On 2014 Feb 20, Tom Kindlon commented:

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.

[2] Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010 Mar 24;8:18. http://www.biomedcentral.com/1741-7015/8/18/

[3] Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010 Mar 23;340:c869. doi: 10.1136/bmj.c869 http://www.bmj.com/cgi/content/full/340/mar23_1/c869

[4] Boutron I, Moher D, Altman DG, Schulz K, Ravaud P, for the CONSORT group. Methods and Processes of the CONSORT Group: Example of an Extension for Trials Assessing Nonpharmacologic Treatments. Ann Intern Med. 2008:W60-W67. http://www.consort-statement.org/index.aspx?o=1416

[5] Boutron I, Moher D, Altman DG, Schulz K, Ravaud P, for the CONSORT group. Extending the CONSORT Statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med. 2008:295-309. http://www.consort-statement.org/index.aspx?o=1415

[6] Psychiatry, Neuroscience and Clinical Psychology University of Edinburgh submission. http://www.rae.ac.uk/submissions/ra5a.aspx?id=176&type=hei&subid=3181

On 2014 Feb 20, Tom Kindlon commented:

CONSORT statement recommends sufficient details to allow replication (for nonpharmacologic treatments, the publishing of manuals is recommended)

(This was originally posted as an e-letter here in 2010: http://www.biomedcentral.com/1471-2377/7/6/comments#415670. However, many people will not read the paper on PubMed Central and so not see it there)

The publishing of this trial protocol [1] is to be welcomed – it is something that the CONSORT statement on Randomized Control Trials (RCTs) recommends[2].

Item 5 of the checklist in the CONSORT guidelines [2] states the following information should be given: "The interventions for each group with sufficient details to allow replication, including how and when they were actually administered."

The explanation for this is given as [3]: "Explanation—Authors should describe each intervention thoroughly, including control interventions. The description should allow a clinician wanting to use the intervention to know exactly how to administer the intervention that was evaluated in the trial.102 For a drug intervention, information would include the drug name, dose, method of administration (such as oral, intravenous), timing and duration of administration, conditions under which interventions are withheld, and titration regimen if applicable. If the control group is to receive “usual care” it is important to describe thoroughly what that constitutes. If the control group or intervention group is to receive a combination of interventions the authors should provide a thorough description of each intervention, an explanation of the order in which the combination of interventions are introduced or withdrawn, and the triggers for their introduction if applicable.

"Specific extensions of the CONSORT statement address the reporting of non-pharmacologic and herbal interventions and their particular reporting requirements (such as expertise, details of how the interventions were standardised).43 44 We recommend readers consult the statements for non-pharma-cologic and herbal interventions as appropriate."

The equivalent item in the Extension for Trials Assessing Nonpharmacologic Treatments is:

"Precise details of both the experimental treatment and comparator

4A Description of the different components of the interventions and, when applicable, descriptions of the procedure for tailoring the interventions to individual participants

4B Details of how the interventions were standardized

4C Details of how adherence of care providers with the protocol was assessed or enhanced"

Here is an extract from the explanation for part a[5]: “It is important to provide a detailed description of nonpharmacologic treatments, which are usually complex interventions involving several components (75), each of which may influence the estimated treatment effect (27–32).”

[..]

“The description of any standardization methods is essential to allow adequate replication of the nonpharmacologic treatment. We recommend that authors allow interested readers to access the materials they used to standardize the interventions, either by including a Web appendix with their article or a link to a stable Web site. Such materials include written manuals, specific guidelines, and materials used to train care providers to uniformly deliver the intervention.”

[..]

“In a review of behavioral medicine interventions, insufficient intervention detail was a barrier to assessment of evidence and development of guidelines (80–82).”

[..]

“For rehabilitation, behavioral treatment, education, and psychotherapy, authors should report qualitative and quantitative data. Qualitative data describe the content of each session, how it is delivered (individual or group), whether the treatment is supervised, the content of the information exchanged with participants, and the instruments used to give information. Quantitative data describe the number of sessions, timing of each session, duration of each session, duration of each main component of each session, and overall duration of the intervention. It is also essential to report how the intervention was tailored to patients’ comorbid conditions, tolerance, and clinical course.”

Here is an extract from the explanation for part b which seems particularly relevant as treatment manuals are referred to in the protocol (but they have not been published):

“The description of any standardization methods is essential to allow adequate replication of the nonpharmacologic treatment. We recommend that authors allow interested readers to access the materials they used to standardize the interventions, either by including a Web appendix with their article or a link to a stable Web site. Such materials include written manuals, specific guidelines, and materials used to train care providers to uniformly deliver the intervention.”

The descriptions of Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET) are 73 and 68 words respectively. These are not sufficient for replication. For example, what is the advice a therapist should give if a patient experiences an exacerbation of symptoms, which is common with this condition e.g. should they maintain their level of activity or exercise or reduce? And if they maintain their level of activity, how long should this continue for? Also what constitutes treatment adherence? In a previous comment, I pointed out a patient who is counting minutes spent doing housework as minutes for her exercise program.

This estimated cost for this trial is now 5m UK pounds of taxpayers' money[6]. It is important that it is reported as well as possible.

On 2014 Feb 20, Tom Kindlon commented:

New paper lists 3 CFS studies where there was no improvement in the actometer readings but an improvement was reported in subjective outcome measures

(This was originally posted as an e-letter here in 2010: http://www.biomedcentral.com/1471-2377/7/6/comments#387679. However, many people will not read the paper on PubMed Central and so not see it there)

I know it might perhaps have seemed to some who have read these posts that I might be concerned about something that was not important (when I was calling for actometers to be used if possible for at least some of the patients at the end of the trial). So I feel "vindicated" in a way by a review[1] that has just been published. It found that in the three Dutch CFS trials looked at, studies which all found improvements in fatigue[2-4], there was no statistically significant increase in physical activity levels as measured by actometers.

The review also found that "changes in physical activity were not related to changes in fatigue."

The authors of the review (who include people who were involved in all the studies) say that, in the three studies, "treatment was based on the manual of CBT for CFS described in detail by Bleijenberg et al. (2003)" [5]. This form of CBT is comparable to the form of CBT being assessed in the PACE Trial [6].

It is useful to point out that fatigue wasn't the only subjective outcome measure that was said to have improved (in these trials where there was no increase in physical activity).

In all of the three studies [2-4], improvements were reported in functional impairment (as measured by questionnaires). In two of the studies [2,3], improvements in physical functioning as measured by the SF-36 physical functioning subscale were reported (this questionnaire does was not used in the third study[4]). So the patients reported improvements in "physical functioning" (as measured by the SF-36 physical functioning subscale) but there was no improvement in physical activity as measured by the actometers. The SF-36 physical functioning subscale is one of the primary outcome measures in the PACE Trial[6].

This discrepancy between objective measures of activity and questionnaire is similar to data I have previously drawn attention to[7] in a study by Friedberg and Sohl[8].

References:

[1] Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Jan 5:1 -7. [Epub ahead of print]

[2] Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G (2005). Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. British Medical Journal 330. Published online : 7 December 2004. doi:10.1136/bmj.38301.587106.63.

[3] Knoop H, van der Meer JW, Bleijenberg G (2008). Guided self-instructions for people with chronic fatigue syndrome: randomised controlled trial. British Journal of Psychiatry 193, 340–341.

[4] Prins JB, Bleijenberg G, Bazelmans E, Elving LD, de Boo TM, Severens JL, van der Wilt GJ, Spinhoven P, van der Meer JW (2001). Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 357, 841–847.

[5] Bleijenberg G, Prins JB, Bazelmans E (2003). Cognitive-behavioral therapies. In Handbook of Chronic Fatigue Syndrome (ed. L. A. Jason, P. A. Fennell and R. R. Taylor), pp. 493–526. Wiley: New York.

[6] White PD, Sharpe MC,Chalder T, DeCesare JC and Walwyn R for the 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 Neurology 2007, 7:6

[7] Kindlon T. Further evidence showing why objective measures are preferable in CFS trials particularly where cognitions could be changed following the intervention http://www.biomedcentral.com/1471-2377/7/6/comments#333618

[8] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

On 2014 Feb 20, Tom Kindlon commented:

Discrepancies between momentary fatigue and recalled fatigue can exist

(This was originally posted as an e-letter here in 2009: http://www.biomedcentral.com/1471-2377/7/6/comments#338630. However, many people will not read the paper on PubMed Central and so not see it there)

One of the primary outcome measures in this study is the bimodal Chalder Fatigue Scale [1] (possible individual scores 0 and 1, total scores can range from 0-11). One of the secondary outcome measures is the Chalder Fatigue Scale[1] using a different method of scoring (possible individual scores: 0-3, total scores can range from 0-33). This asks questions about the last month: "For the next few questions, we would like to know whether or not you have had any problems with feeling tired, weak, or lacking in energy in the last month".

