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Chronic Fatigue & CFS valid clinical entities across countries/healthcare settings?

Discussion in 'Latest ME/CFS Research' started by oceanblue, Jan 27, 2012.

  1. oceanblue

    oceanblue Senior Member

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    This, from 2009, looks like an important study but I've never noticed it before - anyone know anything about it? I saw one brief comment from Dolphin that almost all the contributing studies are by CBT proponents, and a 2010 'General News' thread received no replies.

    Are chronic fatigue and chronic fatigue syndrome valid clinical entities across countries and healthcare settings? 2009 (full text pdf)
    Hickie I, Davenport T, Vernon SD, Nisenbaum R, Reeves WC, Hadzi-Pavlovic D, Lloyd A.
    Australian and New Zealand, Journal of Psychiatry; 43:25-35, 2009.

    It's a vast meta-analysis of symptom data on nearly 38,000 fatigued patients including 1,950 with CFS and was recently cited by van der Meer and Lloyd in their editorial critiquing the ICC to argue that:
    The study was supported by the CDC as part of the International Chronic Fatigue Syndrome Study Group that came up with the 2003 ('Ambiguities') revision of Fukuda.

    From a quick look it appears the majority of CFS cases were Fukuda-defined wiht most of the rest Oxford, and no Empiric.

    Google scholar lists only 10 citations of the paper, so maybe it isn't such a big deal.
  2. oceanblue

    oceanblue Senior Member

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    Abstract

    Objective: The validity of the diagnosis of chronic fatigue syndrome and related chronic fatigue states remains controversial, particularly in psychiatry. This project utilized international epidemiological and clinical research data to test construct validity across diagnostic categories, health-care settings and countries. Relevant demographic, symptom and diagnostic data were obtained from 33 studies in 21 countries. The subjects had fatigue lasting 16 months (prolonged fatigue), or >6 months (chronic fatigue), or met diagnostic criteria for chronic fatigue syndrome.

    Method: Common symptom domains were derived by factor analytic techniques. Mean scores on each symptom factor were compared across diagnostic categories, health-care settings and countries.

    Results: Data were obtained on 37 724 subjects (n = 20 845 female, 57%), including from population-based studies (n = 15 749, 42%), studies in primary care (n = 19 472, 52%), and secondary or specialist tertiary referral clinics (n = 2503, 7%). The sample included 2013 subjects with chronic fatigue, and 1958 with chronic fatigue syndrome. A five-factor model of the key symptom domains was preferred (musculoskeletal pain/fatigue, neurocognitive difficulties, inflammation, sleep disturbance/fatigue and mood disturbance) and was comparable across subject groups and settings. Although the core symptom profiles were similar, some differences in symptoms were observed across diagnostic categories, health-care settings and between countries.

    Conclusions: The construct validity of chronic fatigue and chronic fatigue syndrome is supported by an empirically derived factor structure from existing international datasets.
  3. Dolphin

    Dolphin Senior Member

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  4. Dolphin

    Dolphin Senior Member

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    One problem I recall from the study is that they didn't necessarily ask patients about a full list of symptoms (say 100+ symptoms). And IIRC different lists were used. This restricts the number of factors possible.

    Also I'm not convinced that they proved mood disturbance symptoms were a core symptom. All factor analysis does is group together scores that go together. It doesn't prove they are part of the syndrome. So if one had a few questions about following sport, one might find the various questions factor together - people who follow one sport might be more inclined to also follow another sport on average (and people who don't follow one sport might be less inclined to follow another). So one could group those questions together as an "interest in sport" factor - but it doesn't prove they're a part of the syndrome - what they are is a factor group in the questionnaires.

    Even if they went one step further and showed the scores on mood disturbance symptoms scored more highly than some other group, that still wouldn't show that it was a core symptom of the condition.
    oceanblue likes this.
  5. oceanblue

    oceanblue Senior Member

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    Hi Dolphin, Thanks for the link to Ellen Goudsmit's comments, and your own helpful ones too. I'm still trying to get my mind round what they've done and how it's supposed to support their conclusions; think I'm going to have to work through the paper. But I agree that the general clustering of symptoms (not drawn from a common list) doesn't seem any way to demonstrate core symptoms, especially, as Ellen points out, many of the symptoms are common to many illnesses. And as you say, football fans and rugby fans are not necessarily the same people!

    I do think this study is important. As the authors highlight:
    So they are implying this is it, the 'empirical definition' study, though I'm not quite sure this is quite what the International CFS group meant, and tellingly that 2003 paper added:
  6. Dolphin

    Dolphin Senior Member

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    Oceanblue, your post reminded me of the following:
    I don't the Hickie et al. study justifies the Reeves et al. (2005) study at all (nor does it not justify it).

