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Whole blood RNA signatures have been tested as biomarkers for TB, but have failed to meet the World Health Organization\u2019s (WHO) optimal target product profiles (TPP). Here, we use RNA sequencing and machine-learning to investigate the utility of plasma cell-free RNA (cfRNA) as a host-response biomarker for TB in cohorts from Uganda, Vietnam and Philippines. We report a 6-gene cfRNA signature, which differentiates TB-positive and TB-negative individuals with AUC\u2009=\u20090.95, 0.92, and 0.95 in test, training and validation, respectively. This signature meets WHO TPPs (sensitivity: 97.1% [95% CI: 80.9-100%], specificity: 85.2% [95% CI: 72.4-100%]) regardless of geographic location, sample collection method and HIV status. Overall, our results identify plasma cfRNA as a promising host response biomarker to diagnose TB.<\/jats:p>","DOI":"10.1038\/s41467-024-49245-6","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T11:04:33Z","timestamp":1718017473000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Circulating cell-free RNA in blood as a host response biomarker for detection of tuberculosis"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3497-1561","authenticated-orcid":false,"given":"Adrienne","family":"Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conor J.","family":"Loy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7599-6082","authenticated-orcid":false,"given":"Daniel","family":"Eweis-LaBolle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan S.","family":"Lenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Steadman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred","family":"Andgrama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Viet","family":"Nhung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Worodria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7216-7067","authenticated-orcid":false,"given":"Claudia M.","family":"Denkinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payam","family":"Nahid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6553-2601","authenticated-orcid":false,"given":"Adithya","family":"Cattamanchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6085-7311","authenticated-orcid":false,"given":"Iwijn","family":"De Vlaminck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,10]]},"reference":[{"key":"49245_CR1","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1038\/s41579-022-00763-4","volume":"20","author":"P Chandra","year":"2022","unstructured":"Chandra, P., Grigsby, S. J. & Philips, J. A. Immune evasion and provocation by Mycobacterium tuberculosis. Nat. Rev. Microbiol. 20, 750\u2013766 (2022).","journal-title":"Nat. Rev. Microbiol."},{"key":"49245_CR2","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1038\/s41590-018-0225-9","volume":"19","author":"A Singhania","year":"2018","unstructured":"Singhania, A., Wilkinson, R. J., Rodrigue, M., Haldar, P. & O\u2019Garra, A. The value of transcriptomics in advancing knowledge of the immune response and diagnosis in tuberculosis. Nat. Immunol. 19, 1159\u20131168 (2018).","journal-title":"Nat. Immunol."},{"key":"49245_CR3","doi-asserted-by":"publisher","first-page":"00021","DOI":"10.1128\/CMR.00021-18","volume":"31","author":"PK Drain","year":"2018","unstructured":"Drain, P. K. Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection. Clin. Microbiol. Rev. 31, 00021\u201318 (2018).","journal-title":"Clin. Microbiol. 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Chang, C.J.L, D.E.L, and I.D.V are inventors on submitted patents pertaining to cell-free nucleic acids (US patent applications 63\/237,367 and 63\/429,733). I.D.V. is a member of the Scientific Advisory Board of Karius Inc., Kanvas Biosciences, and GenDX. I.D.V. is listed as an inventor on submitted patents pertaining to cell-free nucleic acids (US patent applications 63\/237,367, 63\/056,249, 63\/015,095, 16\/500,929, 41614P-10551-01-US) and receives consulting fees from Eurofins Viracor. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4949"}}