But is it recalled fatigue, or the memory for fatigue, exactly equal to the fatigue people actually felt during a period?

Friedberg and Sohl have investigated this using electronic diaries[2]. Here is a description of what was involved: "In order to obtain a representative diurnal sample of symptoms without undue subject burden (Stone & Shiffman, 2002), the palm pilots prompted subjects for 21 days, 6 times a day, every 2 hr plus or minus a randomly programmed 1-20 min interval (Stone & Shiffman, 1994). The first daily prompt occurred within 1 hr of the subject's wakening and the last daily prompt approximately 12 hr later. No prompt signals occurred during the subject's reported sleep time. After each prompt, a screen was displayed with a numerical rating scale (0-10) that was labeled "Fatigue Now." The end point anchors on the numerical scales were None (0) and Highest (10). Subjects were instructed to record intensity ratings on the numerical scale for their current levels of fatigue."

What they found was "average weekly recall of fatigue intensity was significantly higher than average momentary ratings" (8.5% higher on average). If one used a scale like the Chalder Fatigue Scale[1] which asked for a period of over the preceding month, one could speculate that the discrepancy would be even higher.

This suggests that self-report fatigue questionnaires may not be ideal for intervention studies particularly in expensive trials like this one where one might be willing to pay a bit extra for greater accuracy; just as it has been shown that self-report questionnaires may not correlate strongly with more objective measures of activity (such as actometers)[3,4] (of course, in this study, the reason actometers are not being used does not seem to be due to the cost of obtaining them or the need to train participants to use them, as baseline measurements from actometers are being used).

References:

[1] Chalder T, Berelowitz G, Hirsch S, Pawlikowska T, Wallace P, Wessely S, Wright D: Development of a fatigue scale. J Psychosom Res 1993, 37:147-153.

[2] Friedberg F, Sohl SJ. Memory for fatigue in chronic fatigue syndrome: the relation between weekly recall and momentary ratings. Int J Behav Med. 2008 Jan-Mar;15(1):29-33.

[3] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

[4] Vercoulen JH, Bazelmans E, Swanink CM, Fennis JF, Galama JM, Jongen PJ, Hommes O, Van der Meer JW, Bleijenberg G. Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. J Psychiatr Res. 1997 Nov-Dec;31(6):661-73.

On 2014 Feb 20, Tom Kindlon commented:

Further evidence showing why objective measures are preferable in CFS trials particularly where cognitions could be changed following the intervention

(This was originally posted as an e-letter here in 2009: http://www.biomedcentral.com/1471-2377/7/6/comments#333618. However, many people will not read the paper on PubMed Central and so not see it there)

Since writing my previous posts, further data on the subject has come to my attention.

Friedberg and Sohl [1] have just published the results of a study on an intervention involving Cognitive Behavior Therapy (CBT) which included encouraging patients for going for longer walks. It found that on the SF-36 Physical Functioning (PF) scale, patients improved from a pre-treatment mean (SD) of 49.44 (25.19) to 58.18 (26.48) post-treatment, equivalent to a Cohen's d value of 0.35. On the Fatigue Severity Scale (FSS), the improvement as measured by the cohen's d value was even great (0.78) from an initial pre-treatment mean (SD) of 5.93 (0.93) to a 5.20 (0.95) post-treatment.

However on actigraphy there was actually a numerical decrease from a pre-treatment mean (SD) of 224696.90 (158389.64) to 203916.67 (122585.92) post-treatment (cohen's d: -0.13). So just because patients report lower fatigue and better scores on the SF-36 PF scale, doesn't mean they're doing more, which is what GET and CBT based on GET claim to bring about. These results seem particularly pertinent for this study given the primary outcome measures are the SF-36 PF scale and a fatigue scale.

Further reading show that another study[2], published over a decade ago, showed the problem of using self-report data in CFS patients. The authors' rationale for the study was: "It is not clear whether subjective accounts of physical activity level adequately reflect the actual level of physical activity. Therefore the primary aims of the present study were to assess actual activity level in patients with CFS to validate claims of lower levels of physical activity and to validate the reported relationship between fatigue and activity level that was found on self-report questionnaires. In addition, we evaluated whether physical activity level adequately can be assessed by self-report measures. An Accelerometer was used as a reference for actual level of physical activity.". The authors reported on the correlations on 7 outcome measures in relation to the actometer readings: "none of the self-report questionnaires had strong correlations with the Actometer. Thus, self-report questionnaires are no perfect parallel tests for the Actometer."

Prof. White seems to be aware of the findings of this study as he has been co-authored at least two papers [3,4] which quoted the findings. One of the times this paper was referenced even shows the problem I'm highlighting e.g. "support for this explanation comes from investigations that have described discrepancies between subjectively reported impairments and objective measures of activity" [4].

The authors of the 1997 study[2] pointed out that "The subjective instruments do not measure actual behaviour. Responses on these instruments appear to be an expression of the patients' views about activity and may be biased by cognitions concerning illness and disability." This was re-iterated in another paper[5]: "In earlier studies of our research group, actual motor activity has been recorded with an ankle-worn motion-sensing device (actometer) in conjunction with self-report measures of physical activity. The data of these studies suggest that self-report measures of activity reflect the patients' view about their physical activity and may have been biased by cognitions concerning illness and disability."

A corollary of the last statement is that reports of improvement in self-report measures in interventions which change "cognitions concerning illness and disability" may not be reliable. "Improvements" in self-report measures may simply show that patients have changed their cognitions with regard to how they view their illness, disability, symptoms, etc rather than actually representing improvements in activity levels and functional capacity.

Thus, I would suggest that actometers should be used whenever possible in CFS trials where one is investigating whether an intervention has brought about increased activity.

It is also interesting to note that in the large Van der Werf (2000) study[5], which involved 277 CFS patients (and 47 healthy controls), the authors divided the patients up "pervasively passive" (representing 24% of the patients), "moderately active" and "pervasively active". They found that "levels of daily experienced fatigue and psychological distress were equal for the three types of activity patterns". So one can't necessarily tell how active a patient is from the fatigue levels they report.

Incidentally they also "there were no significant group, gender or interaction effects for the number of absolute large or relatively large day-to-day fluctuations (Table 2 and Table 3)." "The day-to-day fluctuation measures were based on somewhat arbitrary criteria (1 S.D. and 33% activity change). However, when we post hoc tested alternative criteria (50% or 66% activity change), again no significant group differences between controls and CFS patients emerged." Part of the rationale of many behavioural interventions in CFS patients is said to be to reduce "boom and bust" (sample reference,[6]). However, it may be the case that the frequency of this activity pattern in CFS has been exaggerated.

References:

[1] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

[2] Vercoulen JH, Bazelmans E, Swanink CM, Fennis JF, Galama JM, Jongen PJ, Hommes O, Van der Meer JW, Bleijenberg G. Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. J Psychiatr Res. 1997 Nov-Dec;31(6):661-73.

[3] Fulcher KY, White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 2000 September; 69(3): 302–307.

[4] Smith WR, White PD, Buchwald D. A case control study of premorbid and currently reported physical activity levels in chronic fatigue syndrome. BMC Psychiatry. 2006 Nov 13;6:53.

[5] van der Werf SP, Prins JB, Vercoulen JH, van der Meer JW, Bleijenberg G. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res. 2000 Nov;49(5):373-9.

[6] Deary V, Chalder T: Chapter 11, "Conceptualisation in Chronic Fatigue Syndrome" in Formulation and Treatment in Clinical Health Psychology Edited by Ana V. Nikcevic, Andrzej R. Kuczmierczyk, Michael Bruch Competing interests

On 2014 Jan 04, Tom Kindlon commented:

Does housework count as exercise for somebody in the GET leg of the trial?

