In progress: A systematic review & meta analysis of the incidence of, and risk markers for, [CFS] and [ME] in population studies, 2020, White

Andy

Andy

Retired committee member
Full title: A systematic review and meta analysis of the incidence of, and risk markers for, chronic fatigue syndrome and myalgic encephalomyelitis in population studies of adults
Authors: White and Creed
Review question

What is the current state of knowledge regarding the incidence of, and the risk factors for, chronic fatigue syndrome and myalgic encephalomyelitis in population-based studies of adults?
NB We will regard CFS and ME as the same illness for the purposes of this form.

Specifically:
1. What is the incidence of chronic fatigue syndrome in population based cohorts of adults?
2. What are the risk markers for chronic fatigue syndrome in population based cohorts of adults?
3. What are the risk markers for chronic fatigue syndrome following corroborated infections?
Click to expand...
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=183743
 
Why now? Perhaps to give them something to do during the pandemic that doesn't require meeting any patients. Can all be done on line from home.

My main concern is whether there are actually any reputable studies of predisposing factors or what they call 'risk markers'? Or will they cobble together a few dubious studies that purport to suggest psychological and sociological 'causes'.
 
Thanks for posting. Just saw this. WTF? Looks like a nightmare in the making. Or maybe I am just too cynical?

Questions
"1. What is the incidence of chronic fatigue syndrome in population based cohorts of adults?
2. What are the risk markers for chronic fatigue syndrome in population based cohorts of adults?
3. What are the risk markers for chronic fatigue syndrome following corroborated infections?"

Studies included for first two reviews if
a) a population-based cohort was studied prospectively
b) dx recorded on medical register or by self report or according to a dx criteria - and a dx of CFS-like is okay
c) CFS not preonset but fatigue preonset okay
d) case control okay if prospective data collection before dx

Condition being studied
"Chronic fatigue syndrome, myalgic encephalomyelitis and synonyms. For the purposes of this form, we will refer to CFS as an umbrella term for all these diagnostic labels"​
Labels include "fatigue syndrome, chronic", “Chronic fatigue disorder*”, “fatigue syndrome”, “post viral fatigue*” , “postviral fatigue*”, “postinfectious fatigue*”, “post infectious fatigue*” , “Myalgic Encephal*”, “Royal Free disease”, “chronic fatigue immune dysfunction syndrome”, “chronic Epstein-Barr virus syndrome”, “chronic mononucleosis-like syndrome”, “low natural killer cell syndrome” or “systemic exertion intolerance disease”

Primary outcome
Q1 - a dx of CFS or an accepted synonym for the review of incidence.
Q2 and Q3 - risk markers will include demographic, biological, psychological, and social factors; any measurable factor that is found to increase (or diminish) the risk of developing CFS.
Q3 - In the third review (post-infectious), a diagnosis of CFS will be accepted when recorded six months (or more) after the onset of infection.

Edited to add:
Subgroup analysis
By definition
- definitions include: Holmes et al, 1988, CDC criteria (Fukuda et al, 1994; Reeves et al, 2003), Oxford (Sharpe et al, 1991), Australian criteria (Lloyd et al, 1990), International and Canadian criteria (Carruthers et al, 2003, 2011), myalgic encephalomyelitis (National Taskforce, 1994), post-viral fatigue syndrome (Ho Yen, 1990), epidemiological definition (Osoba et al, 2007), NICE (2007), and systemic exertion intolerance disease (IoM, 2015).

By method of dx - self-report, questionnaire, interviews (with/without medical tests) and diagnoses made by a medical practitioner.

Anticipated completion
Nov 2020
 
Last edited:
Medfeb said:
Thanks for posting. Just saw this. WTF? Looks like a nightmare in the making. Or maybe I am just too cynical?

Questions
"1. What is the incidence of chronic fatigue syndrome in population based cohorts of adults?
2. What are the risk markers for chronic fatigue syndrome in population based cohorts of adults?
3. What are the risk markers for chronic fatigue syndrome following corroborated infections?"

