Abstract
Biomarker discovery applied to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling disease of inconclusive aetiology, has identified several cytokines to potentially fulfil a role as a quantitative blood/serum marker for laboratory diagnosis, with activin B a recent addition. We explored further the potential of serum activin B as a ME/CFS biomarker, alone and in combination with a range of routine test results obtained from pathology laboratories. Previous pilot study results showed that activin B was significantly elevated for the ME/CFS participants compared to healthy (control) participants. All the participants were recruited via CFS Discovery and assessed via the Canadian/International Consensus Criteria. A significant difference for serum activin B was also detected for ME/CFS and control cohorts recruited for this study, but median levels were significantly lower for the ME/CFS cohort. Random Forest (RF) modelling identified five routine pathology blood test markers that collectively predicted ME/CFS at ≥62% when compared via weighted standing time (WST) severity classes. A closer analysis revealed that the inclusion of activin B to the panel of pathology markers improved the prediction of mild to moderate ME/CFS cases. Applying correct WST class prediction from RFA modelling, new reference intervals were calculated for activin B and associated pathology markers, where 24-h urinary creatinine clearance, serum urea and serum activin B showed the best potential as diagnostic markers. While the serum activin B results remained statistically significant for the new participant cohorts, activin B was found to also have utility in enhancing the prediction of symptom severity, as represented by WST class.
Highlights
The quest for a quantitative diagnostic and a specific marker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has yet to identify a reliable candidate, whether through routine pathology markers, or research efforts in immunology, microbiology, neuroscience and elsewhere
To calculate the marker thresholds (e.g., alkaline phosphatase (ALP) > or < 60 U/L), the recursive partitioning algorithm, decision trees, was used on the same dataset classified by Weighted Standing Time (WST), with trees developed for the direct comparison ME/CFS to healthy controls, and the full WST classification from class 0–3 (Table 1a)
Due to the small to moderate starting sample sizes for each WST class, and that the final decision thresholds involved the loss of cases, results must be ascertained with caution, as the final decisions were often drawn from fewer than 10 cases
Summary
The quest for a quantitative diagnostic and a specific marker for ME/CFS has yet to identify a reliable candidate, whether through routine pathology markers, or research efforts in immunology, microbiology, neuroscience and elsewhere. A number of cytokines, for example transforming growth factor-beta (TGF-β) and interleukin-10 (IL-10), have shown previous promise, but have not delivered a validated diagnostic test [1,2,3,4,5,6,7]. Diagnostics 2019, 9, 79 added activin B, which was detected in a pilot research study involving volunteers recruited via CFS. Activin B, along with activin A, is a member of the activin family of proteins, which belong to the TGF-β superfamily of growth and differentiation factors. Follistatin is a high-affinity binding protein for both activins, with diverse roles in physiology that include reproduction, haematopoiesis, immune cell development, as well as inflammation and immunity. The biology of activin A, at the time of writing, is better understood than that of activin B, there is evidence of differences in relation to hepcidin regulation, associated receptor binding and SMAD signalling [9,10,11]
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