I wonder could the authors answer a question which is relevant to the real world application of Graded Exercise Therapy (GET). I have heard a participant in the Graded Exercise Therapy (GET) leg of the trial say that they are counting 10 minutes housework in lieu of a 10-minute walk. I think it would be very useful for the authors to clarify whether they think x minutes housework can be used in lieu of x minutes of walking or whether this is not in compliance with the protocol? I think attention to detail in this matter is very important if one is to apply the findings in the real world. With a drug it is easy to check whether the dosage is the same as published trials. With Graded Exercise Therapy (GET), we need clarification from the authors about what is meant by exercise, so that the protocol can be applied as in the trial, so that people either don't get too low a "dose" or too high a "dose" at the wrong stage.

On 2014 Jan 04, Tom Kindlon commented:

References:

[1] PD White, MC Sharpe, T Chalder, JC DeCesare, R Walwyn, for the PACE trial management group: Response to comments on "Protocol for the PACE trial" http://www.biomedcentral.com/1471-2377/7/6/comments#306608

[2] Goudsmit EM, Stouten B, Howes S: Fatigue in Myalgic Encephalomyelitis. Bulletin of the IACFS/ME - Volume 16, Issue 3. http://tinyurl.com/3zcgw8 i.e. http://www.iacfsme.org/BULLETINFALL2008/Fall08GoudsmitFatigueinMyalgicEnceph/tabid/292/Default.aspx

[3] Bazelmans E, Bleijenberg G, van der Meer JWM, Folgering H. Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity. Psychol Med 2001; 31: 107–14.

[4] Black CD, O’Connor PJ, McCully KK. Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Dyn Med 2005; 4: 3.

[5] Sisto SA, Tapp WN, LaManca JJ et al. Physical activity before and after exercise in women with chronic fatigue syndrome. Q J Med 1998; 91:465–73.

[6] Vercoulen JHMM, Bazelmans E, Swanink CMA et al. Physical activity in chronic fatigue syndrome assessment and its role in fatigue. J Psych Res 1997; 31: 661–73.

[7] Van der Werf SP, Prins JB, Vercoulen JHM, van der Meer JWM, Bleijenberg G. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res 2000; 49: 373–79.

[8] Nijs J, Almond F, De Becker P, Truijen S, Paul L. Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial. Clin Rehabil. 2008 May;22(5):426-35.

[9] Clapp LL, Richardson MT, Smith JF, Wang M, Clapp AJ, Pieroni RE. Acute effects of thirty minutes of light-intensity, intermittent exercise on patients with chronic fatigue syndrome. Phys Ther 1999; 79: 749-56.

[10] Lapp, C (1997). Exercise limits in chronic fatigue syndrome. Am J Med, 103: 83-84.

[11] DL Arnold et al. Excessive intracellular acidosis of skeletal muscles on exercise in the post viral exhaustion / fatigue syndrome: a 31P-NMR Study. Proceedings of third Annual Meeting of the Society for Magnetic Resonance in Medicine, New York, 1984, 12-13.

[12] Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S: Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Journal: J Intern Med., 2005 Mar;257(3):299-310.

[13] Black CD, McCully KK: Time course of exercise induced alterations in daily activity in chronic fatigue syndrome. Dyn Med. 2005 Oct 28;4:10.

On 2014 Jan 04, Tom Kindlon commented:

The dropping of actometers as an outcome measure and other points relating to the outcome measures being used

(I'm posting this e-letter/comment from 2008 here for the same reason as the first e-letter below)

In their reply to my comments, Peter White and colleagues say they are using [i]"several objective outcome measures"[/i] [1]. If they think these tests are useful as objective outcome measures, why is at least one of them not being used as a primary outcome measure rather than the current situation where there are only two subjective outcome measures being used.

I have already made some points on the outcome measures but another one is that the bimodal Chalder Fatigue Scale hardly seems a very good outcome measure for a "CFS/ME" trial where there is likely going to be so many maximum or near maximum scoring initially[2]

Also, there are so many (14) secondary outcome measures in this study, along with so many (18) predictor variables, that it seems unlikely all the different methods of looking at the secondary outcome measures can be explored in the final published paper, given authors are encouraged not to make papers too long (especially journals that have paper editions). The protocol itself is 20 pages long when all the different aspects of it are listed! At least some of the information will need to be re-iterated in the final paper.

It is of course important to take the burden on participants into account when deciding what outcome measures to use. However I find the following point very strange: "Although we originally planned to use actigraphy as an outcome measure, as well as a baseline measure, we decided that a test that required participants to wear an actometer around their ankle for a week was too great a burden at the end of the trial." Firstly they clearly don't find it that great a burden that they drop it altogether as it is being used on patients before the start. If they feel it was that big of a burden, it should probably have been dropped altogether.

Of course, other studies in the area have used measuring over a similar or longer period. For example, Bazelmans [3] used an actometer over 14 days, Black [4] used actigraphy over 14 days, Sisto[5] used actigraphy over 7 days, Vercoulen[6] used an actometer over 12 days and Van der Werf [7] used an actometer for 12 days.

Also if one wants to reduce the burden on patients, why not take out one or both of the exercise tests instead. As the clinicians in the study would know, post-exertional symptoms are part of the condition.

For example, Nijs[8] performed a gentle walking exercise on patients where they walked on average 558m(+/-340) (range: 120-1620) at a speed of 0.9m/s (+/-0.2) (range: 0.6-1.1). This resulted in a statistically significant (p<0.05) worsening of scores in the following areas when comparing pre-exercise, post-exercise and 24 hour post-exercise scores using ANOVA: VAS fatigue, VAS musculoskeletal pain, VAS sore throat, SF-36 bodily pain and SF-36 general health percention. 14 out of 24 subjects experienced a clinically meaningful change (worsening) in bodily pain (i.e. a minimum change of the SF-36 bodily pain subscale score of at least 10).

Those results are similar to another study[9] which involved the acute effects of 10 discontinuous 3-minute exercise bouts on a treadmill in 10 CFS patients. In between exercise bouts, there was a 3-minute recovery period between exercise bouts. The participants walked at a comfortable walking pace self-selected by the subjects. On average, the subjects walked at a speed of 0.71+/-0.20 m/s. Some patients reported experiencing headaches, leg pain, fatigue or sore throats.

In another study, Lapp [10] (not to be confused with Clapp[9]) reported on the effects of 31 patients to his practice who were asked to monitor their symptoms three weeks before to 12 days after a maximal exercise test. 74% of the patients experienced worsening fatigue and 26% stayed the same. None improved. The average relapse lasted 8.82 days although 22% were still in relapse when the study ended at 12 days. There were similar changes with exercise in lymph pain, depression, abdominal pain, sleep quality, joint and muscle pain and sore throat.

These are just a small selection of the studies which show patients experience an exacerbation of their symptoms following exercise testing. So these are the sorts of symptoms the patients may expect following the exercise. This reminds me that there seems to be a lot of concentration on measuring fatigue in this study - there are many other symptoms that are part of "CFS/ME".If they had used actometers instead of, say, doing one of the exercise tests, the response to the exercise could have been followed to see how long and how severe an effect the exercise had on the patient. Or they could have dropped both the exercise tests altogether.

As well as "subjective" findings following exercise testing, there have also been objective findings. Arnold et al[11] found excessive intracellular acidoss of skeletal muscles with exercise. Jammes[12] found an increase of damaging oxidative stress following exercise testing. So patients could not just endure temporary sysptom but possibly also longer-term harm from exercise testing. There are numerous other exercise abnormalities.As the clinicians involved in the study probably hear from patients, one of the frustrating things about ME or CFS is that people don't realise the payback that they can have from doing things. This would have been an opportunity to investigate this as part of the study. But now the effort patients will put in and the payback they will feel in some ways is being wasted as the effects won't be measured.

Anyway, to repeat again, given the authors familiarity with the literature, I find it strange that they would decide using an actometer would be worse than putting patients through two exercise tests.

I also find it surprising that in a study part-funded by the Department of Work and Pensions (DWP) that the objective outcome measures (not involving questionnaires) are all once-off exercise tests. It has been established that patients need to be able to do things on several days during a week before they can be passed fit for work. I have mentioned using actometers following exercise tests after an exercise test above; of course, actometers wouldn't have to be used at that time but also during a "normal week".

