{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:42:16Z","timestamp":1789663336977,"version":"4.0.1"},"reference-count":34,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2023,9,17]],"date-time":"2023-09-17T00:00:00Z","timestamp":1694908800000},"content-version":"unspecified","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Shanghai Outstanding Academic Leader Program","award":["23XD1424900"],"award-info":[{"award-number":["23XD1424900"]}]},{"name":"Singlera Genomics"},{"name":"Dawn Project Foundation of Shanghai","award":["21SG36"],"award-info":[{"award-number":["21SG36"]}]},{"name":"Shanghai Health and Hygiene Discipline Leader Project","award":["2022XD001"],"award-info":[{"award-number":["2022XD001"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81972726"],"award-info":[{"award-number":["81972726"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82241223"],"award-info":[{"award-number":["82241223"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273074"],"award-info":[{"award-number":["82273074"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U20A20360"],"award-info":[{"award-number":["U20A20360"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2023,8,30]]},"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Prompt detection of hepatocellular carcinoma (HCC) in patients with chronic liver diseases is critical for enhancing prognosis. Existing imaging techniques and serum markers fall short of clinical needs. This study aims to establish a non-invasive diagnostic model for early HCC detection in the Chinese population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      This prospective, multicentre, observational study will enrol 2000 participants, including HCC patients, those with chronic liver diseases (hepatitis, cirrhosis and benign liver space-occupying lesions), and healthy individuals. The study will collect demographic data and blood samples, which will be used to test \u03b1-fetoprotein (AFP), des-\u03b3-carboxy-prothrombin (DCP) and circulating tumour DNA (ctDNA) methylation. The GAMAD (\n                      <jats:italic>G<\/jats:italic>\n                      ender+\n                      <jats:italic>A<\/jats:italic>\n                      ge+\n                      <jats:italic>M<\/jats:italic>\n                      ethylation+\n                      <jats:italic>A<\/jats:italic>\n                      FP+\n                      <jats:italic>D<\/jats:italic>\n                      CP) model involving gender, age, ctDNA methylation signature, AFP and DCP will be developed and blindly validated in training and validation sets (1400 and 600 cases, respectively). Primary endpoints include sensitivity, specificity and accuracy (receiver operating characteristic curves; area under the curve value) of GAMAD for HCC and\/or high-risk HCC groups. Secondary endpoints involve comparing GAMAD with the established GALAD (\n                      <jats:italic>G<\/jats:italic>\n                      ender+\n                      <jats:italic>A<\/jats:italic>\n                      ge+AFP-\n                      <jats:italic>L<\/jats:italic>\n                      3+\n                      <jats:italic>A<\/jats:italic>\n                      FP+\n                      <jats:italic>D<\/jats:italic>\n                      CP) model and each blood index (AFP, DCP and methylation signature) to evaluate: (1) GAMAD\u2019s clinical utility for HCC patients in all stages according to different staging systems; (2) GAMAD\u2019s discrimination ability for patients in various subgroups, including liver cirrhosis (LC) related HCC and LC, hepatitis B virus (HBV) related HCC and HBV, hepatitis C virus (HCV) related HCC and HCV, and non-alcoholic fatty liver disease (NAFLD) related HCC and NAFLD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>This trial has been approved by the Medical Ethics Committees of the First Hospital of Jilin University (#22K073-001), the Eastern Hepatobiliary Surgery Hospital, Naval Medical University (#EHBHKY2023-H0003-P001) and Tianjin Third Central Hospital (#IRB2023-007-01). All participants in the trial will provide written informed consent. Results of this study will be disseminated in peer-reviewed scientific journals and at conferences nationally and internationally.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05626985\">NCT05626985<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2023-076467","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T23:14:01Z","timestamp":1695078841000},"page":"e076467","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Refinement and validation of a comprehensive clinical diagnostic model (GAMAD) based on gender, age, multitarget circulating tumour DNA methylation signature and commonly used serological biomarkers for early detection of hepatocellular carcinoma: a multicentre, prospective observational study protocol"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct05626985","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Tian","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China"},{"name":"Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanya","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengmei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0890-4982","authenticated-orcid":false,"given":"Hongmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Affairs, Singlera Genomics (Shanghai) Ltd, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0140-7895","authenticated-orcid":false,"given":"Guoyue","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"2025120519175417000_13.9.e076467.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"2025120519175417000_13.9.e076467.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.08.021"},{"key":"2025120519175417000_13.9.e076467.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)62038-9"},{"key":"2025120519175417000_13.9.e076467.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(00)00053-2"},{"key":"2025120519175417000_13.9.e076467.5","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24033"},{"key":"2025120519175417000_13.9.e076467.6","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3748\/wjg.v28.i2.216","article-title":"Update on the applications and limitations of alpha-Fetoprotein for hepatocellular carcinoma","volume":"28","author":"Hanif","year":"2022","journal-title":"World J Gastroenterol"},{"key":"2025120519175417000_13.9.e076467.