{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:22:32Z","timestamp":1793254952271,"version":"4.5.0"},"reference-count":73,"publisher":"National Academy of Sciences","issue":"33","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U54 AI178855"],"award-info":[{"award-number":["U54 AI178855"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["U54 NS105541"],"award-info":[{"award-number":["U54 NS105541"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,8,19]]},"abstract":"<jats:p>People living with myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS) experience heterogeneous and debilitating symptoms that lack sufficient biological explanation, compounded by the absence of accurate, noninvasive diagnostic tools. To address these challenges, we explored circulating cell-free RNA (cfRNA) as a blood-borne bioanalyte to monitor ME\/CFS. cfRNA is released into the bloodstream during cellular turnover and reflects dynamic changes in gene expression, cellular signaling, and tissue-specific processes. We profiled cfRNA in plasma by RNA sequencing for 93 ME\/CFS cases and 75 healthy sedentary controls, then applied machine learning to develop diagnostic models and advance our understanding of ME\/CFS pathobiology. A generalized linear model with least absolute shrinkage selector operator regression trained on condition-specific signatures achieved a test-set AUC of 0.81 and an accuracy of 77%. Immune cfRNA deconvolution revealed differences in platelet-derived cfRNA between cases and controls, as well as elevated levels of plasmacytoid dendritic, monocyte, and T cell\u2013derived cfRNA in ME\/CFS. Biological network analysis further implicated immune dysfunction in ME\/CFS, with signatures of cytokine signaling and T cell exhaustion. These findings demonstrate the utility of RNA liquid biopsy as a minimally invasive tool for unraveling the complex biology behind chronic illnesses.<\/jats:p>","DOI":"10.1073\/pnas.2507345122","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T19:07:02Z","timestamp":1754939222000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis\/chronic fatigue syndrome"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1860-8316","authenticated-orcid":false,"given":"Anne E.","family":"Gardella","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Cornell University","place":["Ithaca"]},{"name":"Meinig School of Biomedical Engineering, Cornell University","place":["Ithaca"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Eweis-LaBolle","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Cornell University","place":["Ithaca"]},{"name":"Meinig School of Biomedical Engineering, Cornell University","place":["Ithaca"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8816-4293","authenticated-orcid":false,"given":"Conor J.","family":"Loy","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Cornell University","place":["Ithaca"]},{"name":"Meinig School of Biomedical Engineering, Cornell University","place":["Ithaca"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma D.","family":"Belcher","sequence":"additional","affiliation":[{"name":"Meinig School of Biomedical Engineering, Cornell University","place":["Ithaca"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan S.","family":"Lenz","sequence":"additional","affiliation":[{"name":"Meinig School of Biomedical Engineering, Cornell University","place":["Ithaca"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl J.","family":"Franconi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Cornell University","place":["Ithaca"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally Y.","family":"Scofield","sequence":"additional","affiliation":[{"name":"Meinig School of Biomedical Engineering, Cornell University","place":["Ithaca"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Grimson","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Cornell University","place":["Ithaca"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8141-3058","authenticated-orcid":false,"given":"Maureen R.","family":"Hanson","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Cornell University","place":["Ithaca"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6085-7311","authenticated-orcid":false,"given":"Iwijn","family":"De Vlaminck","sequence":"additional","affiliation":[{"name":"Meinig School of Biomedical Engineering, Cornell University","place":["Ithaca"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"CDC Clinical overview of ME\/CFS. Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (2024). https:\/\/www.cdc.gov\/me-cfs\/hcp\/clinical-overview\/index.html. Accessed 16 July 2024."},{"key":"e_1_3_4_2_2","volume-title":"Beyond Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Redefining an Illness","author":"Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome, Board on the Health of Select Populations, Institute of Medicine","year":"2015","unstructured":"Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome, Board on the Health of Select Populations, Institute of Medicine, Beyond Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Redefining an Illness (National Academies Press (US), 2015)."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-020-02269-0"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/metabo10050216"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2018.00412"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1300\/J092v11n01_02"},{"key":"e_1_3_4_7_2","unstructured":"CDC Clinical overview of long COVID. COVID-19 (2024). https:\/\/www.cdc.gov\/covid\/hcp\/clinical-overview\/index.html. Accessed 25 July 2024."},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.3390\/medicina57050418"},{"key":"e_1_3_4_9_2","volume-title":"Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop","author":"Forum on Microbial Threats","year":"2024","unstructured":"Forum on Microbial Threats , Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop, C. Biffl, E. Ashby, J. Liao, M. Snair, Eds. (National Academies Press, 2024)."