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CFS symptom-based phenotypes in two clinical cohorts of adult patients in the UK and The Netherlands

Dolphin

Senior Member
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17,567
Collin Simon M., Nikolaus Stephanie, Heron Jon, Knoop Hans, White Peter D., Crawley Esther, Chronic Fatigue Syndrome (CFS) symptombased phenotypes in two clinical cohorts of adult patients in the UK and The Netherlands,Journal of Psychosomatic Research(2015), doi: 10.1016/j.jpsychores.2015.12.006

Highlights


  • •We explore chronic fatigue syndrome (CFS) phenotypes in two large clinical cohorts.
  • •Adults with CFS may have one of 6 symptom-based phenotypes.
  • •Phenotypes were associated with sex, duration of illness, and comorbidity.
  • •Polysymptomatic patients had more severe illness and more comorbidities.
  • •Phenotypes in UK patients were replicated in Dutch patients.


Abstract

Objective

Studies have provided evidence of heterogeneity within chronic fatigue syndrome (CFS), but few have used data from large cohorts of CFS patients or replication samples.

Methods

29 UK secondary-care CFS services recorded the presence/absence of 12 CFS-related symptoms; 8 of these symptoms were recorded by a Dutch tertiary service.

Latent Class Analysis (LCA) was used to assign symptom profiles (phenotypes).

Regression models were fitted with phenotype as outcome (in relation to age, sex, BMI, duration of illness) and exposure (in relation to comorbidities and patient-reported measures).

Results

Data were available for 7041 UK and 1392 Dutch patients.

Almost all patients in both cohorts presented with post-exertional malaise, cognitive dysfunction and disturbed/unrefreshing sleep, and these 3 symptoms were excluded from LCA. In UK patients, six phenotypes emerged: ‘full’ polysymptomatic (median 8, IQR 7-9 symptoms) 32.8%; ‘pain-only’ (muscle/joint) 20.3%; ‘sore throat/painful lymph node’ 4.5%; and ‘oligosymptomatic’ (median 1, IQR 0-2 symptoms) 4.7%.

Two ‘partial’ polysymptomatic phenotypes were similar to the ‘full’ phenotype, bar absence of dizziness/nausea/palpitations (21.4%) or sore throat/painful lymph nodes (16.3%).

Women and patients with longer duration of illness were more likely to be polysymptomatic.

Polysymptomatic patients had more severe illness and more comorbidities.

LCA restricted to 5 symptoms recorded in both cohorts indicated 3 classes (polysymptomatic, oligosymptomatic, pain-only), which were replicated in Dutch data.

Conclusions

Adults with CFS may have one of 6 symptom-based phenotypes associated with sex, duration and severity of illness, and comorbidity.

Future research needs to determine whether phenotypes predict treatment outcomes, and require different treatments.


Keywords:
Chronic fatigue syndrome, Latent class analysis, Phenotypes, Symptom profiles
 

Dolphin

Senior Member
Messages
17,567
Collin 2015 Table 1 with citation.png

Info on Collin 2015 Table 1 with citation - how symptoms defined.png


UK

A CFS diagnosis was made (or confirmed) at an initial clinical assessment appointment in accordance with NICE guidelines (NICE, 2007).

[..]

Clinicians recorded the presence/absence of each symptom, with the guidance that the symptom should have persisted/recurred during 4 or more consecutive months, did not predate the fatigue and was not caused by some other medical condition.