Proponents of pacing methods including APT would say that there is a "ceiling of activity" that patients can't go above without experiencing a worsening of symptoms. Black[13] has found evidence of this. Proponents of CBT or GET for "CFS/ME" would suggest that patients can gradually just increase how much activity they can do. Actometers would also have tested the hypothesis. As it stands, the study will not give us information on this as just because patients answer questionnaires saying they're improved (which could simply be because they think they're better) or improve their exercise results (which might simply be because they're willing to push themselves more) doesn't prove that they don't have an activity ceiling above which they experience disabling symptoms (esp. when, as in this study, there is no follow-up period following the exercise testing). This is the real "heart" of the issue but given the current design, the question won't be answered.

On 2014 Jan 03, Tom Kindlon commented:

Further information on existing data on management strategies for CFS

(I'm posting this e-letter/comment from 2008 here for the same reason as the first e-letter below)

As well as giving the protocol for the PACE Trial, this paper also gives information and data from some previous studies in the area.

Depending on which pieces of data are presented for any treatment in medicine, a treatment can often look more or less useful or effective. Readers of this paper may be interested to know about a recent meta-analysis of the efficacy of CBT for CFS[1]. The studies involved a total of 1371 patients. This involved calculating the size of an effect measure, the Cohen's d value.They calculated d using the following method: "Separate mean effect sizes were calculated for each category of outcome variable (e.g., fatigue self- rating) and for each type of outcome variable (mental, physical, and mixed mental and physical). Studies generally included multiple outcome measures. For all analyses except those that compared different categories or types of outcome variables, we used the mean effect size of all the relevant outcome variables of the study."d was calculated to be 0.48.

For anyone unfamiliar with Cohen's d values, they are not bounded by 1; also, the higher the score, the bigger the "effect size" i.e. the more "effective" a treatment was found to be. Cohen's d values are considered to be a small effect size at 0.2, a moderate effect size at 0.5, and a large effect size at 0.8[2]. CBT had a more general definition in this paper and included some papers on GET. For example, the current paper gives some information on a study by Fulcher and White[3]. Malouff et al[1] calculated the d value for this study as 0.46 (95% CI: 0.03-0.95).

References:

[1] Malouff, J. M., et al., Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: A meta-analysis. Clinical Psychology Review (2007), doi:10.1016/j.cpr.2007.10.004

[2] Cohen J: Statistical power analysis for the behavioural sciences. Edited by: 2. New Jersey: Lawrence Erlbaum; 1988.

[3] Fulcher KY, White PD: Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ 1997, 314:1647-1652.

On 2014 Jan 03, Tom Kindlon commented:

If CBT for CFS is "to help patients improve activity levels and quality of life", would not actometers be useful for measuring outcomes?

(I'm posting this e-letter/comment from 2007 here for the same reason as the first e-letter below)

Just following up on a previous point: I have just read an oft-quoted paper on CBT for CFS[1], which was co-written by one of the co-authors and principal investigators in the current study, Prof Chalder. [CBT was provided, to the best of my knowledge, in one of the places where CBT will be offered in the PACE Trial].

The current paper says "Two independent systematic reviews have found that rehabilitative cognitive behaviour therapy (CBT) and GET were the most promising treatments for CFS/ME in secondary care". The two reviews reference this paper[1]. The paper[1] states that "cognitive behavior therapy was to help patients improve activity levels and quality of life". Unfortunately there is no mention of pedometers or actometers being used. So it seems disappointing that, according to the design presented, the researchers in the current trial (which many are hoping might be the definitive paper on the subject) will use actometers before the patients start the intervention but will not assess whether the treatment improves activity levels using the sort of measurements actometers can provide.

References:

[1] Deale A, Husain K, Chalder T, Wessely S. Long term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry 2001;158: 2038-42.

On 2014 Jan 03, Tom Kindlon commented:

CFS intervention studies - lessons can be learned from a previous review

(I'm posting this e-letter/comment from 2007 here for the same reason as the first e-letter below)

I have just been reminded that many of the points I have been made, such as suggesting the use of the actometer as an outcome measure, were covered in the Whiting et al review (2001) [1].

The review recommended the use of more objective outcome measures e.g. "Outcomes such as "improvement," in which participants were asked to rate themselves as better or worse than they were before the intervention began, were frequently reported. However, the person may feel better able to cope with daily activities because they have reduced their expectations of what they should achieve, rather than because they have made any recovery as a result of the intervention. A more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities."

This review also recommended long-term follow-up: "The relapsing nature of CFS suggests that follow-up should continue for at least an additional 6 to 12 months after the intervention period has ended, to confirm that any improvement observed was due to the intervention itself and not just to a naturally occurring fluctuation in the course of the illness."

It is slightly disappointing that the follow-up period in this study is scheduled at 52 weeks, only 16 weeks after the session at 36 weeks.

It is particularly disappointing that this current trial didn't learn from the Whiting et al review [1] as both White and Sharpe have shown awareness of the review, having made reference to it in articles [2-5].

Perhaps it is not too late to collect data from even some subjects, using the actometers?

References:

[1] Penny Whiting, Anne-Marie Bagnall, Amanda J. Sowden, John E. Cornell, Cynthia D. Mulrow, Gilbert Ramírez: Interventions for the Treatment and Management of Chronic Fatigue Syndrome - A Systematic Review JAMA. 2001;286:1360-1368 http://jama.ama-assn.org/cgi/content/full/286/11/1360

[2] Peter White: Commentary. Adv. Psychiatr. Treat. 2002;8:363-365. (September 2002)http://apt.rcpsych.org/cgi/content/full/8/5/363

[3] Peter White: Chronic unexplained fatigue.Postgrad. Med. J. 2002;78:445-446. (August 2002) http://pmj.bmj.com/cgi/content/full/78/922/445

[4] Peter White: What causes chronic fatigue syndrome?BMJ 2004;329:928-929.http://www.bmj.com/cgi/content/full/329/7472/928

[5] Michael Sharpe: The symptom of generalised fatigue.PN 2006;6:72-77.http://pn.bmj.com/cgi/content/full/6/2/72

On 2014 Jan 03, Tom Kindlon commented:

Another example as to why objective measures would be useful

(I'm posting this e-letter/comment from 2007 here for the same reason as the first e-letter below)

Another example of why objective measurements are important in studies involving CBT was shown in a recently published study by Knoop et al [1]. Their results state that "the level of self-reported cognitive impairment decreased significantly more after CBT than in the control conditions. Neuropsychological test performance did not improve."

References:

[1] Knoop H, Prins JB, Stulemeijer M, van der Meer JW, Bleijenberg G:The effect of cognitive behaviour therapy for chronic fatigue syndrome on self-reported cognitive impairments and neuropsychological test performance. Journal of Neurology and Neurosurgery Psychiatry. 2007 Apr;78(4):434-6.

On 2014 Jan 03, Tom Kindlon commented:

Would it not be preferable if objective outcome measures were used?

This was originally posted at: http://www.biomedcentral.com/1471-2377/7/6/comments but the line gaps have been removed so don't think many will fancy reading it there (also may click on the PubMed Central link for the paper and not see it).

I find it strange that, particularly in such a costly trial (over UK£3m* [2013: final estimate is around UK£5m]), only subjective outcome measures are being used.

The participants are assessed using actigraphy watches at the baseline assessment stage. Why are not these being used either during and particularly at the end of the trial? This is important given previous studies in the area.

One study (on a single patient)[1] found "using a 26-session graded activity intervention involved gradual increases in physical activity" that "from baseline to treatment termination, the patient’s self-reported increase in walk time from 0 to 155 min a week contrasted with a surprising 10.6% decrease in mean weekly step counts."

Another study [2], investigating CBT this time, found that (of 278 eligible) "241 patients had complete data (83 CBT, 80 support groups, 78 natural course) at 8 months. At 14 months CBT was significantly more effective than both control conditions for fatigue severity (CBT vs support groups 5.8 [2.2-9.4]; CBT vs natural course 5.6 [2.1-9.0]) and for functional impairment (CBT vs support groups 263 [38-488]; CBT vs natural course 222 [3-441]). Support groups were not more effective for CFS patients than the natural course. Among the CBT group, clinically significant improvement was seen in fatigue severity for 20 of 58 (35%), in Karnofsky performance status for 28 of 57 (49%), and self-rated improvement for 29 of 58 (50%)." Yet if one examines the actometer data from this study from the group given CBT, the increases in activity were minimal[3]. For instance, the baseline average was 67.9, which increased to 68.8 after treatment and to 72.2 at follow-up. About 4 points. Not unlike the medical care controls, who went from 64.9 to 68.7 in the same period. [3]

One of the aims of CBT (for CFS) has been said to be "increased confidence in exercise and physical activity"[4]

Thus it may be the case that when asked questions about one's ability to do things, such as in the physical functioning subscale of SF-36 (one of the two primary outcome measures), the patients might say that they are "Limited A Little" or "Not Limited At All" but may be just as limited as patients in other arms of study who say "limited a lot".

