- Jul 2018
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europepmc.org europepmc.org
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On 2017 Nov 23, Tom Kindlon commented:
More data demonstrating why the SF-36 physical functioning threshold of 60+ is problematic
The PACE trial's principal investigators (PIs) argue that scores of 60 or higher on the SF-36 physical function subscale (SF-36 PF) fall within the "normal range" and use this threshold as one component of their revised definition of recovery from Chronic Fatigue Syndrome (CFS), as well as a post hoc measure in this paper[1,2].
Referring to the normal ranges for physical function and fatigue used in the PACE trial, one of the trial's PIs, Trudie Chalder, stated that “twice as many people on graded exercise therapy and cognitive behaviour therapy got back to normal”[3]. This same terminology, "back to normal", was also used by the PIs in a patient information leaflet[4].
The use of this phrase, which implies full restoration of health, merits closer scrutiny following publication of a new paper containing data from CFS patients assessed at one of the PACE trial's treatment centres, the Chronic Fatigue Research and Treatment Unit in London, UK, between November 2007 and January 2014[5].
The paper, whose corresponding author is Trudie Chalder, reports that 39.6% of the patients diagnosed with CFS (228/576) had SF-36 PF scores of more than 60; i.e, despite having a score within the normal range, they were judged as sufficiently disabled to be diagnosed with CFS. Note that the data given were for more than 60 on the SF-36 PF so the figure for 60 or more would likely be higher again.
Moreover, Dutch researchers recently reported that 39% of patients with CFS had SF-36 PF scores of 65 or higher[6], and in the PACE trial itself patients could start with a SF-36 PF score of 65 at baseline[7]. Also, as we reported in a reanalysis of the PACE Trial data, in a large British community sample 90% of people aged 18–59 without a long-term illness or disability actually score 90 or higher[8].
Taken together, these data suggest that the derived normal range threshold for physical function is too low to serve as a meaningful indicator of recovery and does not, in fact, represent getting "back to normal".
References:
1 White PD1, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011; 377: 611–690
2 White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013;43(10):2227–2235.
3 Boseley, S. Study finds therapy and exercise best for ME. The Guardian. Feb 18, 2011 https://www.theguardian.com/society/2011/feb/18/study-exercise-therapy-me-treatment
4 PACE participants newsletter 4. February 2011. http://www.wolfson.qmul.ac.uk/images/pdfs/participantsnewsletter4.pdf
5 Ryan EG, Vitoratou S, Goldsmith KA, Chalder T. Psychometric properties and factor structure of a shortened version of the Cognitive Behavioural Responses Questionnaire (CBRQ). Psychosom Med. 2017 Oct 10. doi: 10.1097/PSY.0000000000000536. [Epub ahead of print]
6 Janse A, Nikolaus S, Wiborg JF, Heins M, van der Meer JWM, Bleijenberg G, Tummers M, Twisk J, Knoop H. Long-term follow-up after cognitive behaviour therapy for chronic fatigue syndrome. J Psychosom Res, 2017. doi: 10.1016/j.jpsychores.2017.03.016.
7 White, PD, Sharpe, MC, Chalder, T et al. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007; 7: 6
8 Wilshire CE, Kindlon T, Matthees A, et al. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue. 2017;5:1–4.
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On 2016 Sep 27, Alem Matthees commented:
Post-hoc outcome switching inflated clinical response rates by several times
The primary outcomes as pre-specified in the published PACE trial protocol [1] were abandoned after the trial was over but before the unmasking of data [2] (although the trial was already open-label). While the new primary outcomes are useful, they were group-level and therefore not a direct replacement of the original primary outcomes, which were individual-level i.e. the proportion of participants meeting thresholds for fatigue and physical function.
The thresholds for individual-level improvement on the measures of fatigue and physical function were eventually replaced with post-hoc analyses after the unmasking of data [3], and it is unclear whether these changes were independently approved. The new thresholds have been criticised for being too lax, much less stringent than the pre-specified version, poorly calculated, and a possible example of "outcome reporting bias" [4,5].
On 8 September 2016, Queen Mary University of London (QMUL) released the PACE trial primary outcome results as defined in the published trial protocol [6]. This happened one day before the deadline to appeal the Information Tribunal’s ruling that QMUL must disclose a selection of de-identified participant-level data under the Freedom of Information Act (see EA/2015/0269).