},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.49.1.1"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241511937"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45107-3"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2415119121"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101373"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13643-019-1202-6"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2005.02935.x"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2003.015511"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbih.2023.100720"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2021.03.023"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0236148"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2009.04.008"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1400121"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2015.07.004"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1710519114"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2021.07.004"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00086.2020"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-bioeng-110222-111259"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101034"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49245-6"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.157621"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04410-z"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2403897121"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-024-05410-5"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom11070961"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0186802"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0231136"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-022-00356-3"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4896"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.09.001"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1097\/COC.0000000000000239"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-44098-2"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-023-01207-z"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.2174\/138161209789105108"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2004.020255"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2009.070466"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.688486"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.000086"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-024-05915-z"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-28955-9"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-04179-3"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.7717\/peerj-cs.1857"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202302146"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2113476118"},{"key":"e_1_3_4_54_2","doi-asserted-by":"crossref","unstructured":"C. Loy Plasma cell-free RNA captures immune dynamics and predicts GVHD after hematopoietic stem cell transplantation. medRxiv [Preprint] (2025). https:\/\/www.medrxiv.org\/content\/10.1101\/2024.05.15.24307448v2 (Accessed 17 April 2025).","DOI":"10.1101\/2024.05.15.24307448"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.3390\/ph15080931"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-12-104"},{"key":"e_1_3_4_57_2","first-page":"167","article-title":"Two age peaks in the incidence of chronic fatigue syndrome\/myalgic encephalomyelitis: A population-based registry study from Norway 2008\u20132012","volume":"12","author":"Bakken I. J.","year":"2014","unstructured":"I. J. Bakken , Two age peaks in the incidence of chronic fatigue syndrome\/myalgic encephalomyelitis: A population-based registry study from Norway 2008\u20132012. BMC Med. 12, 167 (2014).","journal-title":"BMC Med."},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.159.18.2129"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3999(94)00125-O"},{"key":"e_1_3_4_60_2","unstructured":"J. E. Ware User\u2019s Manual for the SF36v2 Health Survey (Quality Metric Lincoln RI ed. 2 2007)."},{"key":"e_1_3_4_61_2","first-page":"53","article-title":"A chronic fatigue syndrome (CFS) severity score based on case designation criteria","volume":"5","author":"Baraniuk J. N.","year":"2013","unstructured":"J. N. Baraniuk , A chronic fatigue syndrome (CFS) severity score based on case designation criteria. Am. J. Transl. Res. 5, 53\u201368 (2013).","journal-title":"Am. J. Transl. Res."},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky955"},{"key":"e_1_3_4_63_2","doi-asserted-by":"crossref","unstructured":"A. Dobin STAR: Ultrafast universal RNA-seq aligner. Bioinformatics 29 15\u201321 (2013).","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts503"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v028.i05"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-77"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01188-9"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts480"},{"key":"e_1_3_4_72_2","unstructured":"A. E. Gardella aegardella\/cfRNA_MECFS. GitHub. https:\/\/github.com\/aegardella\/cfRNA_MECFS. Deposited 1 July 2025."},{"key":"e_1_3_4_73_2","unstructured":"A. E. Gardella Data from \u201cCirculating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis\/chronic fatigue syndrome.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE293840. Deposited 4 April 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2507345122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T19:07:37Z","timestamp":1754939257000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2507345122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,11]]},"references-count":73,"journal-issue":{"issue":"33","published-print":{"date-parts":[[2025,8,19]]}},"alternative-id":["10.1073\/pnas.2507345122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2507345122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,11]]},"assertion":[{"value":"2025-03-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2507345122"}}