Ideally more than one more objective measure would be used. White himself has found immunological changes after both exercise and activity in Chronic Fatigue Syndrome [5]. It would have been interesting to see whether any of these treatments had an effect on such cytokines.

References:

[1]. Friedberg, F. Does graded activity increase activity? A case study of chronic fatigue syndrome. Journal of Behavior Therapy and Experimental Psychiatry, 2002, 33, 3-4, 203-215

[2]. Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 2001; 357: 841-47.

[3]. Van Essen, M and de Winter, LJM. Cognitieve gedragstherapie by het vermoeidheidssyndroom (cognitive behaviour therapy for chronic fatigue syndrome). Report from the College voor Zorgverzekeringen. Amstelveen: Holland. June 27th, 2002. Bijlage B. Table 2.

[4]. O'Dowd, H., Gladwell, P., Rogers, CA., Hollinghurst, S and Gregory, A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technology Assessment, 2006, 10, 37, 1-140.

[5]. White, PD., Nye, KE., Pinching, AJ., Yap, TM., Power, N., Vleck, V., Bentley, DJ., Thomas, JM., Buckland, M and Parkin, JM. Immunological changes after both exercise and activity in chronic fatigue syndrome: a pilot study. Journal of Chronic Fatigue Syndrome, 2004, 12, 2, 51-66.

On 2014 Jan 03, Tom Kindlon commented:

Would it not be preferable if objective outcome measures were used?

This was originally posted at: http://www.biomedcentral.com/1471-2377/7/6/comments but the line gaps have been removed so don't think many will fancy reading it there (also may click on the PubMed Central link for the paper and not see it).

I find it strange that, particularly in such a costly trial (over UK£3m* [2013: final estimate is around UK£5m]), only subjective outcome measures are being used.

The participants are assessed using actigraphy watches at the baseline assessment stage. Why are not these being used either during and particularly at the end of the trial? This is important given previous studies in the area.

One study (on a single patient)[1] found "using a 26-session graded activity intervention involved gradual increases in physical activity" that "from baseline to treatment termination, the patient’s self-reported increase in walk time from 0 to 155 min a week contrasted with a surprising 10.6% decrease in mean weekly step counts."

Another study [2], investigating CBT this time, found that (of 278 eligible) "241 patients had complete data (83 CBT, 80 support groups, 78 natural course) at 8 months. At 14 months CBT was significantly more effective than both control conditions for fatigue severity (CBT vs support groups 5.8 [2.2-9.4]; CBT vs natural course 5.6 [2.1-9.0]) and for functional impairment (CBT vs support groups 263 [38-488]; CBT vs natural course 222 [3-441]). Support groups were not more effective for CFS patients than the natural course. Among the CBT group, clinically significant improvement was seen in fatigue severity for 20 of 58 (35%), in Karnofsky performance status for 28 of 57 (49%), and self-rated improvement for 29 of 58 (50%)." Yet if one examines the actometer data from this study from the group given CBT, the increases in activity were minimal[3]. For instance, the baseline average was 67.9, which increased to 68.8 after treatment and to 72.2 at follow-up. About 4 points. Not unlike the medical care controls, who went from 64.9 to 68.7 in the same period. [3]

One of the aims of CBT (for CFS) has been said to be "increased confidence in exercise and physical activity"[4]

Thus it may be the case that when asked questions about one's ability to do things, such as in the physical functioning subscale of SF-36 (one of the two primary outcome measures), the patients might say that they are "Limited A Little" or "Not Limited At All" but may be just as limited as patients in other arms of study who say "limited a lot".

Ideally more than one more objective measure would be used. White himself has found immunological changes after both exercise and activity in Chronic Fatigue Syndrome [5]. It would have been interesting to see whether any of these treatments had an effect on such cytokines.

References:

[1]. Friedberg, F. Does graded activity increase activity? A case study of chronic fatigue syndrome. Journal of Behavior Therapy and Experimental Psychiatry, 2002, 33, 3-4, 203-215

[2]. Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 2001; 357: 841-47.

[3]. Van Essen, M and de Winter, LJM. Cognitieve gedragstherapie by het vermoeidheidssyndroom (cognitive behaviour therapy for chronic fatigue syndrome). Report from the College voor Zorgverzekeringen. Amstelveen: Holland. June 27th, 2002. Bijlage B. Table 2.

[4]. O'Dowd, H., Gladwell, P., Rogers, CA., Hollinghurst, S and Gregory, A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technology Assessment, 2006, 10, 37, 1-140.

[5]. White, PD., Nye, KE., Pinching, AJ., Yap, TM., Power, N., Vleck, V., Bentley, DJ., Thomas, JM., Buckland, M and Parkin, JM. Immunological changes after both exercise and activity in chronic fatigue syndrome: a pilot study. Journal of Chronic Fatigue Syndrome, 2004, 12, 2, 51-66.

On 2014 Jan 03, Tom Kindlon commented:

Another example as to why objective measures would be useful

(I'm posting this e-letter/comment from 2007 here for the same reason as the first e-letter below)

Another example of why objective measurements are important in studies involving CBT was shown in a recently published study by Knoop et al [1]. Their results state that "the level of self-reported cognitive impairment decreased significantly more after CBT than in the control conditions. Neuropsychological test performance did not improve."

References:

[1] Knoop H, Prins JB, Stulemeijer M, van der Meer JW, Bleijenberg G:The effect of cognitive behaviour therapy for chronic fatigue syndrome on self-reported cognitive impairments and neuropsychological test performance. Journal of Neurology and Neurosurgery Psychiatry. 2007 Apr;78(4):434-6.

On 2014 Jan 03, Tom Kindlon commented:

CFS intervention studies - lessons can be learned from a previous review

(I'm posting this e-letter/comment from 2007 here for the same reason as the first e-letter below)

I have just been reminded that many of the points I have been made, such as suggesting the use of the actometer as an outcome measure, were covered in the Whiting et al review (2001) [1].

The review recommended the use of more objective outcome measures e.g. "Outcomes such as "improvement," in which participants were asked to rate themselves as better or worse than they were before the intervention began, were frequently reported. However, the person may feel better able to cope with daily activities because they have reduced their expectations of what they should achieve, rather than because they have made any recovery as a result of the intervention. A more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities."

This review also recommended long-term follow-up: "The relapsing nature of CFS suggests that follow-up should continue for at least an additional 6 to 12 months after the intervention period has ended, to confirm that any improvement observed was due to the intervention itself and not just to a naturally occurring fluctuation in the course of the illness."

It is slightly disappointing that the follow-up period in this study is scheduled at 52 weeks, only 16 weeks after the session at 36 weeks.

It is particularly disappointing that this current trial didn't learn from the Whiting et al review [1] as both White and Sharpe have shown awareness of the review, having made reference to it in articles [2-5].

Perhaps it is not too late to collect data from even some subjects, using the actometers?

References:

[1] Penny Whiting, Anne-Marie Bagnall, Amanda J. Sowden, John E. Cornell, Cynthia D. Mulrow, Gilbert Ramírez: Interventions for the Treatment and Management of Chronic Fatigue Syndrome - A Systematic Review JAMA. 2001;286:1360-1368 http://jama.ama-assn.org/cgi/content/full/286/11/1360

[2] Peter White: Commentary. Adv. Psychiatr. Treat. 2002;8:363-365. (September 2002)http://apt.rcpsych.org/cgi/content/full/8/5/363

[3] Peter White: Chronic unexplained fatigue.Postgrad. Med. J. 2002;78:445-446. (August 2002) http://pmj.bmj.com/cgi/content/full/78/922/445

[4] Peter White: What causes chronic fatigue syndrome?BMJ 2004;329:928-929.http://www.bmj.com/cgi/content/full/329/7472/928

[5] Michael Sharpe: The symptom of generalised fatigue.PN 2006;6:72-77.http://pn.bmj.com/cgi/content/full/6/2/72

On 2014 Jan 03, Tom Kindlon commented:

If CBT for CFS is "to help patients improve activity levels and quality of life", would not actometers be useful for measuring outcomes?