    The Reeves et al. (2005) picked thresholds out of the air (bottom 25th percentiles, etc.) for certain measures (not picked randomly) and saw these were better than random thresholds. Not a particular good "empirical" approach - a proper empirical approach would have the data taking the lead and suggesting the thresholds.

    --
    Obviously wasn't clear enough in my analogy: I was trying to say that there would be some clustering on interest in sports - I was really thinking of team sports.

    I'll try another analogy: I would think a questionnaire might find a factor that could be "interest in the performing arts" if there were questions on interest in musicals, ballet, dance, opera, etc. Some people would cluster as having an interest or liking them and some would cluster as not having a big interest in them/not particularly liking them. So if those questions had been in the questionnaire, they could be a factor of the questionnaires. But they would tell zero about CFS.
    WillowJ likes this.
  7. oceanblue

    oceanblue Senior Member

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    Yes, I'd spotted that apparently-abitrary endorsement of the Reeves study's arbitrary criteria too. At least this study is empirical in the sense of being based on the data, even if their logic is skewed.

    Ah, see what you mean about the sports/arts analogy, thanks.
  8. Snow Leopard

    Snow Leopard Senior Member

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    The effect size for 'all subjects with fatigue (n=37 724)' was 0.03, and 0.24 for CFS patients. The effect size is weak, but more importantly the directionality is not demonstrated. One of the differences for categorisation is length of fatigue (ie longer than 3 months, less than six) which means it can be argued that mood disturbance occurs as a result of being fatigued for over 6 months.


    The dominant studies were used from:
    http://www.ncbi.nlm.nih.gov/pubmed/12027042
    "The genetic aetiology of somatic distress." n=8392 (Concluded that: These results support previous fndings that somatic symptoms are relatively aetiologically distinct both genetically and environmentally from symptoms of anxiety and depression.)

    http://www.ncbi.nlm.nih.gov/pubmed/11556430
    "Development of a simple screening tool for common mental disorders in general practice." n=17,383
    oceanblue likes this.
  9. oceanblue

    oceanblue Senior Member

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    The Hickie paper that contributed 726 CFS patients (oxford, Holmes or Schudelberg) concluded:
    ETA correction: 529 if the patients were Lloyd/Australian criteria ; only 38 were Oxford and remainder, 159, were Fukuda/holmes. Anyone know anything about the Ozzie criteria? No abstract given:
    Lloyd AR, Wakefield D, Boughton C, Dwyer J. What is myalgic encephalomyelitis? Lancet 1988; 1:1286-1287.
    The Hickie paper summarised them as
  10. oceanblue

    oceanblue Senior Member

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    Commentary

    An important finding?
    This study is important, both because it was done as part of the International CFS Group that came up with the 2003 modified Fukuda definition, and because of its startling conclusion that everything from prolonged fatigue (more than one month) through chronic fatigue (6 months+) and CFS have the same types of symptoms - and probably the same underlying pathophysiology:
    The authors don't report the evidence needed to back up their argument
    The study used Factor Analysis, a statistical technique that tries to find underlying but hidden commonalities between variables, in this case symptoms. According to this study, the symptoms clustered into 5 factors common to all fatigue states:
    So you might imagine that they ran separate factor analyses on each of Prolonged Fatigue patients, Chronic Fatigue pateints and CFS patients - and found the same 5 factors in each case. But they didn't do this. Instead they analysed all 3 types of fatigue together - 88% of the total sample were prolonged fatigue cases and only 5% were CFS cases. Since almost all the cases were prolonged fatigue the only conclusions that can safely be drawn are those about prolonged fatigue. The study tells us nothing about the factors underlying CFS so the conclusion that CFS share the same 5 clusters of symptoms as other fatigue states is not supported by the evidence presented in this paper.


    But maybe they did run the relevant analysis...
    Interestingly, what appears to be an earlier version of this paper (by the same authors on the same dataset with much identical text) did include a separate analysis of CFS patients - and these patients had a different factor solution to that for the sample as a whole.
    So it appears that CFS does not have the same factor structure as other forms of fatigue, though this analysis has never been formally published.

    The lack of a coherent factor structure ties in with an earlier paper by Hickie (which also contributed about half the patients used in the CFS-only analysis above) that concluded:

    Also, the authors didn't evaluate more specific criteria
    The other striking omisson in this study is that they didn't attempt to evaluate more specific criteria, or even (it appears) include Post Exertional Fatigue/Malaise as a symptom. Given that the main criticism of Fukuda is that it's too broad, and that they had accounted for less than half the variance with their own factor structure (which suggests there are better explanations they hadn't discovered), it's bizarre the authors go on to conclude that:

    There are numerous other issues with the paper but I'm not sure it's worth going into the detail.
    WillowJ and Dolphin like this.
  11. Dolphin

    Dolphin Senior Member

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    :thumbsup: Great work, oceanblue. :Sign Good Job:
  12. oceanblue

    oceanblue Senior Member

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    Thanks, Dolphin!

