue are clearly separable components of fatigue. The CFQ can discriminate reliably between clinical and nonclinical conditions.

Which gave a fatigue score in the community sample of 14.2 (SD 4.6)
One has to wonder was part of the motivation for doing this study to give them a new threshold that could be used in the PACE Trial final paper??

Interestingly, 17.6% of the CFS patients has a score of a score of 18 or less before they were treated. This is the score used in the final PACE Trial paper to represent normal fatigue levels or was described in the Knoop & Bleijenberg editorial as representing recovery.

CFS patients were recruited from consecutive referrals to
the Chronic Fatigue Unit at the South London and Maudsley
NHS Trust. The clinic provides a specialized multidisciplinary
assessment and treatment service to CFS patients across
the southeast of England. The patients included in this study
were referred from primary care, assessed by a doctor at the
clinic, and were diagnosed with CFS. All patients undertook
a range of physical and laboratory examinations before
receiving specialized treatment (e.g., cognitive behavior
therapy, specialized medical care, or graded exercise
therapy). A number of self-rated questionnaires were
administered before the start of the treatment assessing
physical symptoms, cognitive style, mood, and disability. In
order to be included in this study, patients had to be 18 or
older and meet either the Oxford [16] or the Fukuda et al.
[17] diagnostic criteria for CFS.

86.4% of the control group had a score of 18 or less.