Studies included for first two reviews if
a) a population-based cohort was studied prospectively
b) dx recorded on medical register or by self report or according to a dx criteria - and a dx of CFS-like is okay
c) CFS not preonset but fatigue preonset okay
d) case control okay if prospective data collection before dx

Condition being studied
"Chronic fatigue syndrome, myalgic encephalomyelitis and synonyms. For the purposes of this form, we will refer to CFS as an umbrella term for all these diagnostic labels"​
Labels include "fatigue syndrome, chronic", “Chronic fatigue disorder*”, “fatigue syndrome”, “post viral fatigue*” , “postviral fatigue*”, “postinfectious fatigue*”, “post infectious fatigue*” , “Myalgic Encephal*”, “Royal Free disease”, “chronic fatigue immune dysfunction syndrome”, “chronic Epstein-Barr virus syndrome”, “chronic mononucleosis-like syndrome”, “low natural killer cell syndrome” or “systemic exertion intolerance disease”

Primary outcome
Q1 - a dx of CFS or an accepted synonym for the review of incidence.
Q2 and Q3 - risk markers will include demographic, biological, psychological, and social factors; any measurable factor that is found to increase (or diminish) the risk of developing CFS.
Q3 - In the third review (post-infectious), a diagnosis of CFS will be accepted when recorded six months (or more) after the onset of infection.

Edited to add:
Subgroup analysis
By definition
- definitions include: Holmes et al, 1988, CDC criteria (Fukuda et al, 1994; Reeves et al, 2003), Oxford (Sharpe et al, 1991), Australian criteria (Lloyd et al, 1990), International and Canadian criteria (Carruthers et al, 2003, 2011), myalgic encephalomyelitis (National Taskforce, 1994), post-viral fatigue syndrome (Ho Yen, 1990), epidemiological definition (Osoba et al, 2007), NICE (2007), and systemic exertion intolerance disease (IoM, 2015).

By method of dx - self-report, questionnaire, interviews (with/without medical tests) and diagnoses made by a medical practitioner.

Anticipated completion
Nov 2020
Click to expand...
The fruit bowl approach again.
Words fail me .
 
I'd say there's a good/very good chance that Peter White will use his own study from the Lancet. They attempted to measure their fitness after they became ill and made inferences about the pre-illness fitness levels!

I discuss problems with it in these comments:

https://pubpeer.com/publications/FD5485965E9A5214679676CBA269EB

This study did not have information on the physical fitness of the patients before becoming ill. The authors suggest that the patients may have been more inactive before becoming ill. However the evidence is stacking up that this is not generally the case and indeed that patients who develop CFS may, on average, be a little more active or fitter than the general population.

A recent prospective population study1 on the illness 4779 people from birth for the first 53 years of their lives. At age 53, 34 reported a diagnosis of CFS. Amongst other things, it found that "increased levels of exercise throughout childhood and early adult life and a lower body mass index were associated with an increased risk of later CFS." As it was a prospective study, there was no issue of recall bias. It also wasn't simply self-rated, as it also involved reporting by a teacher at age 13. Also they used the subject's BMI index - patients who went on to have CFS at age 53 had a (statistically significant) lower BMI than those who did not go on to develop CFS at ages 36 and 43 (before they had CFS). The authors say this "this may provide some indirect but objective evidence of increased levels of activity at these ages, especially as this difference had resolved by the age of 53 years" (when the people with CFS were no longer more active).

A study involving the corresponding author2 found that, compared to healthy controls, patients with chronic, unexplained fatigue rated themselves as more active before their illness. In this study, they also reported that "the high levels of physical activity reported by patients have been corroborated by their spouses, partners, or parents" (in another study3 ). At least three other retrospective studies reporting that CFS patients perceived themselves as more active before their illness began than healthy controls.4-6

In 2006, a CDC-funded prospective cohort study following patients from the time of acute infection with Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis) was published.7 253 patients were enrolled and followed at regular intervals over 12 months by self report, structured interview, and clinical assessment. It found that prolonged illness was "characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness".

