{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T22:21:16Z","timestamp":1793744476925,"version":"4.6.1"},"posted":{"date-parts":[[2025,4,16]]},"group-title":"Genetic and Genomic Medicine","reference-count":85,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS) is a complex, heterogeneous, and systemic disease defined by a suite of symptoms, including unexplained persistent fatigue, post-exertional malaise (PEM), cognitive impairment, myalgia, orthostatic intolerance, and unrefreshing sleep. The disease mechanism of ME\/CFS is unknown, with no effective curative treatments. In this study, we present a multi-site ME\/CFS whole-genome analysis, which is powered by a novel deep learning framework, HEAL2. We show that HEAL2 not only has predictive value for ME\/CFS based on personal rare variants, but also links genetic risk to various ME\/CFS-associated symptoms. Model interpretation of HEAL2 identifies 115 ME\/CFS-risk genes that exhibit significant intolerance to loss-of-function (LoF) mutations. Transcriptome and network analyses highlight the functional importance of these genes across a wide range of tissues and cell types, including the central nervous system (CNS) and immune cells. Patient-derived multi-omics data implicate reduced expression of ME\/CFS risk genes within ME\/CFS patients, including in the plasma proteome, and the transcriptomes of B and T cells, especially cytotoxic CD4 T cells, supporting their disease relevance. Pan-phenotype analysis of ME\/CFS genes further reveals the genetic correlation between ME\/CFS and other complex diseases and traits, including depression and long COVID-19. Overall, HEAL2 provides a candidate genetic-based diagnostic tool for ME\/CFS, and our findings contribute to a comprehensive understanding of the genetic, molecular, and cellular basis of ME\/CFS, yielding novel insights into therapeutic targets. Our deep learning model also offers a potent, broadly applicable framework for parallel rare variant analysis and genetic prediction for other complex diseases and traits.<\/jats:p>","DOI":"10.1101\/2025.04.15.25325899","type":"posted-content","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T08:35:13Z","timestamp":1744965313000},"source":"Crossref","is-referenced-by-count":9,"title":["Dissecting the genetic complexity of myalgic encephalomyelitis\/chronic fatigue syndrome via deep learning-powered genome analysis"],"prefix":"10.64898","author":[{"given":"Sai","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fereshteh","family":"Jahanbani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varuna","family":"Chander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kjellberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menghui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Glass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Iu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faraz","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajan Douglas","family":"Maynard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristan","family":"Chou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan","family":"Cooper-Knock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin Jinye","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Durga","family":"Thota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Zeineh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer K.","family":"Grenier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Grimson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen R.","family":"Hanson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Snyder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025051314101568000_2025.04.15.25325899v2.1","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s12967-020-02269-0","article-title":"Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome\/myalgic encephalomyelitis (CFS\/ME)","volume":"18","year":"2020","journal-title":"J Transl Med"},{"key":"2025051314101568000_2025.04.15.25325899v2.2","unstructured":"Institute of Medicine, Board on the Health of Select Populations & Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome. Beyond Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Redefining an Illness. (National Academies Press, 2015)."