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PACE Trial and PACE Trial Protocol

Discussion in 'Latest ME/CFS Research' started by Dolphin, May 12, 2010.

  1. Angela Kennedy

    Angela Kennedy *****

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    Essex, UK
  2. Dolphin

    Dolphin Senior Member

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    "significance level for ... secondary outcome variables [will be] P = 0.01"

    I haven't been in this thread for a while - hope to get back later or tomorrow.

    Anyway, some people may remember I was going on about this point (apologies if somebody pointed this out - I haven't caught up):
    Somebody pointed out what they probably mean is the following:
    So basically what one is looking at there is p<0.02 for two-tail being equivalent to p<0.01 for one tail (area of 0.01 on each end).

    Some of what they claimed were differences would satisfy this criterion. I personally don't think results which don't meet statistically significance should be ignored. But they should make it clearer if they are claiming they are talking about trends. The wording gives the impression anything p<0.05 is statistically significant. And there is no mention of p<0.01 that they mentioned in the published protocol paper anywhere in the final paper.

     
  3. Dolphin

    Dolphin Senior Member

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    Central Limit Theorem

    The Central Limit Theorem is a funny concept. It doesn't seem particulary intuitive.

    I think the best way to understand it is to look at some demos and even play around with some distributions including skewed ones (make one like the SF-36 PF) and learn from it.

    Googling "central limit theorem demo" gives links to some demos e.g.
    http://www.stat.sc.edu/~west/javahtml/CLT.html

    http://onlinestatbook.com/stat_sim/sampling_dist/index.html

    http://cnx.org/content/m11186/latest/

    Spend 10/20/30 minutes on them and hopefully one might have the concept for life.

    Importantly, it does not say that every distribution is normally distributed (it refers to means).
     
  4. Dolphin

    Dolphin Senior Member

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    I can't remember has this been highlighted or not:
    One of their references is:
    Free at: http://www.mayoclinicproceedings.com/content/77/4/371.long

    In case people forget, they chose the baseline standard deviations rather than population standard deviations.
     
    Esther12 likes this.
  5. Dolphin

    Dolphin Senior Member

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    Thanks Bob.
    Yes, the bit from Ellen Goudsmit means it could have been worse.

    I dislike the impression it gives that the treatments led to people returning to normal functioning:
    This study didn't show the people returned to normal functioning. As has been said plenty of times, a SF-36 PF score is not normal functioning.

    I don't know much about Dr. Peter Spencer (wonder is that the correct name?) - I wouldn't mind putting him on a threadmill for three days in a row and then give him some cognitive tests and see if he's completely normal.

    I functioned at a high level with this illness for a few years. But I wasn't 100% well. Nor do I see that GET or CBT regularly leads to this.
     
  6. Dolphin

    Dolphin Senior Member

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    Editorials generally aren't peer-reviewed as far as I know (editors may look over them)

    e.g.
    The SF-36 is used all the time in CFS research especially the SF-36 PF subscale. Bleijenberg has been in the field 20 years. He was part of the panel reviewing the CDC criteria in 2003 that recommended its use. He has used it in lots of his studies.
    Indeed as oceanblue pointed out, it was used as part of the "full recovery" definition in:
    They would be very interested in what threshold could be used e.g. what could have been used in that paper.
    I don't think they can be given the benefit of the doubt here.
     
  7. Dolphin

    Dolphin Senior Member

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    Yes, no statistical difference in the percentages made worse by GET who did it under an "NHS specialists" (111/355=31.27%) vs any other situation (70/212=33.02%): see slide 9 at: http://afme.wordpress.com/5-treatments-and-symptoms/
     
  8. Dolphin

    Dolphin Senior Member

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    Excellent way of putting it. (And that's giving them 58 as the 15th percentile of the adult population - I'd say it could be a bit lower based on figures I've seen).

    Percentiles are used quite a lot in some areas e.g. in school we did differential aptitude tests to help us decide career choices. Results of the SATs in the US - used for college entry - are often given as percentiles. Indeed GREs (used for grad school entry) and other tests also use percentiles. I think they are used in other areas e.g. height charts for children. So they would not be an alien concept to lots of people.

    The interesting thing about CFS cohorts currently is that other disabling conditions are generally exclusions so they should probably be healthier than the general population.
     
  9. Dolphin

    Dolphin Senior Member

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    Lots of good observations there, IMO. Too tired/busy to go through them individually.
     
  10. Dolphin

    Dolphin Senior Member

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    Thanks for that.

    And on the last point: they didn't use those means and SDs on an objective test, the 6 minute walk data for which we know how 65 year olds do. We weren't given how many did get up to the 600ms (sort of results 65 year olds score) but if around 10% did, the rest had results similar to the other groups. And of course, there is no talk that the recovered/normally functioning group is around 10% in size.
    One can also add into the mix that 31% of the GET group (the biggest percentage of the 4 arms) didn't do the 6MWT. On average, the sort of people who wouldn't do it one would think would score lower than those who would do it esp. as they could have done the test twice before.

    But going on the theme of what you said, we should use what we have and can criticise them on the SF-36 PF scores.
     
  11. Dolphin

    Dolphin Senior Member

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    As I alluded to earlier, this is only relevant for means. So it makes sense for example to have symmetrical CIs for the means of each group in each arm.

    But not all distributions of individual scores are normal or even close to it.
     
