{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:04:43Z","timestamp":1760148283946,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072384","82101775"],"award-info":[{"award-number":["82072384","82101775"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: The aim of the present study was to develop an improved diagnostic and prognostic model for HBV-associated HCC by combining AFP with PIVKA-II and other potential serum\/plasma protein biomarkers. Methods: A total of 578 patients, including 352 patients with HBV-related HCC, 102 patients with HBV-associated liver cirrhosis (LC), 124 patients with chronic HBV, and 127 healthy subjects (HS), were enrolled in the study. The serum levels of AFP, PIVKA-II, and other laboratory parameters were collected. Univariate and multivariate logistic regression and Cox regression analyses were performed to identify independent diagnostic and prognostic factors, respectively. The diagnostic efficacy of the nomogram was evaluated using receiver operator curve (ROC) analysis and the prognostic performance was measured by Harrell\u2019s concordance index (C-index). Results: AFP and PIVKA-II levels were significantly increased in HBV-related HCC, compared with those in HBV-associated LC and chronic HBV participants (p &lt; 0.05 and p &lt; 0.001, respectively). The diagnostic nomogram, which included age, gender, AFP, PIVKA-II, prothrombin time (PT), and total protein (TP), discriminated patients with HBV-HCC from those with HBV-LC or chronic HBV with an AUC of 0.970. In addition, based on the univariate and multivariate Cox regression analysis, PIVKA-II, \u03b3-glutamyl transpeptidase, and albumin were found to be significantly associated with the prognosis of HBV-related HCC and were incorporated into a nomogram. The C-index of the nomogram for predicting 3-year survival in the training and validation groups was 0.75 and 0.78, respectively. The calibration curves for the probability of 3-year OS showed good agreement between the nomogram prediction and the actual observation in the training and the validation groups. Furthermore, the nomogram had a higher C-index (0.74) than that of the Child\u2212Pugh grade (0.62), the albumin\u2212bilirubin (ALBI) score (0.64), and Barcelona Clinic Liver Cancer (0.56) in all follow-up cases. Conclusion: Our study suggests that the nomograms based on AFP, PIVKA-II, and potential serum protein biomarkers showed a better performance in the diagnosis and prognosis of HCC, which may help to guide therapeutic strategies and assess the prognosis of HCC.<\/jats:p>","DOI":"10.3390\/diagnostics13081442","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T04:45:32Z","timestamp":1681706732000},"page":"1442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Diagnostic and Prognostic Nomograms for Hepatocellular Carcinoma Based on PIVKA-II and Serum Biomarkers"],"prefix":"10.3390","volume":"13","author":[{"given":"Shu","family":"An","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoxia","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laisheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Wu","sequence":"additional","affiliation":[{"name":"Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Komuta, M. (2021). Histological Heterogeneity of Primary Liver Cancers: Clinical Relevance, Diagnostic Pitfalls and the Pathologist\u2019s Role. Cancers, 13.","DOI":"10.3390\/cancers13122871"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Shen, C., Jiang, X., Li, M., and Luo, Y. (2023). Hepatitis Virus and Hepatocellular Carcinoma: Recent Advances. Cancers, 15.","DOI":"10.3390\/cancers15020533"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41575-018-0055-0","article-title":"The changing epidemiology of liver diseases in the Asia-Pacific region","volume":"16","author":"Wong","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/S0140-6736(18)30010-2","article-title":"Hepatocellular carcinoma","volume":"391","author":"Forner","year":"2018","journal-title":"Lancet"},{"key":"ref_6","unstructured":"European Association for the Study of the Liver (2018). EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol., 69, 182\u2013236."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lee, Y.T., Fujiwara, N., Yang, J.D., and Hoshida, Y. (2022). Risk stratification and early detection biomarkers for precision HCC screening. Hepatology.","DOI":"10.1002\/hep.32779"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s12072-017-9799-9","article-title":"Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: A 2017 update","volume":"11","author":"Omata","year":"2017","journal-title":"Hepatol. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1053\/j.gastro.2018.01.064","article-title":"Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis","volume":"154","author":"Tzartzeva","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/hep.28765","article-title":"Identifying barriers to hepatocellular carcinoma surveillance in a national sample of patients with cirrhosis","volume":"65","author":"Goldberg","year":"2017","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1111\/liv.12516","article-title":"Reappraisal of serum alpha-foetoprotein as a surveillance test for hepatocellular carcinoma during entecavir treatment","volume":"35","author":"Kim","year":"2015","journal-title":"Liver Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"328","DOI":"10.3748\/wjg.v19.i3.328","article-title":"Alpha-fetoprotein: A controversial prognostic biomarker for small hepatocellular carcinoma","volume":"19","author":"Asrih","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1001\/jamasurg.2016.3310","article-title":"Evaluation of Patients With Hepatocellular Carcinomas That Do Not Produce alpha-Fetoprotein","volume":"152","author":"Agopian","year":"2017","journal-title":"JAMA Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10573","DOI":"10.3748\/wjg.v21.i37.10573","article-title":"Biomarkers for the early diagnosis of hepatocellular carcinoma","volume":"21","author":"Tsuchiya","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3350\/cmh.2022.0212","article-title":"Utility of Combining PIVKA-II and AFP in the Surveillance and Monitoring of Hepatocellular Carcinoma in the Asia-Pacific Region","volume":"29","author":"Kim","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1055\/s-0039-1677768","article-title":"Alpha-fetoprotein for Diagnosis, Prognosis, and Transplant Selection","volume":"39","author":"Trevisani","year":"2019","journal-title":"Semin Liver. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6673","DOI":"10.7314\/APJCP.2014.15.16.6673","article-title":"Elevated PIVKA-II is associated with early recurrence and poor prognosis in BCLC 0-A hepatocellular carcinomas","volume":"15","author":"Wang","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.jhep.2014.11.005","article-title":"Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion","volume":"62","author":"Pote","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3233\/CBM-181402","article-title":"Diagnostic value of serum PIVKA-II levels for BCLC early hepatocellular carcinoma and correlation with HBV DNA","volume":"23","author":"Wu","year":"2018","journal-title":"Cancer Biomark."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"726213","DOI":"10.3389\/fonc.2021.726213","article-title":"Progression of Prothrombin Induced by Vitamin K Absence-II in Hepatocellular Carcinoma","volume":"11","author":"Yang","year":"2021","journal-title":"Front Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s13027-020-00337-0","article-title":"Value of AFP and PIVKA-II in diagnosis of HBV-related hepatocellular carcinoma and prediction of vascular invasion and tumor differentiation","volume":"15","author":"Si","year":"2020","journal-title":"Infect. Agents Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3928","DOI":"10.3748\/wjg.v21.i13.3928","article-title":"Diagnostic value of PIVKA-II and alpha-fetoprotein in hepatitis B virus-associated hepatocellular carcinoma","volume":"21","author":"Seo","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1097\/MPG.0b013e31819a61ff","article-title":"Prevalence of subclinical vitamin K deficiency in cholestatic liver disease","volume":"49","author":"Strople","year":"2009","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8906023","DOI":"10.1155\/2018\/8906023","article-title":"Evaluation of Serum Des-Gamma-Carboxy Prothrombin for the Diagnosis of Hepatitis B Virus-Related Hepatocellular Carcinoma: A Meta-Analysis","volume":"2018","author":"Chen","year":"2018","journal-title":"Dis. Markers"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"743","DOI":"10.3233\/CBM-170088","article-title":"Rule of changes in serum GGT levels and GGT\/ALT and AST\/ALT ratios in primary hepatic carcinoma patients with different AFP levels","volume":"21","author":"Yang","year":"2018","journal-title":"Cancer Biomark"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4836","DOI":"10.7150\/jca.33877","article-title":"Combined preoperative albumin-bilirubin (ALBI) and serum gamma-glutamyl transpeptidase (GGT) predicts the outcome of hepatocellular carcinoma patients following hepatic resection","volume":"10","author":"Zhang","year":"2019","journal-title":"J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1159\/000471807","article-title":"Role of Albumin in Growth Inhibition in Hepatocellular Carcinoma","volume":"93","author":"Bagirsakci","year":"2017","journal-title":"Oncology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9934189","DOI":"10.1155\/2022\/9934189","article-title":"Alpha-Fetoprotein+Alkaline Phosphatase (A-A) Score Can Predict the Prognosis of Patients with Ruptured Hepatocellular Carcinoma Underwent Hepatectomy","volume":"2022","author":"Xia","year":"2022","journal-title":"Dis. Markers"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1073274820915520","DOI":"10.1177\/1073274820915520","article-title":"Novel Prognostic Scores Based on Plasma Prothrombin Time and Fibrinogen Levels in Patients With AFP-Negative Hepatocellular Carcinoma","volume":"27","author":"Mao","year":"2020","journal-title":"Cancer Control"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.surg.2018.02.022","article-title":"Risk stratification using a novel liver functional reserve score of combination prothrombin time-international normalized ratio to albumin ratio and albumin in patients with hepatocellular carcinoma","volume":"164","author":"Haruki","year":"2018","journal-title":"Surgery"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/S0140-6736(08)60383-9","article-title":"Liver cirrhosis","volume":"371","author":"Schuppan","year":"2008","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1373\/clinchem.2019.308965","article-title":"A Novel Online Calculator Based on Serum Biomarkers to Detect Hepatocellular Carcinoma among Patients with Hepatitis B","volume":"65","author":"Yang","year":"2019","journal-title":"Clin Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"W1","DOI":"10.7326\/M14-0698","article-title":"Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): Explanation and elaboration","volume":"162","author":"Moons","year":"2015","journal-title":"Ann. Intern. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"310427","DOI":"10.1155\/2013\/310427","article-title":"Clinical significance of AFP and PIVKA-II responses for monitoring treatment outcomes and predicting prognosis in patients with hepatocellular carcinoma","volume":"2013","author":"Park","year":"2013","journal-title":"Biomed Res. Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1080\/00365521.2016.1183705","article-title":"Protein induced by vitamin K absence or antagonist-II (PIVKA-II) specifically increased in Italian hepatocellular carcinoma patients","volume":"51","author":"Viggiani","year":"2016","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Feng, H., Li, B., Li, Z., Wei, Q., and Ren, L. (2021). PIVKA-II serves as a potential biomarker that complements AFP for the diagnosis of hepatocellular carcinoma. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-08138-3"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Shahini, E., Pasculli, G., Solimando, A.G., Tiribelli, C., Cozzolongo, R., and Giannelli, G. (2023). Updating the Clinical Application of Blood Biomarkers and Their Algorithms in the Diagnosis and Surveillance of Hepatocellular Carcinoma: A Critical Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054286"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.rmed.2012.11.007","article-title":"Clinical and prognostic significance of coagulation assays in lung cancer","volume":"107","author":"Tas","year":"2013","journal-title":"Respir. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.7150\/jca.19181","article-title":"A retrospective discussion of the prognostic value of combining prothrombin time(PT) and fibrinogen(Fbg) in patients with Hepatocellular carcinoma","volume":"8","author":"Wang","year":"2017","journal-title":"J. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8481","DOI":"10.2147\/CMAR.S264856","article-title":"Prognostic Role of Prothrombin Time Activity, Prothrombin Time, Albumin\/Globulin Ratio, Platelets, Sex, and Fibrinogen in Predicting Recurrence-Free Survival Time of Renal Cancer","volume":"12","author":"Bian","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.jhep.2021.11.018","article-title":"BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update","volume":"76","author":"Reig","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1111\/jgh.13250","article-title":"Usefulness of albumin-bilirubin grade for evaluation of prognosis of 2584 Japanese patients with hepatocellular carcinoma","volume":"31","author":"Hiraoka","year":"2016","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"100347","DOI":"10.1016\/j.jhepr.2021.100347","article-title":"ALBI grade: Evidence for an improved model for liver functional estimation in patients with hepatocellular carcinoma","volume":"3","author":"Demirtas","year":"2021","journal-title":"JHEP Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.21037\/tcr-22-244","article-title":"The comparison between albumin-bilirubin grade and Child-Pugh grade for assessing the prognosis of hepatocellular carcinoma after thermal ablation: A propensity score-matched analysis","volume":"11","author":"Zhang","year":"2022","journal-title":"Transl. Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"749","DOI":"10.3748\/wjg.v26.i7.749","article-title":"Modified Child-Pugh grade vs albumin-bilirubin grade for predicting prognosis of hepatocellular carcinoma patients after hepatectomy","volume":"26","author":"Huang","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver, and European Organisation for Research and Treatment of Cancer (2012). EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J. Hepatol., 56, 908\u2013943.","DOI":"10.1016\/j.jhep.2011.12.001"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"224","DOI":"10.5009\/gnl14047","article-title":"The influence of alcoholic liver disease on serum PIVKA-II levels in patients without hepatocellular carcinoma","volume":"9","author":"Kang","year":"2015","journal-title":"Gut. Liver"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"221","DOI":"10.7150\/ijbs.28720","article-title":"Development and Validation of a Prognostic Nomogram in AFP-negative hepatocellular carcinoma","volume":"15","author":"Wang","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2147\/JHC.S286213","article-title":"The Significance of Gamma-Glutamyl Transpeptidase to Lymphocyte Count Ratio in the Early Postoperative Recurrence Monitoring and Prognosis Prediction of AFP-Negative Hepatocellular Carcinoma","volume":"8","author":"Li","year":"2021","journal-title":"J. Hepatocell Carcinoma."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ijsu.2016.10.033","article-title":"Prognostic value of alkaline phosphatase, gamma-glutamyl transpeptidase and lactate dehydrogenase in hepatocellular carcinoma patients treated with liver resection","volume":"36","author":"Wu","year":"2016","journal-title":"Int. J. Surg."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10944","DOI":"10.3748\/wjg.v20.i31.10944","article-title":"Model based on gamma-glutamyltransferase and alkaline phosphatase for hepatocellular carcinoma prognosis","volume":"20","author":"Xu","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/liv.12274","article-title":"Clinical usefulness of double biomarkers AFP and PIVKA-II for subdividing prognostic groups in locally advanced hepatocellular carcinoma","volume":"34","author":"Park","year":"2014","journal-title":"Liver Int."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.ejca.2021.07.009","article-title":"Development and validation of prognostic nomograms for single large and huge hepatocellular carcinoma after curative resection","volume":"155","author":"Wang","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/ijc.33516","article-title":"Multi-institutional validation of novel models for predicting the prognosis of patients with huge hepatocellular carcinoma","volume":"149","author":"Wang","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1016\/j.ejso.2022.01.023","article-title":"Clinicopathologic features, treatment, survival, and prognostic factors of combined hepatocellular and cholangiocarcinoma: A nomogram development based on SEER database and validation in multicenter study","volume":"48","author":"Zhou","year":"2022","journal-title":"Eur. J. Surg. Oncol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/13\/8\/1442\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:17:10Z","timestamp":1760123830000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/13\/8\/1442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,17]]},"references-count":56,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["diagnostics13081442"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics13081442","relation":{},"ISSN":["2075-4418"],"issn-type":[{"type":"electronic","value":"2075-4418"}],"subject":[],"published":{"date-parts":[[2023,4,17]]}}}