Dutch CFS patient cohort (replication sample)
Study population
The Dutch cohort comprised adults diagnosed with CFS at a tertiary specialist care centre during the period 2007-2012 in accordance with Centers for Disease Control and Prevention (CDC) criteria (Fukuda et al., 1994, Reeves et al., 2003) and Dutch guidelines (CBO, 2013, Prins et al., 2003). A Checklist Individual Strength (CIS20-R) fatigue severity subscale score ≥35 (Vercoulen et al., 1994) and a Sickness Impact Profile (SIP) score ≥700 were used as operational criteria for fatigue that was severe enough to cause substantial functional impairment (Knoop et al., 2007a). Consultants of the outpatient clinic of the Department of Internal Medicine assessed the medical status of all patients and decided whether patients had been sufficiently evaluated to rule out a medical explanation for the fatigue. If patients had not been sufficiently examined, they were seen for full physical examination, case history evaluation and laboratory tests. Psychiatric comorbidity that could explain the presence of fatigue was ruled out by clinical interview at the specialist service with experienced clinical psychologists using Beck Depression Inventory for Primary Care (BDI-PC) (Beck et al., 1997, Brown et al., 2012) and SCL-90 (Arrindell et al., 2004) questionnaires. Symptoms, comorbidities and patient-reported measures

Differences in patient characteristics and CFS phenotypes between the two cohorts could be attributable to differences in UK and Dutch referral pathways, clinical settings and diagnostic criteria. Dutch patients were diagnosed in accordance with CDC criteria (Fukuda et al., 1994, Reeves et al., 2003), which require fatigue of ≥6 months’ duration plus the presence of at least 4 symptoms (including feeling ill after exertion, impaired memory or concentration, and unrefreshing sleep), compared to fatigue of ≥4 months’ duration and no specific symptom requirements in UK NICE guidelines (NICE, 2007). Dutch patients also had to exceed thresholds for fatigue (CIS20-R) and disability (SIP) (Knoop et al., 2007a). However, the substantial differences in the proportions of Dutch versus UK patients presenting with each CFS phenotype in our replication analyses are perhaps more likely to be a consequence of other differences in the assessment pathway, in particular, more rigorous psychological assessment to exclude somatic or psychiatric disorders.
 
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Dolphin

Senior Member
Messages
17,567
For example, CFS patients presenting with a sore throat/painful lymph node phenotype had a mean Chalder Fatigue score within 1 standard deviation (SD) of the mean score for adult attendees at UK general practice (14·2 ±4·6) (Cella and halder, 2010), and an SF-36 physical function score within 1 SD of the mean score for the UK working age population (84 ±24) (Bowling et al., 1999).
The PACE Trial authors previously claimed that these were the figures for the working age population. Following a letter in the Lancet, they admitted this was an error. Now we see it repeated again. And Peter White is one of the authors of this paper.
 

Dolphin

Senior Member
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17,567
I would be interested in seeing the supplemental files. If anyone has access to them, please send me a private message.

For example, perhaps they include data on the prevalence of the following:

Clinicians also record the presence/absence of 6 common comorbidities (migraine, Irritable Bowel Syndrome, Fibromyalgia, Chronic Regional Pain Disorder, depression, and anxiety), the patient’s height and weight, and the duration of illness (months since onset of chronic fatigue).

No overall figures for these are given in the main text that I can see and I don't think the overall prevalence figures can be calculated either from what is presented.
 

duncan

Senior Member
Messages
2,240
"...one of 6 symptom-based phenotypes associated with sex...."

Please let them mean gender.

Also, why did they spell out the number 1 as "one" - which is correct - but not the number 6?

Yes, I expect a certain degree of accuracy. Details matter.

I cannot begin to imagine what I would find if I bothered to read the entire study.
 

Jenny

Senior Member
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1,388
Location
Dorset
"...one of 6 symptom-based phenotypes associated with sex...."

Please let them mean gender.

Also, why did they spell out the number 1 as "one" - which is correct - but not the number 6?

Yes, I expect a certain degree of accuracy. Details matter.

I cannot begin to imagine what I would find if I bothered to read the entire study.

Most publications have a preferred style convention where the number 'one', where it does not refer to a particular statistic or metric, is spelled out, while higher values are written as numbers.
 