    What I'd meant to include but forgot was a thank you to you for tipping me off about the unpublished paper (have updated the post now).
  13. DaiWelsh

    DaiWelsh

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    Sorry if I am being naive, but how are they allowed to get away with what appears to be blatantly biased data analysis, particular if as you say the fuller analysis is "known". Is this a feature of the science world's "publication" concept, i.e. that until they publish it is not officially recognised as existing Or is it a case of complex statistics having multiple "valid" interpretations?

    As an aside the question of scientists as sub-standard statisticians has come up a couple of times recently. As not all scientists can be expected to be expert statisticians, why is it not standard practice to pass data for statistical analysis by statisticians, rather by the researchers themselves? Is there a valid reason, or is it just historical?
  14. oceanblue

    oceanblue Senior Member

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    Can't explain the first part. The published paper makes no sense without the CFS-only analysis, so I'm surprised it was published (the draft may have been declined by the BMJ). One of the authors, Rosane Nisenbaum, is a Biostatistician. The PACE trial has at least 2 biostatisticians on board.
  15. Enid

    Enid Senior Member

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    I cannot believe after decades the talk of neuropsychiatic mumbo jumbos - come on.
  16. WillowJ

    WillowJ Senior Member

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    oceanblue likes this.
  17. WillowJ

    WillowJ Senior Member

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    and well done :)
  18. oceanblue

    oceanblue Senior Member

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    Thanks for that, and you feedback! Dolphin sent me a copy of the Ozzie criteria (PM me if you want them) and it does appear to drop the psychiatric exclusions, which sems like a major flaw.

    I don't necessarily see Fukuda as conflating CF with CFS. The whole strategy of Fukuda is to specifically exclude a whole number of known causes of CF, then to apply a severity threshold (of sorts), and then requires a set of required symptoms (even if it's not a satisfactory set of symptoms). If I'd had the energy, I was going to point out in my original post that this 2009 Hickie paper differs from Fukuda precisely by conflating CFS with CF, and even with prolonged (1 month+) fatigue. Which is quite a shocking thing to do when their own evidence actually points to Fukuda being too broad.
  19. oceanblue

    oceanblue Senior Member

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    In the case of the technique used here, Factor Analysis, there's a lot of user input/judgement required, which is probably why the authors said
    Different groups could have taken the same data and come up with 4 or 6 factors, and they could all be right, ie it's a matter of opinion - to some extent (with 4, 5 or 6 factor solutions, 4 of the factors would be very similar across all solutions). For that reason, Factor Analysis findings shouldn't be seen as absolute.

    It's notable that the authors 'Inflammation' factor included both sharp chest pains and dizziness, neither of which is obviously linked to inflammation (and neither of which is part of Fukuda), which helps to illustrate how the factors are not exactly absolute.

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  20. oceanblue

    oceanblue Senior Member

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    Just some washing up - only if you're really interested

    Other issues with the study

    No exclusions for known medical and psychiatric illnesses.
    There are many causes of chronic fatigue, just look at the standard exclusions in the Fukuda criteria:
    The authors dataset included "exclusionary and non-exclusionary medical and psychiatric illness" yet no patients with known causes of chronic fatigue were excluded from the data.

    So although I agree with the authors to some extent when they say:
    in that their may be final common pathways eg for fatigue, the causal pathology is likely to be different. Diabetes, cancer and hypothyroidism can all lead to chronic fatigue but you wouldn't treat them all the same way, as the authors propose:
    Also:

    1. All symptoms were dichotomised (ie Yes/No)even if there was frequency/severity data on the symptom in the orginal data. This inevitably increases number of symptoms each patient has, and so increases the level of correlation between symptoms, which will increase the apparent strength of factors. Also, while fukuda specifies headaches of new onset as a symptom, another patient with chronic fatigue may reports headaches, but they may have had that problem well before the fatigue started. Apparently there are technical reasons why dichomisded variables can produce unreliable results in factor analysis.

    2.
    Imagine a patient has missing values for symptoms A and B - these will be replaced by the mean value for A and B. So every patient with missing data for symptoms A & B will then be given identical results for A and B, which will again articficially inflate the correlation between A and B (and so the strength of the factors).

    3. Because different studies measured symptoms using different questionnaire, the answers to questions from different questionnaires were merged:
    This adds more uncertainty to the study.

    Taking 1-3 together just adds to the doubt about the robustness of the findings.
    WillowJ likes this.

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