},{"key":"2025051314101568000_2025.04.15.25325899v2.3","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3390\/healthcare9040459","article-title":"Life-Threatening Malnutrition in Very Severe ME\/CFS","volume":"9","year":"2021","journal-title":"Healthcare"},{"key":"2025051314101568000_2025.04.15.25325899v2.4","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1186\/s12916-023-02893-9","article-title":"Biomarkers for myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS): a systematic review","volume":"21","year":"2023","journal-title":"BMC Med"},{"key":"2025051314101568000_2025.04.15.25325899v2.5","first-page":"412","article-title":"Estimating Prevalence, Demographics, and Costs of ME\/CFS Using Large Scale Medical Claims Data and Machine Learning","volume":"6","year":"2018","journal-title":"Front Pediatr"},{"key":"2025051314101568000_2025.04.15.25325899v2.6","doi-asserted-by":"crossref","first-page":"e1011523","DOI":"10.1371\/journal.ppat.1011523","article-title":"The viral origin of myalgic encephalomyelitis\/chronic fatigue syndrome","volume":"19","year":"2023","journal-title":"PLoS Pathog"},{"key":"2025051314101568000_2025.04.15.25325899v2.7","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa169"},{"key":"2025051314101568000_2025.04.15.25325899v2.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2022.03.010"},{"key":"2025051314101568000_2025.04.15.25325899v2.9","doi-asserted-by":"crossref","first-page":"e730","DOI":"10.1038\/tp.2015.208","article-title":"Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis\/chronic fatigue syndrome","volume":"6","year":"2016","journal-title":"Transl Psychiatry"},{"key":"2025051314101568000_2025.04.15.25325899v2.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1879-7"},{"key":"2025051314101568000_2025.04.15.25325899v2.11","doi-asserted-by":"crossref","unstructured":"Bergstr\u00f6m, A. et al. Insights into human genetic variation and population history from 929 diverse genomes. Science 367, (2020).","DOI":"10.1126\/science.aay5012"},{"key":"2025051314101568000_2025.04.15.25325899v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.021"},{"key":"2025051314101568000_2025.04.15.25325899v2.13","doi-asserted-by":"publisher","DOI":"10.1126\/science.abo1131"},{"key":"2025051314101568000_2025.04.15.25325899v2.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32009-5"},{"key":"2025051314101568000_2025.04.15.25325899v2.15","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3810"},{"key":"2025051314101568000_2025.04.15.25325899v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0167-z"},{"key":"2025051314101568000_2025.04.15.25325899v2.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1530509100"},{"key":"2025051314101568000_2025.04.15.25325899v2.18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"2025051314101568000_2025.04.15.25325899v2.19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003709"},{"key":"2025051314101568000_2025.04.15.25325899v2.20","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"2025051314101568000_2025.04.15.25325899v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"2025051314101568000_2025.04.15.25325899v2.22","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260419"},{"key":"2025051314101568000_2025.04.15.25325899v2.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.036"},{"key":"2025051314101568000_2025.04.15.25325899v2.24","doi-asserted-by":"publisher","DOI":"10.1126\/science.abo1261"},{"key":"2025051314101568000_2025.04.15.25325899v2.25","doi-asserted-by":"publisher","DOI":"10.1016\/J.MOLMED.2021.06.002"},{"key":"2025051314101568000_2025.04.15.25325899v2.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.12.019"},{"key":"2025051314101568000_2025.04.15.25325899v2.27","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.cels.2022.05.007","article-title":"Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity","volume":"13","year":"2022","journal-title":"Cell Syst"},{"key":"2025051314101568000_2025.04.15.25325899v2.28","doi-asserted-by":"publisher","DOI":"10.1101\/2024.05.14.594252"},{"key":"2025051314101568000_2025.04.15.25325899v2.29","doi-asserted-by":"publisher","DOI":"10.1101\/2024.03.30.24305115"},{"key":"2025051314101568000_2025.04.15.25325899v2.30","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAC1000"},{"key":"2025051314101568000_2025.04.15.25325899v2.31","doi-asserted-by":"crossref","unstructured":"Germain, A. , Levine, S. M. & Hanson, M. R . In-Depth Analysis of the Plasma Proteome in ME\/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling. Proteomes 9, (2021).","DOI":"10.3390\/proteomes9010006"},{"key":"2025051314101568000_2025.04.15.25325899v2.32","doi-asserted-by":"publisher","DOI":"10.1101\/2021.01.29.21250755"},{"key":"2025051314101568000_2025.04.15.25325899v2.33","doi-asserted-by":"crossref","unstructured":"Vu, L. T. et al. Single-cell transcriptomics of the immune system in ME\/CFS at baseline and following symptom provocation. Cell Rep Med 5, 101373 (2024).","DOI":"10.1016\/j.xcrm.2023.101373"},{"key":"2025051314101568000_2025.04.15.25325899v2.34","doi-asserted-by":"crossref","first-page":"e2415119121","DOI":"10.1073\/pnas.2415119121","article-title":"Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis\/chronic fatigue