{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T21:24:35Z","timestamp":1778793875066,"version":"3.51.4"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000},"content-version":"vor","delay-in-days":50,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFF0710800"],"award-info":[{"award-number":["2022YFF0710800"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>DNA methylation is a key epigenetic modification underlying cellular identity. Conventional methods based on CpG site-level data often lack sensitivity in detecting low-frequency methylation signals. Here, we present Alpha, a novel method combining unbiased segmentation with robust read-level identification of low frequency cell-type-specific methylation signals. Methylation markers identified by Alpha exhibited significant enrichment in regulatory genomic elements such as enhancers, active promoters, and transcription factor binding sites. In simulated cell-type admixtures, Alpha-derived markers demonstrated improved deconvolution performance, exhibiting lower error metrics compared to beta-value based methods (DSS), even with limited marker numbers (N\u2009&amp;lt;\u200950). We combined Alpha with a non-negative least squares approach (Alpha-NNLS) to enable sensitive detection of circulating tumor DNA (ctDNA) in simulated cell-free DNA from breast and colon cancers, outperforming existing read-level methylation-based tumor fraction estimation methods (CelFEER and UXM). We applied Alpha-NNLS to targeted bisulfite sequencing data from early-stage colon cancer plasma samples and demonstrated strong concordance with existing approaches (R2\u2009=\u20090.98), supporting its potential for sensitive detection of ctDNA.<\/jats:p>","DOI":"10.1093\/bib\/bbaf551","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T12:26:08Z","timestamp":1760617568000},"source":"Crossref","is-referenced-by-count":1,"title":["Read-level DNA methylation deconvolution enhances circulating tumor DNA detection"],"prefix":"10.1093","volume":"26","author":[{"given":"Ting","family":"Qi","sequence":"first","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University , Sipailou No. 2, Nanjing 210096 ,","place":["China"]},{"name":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research , 60 Biopolis Street, Singapore 138672 ,","place":["Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lakshmi Narayanan","family":"Lakshmanan","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research , 60 Biopolis Street, Singapore 138672 ,","place":["Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuwei","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University , Sipailou No. 2, Nanjing 210096 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University , Sipailou No. 2, Nanjing 210096 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Pan","sequence":"additional","affiliation":[{"name":"School of Medicine, Southeast University , Sipailou No. 2, Nanjing 210096 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anders Jacobsen","family":"Skanderup","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research , 60 Biopolis Street, Singapore 138672 ,","place":["Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1708-1949","authenticated-orcid":false,"given":"Qinyu","family":"Ge","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University , Sipailou No. 2, Nanjing 210096 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