How have selection bias and disease misclassification undermined the validity of myalgic encephalomy

[AndyPR]

Luis Nacul, Eliana M Lacerda, Caroline C Kingdon, Hayley Curran, Erinna W Bowman

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome has been a controversial diagnosis, resulting in tensions between patients and professionals providing them with care. A major constraint limiting progress has been the lack of a ‘gold standard’ for diagnosis; with a number of imperfect clinical and research criteria used, each defining different, though overlapping, groups of people with myalgic encephalomyelitis or chronic fatigue syndrome. We review basic epidemiological concepts to illustrate how the use of more specific and restrictive case definitions could improve research validity and drive progress in the field by reducing selection bias caused by diagnostic misclassification.

Conclusion
The inclusion in research studies of only those patients that simultaneously meet a small number of selected case definitions could improve research cost-effectiveness and, by reducing bias, optimise the chances of diagnostic biomarkers discovery and the development of effective treatments. A research strategy that values robustness of methods will speed the process of knowledge generation and its translation to better clinical practice. The care of those with chronic fatigue should continue, based on the best existing practice and evidence, when available, in open and transparent dialogue with patients. This will enable positive relationships built on trust between patients and professionals, with informed disease management decisions taken in partnership.

http://journals.sagepub.com/doi/full/10.1177/1359105317695803

I did search but couldn't see this posted on PR yet.

 

[ScottTriGuy]

May this research be helpful in your ICD efforts @Dx Revision Watch ?

 

[A.B.]

The peril of diagnosis misclassification can be illustrated with a hypothetical example on diabetes mellitus. While both the better-known types of diabetes (types 1 and 2) share hyperglycaemia as the common factor defining the diagnosis, the classification of the disease into subtypes is essential for effective management and prediction of prognosis. The distinct pathophysiologies of the two types of diabetes demand quite different approaches: targeting insulin resistance with lifestyle changes and/or oral medication for the initial management of type 2 diabetes, in contrast to mandatory insulin usage for type 1.

Consider a clinical trial of a non-insulin hypoglycaemic agent effective against type 2 diabetes (but not type 1) recruiting cases of both type 1 and type 2 diabetes. If recruitment were population-based, and because type 2 diabetes is much more common than type 1, in the absence of stratification, it could be concluded that the hypoglycaemic agent is effective in reducing blood glucose concentration in all cases, as the average decrease in glycaemia would be driven by the predominance of study participants with type 2 diabetes. This would mask the complete ineffectiveness of the treatment among the sub-group of participants with type 1 diabetes, for whom the treatment could lead to dangerous increases in glucose levels.

Similar problems may well be happening in research on other less well-understood diseases including ME/CFS, where the danger lies in generalising the results of studies using patients with unspecific ‘chronic fatigue’ (which could include people with a range of diagnoses, including mental health conditions) to people with ME/CFS. Beth Smith et al. (2014, addendum 2016) recently reappraised the evidence for ME/CFS treatments. When studies using the broad Oxford criteria (Sharpe et al., 1991) were excluded, a virtual disappearance of effect for graded exercise therapy (GET), cognitive behaviour therapy (CBT) and other psychological therapies recommended by the NICE guidelines (National Institute for Health and Care Excellence (NICE), 2007) was revealed. Studies included the pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation (PACE) trial (White et al., 2011) where psychological and exercise-based treatments had some efficacy against chronic fatigue as a symptom in the sample., but were shown to have little effect for those people with ME/CFS when defined according to more restrictive criteria (Beth Smith et al., 2014, addendum 2016; Geraghty and Esmail, 2016).

The effect seen in PACE is likely an artifact of poor methodology and post-hoc protocol changes, and is comparable in strength to a placebo (the placebo effect size is about 19% for psychological interventions in CFS according to a review by some CBT/GET proponents themselves). The transient nature of this effect and the lack of objective improvements show us that CBT/GET don't even work for a "chronic fatigue" sample. I suspect that a "chronic fatigue" sample is less at risk of GET induced deterioration though.

This said, I think this is an outstanding article. Some of the confusion and uncertainty surrounding this illness is simply due to bad definitions.

 

[charles shepherd]

This paper comes from the ME Biobank team at LSHTM and has been published in the Journal of Health Psychology - which seems to be adopting a helpful and constructive approach to the biomedical model of causation and management of ME/CFS

There is more to come!

CS

 

[Barry53]

Consider a clinical trial of a non-insulin hypoglycaemic agent effective against type 2 diabetes (but not type 1) recruiting cases of both type 1 and type 2 diabetes. If recruitment were population-based, and because type 2 diabetes is much more common than type 1, in the absence of stratification, it could be concluded that the hypoglycaemic agent is effective in reducing blood glucose concentration in all cases, as the average decrease in glycaemia would be driven by the predominance of study participants with type 2 diabetes. This would mask the complete ineffectiveness of the treatment among the sub-group of participants with type 1 diabetes, for whom the treatment could lead to dangerous increases in glucose levels.

[My italics/underline]
A nice illustration of how the PACE trial epitomises "a little knowledge is dangerous thing" when the authors are effectively claiming to be the world's leading experts.