Here is a comparison of the different rates: the clinically useful difference in both fatigue and physical function (Lancet 2011) [3] was 45% for SMC, 59% for CBT, and 61% for GET; the overall improvers or positive outcomes for both fatigue and physical function (QMUL 2016) [6] were 10% for SMC, 20% for CBT, and 21% for GET.
Without going into the issues with the nature and generalisability of the reported benefits, these new results provide a more realistic estimation of the clinical response rates of CBT and GET. However it also indicates that post-hoc outcome switching had inflated the estimated response rates in the PACE trial by several times. This exaggeration allowed proponents of CBT and GET to claim that 60% improved after these therapies (often without mentioning the SMC control rate of 45%). Outcome switching is recognised as a major problem in the research community [7].
There is also evidence that the PACE trial investigators changed the primary outcome measures in the trial registration entry (ISRCTN54285094 [8]). Using web.archive.org shows that an earlier version dated May 2005 [9] describes the primary outcomes with details about the pre-specified thresholds for improvement, but the current version only describes the primary hypotheses being tested or general objectives, without those additional details, allowing the investigators to change their primary outcomes without appearing to be deviating from the trial registration details.
References
1) White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6. PMID: 17397525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2147058/
2) Walwyn R, Potts L, McCrone P, Johnson AL, DeCesare JC, Baber H, Goldsmith K, Sharpe M, Chalder T, White PD. A randomised trial of adaptive pacing therapy, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome (PACE): statistical analysis plan. Trials. 2013 Nov 13;14:386. doi: 10.1186/1745-6215-14-386. PMID: 24225069. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226009/
3) White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18. PMID: 21334061. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065633/
4) Giakoumakis J. The PACE trial in chronic fatigue syndrome. Lancet. 2011 May 28;377(9780):1831; author reply 1834-5. doi: 10.1016/S0140-6736(11)60689-2. Epub 2011 May 16. PMID: 21592554. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60689-2/fulltext
5) Stouten B, Goudsmit EM, Riley N. The PACE trial in chronic fatigue syndrome. Lancet. 2011 May 28;377(9780):1832-3; author reply 1834-5. doi: 10.1016/S0140-6736(11)60685-5. Epub 2011 May 16. PMID: 21592558. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60685-5/fulltext
6) Goldsmith KA, White PD, Chalder T, Johnson AL, Sharpe M. The PACE trial: analysis of primary outcomes using composite measures of improvement. 8 September 2016. http://www.wolfson.qmul.ac.uk/images/pdfs/pace/PACE_published_protocol_based_analysis_final_8th_Sept_2016.pdf
8) http://www.controlled-trials.com/ISRCTN54285094
9) <http://web.archive.org/web/20050524130106/http://www.controlled-trials.com/mrct/trial/CHRONIC FATIGUE SYNDROME/1042/40645.html>
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On 2016 Aug 29, Ellen M Goudsmit commented:
See Goudsmit et al. Editorial bias in the Lancet. ME research Online. http://www.axfordsabode.org.uk/me/melist.htm
Things have not changed yet.
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On 2016 Aug 29, VINCENT RACANIELLO commented:
Below is the text of a letter sent to The Lancet earlier this year, asking for an independent review of the PACE trial. The Lancet invited us to submit this letter, then rejected it for no reason. To keep the text within the limits of PubMedCommons, only the first six names of those who signed the letter are shown.
Sir: The PACE trial reported that exercise and psychotherapy were effective treatments for chronic fatigue syndrome. Yet PACE was an unblinded study with subjective primary outcomes—a design already vulnerable to bias. As patients have long noted, PACE also suffered from additional methodological lapses likely to produce unreliable results. A recent investigation by David Tuller of the University of California, Berkeley, heightened public awareness of PACE’s flaws and sparked an open letter from us to The Lancet requesting an independent review.
Among PACE’s serious missteps:
*In a paradox, participants could—before treatment—already qualify as improved or “within the normal range” for fatigue and physical function, the primary outcomes. How? Because PACE’s “normal range” outcome scores actually allowed for worse health status than the eligibility scores required at entry to demonstrate serious disability. At entry, 13 percent of participants scored “within normal range” on one or both measures—details unreported in the paper. One PACE investigator described participants meeting these lax “normal ranges” as “back to normal”—a misleading statement highlighted in news coverage. An accompanying commentary, reviewed pre-publication by the PACE investigators, called this “a strict criterion for recovery.”