  12. Dolphin

    Dolphin Senior Member

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    I think one can argue that "top box" scoring could have a place in health.
    One could argue that being in full health should mean that one would score 100/100 on the SF-36 PF (or 11 or less on the Chalder Fatigue Scale). Why should one include the "norm" of the population which includes a huge range of people.

    It wouldn't have the be the only measure used but could be one measure. If they're saying something can lead to recovery/full recovery, let's see the evidence. Isn't there some famous quote like grand claims need grand evidence or something along those lines.*

    One could them compare the proportion who scored the optimal score compared to the proportion in the population.

    * I remember QED in the 1980s (BBC1 show) (think it was that show - it may have also shown up in Arthur C. Clarke's wonders program) where they had a sceptic on about spoon bending and the like (think Uri Geller, for example). The sceptic had a steel bar in a glass box. There was a big prize for anyone who could bend it.
     
  13. Dolphin

    Dolphin Senior Member

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    Thanks for your detailed responses, biophile.

    If I can nit-pick for a moment.
    The 28% related to those with SF-36 PF scores of >=60 and Chalder Fatigue Questionnaire scores of >=18.

    The percentages across the four groups for
    "much better or very much better"
    were:
    APT: 31%
    CBT: 41%
    GET: 41%
    SMC: 25%
    (See Table 5)




    I am a bit confused by what you are saying here?
    If you are saying that any side-effects from the test would have been picked up in "non-serious adverse events", "serious adverse events", "serious adverse reactions" etc., I'm not sure that is correct for the 52 week test which was at the end of the trial.
     
  14. Dolphin

    Dolphin Senior Member

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    I mean because they are entry criteria. Take for example weights of adult females in the population - they would have a fairly wide spread. Then say for a trial one only wants adult females who are 8 stone or less (8 stone = 112lbs = 50.8 Kg). If one says that half of 1SD is sufficient for a clinical meaningful result (for some regime that increases weight?), this might be quite a small amount because they're already bunched together.

    Looking for "raw data" would be a request they might turn down. But the spirit of what you are saying could be true - in this case, we're looking for one of the secondary outcome measures. It shouldn't be sensitive information.
     
  15. Dolphin

    Dolphin Senior Member

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    Thanks oceanblue.

    Look at the authors:
    Trudie Chalder was one of the PIs (Principal Investigators) for the PACE Trial.

    Rona Moss-Morris has done a GET trial on CFS and co-wrote editorial on FINE Trial.

    I doubt I've read either of them say anything like that in all their articles on CFS. Certainly they're not regularly mentioned. I mainly read ME/CFS articles and I'm not sure I've heard the phrase "social desirability effects" in any paper and not sure about "response bias" either - it's certainly not regularly mentioned.

    -------
    The following is interesting and contrasts with the PACE Trial:
    If one looks at Figure 2, they don't use the mean plus 1 SD but simply the mean.

    They didn't use a healthy comparison group in the PACE Trial just a group who attended the GP. The figures for that group were higher (worse): Mean: 14.2 (SD: 4.6).

    The healthy comparison group would have been pretty good for the PACE Trial. Average age 44.90 (+/- 9.59) 75% female.
    If they'd used mean+ 1 SD (not done for MS trial) for PACE Trial, it would have been 15 rather than 18 as a threshold. A bigger difference when 11 is the neutral score.

    Also the comparison group only came into the PACE Trial for the "normal functioning""normal fatigue" bit.
    For clinically useful difference, it was:
    Compare that to the MS trial where they were looking to see whether the scores got down to 12.49 for the "clinically significant improvement" (possibly they would have used this score + 1 SD if the results had been worse).
     
  16. oceanblue

    oceanblue Senior Member

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    I hadn't realised percentiles were so widely used, that's good.

    Very good point about the physical exclusions used by the trial changing who the reference population should be. It just reinforces the point that the reference population should be healthy individuals ie excluding those with chronic ill health, as proposed by Knoop (& White, at the time).
     
  17. oceanblue

    oceanblue Senior Member

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    I know I'd meant to flag that up when I read it, but not sure I managed to post it here. Has anyone really got to the bottom of the data for harm/deterioration in the trial? They seem incomprehensible to me, and I wondered if that was just as the authors had planned.
     
  18. oceanblue

    oceanblue Senior Member

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    Nice quote.

    Re Top Box, I think 100/100 might be a bit too high. I've tried to estimate the data from the graph in the Bowling study - only 57% scored in the top box, and it looks like the top box is scores of 95 or 100.
    mySF36.jpg
     
  19. oceanblue

    oceanblue Senior Member

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    Yes, I'm sure Professors Chalder and Moss-Morris didn't mean to be so helpful or so reasonable. Some kind of collective brainstorm?
    Very interesting to see a mean and SD for a healthy population. This MS study is another using a healthy population for reference; there really doesn't seem to be a precedent for PACE to use a general population.
     
  20. oceanblue

    oceanblue Senior Member

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    According to Figure 1, only 33 people were excluded (5% of total recruits) on entry criteria of bimodal CFQ<6, as opposed to over 300 for SF36>65 (50% of total recruits). So potentially that's a very big effect on SD for SF36. On top of this is the exclusion of those too ill to participate which probably has a huge effect (though maybe not for CFQ as the ceiling effect means most of those excluded as too ill would have scored max of 33 anyway).
     

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