(I'm posting this e-letter/comment from 2007 here for the same reason as the first e-letter below)

Just following up on a previous point: I have just read an oft-quoted paper on CBT for CFS[1], which was co-written by one of the co-authors and principal investigators in the current study, Prof Chalder. [CBT was provided, to the best of my knowledge, in one of the places where CBT will be offered in the PACE Trial].

The current paper says "Two independent systematic reviews have found that rehabilitative cognitive behaviour therapy (CBT) and GET were the most promising treatments for CFS/ME in secondary care". The two reviews reference this paper[1]. The paper[1] states that "cognitive behavior therapy was to help patients improve activity levels and quality of life". Unfortunately there is no mention of pedometers or actometers being used. So it seems disappointing that, according to the design presented, the researchers in the current trial (which many are hoping might be the definitive paper on the subject) will use actometers before the patients start the intervention but will not assess whether the treatment improves activity levels using the sort of measurements actometers can provide.

References:

[1] Deale A, Husain K, Chalder T, Wessely S. Long term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry 2001;158: 2038-42.

On 2014 Jan 03, Tom Kindlon commented:

Further information on existing data on management strategies for CFS

(I'm posting this e-letter/comment from 2008 here for the same reason as the first e-letter below)

As well as giving the protocol for the PACE Trial, this paper also gives information and data from some previous studies in the area.

Depending on which pieces of data are presented for any treatment in medicine, a treatment can often look more or less useful or effective. Readers of this paper may be interested to know about a recent meta-analysis of the efficacy of CBT for CFS[1]. The studies involved a total of 1371 patients. This involved calculating the size of an effect measure, the Cohen's d value.They calculated d using the following method: "Separate mean effect sizes were calculated for each category of outcome variable (e.g., fatigue self- rating) and for each type of outcome variable (mental, physical, and mixed mental and physical). Studies generally included multiple outcome measures. For all analyses except those that compared different categories or types of outcome variables, we used the mean effect size of all the relevant outcome variables of the study."d was calculated to be 0.48.

For anyone unfamiliar with Cohen's d values, they are not bounded by 1; also, the higher the score, the bigger the "effect size" i.e. the more "effective" a treatment was found to be. Cohen's d values are considered to be a small effect size at 0.2, a moderate effect size at 0.5, and a large effect size at 0.8[2]. CBT had a more general definition in this paper and included some papers on GET. For example, the current paper gives some information on a study by Fulcher and White[3]. Malouff et al[1] calculated the d value for this study as 0.46 (95% CI: 0.03-0.95).

References:

[1] Malouff, J. M., et al., Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: A meta-analysis. Clinical Psychology Review (2007), doi:10.1016/j.cpr.2007.10.004

[2] Cohen J: Statistical power analysis for the behavioural sciences. Edited by: 2. New Jersey: Lawrence Erlbaum; 1988.

[3] Fulcher KY, White PD: Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ 1997, 314:1647-1652.

On 2014 Jan 04, Tom Kindlon commented:

The dropping of actometers as an outcome measure and other points relating to the outcome measures being used

(I'm posting this e-letter/comment from 2008 here for the same reason as the first e-letter below)

In their reply to my comments, Peter White and colleagues say they are using [i]"several objective outcome measures"[/i] [1]. If they think these tests are useful as objective outcome measures, why is at least one of them not being used as a primary outcome measure rather than the current situation where there are only two subjective outcome measures being used.

I have already made some points on the outcome measures but another one is that the bimodal Chalder Fatigue Scale hardly seems a very good outcome measure for a "CFS/ME" trial where there is likely going to be so many maximum or near maximum scoring initially[2]

Also, there are so many (14) secondary outcome measures in this study, along with so many (18) predictor variables, that it seems unlikely all the different methods of looking at the secondary outcome measures can be explored in the final published paper, given authors are encouraged not to make papers too long (especially journals that have paper editions). The protocol itself is 20 pages long when all the different aspects of it are listed! At least some of the information will need to be re-iterated in the final paper.

It is of course important to take the burden on participants into account when deciding what outcome measures to use. However I find the following point very strange: "Although we originally planned to use actigraphy as an outcome measure, as well as a baseline measure, we decided that a test that required participants to wear an actometer around their ankle for a week was too great a burden at the end of the trial." Firstly they clearly don't find it that great a burden that they drop it altogether as it is being used on patients before the start. If they feel it was that big of a burden, it should probably have been dropped altogether.

Of course, other studies in the area have used measuring over a similar or longer period. For example, Bazelmans [3] used an actometer over 14 days, Black [4] used actigraphy over 14 days, Sisto[5] used actigraphy over 7 days, Vercoulen[6] used an actometer over 12 days and Van der Werf [7] used an actometer for 12 days.

Also if one wants to reduce the burden on patients, why not take out one or both of the exercise tests instead. As the clinicians in the study would know, post-exertional symptoms are part of the condition.

For example, Nijs[8] performed a gentle walking exercise on patients where they walked on average 558m(+/-340) (range: 120-1620) at a speed of 0.9m/s (+/-0.2) (range: 0.6-1.1). This resulted in a statistically significant (p<0.05) worsening of scores in the following areas when comparing pre-exercise, post-exercise and 24 hour post-exercise scores using ANOVA: VAS fatigue, VAS musculoskeletal pain, VAS sore throat, SF-36 bodily pain and SF-36 general health percention. 14 out of 24 subjects experienced a clinically meaningful change (worsening) in bodily pain (i.e. a minimum change of the SF-36 bodily pain subscale score of at least 10).

Those results are similar to another study[9] which involved the acute effects of 10 discontinuous 3-minute exercise bouts on a treadmill in 10 CFS patients. In between exercise bouts, there was a 3-minute recovery period between exercise bouts. The participants walked at a comfortable walking pace self-selected by the subjects. On average, the subjects walked at a speed of 0.71+/-0.20 m/s. Some patients reported experiencing headaches, leg pain, fatigue or sore throats.

In another study, Lapp [10] (not to be confused with Clapp[9]) reported on the effects of 31 patients to his practice who were asked to monitor their symptoms three weeks before to 12 days after a maximal exercise test. 74% of the patients experienced worsening fatigue and 26% stayed the same. None improved. The average relapse lasted 8.82 days although 22% were still in relapse when the study ended at 12 days. There were similar changes with exercise in lymph pain, depression, abdominal pain, sleep quality, joint and muscle pain and sore throat.

These are just a small selection of the studies which show patients experience an exacerbation of their symptoms following exercise testing. So these are the sorts of symptoms the patients may expect following the exercise. This reminds me that there seems to be a lot of concentration on measuring fatigue in this study - there are many other symptoms that are part of "CFS/ME".If they had used actometers instead of, say, doing one of the exercise tests, the response to the exercise could have been followed to see how long and how severe an effect the exercise had on the patient. Or they could have dropped both the exercise tests altogether.

As well as "subjective" findings following exercise testing, there have also been objective findings. Arnold et al[11] found excessive intracellular acidoss of skeletal muscles with exercise. Jammes[12] found an increase of damaging oxidative stress following exercise testing. So patients could not just endure temporary sysptom but possibly also longer-term harm from exercise testing. There are numerous other exercise abnormalities.As the clinicians involved in the study probably hear from patients, one of the frustrating things about ME or CFS is that people don't realise the payback that they can have from doing things. This would have been an opportunity to investigate this as part of the study. But now the effort patients will put in and the payback they will feel in some ways is being wasted as the effects won't be measured.

Anyway, to repeat again, given the authors familiarity with the literature, I find it strange that they would decide using an actometer would be worse than putting patients through two exercise tests.

I also find it surprising that in a study part-funded by the Department of Work and Pensions (DWP) that the objective outcome measures (not involving questionnaires) are all once-off exercise tests. It has been established that patients need to be able to do things on several days during a week before they can be passed fit for work. I have mentioned using actometers following exercise tests after an exercise test above; of course, actometers wouldn't have to be used at that time but also during a "normal week".