syndrome","volume":"121","year":"2024","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025051314101568000_2025.04.15.25325899v2.35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1907883116"},{"key":"2025051314101568000_2025.04.15.25325899v2.36","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"2025051314101568000_2025.04.15.25325899v2.37","doi-asserted-by":"crossref","first-page":"100168","DOI":"10.1016\/j.xgen.2022.100168","article-title":"Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes","volume":"2","year":"2022","journal-title":"Cell Genom"},{"key":"2025051314101568000_2025.04.15.25325899v2.38","doi-asserted-by":"publisher","DOI":"10.1101\/2023.06.29.23292056"},{"key":"2025051314101568000_2025.04.15.25325899v2.39","doi-asserted-by":"crossref","first-page":"e2423555","DOI":"10.1001\/jamanetworkopen.2024.23555","article-title":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome After SARS-CoV-2 Infection","volume":"7","year":"2024","journal-title":"JAMA Netw Open"},{"key":"2025051314101568000_2025.04.15.25325899v2.40","first-page":"1187163","article-title":"ME\/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature","volume":"10","year":"2023","journal-title":"Front Med (Lausanne"},{"key":"2025051314101568000_2025.04.15.25325899v2.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01167-z"},{"key":"2025051314101568000_2025.04.15.25325899v2.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03767-x"},{"key":"2025051314101568000_2025.04.15.25325899v2.43","doi-asserted-by":"crossref","first-page":"122903","DOI":"10.1016\/j.lfs.2024.122903","article-title":"Role of angiotensin converting enzyme in pathogenesis associated with immunity in cardiovascular diseases","volume":"352","year":"2024","journal-title":"Life Sci"},{"key":"2025051314101568000_2025.04.15.25325899v2.44","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1093\/qjmed\/hcac119","article-title":"Elevated serum ACE levels in patients with post-acute COVID-19 syndrome","volume":"115","year":"2022","journal-title":"QJM"},{"key":"2025051314101568000_2025.04.15.25325899v2.45","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s11906-023-01248-2","article-title":"ACE-inhibitors in hypertension: A historical perspective and current insights","volume":"25","year":"2023","journal-title":"Curr. Hypertens. Rep"},{"key":"2025051314101568000_2025.04.15.25325899v2.46","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1002\/jcsm.13182","article-title":"Nicotinamide Phosphoribosyltransferase-elevated NAD+ biosynthesis prevents muscle disuse atrophy by reversing mitochondrial dysfunction","volume":"14","year":"2023","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"2025051314101568000_2025.04.15.25325899v2.47","doi-asserted-by":"crossref","first-page":"698","DOI":"10.14336\/AD.2021.0824","article-title":"The role of kynurenine pathway and NAD+ metabolism in myalgic encephalomyelitis\/chronic fatigue syndrome","volume":"13","year":"2022","journal-title":"Aging Dis"},{"key":"2025051314101568000_2025.04.15.25325899v2.48","doi-asserted-by":"crossref","unstructured":"Low, R. N. , Low, R. J. & Akrami, A . A review of cytokine-based pathophysiology of Long COVID symptoms. Front. Med. (Lausanne ) 10, 1011936 (2023).","DOI":"10.3389\/fmed.2023.1011936"},{"key":"2025051314101568000_2025.04.15.25325899v2.49","first-page":"2103","article-title":"PSMB5 plays a dual role in cancer development and immunosuppression","volume":"7","year":"2017","journal-title":"Am. J. Cancer Res"},{"key":"2025051314101568000_2025.04.15.25325899v2.50","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0529-1"},{"key":"2025051314101568000_2025.04.15.25325899v2.51","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s12253-020-00797-0","article-title":"The function of NM23-H1\/NME1 and its homologs in major processes linked to metastasis","volume":"26","year":"2020","journal-title":"Pathol. Oncol. Res"},{"key":"2025051314101568000_2025.04.15.25325899v2.52","doi-asserted-by":"crossref","first-page":"1151246","DOI":"10.3389\/fimmu.2023.1151246","article-title":"Ras family signaling pathway in immunopathogenesis of inflammatory rheumatic diseases","volume":"14","year":"2023","journal-title":"Front. Immunol"},{"key":"2025051314101568000_2025.04.15.25325899v2.53","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1367-20.2020"},{"key":"2025051314101568000_2025.04.15.25325899v2.54","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2016.00032"},{"key":"2025051314101568000_2025.04.15.25325899v2.55","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4827(02)00102-7"},{"key":"2025051314101568000_2025.04.15.25325899v2.56","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-022-01277-6"},{"key":"2025051314101568000_2025.04.15.25325899v2.