*PACE claimed success based solely on subjective outcomes. Participants in one arm improved slightly on a walking test but remained severely disabled. The investigators subsequently dismissed this test and other objective measures--which all failed to demonstrate success--as irrelevant or non-objective. They describe their findings as robust, but unblinded trials with subjective endpoints, even without PACE’s many other problems, can only yield low-quality evidence.
*PACE used one symptom to identify participants—six months of disabling, unexplained fatigue. A 2015 National Institutes of Health report recommended abandoning this broad definition because it generates heterogeneous samples that could “impair progress and cause harm.” PACE’s sub-group analyses of two alternate criteria are also difficult to interpret—an unknown number of patients might have met these criteria but been excluded by the initial definition and thus unobserved.
*PACE significantly revised its protocol strategy for assessing primary measures and “recovery” criteria but did not include sensitivity analyses, the accepted method of evaluating the impact and dispelling concerns about bias. Whether or not investigators made revisions before reviewing outcome data is irrelevant: Outcome trends in unblinded trials are often apparent to trial leadership early on, even if assessors do not know treatment assignment. The investigators have declined to provide the protocol results and rebuffed data requests as “vexatious.”
*A newsletter for participants--published while a third were still undergoing assessment-- included glowing testimonials from earlier participants about excellent outcomes but none reporting poor outcomes, potentially biasing subjective ratings toward the positive. The same newsletter reported that new U.K. treatment guidelines, “based on the best available evidence,” recommended the two PACE interventions favored by the investigators. Adaptive Pacing Therapy, an untested intervention developed specifically for PACE, was not mentioned.
*Despite investigators’ explicit protocol promise to inform participants of “any possible conflicts of interest,” consent forms did not mention their ME/CFS-related work for disability insurers. It is irrelevant that they disclosed these conflicts in The Lancet and that insurers played no role in PACE. Given the omission, the signed consents are of questionable legitimacy.
The investigators’ previous responses to such concerns have been unsatisfactory. We firmly believe the trial data should undergo a fully independent review.
Vincent R. Racaniello, PhD Professor of Microbiology and Immunology Columbia University
Ronald W. Davis, PhD Professor of Biochemistry and Genetics Stanford University
Jonathan C.W. Edwards, MD Emeritus Professor of Medicine University College London
Leonard A. Jason, PhD Professor of Psychology DePaul University
Bruce Levin, PhD Professor of Biostatistics Columbia University
Arthur L. Reingold, MD Professor of Epidemiology University of California, Berkeley
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On 2016 Jan 08, Tom Kindlon commented:
"Trial By Error, Continued: Did the PACE Trial Really Prove that Graded Exercise Is Safe?"
By two journalists: Julie Rehmeyer is a journalist and Ted Scripps Environmental Journalism Fellow at the University of Colorado, Boulder, who has written extensively about ME/CFS.
David Tuller DrPH is academic coordinator of the concurrent masters degree program in public health and journalism at the University of California, Berkeley.
I am quoted in it.
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On 2015 Oct 23, Lily Chu commented:
No study is perfect but this trial suffered from some major flaws. These are covered by Dr. David Tuller in the following link:
http://www.virology.ws/2015/10/21/trial-by-error-i/
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On 2014 Sep 28, Tom Kindlon commented:
Letter published criticising the threshold for normal functioning and recovery in the PACE Trial:
Quotes some population data to show how ridiculous a threshold of 60+ on the SF-36 physical functioning is to define "normal functioning" and recovery.
Kindlon T, Baldwin A. Response to: reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evid Based Mental Health doi:10.1136/eb-2014-101961 http://ebmh.bmj.com/content/early/2014/09/19/eb-2014-101961.extract
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On 2013 Nov 15, Ellen M Goudsmit commented:
As a co-author of the London criteria for myalgic encephalomyelitis, I wish it to be known that this stdy did not use the criteria and that their citation refers to an incomplete and flawed version written by someone without permission from the original authors. It is therefore unclear if there were any patients with ME who participated in this trial.