Proponents of pacing methods including APT would say that there is a "ceiling of activity" that patients can't go above without experiencing a worsening of symptoms. Black[13] has found evidence of this. Proponents of CBT or GET for "CFS/ME" would suggest that patients can gradually just increase how much activity they can do. Actometers would also have tested the hypothesis. As it stands, the study will not give us information on this as just because patients answer questionnaires saying they're improved (which could simply be because they think they're better) or improve their exercise results (which might simply be because they're willing to push themselves more) doesn't prove that they don't have an activity ceiling above which they experience disabling symptoms (esp. when, as in this study, there is no follow-up period following the exercise testing). This is the real "heart" of the issue but given the current design, the question won't be answered.

On 2014 Jan 04, Tom Kindlon commented:

Does housework count as exercise for somebody in the GET leg of the trial?

I wonder could the authors answer a question which is relevant to the real world application of Graded Exercise Therapy (GET). I have heard a participant in the Graded Exercise Therapy (GET) leg of the trial say that they are counting 10 minutes housework in lieu of a 10-minute walk. I think it would be very useful for the authors to clarify whether they think x minutes housework can be used in lieu of x minutes of walking or whether this is not in compliance with the protocol? I think attention to detail in this matter is very important if one is to apply the findings in the real world. With a drug it is easy to check whether the dosage is the same as published trials. With Graded Exercise Therapy (GET), we need clarification from the authors about what is meant by exercise, so that the protocol can be applied as in the trial, so that people either don't get too low a "dose" or too high a "dose" at the wrong stage.

On 2014 Feb 20, Tom Kindlon commented:

Further evidence showing why objective measures are preferable in CFS trials particularly where cognitions could be changed following the intervention

(This was originally posted as an e-letter here in 2009: http://www.biomedcentral.com/1471-2377/7/6/comments#333618. However, many people will not read the paper on PubMed Central and so not see it there)

Since writing my previous posts, further data on the subject has come to my attention.

Friedberg and Sohl [1] have just published the results of a study on an intervention involving Cognitive Behavior Therapy (CBT) which included encouraging patients for going for longer walks. It found that on the SF-36 Physical Functioning (PF) scale, patients improved from a pre-treatment mean (SD) of 49.44 (25.19) to 58.18 (26.48) post-treatment, equivalent to a Cohen's d value of 0.35. On the Fatigue Severity Scale (FSS), the improvement as measured by the cohen's d value was even great (0.78) from an initial pre-treatment mean (SD) of 5.93 (0.93) to a 5.20 (0.95) post-treatment.

However on actigraphy there was actually a numerical decrease from a pre-treatment mean (SD) of 224696.90 (158389.64) to 203916.67 (122585.92) post-treatment (cohen's d: -0.13). So just because patients report lower fatigue and better scores on the SF-36 PF scale, doesn't mean they're doing more, which is what GET and CBT based on GET claim to bring about. These results seem particularly pertinent for this study given the primary outcome measures are the SF-36 PF scale and a fatigue scale.

Further reading show that another study[2], published over a decade ago, showed the problem of using self-report data in CFS patients. The authors' rationale for the study was: "It is not clear whether subjective accounts of physical activity level adequately reflect the actual level of physical activity. Therefore the primary aims of the present study were to assess actual activity level in patients with CFS to validate claims of lower levels of physical activity and to validate the reported relationship between fatigue and activity level that was found on self-report questionnaires. In addition, we evaluated whether physical activity level adequately can be assessed by self-report measures. An Accelerometer was used as a reference for actual level of physical activity.". The authors reported on the correlations on 7 outcome measures in relation to the actometer readings: "none of the self-report questionnaires had strong correlations with the Actometer. Thus, self-report questionnaires are no perfect parallel tests for the Actometer."

Prof. White seems to be aware of the findings of this study as he has been co-authored at least two papers [3,4] which quoted the findings. One of the times this paper was referenced even shows the problem I'm highlighting e.g. "support for this explanation comes from investigations that have described discrepancies between subjectively reported impairments and objective measures of activity" [4].

The authors of the 1997 study[2] pointed out that "The subjective instruments do not measure actual behaviour. Responses on these instruments appear to be an expression of the patients' views about activity and may be biased by cognitions concerning illness and disability." This was re-iterated in another paper[5]: "In earlier studies of our research group, actual motor activity has been recorded with an ankle-worn motion-sensing device (actometer) in conjunction with self-report measures of physical activity. The data of these studies suggest that self-report measures of activity reflect the patients' view about their physical activity and may have been biased by cognitions concerning illness and disability."

A corollary of the last statement is that reports of improvement in self-report measures in interventions which change "cognitions concerning illness and disability" may not be reliable. "Improvements" in self-report measures may simply show that patients have changed their cognitions with regard to how they view their illness, disability, symptoms, etc rather than actually representing improvements in activity levels and functional capacity.

Thus, I would suggest that actometers should be used whenever possible in CFS trials where one is investigating whether an intervention has brought about increased activity.

It is also interesting to note that in the large Van der Werf (2000) study[5], which involved 277 CFS patients (and 47 healthy controls), the authors divided the patients up "pervasively passive" (representing 24% of the patients), "moderately active" and "pervasively active". They found that "levels of daily experienced fatigue and psychological distress were equal for the three types of activity patterns". So one can't necessarily tell how active a patient is from the fatigue levels they report.

Incidentally they also "there were no significant group, gender or interaction effects for the number of absolute large or relatively large day-to-day fluctuations (Table 2 and Table 3)." "The day-to-day fluctuation measures were based on somewhat arbitrary criteria (1 S.D. and 33% activity change). However, when we post hoc tested alternative criteria (50% or 66% activity change), again no significant group differences between controls and CFS patients emerged." Part of the rationale of many behavioural interventions in CFS patients is said to be to reduce "boom and bust" (sample reference,[6]). However, it may be the case that the frequency of this activity pattern in CFS has been exaggerated.

References:

[1] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

[2] Vercoulen JH, Bazelmans E, Swanink CM, Fennis JF, Galama JM, Jongen PJ, Hommes O, Van der Meer JW, Bleijenberg G. Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. J Psychiatr Res. 1997 Nov-Dec;31(6):661-73.

[3] Fulcher KY, White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 2000 September; 69(3): 302–307.

[4] Smith WR, White PD, Buchwald D. A case control study of premorbid and currently reported physical activity levels in chronic fatigue syndrome. BMC Psychiatry. 2006 Nov 13;6:53.

[5] van der Werf SP, Prins JB, Vercoulen JH, van der Meer JW, Bleijenberg G. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res. 2000 Nov;49(5):373-9.

[6] Deary V, Chalder T: Chapter 11, "Conceptualisation in Chronic Fatigue Syndrome" in Formulation and Treatment in Clinical Health Psychology Edited by Ana V. Nikcevic, Andrzej R. Kuczmierczyk, Michael Bruch Competing interests

On 2014 Feb 20, Tom Kindlon commented:

Discrepancies between momentary fatigue and recalled fatigue can exist

(This was originally posted as an e-letter here in 2009: http://www.biomedcentral.com/1471-2377/7/6/comments#338630. However, many people will not read the paper on PubMed Central and so not see it there)

One of the primary outcome measures in this study is the bimodal Chalder Fatigue Scale [1] (possible individual scores 0 and 1, total scores can range from 0-11). One of the secondary outcome measures is the Chalder Fatigue Scale[1] using a different method of scoring (possible individual scores: 0-3, total scores can range from 0-33). This asks questions about the last month: "For the next few questions, we would like to know whether or not you have had any problems with feeling tired, weak, or lacking in energy in the last month".

But is it recalled fatigue, or the memory for fatigue, exactly equal to the fatigue people actually felt during a period?

Friedberg and Sohl have investigated this using electronic diaries[2]. Here is a description of what was involved: "In order to obtain a representative diurnal sample of symptoms without undue subject burden (Stone & Shiffman, 2002), the palm pilots prompted subjects for 21 days, 6 times a day, every 2 hr plus or minus a randomly programmed 1-20 min interval (Stone & Shiffman, 1994). The first daily prompt occurred within 1 hr of the subject's wakening and the last daily prompt approximately 12 hr later. No prompt signals occurred during the subject's reported sleep time. After each prompt, a screen was displayed with a numerical rating scale (0-10) that was labeled "Fatigue Now." The end point anchors on the numerical scales were None (0) and Highest (10). Subjects were instructed to record intensity ratings on the numerical scale for their current levels of fatigue."

