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The authors review claims of high diagnostic sensitivity and specificity and highlight how 3D chromatin conformation signatures could inform disease-specific gene regulation. They then critique scientific weaknesses, including incomplete immunological citation history, unclear diagnostic inclusion criteria, subjective cohort selection, and ambiguous control-group definitions, arguing these issues weaken validity and translational relevance.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/wheat-and-chaff-in-myalgic-encephalomyelitischronic-fatigue-syndrome-mecfs-in-clinics-and-laboratory-letter-to-the-editor/442669/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/wheat-and-chaff-in-myalgic-encephalomyelitischronic-fatigue-syndrome-mecfs-in-clinics-and-laboratory-letter-to-the-editor/442669.png","ImageObject",300,407,{"name":92,"@type":93},"awa","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-02","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What study is being discussed in this letter?","Question",{"text":112,"@type":113},"The letter addresses Hunter et al.’s work on blood-based diagnostic biomarkers for ME/CFS using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which main diagnostic performance values does the letter reference?",{"text":117,"@type":113},"It notes the reported diagnostic model sensitivity of 92% and specificity of 98% for distinguishing ME/CFS patients from controls.",{"name":119,"@type":110,"acceptedAnswer":120},"What methodological problems does the letter emphasize?",{"text":121,"@type":113},"It highlights omissions in foundational immunology citations, unclear specification of which ME/CFS diagnostic criteria were used, subjective “severe housebound” cohort selection, and ambiguity in how the control group was defined.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},442669,1790950307,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":81,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":39},3985747858093,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Tirelli et al. Journal of Translational Medicine (2026) 24:20  \n[https://doi.org/10.1186/s12967-025-07397-z](https://doi.org/10.1186/s12967-025-07397-z)  \nJournal of Translational Medicine  \nLETTER TO THE EDITOR Open Access  \nWheat and chaff in Myalgic   \nEncephalomyelitis/Chronic fatigue syndrome (ME/CFS) in clinics and laboratory  \nUmberto Tirelli 1, Marianno Franzini2 and Salvatore Chirumbolo3*  \nTo the Editor,  \nWe read the contribution by Hunter et al., titled“Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling” in this journal, initially impressed for the large collection of data. They actually presented a novel, genome-wide epigenetic profiling approach using EpiSwitch® technology to identify potential diagnostic biomarkers for ME/ CFS [1]. The use of 3D chromatin conformation signatures provides a fresh perspective on disease-specific gene regulation, moving beyond conventional transcriptomics and methylation analyses. In general, the diagnostic model demonstrates impressive sensitivity (92%) and specificity (98%) in distinguishing ME/CFS patients from controls, suggesting real clinical potential [1]. Moreover, the application of advanced machine learning techniques adds analytical robustness, while pathway analysis identifies biologically plausible immune-related mechanisms. This integrative approach sets a promising foundation for future biomarker-driven diagnostics and personalized therapy stratification in ME/CFS. Fundamentally, they presented a retrospective case-control analysis aiming to identify diagnostic epigenetic markers for ME/CFS using 3D chromatin conformation profiling (EpiSwitch®). However, while the authors make bold claims regarding  \ndiagnostic sensitivity and specificity, the paper suffers from multiple scientific weaknesses and methodological ambiguities that undermine its validity and translational relevance.  \nFirst, the article repeatedly asserts that “immune dysregulation” is a hallmark of ME/CFS, citing elevated pro-inflammatory cytokines and natural killer (NK) cell dysfunction. However, whereas the authors cite updated papers with a presumptive relationship with the issue, a critical omission here is the lack of citation of early foundational immunological studies in ME/CFS [2]. Notably absent is the 1994 work by Tirelli et al. in the Scandinavian Journal of Immunology, which documented, for the first time, immunological abnormalities in CFS patients and could serve as an important historical anchor for claims of immune dysregulation [2]. This omission raises concerns about reporting bias and selective citation to frame the narrative around newer, possibly more aligned findings with the current study methodology [2, 3].  \nAdditionally, the paper refers to “ME/CFS inclusion criteria” as requiring severe CFS with patients being“housebound,” but fails to specify which diagnostic criteria were used, whether the Fukuda, Canadian Consensus, International Consensus, or IOM/NAM criteria [1]. This lack of precision is critical, as different case definitions yield different cohorts in terms of clinical features and biological signatures. Using “severe housebound” as  \nThe online version of the original article can be found at [https://doi.o](https://doi.o)[rg/10.1186/s12967-025-07203-w](rg/10.1186/s12967-025-07203-w.)[.](rg/10.1186/s12967-025-07203-w.)  \n*Correspondence:  \nSalvatore Chirumbolo [salvatore.chirumbolo@univr.it](salvatore.chirumbolo@univr.it)  \n1Tirelli Medical Group, Pordenone, Italy  \n2Italian Scientific Society of Oxygen-Ozone Therapy (SIOOT), Bergamo, Italy  \n3Department of Engineering for Innovation Medicine, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits ","cbCailC4ZjinPtXQ","https://ap.wps.com/l/cbCailC4ZjinPtXQ","pdf",724322,"English","# Letter to the Editor\n## Overview of the original study and reported diagnostic performance\n## Key scientific concerns: citation gaps and immunological claims\n## Methodological ambiguities: inclusion criteria and control group definition","[{\"question\":\"What study is being discussed in this letter?\",\"answer\":\"The letter addresses Hunter et al.’s work on blood-based diagnostic biomarkers for ME/CFS using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling.\"},{\"question\":\"Which main diagnostic performance values does the letter reference?\",\"answer\":\"It notes the reported diagnostic model sensitivity of 92% and specificity of 98% for distinguishing ME/CFS patients from controls.\"},{\"question\":\"What methodological problems does the letter emphasize?\",\"answer\":\"It highlights omissions in foundational immunology citations, unclear specification of which ME/CFS diagnostic criteria were used, subjective “severe housebound” cohort selection, and ambiguity in how the control group was defined.\"}]","Wheat and chaff in Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) in clinics and laboratory - Letter to the Editor | PDF",1790701145]