{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T13:56:45Z","timestamp":1792245405181,"version":"4.4.0"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"44","license":[{"start":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T00:00:00Z","timestamp":1666742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002920","name":"Research Grants Council, University Grants Committee","doi-asserted-by":"publisher","award":["T12-403\/15-N"],"award-info":[{"award-number":["T12-403\/15-N"]}],"id":[{"id":"10.13039\/501100002920","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002920","name":"Research Grants Council, University Grants Committee","doi-asserted-by":"publisher","award":["T12-401\/16-W"],"award-info":[{"award-number":["T12-401\/16-W"]}],"id":[{"id":"10.13039\/501100002920","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003452","name":"Innovation and Technology Commission","doi-asserted-by":"publisher","award":["InnoHK initiative"],"award-info":[{"award-number":["InnoHK initiative"]}],"id":[{"id":"10.13039\/501100003452","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":[[2022,11]]},"abstract":"<jats:p>\n                    Cell-free DNA (cfDNA) fragmentation patterns contain important molecular information linked to tissues of origin. We explored the possibility of using fragmentation patterns to predict cytosine-phosphate-guanine (CpG) methylation of cfDNA, obviating the use of bisulfite treatment and associated risks of DNA degradation. This study investigated the cfDNA cleavage profile surrounding a CpG (i.e., within an 11-nucleotide [nt] window) to analyze cfDNA methylation. The cfDNA cleavage proportion across positions within the window appeared nonrandom and exhibited correlation with methylation status. The mean cleavage proportion was \u223ctwofold higher at the cytosine of methylated CpGs than unmethylated ones in healthy controls. In contrast, the mean cleavage proportion rapidly decreased at the 1-nt position immediately preceding methylated CpGs. Such differential cleavages resulted in a characteristic change in relative presentations of CGN and NCG motifs at 5\u2032 ends, where N represented any nucleotide. CGN\/NCG motif ratios were correlated with methylation levels at tissue-specific methylated CpGs (e.g., placenta or liver) (Pearson\u2019s absolute\n                    <jats:italic>r<\/jats:italic>\n                    &gt; 0.86). cfDNA cleavage profiles were thus informative for cfDNA methylation and tissue-of-origin analyses. Using CG-containing end motifs, we achieved an area under a receiver operating characteristic curve (AUC) of 0.98 in differentiating patients with and without hepatocellular carcinoma and enhanced the positive predictive value of nasopharyngeal carcinoma screening (from 19.6 to 26.8%). Furthermore, we elucidated the feasibility of using cfDNA cleavage patterns to deduce CpG methylation at single CpG resolution using a deep learning algorithm and achieved an AUC of 0.93. FRAGmentomics-based Methylation Analysis (FRAGMA) presents many possibilities for noninvasive prenatal, cancer, and organ transplantation assessment.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2209852119","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T13:54:37Z","timestamp":1666792477000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":151,"title":["Epigenetic analysis of cell-free DNA by fragmentomic profiling"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7737-9643","authenticated-orcid":false,"given":"Qing","family":"Zhou","sequence":"first","affiliation":[{"name":"Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China"},{"name":"Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guannan","family":"Kang","sequence":"additional","affiliation":[{"name":"Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China"},{"name":"Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4523-3476","authenticated-orcid":false,"given":"Peiyong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China"},{"name":"Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Qiao","sequence":"additional","affiliation":[{"name":"Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China"},{"name":"Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. K. Jacky","family":"Lam","sequence":"additional","affiliation":[{"name":"Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China"},{"name":"Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie C. 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Y.","family":"Chan","sequence":"additional","affiliation":[{"name":"Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China"},{"name":"Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8998-5480","authenticated-orcid":false,"given":"Stephen L.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace L. 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