Researchers have developed what could be the first clinically viable blood test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), achieving remarkable diagnostic accuracy in a proof-of-concept study published in the Journal of Translational Medicine. The epigenetic-based test demonstrated 96% overall accuracy, with 92% sensitivity and 98% specificity in distinguishing patients with severe ME/CFS from healthy controls.
The breakthrough comes from a team at the University of East Anglia, led by researcher-clinician Dmitry Pshezhetskiy, who utilized a novel epigenetic assay called EpiSwitch® to analyze 3D chromosomal conformations in blood cells. "With no definitive tests, many patients have gone undiagnosed or misdiagnosed for years," Pshezhetskiy noted, emphasizing that the discovery "offers the potential for a simple, accurate blood test to help confirm a diagnosis, which could lead to earlier support and more effective management."
Revolutionary Diagnostic Approach
The study analyzed whole blood samples from 47 patients with severe ME/CFS (housebound individuals) and 61 age-matched healthy controls using a comprehensive DNA microarray platform encompassing one million conformational capture markers. Unlike previous studies that focused on limited biomarkers, this whole-genome approach preserved the complexity of epigenetic signatures associated with ME/CFS.
The researchers employed a robust five-step machine learning model using XGBoost algorithm, identifying the top 200 differentially expressed markers through both parametric and non-parametric statistical approaches. These markers were distributed across multiple chromosomal regions, suggesting ME/CFS involves a polygenic signature rather than single-locus dysregulation.
An independent validation cohort of 24 ME/CFS patients and 45 controls, completely separate from the training dataset, confirmed the test's exceptional performance. The diagnostic accuracy surpassed previously published biomarker-based approaches for ME/CFS, which typically achieved around 90% accuracy but required complex laboratory workflows beyond current clinical settings.
Immune Dysfunction at the Molecular Level
Pathway enrichment analysis using STRING database revealed that the identified epigenetic markers were strongly enriched for immune and inflammatory signaling pathways. The key enriched pathways included interleukin signaling (particularly IL-2 and IL-10 cascades), TNF/NF-κB axis, Toll-like receptor signaling, and JAK/STAT signaling pathways.
IL-2 emerged as a central hub in the protein interaction network, with multiple top markers connecting to IL-2 signaling and T-cell regulation modules. This finding aligns with previous cytokine studies reporting altered circulating interleukins in ME/CFS patients and supports the growing evidence that ME/CFS is fundamentally a neuroinflammatory condition.
The epigenetic signature showed substantial overlap with pathways implicated in other chronic inflammatory disorders, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. This convergence suggests shared immune pathways across neuroimmune and systemic inflammatory diseases, though it doesn't imply identical etiology.
Therapeutic Stratification Potential
One of the most promising aspects of the research was the identification of patient subgroups based on IL-2-associated pathways. When the researchers analyzed the most significant chromosomal conformations associated with 50 IL-2 STRING genes, ME/CFS patients exhibited clear clustering with an 18/29 division of the 47 patients analyzed.
This stratification has significant therapeutic implications. Comparative network analysis revealed that the ME/CFS epigenetic signature shares key molecular nodes (IL-2, IL-10, CD4) with immunomodulatory therapies such as rituximab and copaxone, which have shown promise in ME/CFS treatment. The overlap suggests that epigenetic profiles could inform therapeutic stratification and identify patients more likely to benefit from specific immunomodulatory treatments.
The researchers identified 12 potential therapies that may simultaneously reduce IL-2 and CD4+ cells while increasing IL-10, ranging from biologics like rituximab to small molecules like tofacitinib. Several of these have already been trialed in ME/CFS or closely related conditions, with rituximab showing symptom improvement in some patients in Norwegian randomized controlled trials.
Clinical Translation Pathway
The EpiSwitch® technology platform offers a clear advantage for clinical translation, as it has already been successfully implemented in clinical diagnostics for other conditions. The platform operates under ISO 13,485, ISO 9001, and ISO 15,189 standards in CLIA- and UKAS-accredited laboratories, ensuring assay reproducibility, stability, and scalability.
Examples of successful translation include the EpiSwitch PSE test for prostate cancer, which achieved 94% accuracy and reduced unnecessary biopsies by 79%, and the CiRT test for immunotherapy response, which predicts PD-1/PD-L1 response with 85% accuracy. Both tests are now commercially available in the US and UK with established reimbursement pathways.
Scientific Community Response
The research has received cautious optimism from the ME/CFS research community. Katie Glass, a molecular biologist who studies ME/CFS at Cornell University, praised the innovative approach: "I think it's really cool they brought this method to the field." However, she noted that "as far as it being a biomarker, my enthusiasm would be pretty tempered because the cohort is very small and they looked at only very severe patients."
The study's limitations include its focus on severe, housebound patients, which may limit applicability to moderate or mild ME/CFS cases. Additionally, while the researchers employed independent training and validation subsets, both were derived from overlapping biobank sources, necessitating larger-scale, prospective validation in multi-center cohorts.
Addressing a Critical Medical Need
ME/CFS affects an estimated 17-24 million people worldwide, though these numbers are crude estimates due to the lack of reliable diagnostic tools. The condition is characterized by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction, significantly impacting quality of life.
The absence of specific diagnostic tests has necessitated reliance on clinical criteria, often leading to misdiagnosis or delayed diagnosis. Many patients have gone years without proper diagnosis, highlighting the critical need for objective diagnostic tools.
The new epigenetic test represents a significant advancement in ME/CFS diagnostics, offering hope for earlier diagnosis and better disease management. As the researchers noted, the comprehensive whole-genome approach reflects the underlying complexity and heterogeneity of disease-related gene regulation, potentially offering a more reliable, reproducible, and clinically actionable diagnostic platform than previous approaches focused on individual pathways or isolated biomarkers.
