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Here, 11 methylated DNA markers (MDMs) are identified during marker discovery. In phase I, each selected MDM is validated in 175 plasma samples (HCC, n = 85; LC\/HVI, n = 72) by the CO\u2010methylation aMplification rEal\u2010Time PCR (COMET) assay. Of these, 8 MDMs are qualified for phase II study, where a logistic regression model (COMET\u2010LR) is trained and validated with 336 plasma samples (HCC, n = 211; LC\/HVI, n = 113; training vs validation, 2:1). In the validation, the COMET\u2010LR achieved 90.0% sensitivity at 97.4% specificity. Notably, sensitivity in patients with TNM stage I, diameter&lt;3\u00a0cm, AFP\u2010negative (&lt;20\u00a0ng\u00a0mL<jats:sup>\u22121<\/jats:sup>), PIVKA\u2010II\u2010negative (&lt;40 mAU\u00a0mL<jats:sup>\u22121<\/jats:sup>) is 82.4%, 77.8%, 88.6%, and 85.7%, respectively. The COMET\u2010LR outperformed multiple protein markers (AFP, AFP\u2010L3, and PIVKA\u2010II) and published scores for HCC screening (GALAD, Doylestown, and ASAP), in terms of both sensitivity and specificity. The assay represents a significant advancement in addressing the unmet need for accurate, non\u2010invasive, accessible, and cost\u2010effective early detection tools for LC\/HVI individuals. Further validation in a prospective cohort is warranted.<\/jats:p>","DOI":"10.1002\/advs.202411945","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T04:05:30Z","timestamp":1743221130000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cost\u2010Effective Identification of Hepatocellular Carcinoma from Cirrhosis or Chronic Hepatitis Virus Infection Using Eight Methylated Plasma DNA Markers"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1544-0976","authenticated-orcid":false,"given":"Tian","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery Eastern Hepatobiliary Surgery Hospital Naval Medical University  Shanghai 200438 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingda","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery 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