Dr E Goudsmit PhD FBPsS
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- Feb 2018
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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On 2013 Nov 15, Ellen M Goudsmit commented:
As a co-author of the London criteria for myalgic encephalomyelitis, I wish it to be known that this stdy did not use the criteria and that their citation refers to an incomplete and flawed version written by someone without permission from the original authors. It is therefore unclear if there were any patients with ME who participated in this trial.
Dr E Goudsmit PhD FBPsS
This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY. -
On 2014 Sep 28, Tom Kindlon commented:
Letter published criticising the threshold for normal functioning and recovery in the PACE Trial:
Quotes some population data to show how ridiculous a threshold of 60+ on the SF-36 physical functioning is to define "normal functioning" and recovery.
Kindlon T, Baldwin A. Response to: reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evid Based Mental Health doi:10.1136/eb-2014-101961 http://ebmh.bmj.com/content/early/2014/09/19/eb-2014-101961.extract
This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY. -
On 2015 Oct 23, Lily Chu commented:
No study is perfect but this trial suffered from some major flaws. These are covered by Dr. David Tuller in the following link:
http://www.virology.ws/2015/10/21/trial-by-error-i/
This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY. -
On 2016 Jan 08, Tom Kindlon commented:
"Trial By Error, Continued: Did the PACE Trial Really Prove that Graded Exercise Is Safe?"
By two journalists: Julie Rehmeyer is a journalist and Ted Scripps Environmental Journalism Fellow at the University of Colorado, Boulder, who has written extensively about ME/CFS.
David Tuller DrPH is academic coordinator of the concurrent masters degree program in public health and journalism at the University of California, Berkeley.
I am quoted in it.
This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY. -
On 2016 Aug 29, VINCENT RACANIELLO commented:
Below is the text of a letter sent to The Lancet earlier this year, asking for an independent review of the PACE trial. The Lancet invited us to submit this letter, then rejected it for no reason. To keep the text within the limits of PubMedCommons, only the first six names of those who signed the letter are shown.
Sir: The PACE trial reported that exercise and psychotherapy were effective treatments for chronic fatigue syndrome. Yet PACE was an unblinded study with subjective primary outcomes—a design already vulnerable to bias. As patients have long noted, PACE also suffered from additional methodological lapses likely to produce unreliable results. A recent investigation by David Tuller of the University of California, Berkeley, heightened public awareness of PACE’s flaws and sparked an open letter from us to The Lancet requesting an independent review.
Among PACE’s serious missteps:
*In a paradox, participants could—before treatment—already qualify as improved or “within the normal range” for fatigue and physical function, the primary outcomes. How? Because PACE’s “normal range” outcome scores actually allowed for worse health status than the eligibility scores required at entry to demonstrate serious disability. At entry, 13 percent of participants scored “within normal range” on one or both measures—details unreported in the paper. One PACE investigator described participants meeting these lax “normal ranges” as “back to normal”—a misleading statement highlighted in news coverage. An accompanying commentary, reviewed pre-publication by the PACE investigators, called this “a strict criterion for recovery.”
*PACE claimed success based solely on subjective outcomes. Participants in one arm improved slightly on a walking test but remained severely disabled. The investigators subsequently dismissed this test and other objective measures--which all failed to demonstrate success--as irrelevant or non-objective. They describe their findings as robust, but unblinded trials with subjective endpoints, even without PACE’s many other problems, can only yield low-quality evidence.
*PACE used one symptom to identify participants—six months of disabling, unexplained fatigue. A 2015 National Institutes of Health report recommended abandoning this broad definition because it generates heterogeneous samples that could “impair progress and cause harm.” PACE’s sub-group analyses of two alternate criteria are also difficult to interpret—an unknown number of patients might have met these criteria but been excluded by the initial definition and thus unobserved.
*PACE significantly revised its protocol strategy for assessing primary measures and “recovery” criteria but did not include sensitivity analyses, the accepted method of evaluating the impact and dispelling concerns about bias. Whether or not investigators made revisions before reviewing outcome data is irrelevant: Outcome trends in unblinded trials are often apparent to trial leadership early on, even if assessors do not know treatment assignment. The investigators have declined to provide the protocol results and rebuffed data requests as “vexatious.”