Given only a correlation was found and that no intervention was tested in the current study, along with the preceeding information, I believe the authors' suggestion that "prevention of postinfectious fatigue by an early return to physical activity may be possible" is highly speculative (this claim was recently re-iterated by the corresponding author at a conference on CFS when presenting data from this study8 ).

1 Harvey SB, Wadsworth M, Wessely S, Hotopf M: Etiology of Chronic Fatigue Syndrome: Testing Popular Hypotheses Using a National Birth Cohort Study. Psychosom Med. 2008 Mar 31

2 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.

3 Van Houdenhove B, Neerinckx E, Onghena P, Lysens R, Vertommnen H: Premorbid "overactive" lifestyle in chronic fatigue syndrome and fibromyalgia: an etiological relationship or proof of good citizenship? J Psychosom Res 2001, 51:571-6.

4 Riley MS, O'Brien CJ, McCluskey DR, Bell NP, Nicholls DP: Aerobic work capacity in patients with chronic fatigue syndrome. BMJ 1990, 301:953-6.

5 Van Houdenhove B, Onghena P, Neerinckx E, Hellin J: Does high "action-proneness" make people more vulnerable to chronic fatigue syndrome? A controlled psychometric study. J Psychosom Res 1995, 39:633-40.

6 MacDonald KL, Osterholm MT, LeDell KH, White KE, Schenck CH, Chao CC, Persing DH, Johnson RC, Barker JM, Peterson PK: A case-control study to assess possible triggers and cofactors in chronic fatigue syndrome. Am J Med 1996, 100:548-54.

7 Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006 Sep 16;333(7568):575. Epub 2006 Sep 1.

8 White PD. "Overview of post-viral fatigue: CFS or what?". International Symposium on Viruses in CFS & Post-viral Fatigue - A satellite meeting of the 6th International Conference on HHV-6 & 7 in Baltimore (2008). http://scivee.tv/node/6895
Click to expand...

Test of "physical fitness" used seems far from ideal for this cohort
The authors state in the abstract that "an empirically defined fatigue syndrome 6 months after onset" was associated with "lower physical fitness". "Lower physical fitness" is a term that is regularly used throughout this paper. However, has it been properly defined especially for this post-viral group? And what can be inferred from the correlation?

Firstly it should be remembered that the study used two measures of physical fitness from the exercise test: What they called "exercise power" was calculated as "the number of stairs climbed, multiplied by the height of each stair, and the participant's weight." A measure of "physical fitness" was calculated by "dividing the number of stairs climbed by the exercise pulse-rate difference". It seems rather arbitrary to ignore the first when mentioning "physical fitness" in the study and abstract.

It also needs to be pointed out that this is an unusual way to define fitness and may not be suitable for people with CFS and related post-viral syndromes. For example, Postural Orthostatic Tachycardia Syndrome (POTS) has found to be more common in this sort of population than in other populations. A recent study1 using a standing test of 2 minutes duration found a prevalence rate of POTS of 27% compared to 9% in a control group (p=0.006). A previous case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome had found a significant higher rate (p=0.01) POTS without hypotension in the patients with CFS compared to the controls (but no difference of the rate of POTS with hypotension).2 Other researchers in the field feel POTS is an important issue in the area of CFS, ME and related syndromes.3 So in the light of these findings it seems questionable that this is a suitable test to test for "physical fitness".

It should also be remembered that it is not easy to test somebody's fitness when they have an infection - a "fit" person such as (say) a sportsperson can seem unfit if one tests them when they are ill but within a short period of time could be playing sport competitively and generally showing better physical fitness than could be explained by any physical training in the interim.

References:

[1] Hoad A, Spickett G, Elliott J, Newton J. Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome. QJM. 2008 Sep 19.

[2] Galland BC, Jackson PM, Sayers RM, Taylor BJ. A matched case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome. Pediatr Res. 2008 Feb;63(2):196-202.