What they found was "average weekly recall of fatigue intensity was significantly higher than average momentary ratings" (8.5% higher on average). If one used a scale like the Chalder Fatigue Scale[1] which asked for a period of over the preceding month, one could speculate that the discrepancy would be even higher.

This suggests that self-report fatigue questionnaires may not be ideal for intervention studies particularly in expensive trials like this one where one might be willing to pay a bit extra for greater accuracy; just as it has been shown that self-report questionnaires may not correlate strongly with more objective measures of activity (such as actometers)[3,4] (of course, in this study, the reason actometers are not being used does not seem to be due to the cost of obtaining them or the need to train participants to use them, as baseline measurements from actometers are being used).

References:

[1] Chalder T, Berelowitz G, Hirsch S, Pawlikowska T, Wallace P, Wessely S, Wright D: Development of a fatigue scale. J Psychosom Res 1993, 37:147-153.

[2] Friedberg F, Sohl SJ. Memory for fatigue in chronic fatigue syndrome: the relation between weekly recall and momentary ratings. Int J Behav Med. 2008 Jan-Mar;15(1):29-33.

[3] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

[4] Vercoulen JH, Bazelmans E, Swanink CM, Fennis JF, Galama JM, Jongen PJ, Hommes O, Van der Meer JW, Bleijenberg G. Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. J Psychiatr Res. 1997 Nov-Dec;31(6):661-73.

On 2014 Feb 20, Tom Kindlon commented:

New paper lists 3 CFS studies where there was no improvement in the actometer readings but an improvement was reported in subjective outcome measures

(This was originally posted as an e-letter here in 2010: http://www.biomedcentral.com/1471-2377/7/6/comments#387679. However, many people will not read the paper on PubMed Central and so not see it there)

I know it might perhaps have seemed to some who have read these posts that I might be concerned about something that was not important (when I was calling for actometers to be used if possible for at least some of the patients at the end of the trial). So I feel "vindicated" in a way by a review[1] that has just been published. It found that in the three Dutch CFS trials looked at, studies which all found improvements in fatigue[2-4], there was no statistically significant increase in physical activity levels as measured by actometers.

The review also found that "changes in physical activity were not related to changes in fatigue."

The authors of the review (who include people who were involved in all the studies) say that, in the three studies, "treatment was based on the manual of CBT for CFS described in detail by Bleijenberg et al. (2003)" [5]. This form of CBT is comparable to the form of CBT being assessed in the PACE Trial [6].

It is useful to point out that fatigue wasn't the only subjective outcome measure that was said to have improved (in these trials where there was no increase in physical activity).

In all of the three studies [2-4], improvements were reported in functional impairment (as measured by questionnaires). In two of the studies [2,3], improvements in physical functioning as measured by the SF-36 physical functioning subscale were reported (this questionnaire does was not used in the third study[4]). So the patients reported improvements in "physical functioning" (as measured by the SF-36 physical functioning subscale) but there was no improvement in physical activity as measured by the actometers. The SF-36 physical functioning subscale is one of the primary outcome measures in the PACE Trial[6].

This discrepancy between objective measures of activity and questionnaire is similar to data I have previously drawn attention to[7] in a study by Friedberg and Sohl[8].

References:

[1] Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Jan 5:1 -7. [Epub ahead of print]

[2] Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G (2005). Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. British Medical Journal 330. Published online : 7 December 2004. doi:10.1136/bmj.38301.587106.63.

[3] Knoop H, van der Meer JW, Bleijenberg G (2008). Guided self-instructions for people with chronic fatigue syndrome: randomised controlled trial. British Journal of Psychiatry 193, 340–341.

[4] Prins JB, Bleijenberg G, Bazelmans E, Elving LD, de Boo TM, Severens JL, van der Wilt GJ, Spinhoven P, van der Meer JW (2001). Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 357, 841–847.

[5] Bleijenberg G, Prins JB, Bazelmans E (2003). Cognitive-behavioral therapies. In Handbook of Chronic Fatigue Syndrome (ed. L. A. Jason, P. A. Fennell and R. R. Taylor), pp. 493–526. Wiley: New York.

[6] White PD, Sharpe MC,Chalder T, DeCesare JC and Walwyn R for the 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 Neurology 2007, 7:6

[7] Kindlon T. Further evidence showing why objective measures are preferable in CFS trials particularly where cognitions could be changed following the intervention http://www.biomedcentral.com/1471-2377/7/6/comments#333618

[8] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

On 2014 Feb 20, Tom Kindlon commented:

CONSORT statement recommends sufficient details to allow replication (for nonpharmacologic treatments, the publishing of manuals is recommended)

(This was originally posted as an e-letter here in 2010: http://www.biomedcentral.com/1471-2377/7/6/comments#415670. However, many people will not read the paper on PubMed Central and so not see it there)

The publishing of this trial protocol [1] is to be welcomed – it is something that the CONSORT statement on Randomized Control Trials (RCTs) recommends[2].

Item 5 of the checklist in the CONSORT guidelines [2] states the following information should be given: "The interventions for each group with sufficient details to allow replication, including how and when they were actually administered."

The explanation for this is given as [3]: "Explanation—Authors should describe each intervention thoroughly, including control interventions. The description should allow a clinician wanting to use the intervention to know exactly how to administer the intervention that was evaluated in the trial.102 For a drug intervention, information would include the drug name, dose, method of administration (such as oral, intravenous), timing and duration of administration, conditions under which interventions are withheld, and titration regimen if applicable. If the control group is to receive “usual care” it is important to describe thoroughly what that constitutes. If the control group or intervention group is to receive a combination of interventions the authors should provide a thorough description of each intervention, an explanation of the order in which the combination of interventions are introduced or withdrawn, and the triggers for their introduction if applicable.

"Specific extensions of the CONSORT statement address the reporting of non-pharmacologic and herbal interventions and their particular reporting requirements (such as expertise, details of how the interventions were standardised).43 44 We recommend readers consult the statements for non-pharma-cologic and herbal interventions as appropriate."

The equivalent item in the Extension for Trials Assessing Nonpharmacologic Treatments is:

"Precise details of both the experimental treatment and comparator

4A Description of the different components of the interventions and, when applicable, descriptions of the procedure for tailoring the interventions to individual participants

4B Details of how the interventions were standardized

4C Details of how adherence of care providers with the protocol was assessed or enhanced"

Here is an extract from the explanation for part a[5]: “It is important to provide a detailed description of nonpharmacologic treatments, which are usually complex interventions involving several components (75), each of which may influence the estimated treatment effect (27–32).”

[..]

“The description of any standardization methods is essential to allow adequate replication of the nonpharmacologic treatment. We recommend that authors allow interested readers to access the materials they used to standardize the interventions, either by including a Web appendix with their article or a link to a stable Web site. Such materials include written manuals, specific guidelines, and materials used to train care providers to uniformly deliver the intervention.”

[..]

“In a review of behavioral medicine interventions, insufficient intervention detail was a barrier to assessment of evidence and development of guidelines (80–82).”

[..]

“For rehabilitation, behavioral treatment, education, and psychotherapy, authors should report qualitative and quantitative data. Qualitative data describe the content of each session, how it is delivered (individual or group), whether the treatment is supervised, the content of the information exchanged with participants, and the instruments used to give information. Quantitative data describe the number of sessions, timing of each session, duration of each session, duration of each main component of each session, and overall duration of the intervention. It is also essential to report how the intervention was tailored to patients’ comorbid conditions, tolerance, and clinical course.”

Here is an extract from the explanation for part b which seems particularly relevant as treatment manuals are referred to in the protocol (but they have not been published):

“The description of any standardization methods is essential to allow adequate replication of the nonpharmacologic treatment. We recommend that authors allow interested readers to access the materials they used to standardize the interventions, either by including a Web appendix with their article or a link to a stable Web site. Such materials include written manuals, specific guidelines, and materials used to train care providers to uniformly deliver the intervention.”

The descriptions of Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET) are 73 and 68 words respectively. These are not sufficient for replication. For example, what is the advice a therapist should give if a patient experiences an exacerbation of symptoms, which is common with this condition e.g. should they maintain their level of activity or exercise or reduce? And if they maintain their level of activity, how long should this continue for? Also what constitutes treatment adherence? In a previous comment, I pointed out a patient who is counting minutes spent doing housework as minutes for her exercise program.

This estimated cost for this trial is now 5m UK pounds of taxpayers' money[6]. It is important that it is reported as well as possible.