*A newsletter for participants--published while a third were still undergoing assessment-- included glowing testimonials from earlier participants about excellent outcomes but none reporting poor outcomes, potentially biasing subjective ratings toward the positive. The same newsletter reported that new U.K. treatment guidelines, “based on the best available evidence,” recommended the two PACE interventions favored by the investigators. Adaptive Pacing Therapy, an untested intervention developed specifically for PACE, was not mentioned.
*Despite investigators’ explicit protocol promise to inform participants of “any possible conflicts of interest,” consent forms did not mention their ME/CFS-related work for disability insurers. It is irrelevant that they disclosed these conflicts in The Lancet and that insurers played no role in PACE. Given the omission, the signed consents are of questionable legitimacy.
The investigators’ previous responses to such concerns have been unsatisfactory. We firmly believe the trial data should undergo a fully independent review.
Vincent R. Racaniello, PhD Professor of Microbiology and Immunology Columbia University
Ronald W. Davis, PhD Professor of Biochemistry and Genetics Stanford University
Jonathan C.W. Edwards, MD Emeritus Professor of Medicine University College London
Leonard A. Jason, PhD Professor of Psychology DePaul University
Bruce Levin, PhD Professor of Biostatistics Columbia University
Arthur L. Reingold, MD Professor of Epidemiology University of California, Berkeley
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On 2016 Sep 27, Alem Matthees commented:
Post-hoc outcome switching inflated clinical response rates by several times
The primary outcomes as pre-specified in the published PACE trial protocol [1] were abandoned after the trial was over but before the unmasking of data [2] (although the trial was already open-label). While the new primary outcomes are useful, they were group-level and therefore not a direct replacement of the original primary outcomes, which were individual-level i.e. the proportion of participants meeting thresholds for fatigue and physical function.
The thresholds for individual-level improvement on the measures of fatigue and physical function were eventually replaced with post-hoc analyses after the unmasking of data [3], and it is unclear whether these changes were independently approved. The new thresholds have been criticised for being too lax, much less stringent than the pre-specified version, poorly calculated, and a possible example of "outcome reporting bias" [4,5].
On 8 September 2016, Queen Mary University of London (QMUL) released the PACE trial primary outcome results as defined in the published trial protocol [6]. This happened one day before the deadline to appeal the Information Tribunal’s ruling that QMUL must disclose a selection of de-identified participant-level data under the Freedom of Information Act (see EA/2015/0269).
Here is a comparison of the different rates: the clinically useful difference in both fatigue and physical function (Lancet 2011) [3] was 45% for SMC, 59% for CBT, and 61% for GET; the overall improvers or positive outcomes for both fatigue and physical function (QMUL 2016) [6] were 10% for SMC, 20% for CBT, and 21% for GET.
Without going into the issues with the nature and generalisability of the reported benefits, these new results provide a more realistic estimation of the clinical response rates of CBT and GET. However it also indicates that post-hoc outcome switching had inflated the estimated response rates in the PACE trial by several times. This exaggeration allowed proponents of CBT and GET to claim that 60% improved after these therapies (often without mentioning the SMC control rate of 45%). Outcome switching is recognised as a major problem in the research community [7].
There is also evidence that the PACE trial investigators changed the primary outcome measures in the trial registration entry (ISRCTN54285094 [8]). Using web.archive.org shows that an earlier version dated May 2005 [9] describes the primary outcomes with details about the pre-specified thresholds for improvement, but the current version only describes the primary hypotheses being tested or general objectives, without those additional details, allowing the investigators to change their primary outcomes without appearing to be deviating from the trial registration details.