[3] Spence V & Stewart J (2004) Standing up for ME, Biologist 51(2): 65-70.
Click to expand...
 
InitialConditions said:
Here is a presentation by Francis Creed that has been uploaded onto the dxrevisionwatch website: https://dxrevisionwatch.files.wordpress.com/2010/01/hackettaward-creed.pdf
Click to expand...
Oof. This is especially bad. Some of the graphics make me think of conspiracy theorists putting random labels and arrows on various concepts and pretending it means something. Seriously you have to look at it to appreciate it in full. It mostly boils down to cheap philosophy over the duality of mind-body. Same as in the early days of psychosomatics, the same nonsense being argued in a loop.

He defines "somatization" as "high number of symptoms" and that's just a special kind of ridiculous. I love that it has a few bits of imaginary quotes from patients that are so clearly made-up, instead reflecting their own personal opinions, it would be hilarious if it wasn't deadly.

I can't go through this, it's 183 pages of mediocrity and circular reasoning. It belongs in a museum of how not to science. He seems to either have a weird fetish for Wessely or Wessely was in the audience that day and he was trying to impress him or something. Weird.

Anyway those are the delusional ramblings of very sick people, which is seriously ironic.
 
Participants/population

The diagnosis of CFS will be recorded on a medical register (i.e. diagnosis made by a doctor), or by self-report of being given such a diagnosis, or according to recognised diagnostic criteria (e.g. CDC or Oxford criteria). (...) A diagnosis of a CFS-like illness will be accepted.
Click to expand...

:banghead::banghead::banghead:

They say there will be a subset analysis based on different diagnostic criteria, but they could very well just lump IOM, CCC or ICC with other criteria that do not require PEM.

Here is a nice one too:
Conflicts of interest

[Peter D. White] was a co-author of some potentially contributing papers.
Click to expand...

And yet:
Risk of bias (quality) assessment

Quality of the selected studies will be assessed using the Newcastle-Ottawa Scale for cohort studies (Wells et al, accessed 24.05.2020). (...) Discrepancies between the two raters will be resolved by review and discussion.
Click to expand...
But it's not like there could be any rating discrepancy on White's papers between White and Creed anyway.

Just quoting from @Hilda Bastian's latest blog post about bias in systematic reviews:
All this requires of course, that authors are genuinely striving for rigor and fairness. People who use or are affected by the review deserve to have confidence that that’s what’s happening. A fundamental problem with the original exercise therapy and ME/CFS protocol, it seems to me, was evident author bias in the text about both the intervention and the condition.
Click to expand...
 
Last edited:
The 2019 Cvejic/Hickie paper looks to have been made expressly for the review. Discussed here:
Contribution of individual psychological and psychosocial factors, Dubbo Infection Outcomes Study, 2019, Cvejic, Hickie et al

The findings from the Dubbo study were that no personality/psychological findings predicted development of CFS. This 2019 paper worked with the same data but spun it differently. There was still no evidence for personality factors being of significance, but that's not the message you get from the abstract. It very definitely needs to be challenged, especially as it will no doubt be rolled into this "review" as another data point confirming the planned conclusion.
 
Last edited:
Except for the EBV-studies, there probably is no research on risk markers for CFS or ME.

I only know of studies that used longitudinal data from other research (that wasn't interested in CFS and focused on other things). So these studies tend to use some unrelated symptom questionnaires to reconstruct a CFS-like illness or in best case scenario they asked the patients in those longitudinal studies whether they had CFS (usually more than 1% says yes, which indicates this probably is an overestimate).

It is possible that they will find that less activity will lead to a higher chance of developing CFS, partly because a CFS diagnosis often comes after many years of being ill and undiagnosed or because lower activity levels might predispose to other illnesses that might resemble CFS (atypical depression, sleep disorders, obesity etc.) if patients don't get a thorough clinical examination.
 
