A paper, published in the International Journal of Molecular Sciences, has emphasised the challenges relating to heterogeneity (how a disease can differ from person to person, and between subgroups of the population) in ME/CFS research.
One way to manage heterogeneity in studies is to consider factors such as age, sex, disease severity, duration of disease, and age of onset, in either study design (by grouping participants based on certain characteristics, or only looking at one group e.g. females and not males) or in statistical analysis (by using methods that either adjust for these factors, or where appropriate, carrying out the analysis in different subgroups within the study population).
If heterogeneity is not accounted for in research, study findings may be affected by a phenomenon known as ‘effect modification’ (or ‘interaction’).
Effect modification occurs when the association of interest, for example the link between a specific hormone and ME/CFS severity level, differs by a third factor such as sex. Here, if the results are presented for males and females together, it is possible that no significant association would be observed. However, if the analysis was to be done separately for males and females, results could show that there was a significant association in females that had been masked by the lack of significance of findings in the male population.
In their paper, the team led by Dr Jessica Maya at the Centres for Disease Control (CDC), identified that heterogeneity may also stem from disease mechanisms leading to ‘biologically distinct subgroups’ within the ME/CFS population.
Using information from 171 participants (50 with ‘ME/CFS’ and 121 ‘non-fatigued’) in a previously published study, Dr Maya’s team investigated whether there might be genetic drivers of immune dysregulation in ‘ME/CFS’, specifically dysregulation of the compliment pathway, a crucial part of the immune system that enhances the body’s ability to:
- Promote a protective inflammatory response to injury and infection,
- Attack microorganisms, known as pathogens, that can cause disease that can cause disease,
- Clear pathogens and remove any damaged cells.
It is important to note that in this study, the researchers use the term ‘ME/CFS’ despite the fact participants were identified using a definition based on the 1994 Fukuda criteria for CFS which, unlike criteria for ME/CFS – such as the Canadian Consensus Criteria, the 2015 Institute of Medicine Criteria, and the 2021 NICE criteria – does not require a the presence of post exertional malaise (PEM) for a diagnosis to be made.
Results suggested that a subgroup of people with ‘ME/CFS’ who had certain genetic traits exhibited dysregulation of the complement pathway. Interestingly, the authors noted that some of these traits have also been linked to fatigue-related phenotypes (the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment) using data from the UK Biobank.
In their paper, the researchers explain that although heterogeneity in ME/CFS research complicates identification of disease mechanisms, biomarkers for the disease, and potential targets for treatment, development of methods (such as those used in this study) which identify distinct subgroups of those with the disease may lead to advances in research and understanding that would not otherwise be possible.
ME Research UK adds that despite the findings in this study may have been impacted by the diagnostic criteria used. While the 50 participants with ‘ME/CFS’ all met the Fukuda criteria for ‘CFS’, it is possible that only a subset would have met more stringent ME/CFS criteria. Therefore, it would be important to repeat this study in not only a larger sample, but also to ensure that participants in the ME/CFS group all met criteria requiring PEM for a diagnosis of the disease to be made.
Despite the methodological limitations, the authors narrative around heterogeneity is important, and echoes a comment made at the 1st International Conference on Clinical and Scientific Advances in ME/CFS and Long COVID in 2024, where former ME Research UK grant award-holder Dr Nuno Sepúlveda stated that disease heterogeneity – how a disease can present differently from person to person – is one of the biggest challenges in ME/CFS research.