References
1) White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6. PMID: 17397525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2147058/
2) Walwyn R, Potts L, McCrone P, Johnson AL, DeCesare JC, Baber H, Goldsmith K, Sharpe M, Chalder T, White PD. A randomised trial of adaptive pacing therapy, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome (PACE): statistical analysis plan. Trials. 2013 Nov 13;14:386. doi: 10.1186/1745-6215-14-386. PMID: 24225069. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226009/
3) White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18. PMID: 21334061. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065633/
4) Giakoumakis J. The PACE trial in chronic fatigue syndrome. Lancet. 2011 May 28;377(9780):1831; author reply 1834-5. doi: 10.1016/S0140-6736(11)60689-2. Epub 2011 May 16. PMID: 21592554. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60689-2/fulltext
5) Stouten B, Goudsmit EM, Riley N. The PACE trial in chronic fatigue syndrome. Lancet. 2011 May 28;377(9780):1832-3; author reply 1834-5. doi: 10.1016/S0140-6736(11)60685-5. Epub 2011 May 16. PMID: 21592558. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60685-5/fulltext
6) Goldsmith KA, White PD, Chalder T, Johnson AL, Sharpe M. The PACE trial: analysis of primary outcomes using composite measures of improvement. 8 September 2016. http://www.wolfson.qmul.ac.uk/images/pdfs/pace/PACE_published_protocol_based_analysis_final_8th_Sept_2016.pdf
8) http://www.controlled-trials.com/ISRCTN54285094
9) <http://web.archive.org/web/20050524130106/http://www.controlled-trials.com/mrct/trial/CHRONIC FATIGUE SYNDROME/1042/40645.html>
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On 2017 Nov 23, Tom Kindlon commented:
More data demonstrating why the SF-36 physical functioning threshold of 60+ is problematic
The PACE trial's principal investigators (PIs) argue that scores of 60 or higher on the SF-36 physical function subscale (SF-36 PF) fall within the "normal range" and use this threshold as one component of their revised definition of recovery from Chronic Fatigue Syndrome (CFS), as well as a post hoc measure in this paper[1,2].
Referring to the normal ranges for physical function and fatigue used in the PACE trial, one of the trial's PIs, Trudie Chalder, stated that “twice as many people on graded exercise therapy and cognitive behaviour therapy got back to normal”[3]. This same terminology, "back to normal", was also used by the PIs in a patient information leaflet[4].
The use of this phrase, which implies full restoration of health, merits closer scrutiny following publication of a new paper containing data from CFS patients assessed at one of the PACE trial's treatment centres, the Chronic Fatigue Research and Treatment Unit in London, UK, between November 2007 and January 2014[5].
The paper, whose corresponding author is Trudie Chalder, reports that 39.6% of the patients diagnosed with CFS (228/576) had SF-36 PF scores of more than 60; i.e, despite having a score within the normal range, they were judged as sufficiently disabled to be diagnosed with CFS. Note that the data given were for more than 60 on the SF-36 PF so the figure for 60 or more would likely be higher again.
Moreover, Dutch researchers recently reported that 39% of patients with CFS had SF-36 PF scores of 65 or higher[6], and in the PACE trial itself patients could start with a SF-36 PF score of 65 at baseline[7]. Also, as we reported in a reanalysis of the PACE Trial data, in a large British community sample 90% of people aged 18–59 without a long-term illness or disability actually score 90 or higher[8].
Taken together, these data suggest that the derived normal range threshold for physical function is too low to serve as a meaningful indicator of recovery and does not, in fact, represent getting "back to normal".
References:
1 White PD1, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011; 377: 611–690
2 White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013;43(10):2227–2235.
3 Boseley, S. Study finds therapy and exercise best for ME. The Guardian. Feb 18, 2011 https://www.theguardian.com/society/2011/feb/18/study-exercise-therapy-me-treatment
4 PACE participants newsletter 4. February 2011. http://www.wolfson.qmul.ac.uk/images/pdfs/participantsnewsletter4.pdf
5 Ryan EG, Vitoratou S, Goldsmith KA, Chalder T. Psychometric properties and factor structure of a shortened version of the Cognitive Behavioural Responses Questionnaire (CBRQ). Psychosom Med. 2017 Oct 10. doi: 10.1097/PSY.0000000000000536. [Epub ahead of print]
6 Janse A, Nikolaus S, Wiborg JF, Heins M, van der Meer JWM, Bleijenberg G, Tummers M, Twisk J, Knoop H. Long-term follow-up after cognitive behaviour therapy for chronic fatigue syndrome. J Psychosom Res, 2017. doi: 10.1016/j.jpsychores.2017.03.016.
7 White, PD, Sharpe, MC, Chalder, T et al. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007; 7: 6
8 Wilshire CE, Kindlon T, Matthees A, et al. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue. 2017;5:1–4.
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