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.08.005"},{"key":"2025051314101568000_2025.04.15.25325899v2.58","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-017-0324-9"},{"key":"2025051314101568000_2025.04.15.25325899v2.59","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.pnpbp.2017.12.001","article-title":"Neurodevelopmental synaptopathies: Insights from behaviour in rodent models of synapse gene mutations","volume":"84","year":"2018","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"2025051314101568000_2025.04.15.25325899v2.60","doi-asserted-by":"publisher","DOI":"10.1038\/S41380-022-01828-9"},{"key":"2025051314101568000_2025.04.15.25325899v2.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2015.09.004"},{"key":"2025051314101568000_2025.04.15.25325899v2.62","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-014-0167-5"},{"key":"2025051314101568000_2025.04.15.25325899v2.63","doi-asserted-by":"crossref","first-page":"1386607","DOI":"10.3389\/fimmu.2024.1386607","article-title":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: the biology of a neglected disease","volume":"15","year":"2024","journal-title":"Front. Immunol"},{"key":"2025051314101568000_2025.04.15.25325899v2.64","doi-asserted-by":"publisher","DOI":"10.1101\/2024.10.07.24315052"},{"key":"2025051314101568000_2025.04.15.25325899v2.65","doi-asserted-by":"publisher","DOI":"10.1101\/gr.279694.124"},{"key":"2025051314101568000_2025.04.15.25325899v2.66","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/s41576-023-00598-6","article-title":"Interpreting non-coding disease-associated human variants using single-cell epigenomics","volume":"24","year":"2023","journal-title":"Nat Rev Genet"},{"key":"2025051314101568000_2025.04.15.25325899v2.67","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07510-0"},{"key":"2025051314101568000_2025.04.15.25325899v2.68","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06957-x"},{"key":"2025051314101568000_2025.04.15.25325899v2.69","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2021.07.004"},{"key":"2025051314101568000_2025.04.15.25325899v2.70","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2011.02428.x"},{"key":"2025051314101568000_2025.04.15.25325899v2.71","unstructured":"Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis\/ChronicFatigue Syndrome, Board on the Health of Select Populations & Institute of Medicine. Beyond Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Redefining an Illness. (National Academies Press (US), Washington (DC), 2015)."},{"key":"2025051314101568000_2025.04.15.25325899v2.72","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1236-x"},{"key":"2025051314101568000_2025.04.15.25325899v2.73","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.009"},{"key":"2025051314101568000_2025.04.15.25325899v2.74","doi-asserted-by":"crossref","unstructured":"Lacerda, E. M. et al. The UK ME\/CFS Biobank for biomedical research on Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS) and Multiple Sclerosis. Open J Bioresour 4, (2017).","DOI":"10.5334\/ojb.28"},{"key":"2025051314101568000_2025.04.15.25325899v2.75","doi-asserted-by":"crossref","unstructured":"Moore, G. E. et al. Recovery from Exercise in Persons with Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS). Medicina (Kaunas , Lithuania ) 59, (2023).","DOI":"10.3390\/medicina59030571"},{"key":"2025051314101568000_2025.04.15.25325899v2.76","doi-asserted-by":"publisher","DOI":"10.48550\/ARXIV.1810.00826"},{"key":"2025051314101568000_2025.04.15.25325899v2.77","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"2025051314101568000_2025.04.15.25325899v2.78","doi-asserted-by":"publisher","DOI":"10.1101\/gr.094052.109"},{"key":"2025051314101568000_2025.04.15.25325899v2.79","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"2025051314101568000_2025.04.15.25325899v2.80","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-020-00803-9"},{"key":"2025051314101568000_2025.04.15.25325899v2.81","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4353"},{"key":"2025051314101568000_2025.04.15.25325899v2.82","doi-asserted-by":"publisher","DOI":"10.48550\/ARXIV.0803.0476"},{"key":"2025051314101568000_2025.04.15.25325899v2.83","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"},{"key":"2025051314101568000_2025.04.15.25325899v2.84","doi-asserted-by":"publisher","DOI":"10.1101\/060012"},{"key":"2025051314101568000_2025.04.15.25325899v2.85","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004219"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.04.15.25325899","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:34:04Z","timestamp":1768509244000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.04.15.25325899"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,16]]},"references-count":85,"URL":"https:\/\/doi.org\/10.1101\/2025.04.15.25325899","relation":{},"subject":[],"published":{"date-parts":[[2025,4,16]]},"subtype":"preprint"}}