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30010-2"},{"key":"2025120519175417000_13.9.e076467.8","doi-asserted-by":"crossref","DOI":"10.1155\/2021\/8868370","article-title":"The diagnostic value of serum PIVKA-II alone or in combination with AFP in Chinese hepatocellular carcinoma patients","volume":"2021","author":"Xu","year":"2021","journal-title":"Dis Markers"},{"key":"2025120519175417000_13.9.e076467.9","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-13-0870"},{"key":"2025120519175417000_13.9.e076467.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2015.12.042"},{"key":"2025120519175417000_13.9.e076467.11","doi-asserted-by":"crossref","first-page":"219","DOI":"10.2147\/JHC.S271790","article-title":"Validation of the GALAD model and establishment of GAAP model for diagnosis of hepatocellular carcinoma in Chinese patients","volume":"7","author":"Liu","year":"2020","journal-title":"J Hepatocell Carcinoma"},{"key":"2025120519175417000_13.9.e076467.12","doi-asserted-by":"crossref","DOI":"10.3390\/jcm11175075","article-title":"Diagnostic performance of AFP, AFP-L3, or PIVKA-II for hepatitis C virus-associated hepatocellular carcinoma: A multicenter analysis","volume":"11","author":"Liu","year":"2022","journal-title":"J Clin Med"},{"key":"2025120519175417000_13.9.e076467.13","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000005811","article-title":"Usefulness of AFP, AFP-L3, and PIVKA-II, and their combinations in diagnosing hepatocellular carcinoma","volume":"96","author":"Park","year":"2017","journal-title":"Medicine (Baltimore)"},{"key":"2025120519175417000_13.9.e076467.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2020.12.011"},{"key":"2025120519175417000_13.9.e076467.15","doi-asserted-by":"crossref","DOI":"10.1186\/s13045-022-01351-y","article-title":"Liquid biopsy: Current technology and clinical applications","volume":"15","author":"Nikanjam","year":"2022","journal-title":"J Hematol Oncol"},{"key":"2025120519175417000_13.9.e076467.16","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.02.006"},{"key":"2025120519175417000_13.9.e076467.17","doi-asserted-by":"crossref","first-page":"3478","DOI":"10.3892\/ol.2015.3771","article-title":"Quantitative analysis of cell-free DNA in ovarian cancer","volume":"10","author":"Shao","year":"2015","journal-title":"Oncol Lett"},{"key":"2025120519175417000_13.9.e076467.18","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9453"},{"key":"2025120519175417000_13.9.e076467.19","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0436"},{"key":"2025120519175417000_13.9.e076467.20","doi-asserted-by":"crossref","first-page":"13111","DOI":"10.1007\/s13277-016-5190-z","article-title":"Methylation analysis of plasma cell-free DNA for breast cancer early detection using Bisulfite next-generation sequencing","volume":"37","author":"Li","year":"2016","journal-title":"Tumor Biol"},{"key":"2025120519175417000_13.9.e076467.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2015.12.001"},{"key":"2025120519175417000_13.9.e076467.22","doi-asserted-by":"crossref","first-page":"6549","DOI":"10.2147\/OTT.S100901","article-title":"Cell-free DNA as a diagnostic marker for cancer: Current insights","volume":"9","author":"Salvi","year":"2016","journal-title":"Onco Targets Ther"},{"key":"2025120519175417000_13.9.e076467.23","doi-asserted-by":"publisher","DOI":"10.1038\/ncponc0354"},{"key":"2025120519175417000_13.9.e076467.24","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63469-4"},{"key":"2025120519175417000_13.9.e076467.25","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2008.104653"},{"key":"2025120519175417000_13.9.e076467.26","doi-asserted-by":"crossref","first-page":"6406","DOI":"10.18632\/oncotarget.14115","article-title":"Cell-free methylation markers with Diagnostic and Prognostic potential in hepatocellular carcinoma","volume":"8","author":"Lu","year":"2017","journal-title":"Oncotarget"},{"key":"2025120519175417000_13.9.e076467.27","doi-asserted-by":"crossref","first-page":"7239","DOI":"10.7150\/thno.35573","article-title":"Genome-wide discovery and validation of diagnostic DNA methylation-based biomarkers for hepatocellular cancer detection in circulating cell free DNA","volume":"9","author":"Hlady","year":"2019","journal-title":"Theranostics"},{"key":"2025120519175417000_13.9.e076467.28","doi-asserted-by":"crossref","unstructured":"Chen X , Gole J , Gore A , et al . Non-invasive early detection of cancer four years before conventional diagnosis using a blood test. Nat Commun 2020;11. doi:10.1038\/s41467-020-17316-z","DOI":"10.1038\/s41467-020-17316-z"},{"key":"2025120519175417000_13.9.e076467.29","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2019.308965"},{"key":"2025120519175417000_13.9.e076467.30","doi-asserted-by":"crossref","DOI":"10.1186\/s12916-021-02201-3","article-title":"Cell-free DNA methylation markers for differential diagnosis of hepatocellular carcinoma","volume":"20","author":"Luo","year":"2022","journal-title":"BMC Med"},{"key":"2025120519175417000_13.9.e076467.31","doi-asserted-by":"publisher","DOI":"10.1038\/nmat4997"},{"key":"2025120519175417000_13.9.e076467.32","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.abp8704","article-title":"Simultaneous analysis of mutations and Methylations in circulating cell-free DNA for hepatocellular carcinoma detection","volume":"14","author":"Wang","year":"2022","journal-title":"Sci Transl Med"},{"key":"2025120519175417000_13.9.e076467.33","doi-asserted-by":"publisher","DOI":"10.1177\/1756283X10385964"},{"key":"2025120519175417000_13.9.e076467.34","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.mcna.2020.02.010","article-title":"Acute liver injury and decompensated cirrhosis","volume":"104","author":"Crismale","year":"2020","journal-title":"Med Clin North Am"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2023-076467","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T03:18:04Z","timestamp":1764991084000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2023-076467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9,18]]},"published-print":{"date-parts":[[2023,9]]}},"alternative-id":["10.1136\/bmjopen-2023-076467"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2023-076467","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9]]}}}