Dolphin

Senior Member
Messages
17,567
Maybe the most important question regarding this "research" is: who approved the funding?
Acknowledgements
We thank the clinical leads and team members of all services participating in the UK CFS National Outcomes Database, Jan Wiborg and Lianne Vermeeren for their assistance in forming the Dutch database. This paper presents independent research funded by the NIHR (PDF-2013-06-011). The views expressed are those of the authors, and not necessarily those of the NHS, the NIHR or the Department of Health. EC is funded by an NIHR Senior Research Fellowship (SRF-2013-06-013). SN, HK and PDW did not receive specific funding for this study.
 

Dolphin

Senior Member
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17,567
UK and Dutch patient characteristics
Data were available for 7,041 UK and 1,392 Dutch patients. Demographic characteristics of the UK and Dutch patients were broadly similar (Table S1), although the Dutch cohort was slightly younger (mean age 37.2 (95% CI 36.6 to 37.9) years, compared to 40.5 (40.2 to 40.7) years, P<0.001) and had a slightly higher proportion of men (25.6% compared to 22.1%, P=0.004). Dutch patients had lower Chalder fatigue (median 25 compared to 28) and higher SF36 physical function (median 55 compared to 40, where high score = less disabled) scores (P<0.001 for both).
 

jimells

Senior Member
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Location
northern Maine
It's discouraging to see UK authorities are still willing to fund such useless research.

I doubt there will be much demand to see the data.
 

duncan

Senior Member
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2,240
@Jenny, I didn't mean to sound so picky. A good rule of thumb, btw, is numbers one through nine are spelled out, anything two or more digits, e.g., 11, the number itself is appropriate. Either way, consistency can be a plus (although I am aware of Emerson's admonition about "a foolish inconsistency").

My broader point is that a cavalier attitude to specifics can be reflective of the final product. Case in point would be a Lyme study I recently reviewed, where the authors referred to a group of patients that remained symptomatic as "a small subgroup" - even though they were alluding to over 35% of the study's population.

A quality measurement of the results can sometimes be ascertained just by observing the authors' attitude to specificity and accuracy in secondary or even non-pertinent exercises.
 

Marco

Grrrrrrr!
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Location
Near Cognac, France
I would be interested in seeing the supplemental files. If anyone has access to them, please send me a private message.

For example, perhaps they include data on the prevalence of the following:

No overall figures for these are given in the main text that I can see and I don't think the overall prevalence figures can be calculated either from what is presented.

Ditto. These are fairly commen complaints with the exception of 'Chronic Regional Pain Disorder' which I'm assuming means complex regional pain syndrome as there doesn't appear to be such as thing as Chronic Regional Pain Disorder.

This is a much rarer condition with prevalance in the order of 26 per 100,000 compared to 300-500 for ME/CFS. At that rate we would expect around 2 cases from a cohort of 8400. Hardly worth mentioning you would think?
 

Gijs

Senior Member
Messages
690
Though i do find table 1 quite interesting. I think symptoms could be very important to separate subgroups. But the main symptoms PEM, Cognitive disfunction and sleep problems (together with orthostatic intolerance) can be objectified. Also you see 30- 40% of the CFS patiënts have palpitations this can be a different subgroup with bloodflow problems and POTS.
 

Kati

Patient in training
Messages
5,497
Though i do find table 1 quite interesting. I think symptoms could be very important to separate subgroups. But the main symptoms PEM, Cognitive disfunction and sleep problems (together with orthostatic intolerance) can be objectified. Also you see 30- 40% of the CFS patiënts have palpitations this can be a different subgroup with bloodflow problems and POTS.
There are other ways to subgroup our patient population. I am sure that I am preaching the choir but for the gist of it, here are my suggestions:

1) by acute vs gradual onset.
2) length of illness
3) severity scale
4) biological measures - NK cell function, bright cells, POTS, exercise test, MRI or whatever useful brain imaging, gut microbiome, etc?
 

lilpink

Senior Member
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988
Location
UK
This appears to make use of the National Outcomes Database for CFS/ME which has never had ethics approval to be used a part of 'research'. This IS 'research'.