PDW is an appointed member of the Independent Medical Experts Group, which advises the UK Ministry of Defence regarding its Armed Forces Compensation Scheme. He also provides paid consultancy to Swiss Re, a re-insurance company. PDW was a co-author of some potentially contributing papers.
Click to expand...
This wording always frustrates me. Both in the early 2000's and over 10 years later he was a chief medical officer and very likely still is now (I saw someone else describe themselves as a senior medical officer in the same company showing the significance of being a chief medical officer). I don't think he has ever said he is a chief medical officer in any of his conflicts of interest statements.
 
Last edited:
Michiel Tack said:
Except for the EBV-studies, there probably is no research on risk markers for CFS or ME.
Click to expand...

What about this?

I don't quite understand the "onset" criteria in the review for the types of studies to be included but CDC did a population study in the mid 2000s that found childhood trauma increased risk of CFS:
"Individuals with CFS reported significantly higher levels of childhood trauma and psychopathological symptoms than control subjects. Exposure to childhood trauma was associated with a 6-fold increased risk of CFS." (Heim et al, Childhood Trauma and Risk for Chronic Fatigue Syndrome, 2009)

​
 
Last edited:
Medfeb said:
What about this?

I don't quite understand the "onset" criteria in the types of studies included but CDC did a population study in the mid 2000s that found childhood trauma increased risk of CFS:
"Individuals with CFS reported significantly higher levels of childhood trauma and psychopathological symptoms than control subjects. Exposure to childhood trauma was associated with a 6-fold increased risk of CFS." (Heim et al, Childhood Trauma and Risk for Chronic Fatigue Syndrome, 2009)​
Click to expand...
The highly publicized 2009 Reeves CDC study* used the Childhood Trauma Questionnaire (CTQ). This questionnaire measures severely traumatic childhood events in six categories.
  • Physical abuse
  • Sexual abuse
  • Emotional abuse
  • Physical neglect
  • Emotional neglect
I've wondered if one possible explanation for patients scoring higher than controls might simply be the deeply personal nature of these questions. One might have to be highly motivated to answer these questions honestly if they applied to oneself. Positive results could simply reflect the fact that people desperate to find a "cause" for a harrowing and unexplained illness are simply more motivated to answer the questions honestly than are controls.


*"Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction."
http://www.researchgate.net/publica...e_Association_with_Neuroendocrine_Dysfunction
 
Questionnaire self-reported childhood trauma is unreliable. I can't recall the details but I think in one study of depression it was found to not correlate with recorded events and (in another study?) the association (nearly?) disappeared when socioeconomic factors were controlled for. That suggests the possibility that childhood trauma is first of all overestimated due to unreliable methodology, and second not an important cause of chronic health problems later in life (rather, growing up in poverty and deprivation will "cause" both childhood trauma and later health problems).

What I think is happening that being in a poor mood makes past problems seem much worse than they were and people are possibly biased towards this interpretation because it has been repeatedly suggested to them by society that childhood trauma is the cause of their problems.
 
strategist said:
What I think is happening that being in a poor mood makes past problems seem much worse than they were and people are possibly biased towards this interpretation because it has been repeatedly suggested to them by society that childhood trauma is the cause of their problems.
Click to expand...
And vice-versa. If your life has gone well, then you might tend to downplay or even forget past troubles.

This is a huge problem with these post-hoc studies.
 
Forbin said:
I've wondered if one possible explanation for patients scoring higher than controls might simply be the deeply personal nature of these questions. One might have to be highly motivated to answer these questions honestly if they applied to oneself. Positive results could simply reflect the fact that people desperate to find a "cause" for a harrowing and unexplained illness are simply more motivated to answer the questions honestly than are controls.


*"Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction."
http://www.researchgate.net/publica...e_Association_with_Neuroendocrine_Dysfunction
Click to expand...

Yes, participation biases, a desire to please the investigators, and the fact that this is not an unheard of explanation can lead to an exaggeration of questionnaire reports.
 
You must log in or register to reply here.
Back
Top