{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:01:10Z","timestamp":1790071270050,"version":"4.0.1"},"reference-count":21,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000350","name":"Guts UK","doi-asserted-by":"publisher","award":["TRN2021_05"],"award-info":[{"award-number":["TRN2021_05"]}],"id":[{"id":"10.13039\/501100000350","id-type":"DOI","asserted-by":"publisher"}]},{"award":["TRN2021_05"],"award-info":[{"award-number":["TRN2021_05"]}],"id":[{"id":"https:\/\/ror.org\/002kcsx52","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sensors"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) typically arises on a background of cirrhosis and carries high mortality, in large part because current surveillance tools\u2014ultrasound and serum AFP\u2014have suboptimal sensitivity for early-stage disease. We investigated whether urinary volatile organic compounds (VOCs) could provide a more accurate non-invasive approach. Across four UK centres, 256 participants were recruited: 72 with confirmed HCC and 184 with cirrhosis but no malignancy. Complete urine VOC profiles were obtained using an eight-sensor electronic nose in 190 participants (58 HCC, 132 cirrhosis). Seven of the eight sensors showed statistically significant differences between groups, all reaching p &lt; 0.001 (S1\u2013S4, S6\u2013S8), while one (S5) did not reach significance (p = 0.682). Principal components analysis demonstrated clear separation between HCC and cirrhosis populations, with the first two components accounting for 70.7% of total variance. A radial basis function neural network, trained on 20% of the data and tested on an independent second replicate, achieved sensitivity of 98.28% (95% CI: 90.76% to 99.96%), specificity of 96.97% (95% CI: 92.42% to 99.17%), PPV of 93.4% (95% CI: 84.44% to 97.40%) and NPV of 99.2% (95% CI: 94.83% to 99.89%). The area under the ROC curve was 0.99 (95% CI: 0.959\u20131.000). Performance was robust in a mixed treated\/untreated cohort, with 50% of HCC patients untreated at sampling; two treated cases fell within the cirrhosis cluster, indicating that VOC profiling may be most sensitive for active, untreated disease. What\u2019s New? Urinary VOC profiling demonstrates improved diagnostic accuracy for distinguishing HCC from cirrhosis compared to conventional screening of serum alpha-fetoprotein combined with ultrasound imaging. This non-invasive approach offers substantial clinical potential for HCC screening in high-risk cirrhotic populations at lower cost but will need validation and economic evaluation in larger independent cohorts.<\/jats:p>","DOI":"10.3390\/s26185907","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:04:17Z","timestamp":1790067857000},"page":"5907","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Urinary Volatile Organic Compounds as Non-Invasive Biomarkers to Distinguish Hepatocellular Carcinoma from Cirrhosis: A Multicentre Diagnostic Accuracy Study"],"prefix":"10.3390","volume":"26","author":[{"given":"Yaqza","family":"Hussain","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Sandwell and West Birmingham NHS Trust, Birmingham B71 4HJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2598-8760","authenticated-orcid":false,"given":"Arif","family":"Atique","sequence":"additional","affiliation":[{"name":"Institute of Precision Diagnostics & Translational Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK"},{"name":"Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4814-7864","authenticated-orcid":false,"given":"Ayman","family":"Bannaga","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Queen Elizabeth Hospital Birmingham, Birmingham B15 2GW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna C.","family":"Persaud","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Analytical Science, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2231-3062","authenticated-orcid":false,"given":"Ramesh P.","family":"Arasaradnam","sequence":"additional","affiliation":[{"name":"Institute of Precision Diagnostics & Translational Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK"},{"name":"Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Tendency 2 Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref_1","first-page":"209","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","first-page":"e71330","DOI":"10.1002\/cam4.71330","article-title":"Recent Advancements in Known and Emerging Risk Factors of Hepatocellular Carcinoma","volume":"14","author":"Hussain","year":"2025","journal-title":"Cancer Med."},{"key":"ref_3","first-page":"15","article-title":"Progression of liver disease and associated risk of hepatocellular carcinoma","volume":"10","author":"Poli","year":"2024","journal-title":"Hepatoma Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1053\/j.gastro.2023.06.027","article-title":"Incidence and Risk Factors for Hepatocellular Carcinoma in Cirrhosis: The Multicenter Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study","volume":"165","author":"Reddy","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/cld.129","article-title":"Natural history and staging for hepatocellular carcinoma","volume":"1","author":"Forner","year":"2012","journal-title":"Clin. Liver Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.jhep.2024.08.028","article-title":"EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma","volume":"82","author":"Sangro","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","unstructured":"Zhang, J., Chen, G., Zhang, P., Zhang, J., Li, X., Gan, D., Cao, X., Han, M., Du, H., and Ye, Y.A. (2020). The threshold of alpha-fetoprotein (AFP) for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0228857"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/1475-2867-13-72","article-title":"Release and uptake of volatile organic compounds by human hepatocellular carcinoma cells (HepG2) in vitro","volume":"13","author":"Mochalski","year":"2013","journal-title":"Cancer Cell Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"117831","DOI":"10.1016\/j.cca.2024.117831","article-title":"Volatile organic compounds for diagnosis of early hepatocellular carcinoma in at-risk patients","volume":"556","author":"Sukaram","year":"2024","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ain Nazir, N.U., Shaukat, M.H., Luo, R., and Abbas, S.R. (2023). Novel breath biomarkers identification for early detection of hepatocellular carcinoma and cirrhosis using ML tools and GCMS. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0287465"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bannaga, A.S., Tyagi, H., Daulton, E., Covington, J.A., and Arasaradnam, R.P. (2021). Exploratory Study Using Urinary Volatile Organic Compounds for the Detection of Hepatocellular Carcinoma. Molecules, 26.","DOI":"10.3390\/molecules26092447"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/j.hpb.2021.03.015","article-title":"Role of methylated septin 9 as an adjunct diagnostic and prognostic biomarker in hepatocellular carcinoma","volume":"23","author":"Bannaga","year":"2021","journal-title":"HPB"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"017102","DOI":"10.1088\/1752-7163\/abc36b","article-title":"Differentiating cancer types using a urine test for volatile organic compounds","volume":"15","author":"Bannaga","year":"2020","journal-title":"J. Breath Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/978-1-4615-1247-9_6","article-title":"Solid phase microextraction","volume":"488","author":"Pawliszyn","year":"2001","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.3390\/s110101105","article-title":"Advances in Electronic-Nose Technologies Developed for Biomedical Applications","volume":"11","author":"Wilson","year":"2011","journal-title":"Sensors"},{"key":"ref_17","first-page":"20150202","article-title":"Principal component analysis: A review and recent developments","volume":"374","author":"Jolliffe","year":"2016","journal-title":"Philos. Trans. Ser. A Math. Phys. Eng. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e078378","DOI":"10.1136\/bmj-2023-078378","article-title":"TRIPOD+AI statement: Updated guidance for reporting clinical prediction models that use regression or machine learning methods","volume":"385","author":"Collins","year":"2024","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the Areas under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cgh.2019.11.012","article-title":"GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis","volume":"18","author":"Best","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Fiala, C., and Diamandis, E.P. (2018). Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection. BMC Med., 16.","DOI":"10.1186\/s12916-018-1157-9"}],"container-title":["Sensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8220\/26\/18\/5907\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:11:13Z","timestamp":1790068273000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8220\/26\/18\/5907"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,18]]},"references-count":21,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["s26185907"],"URL":"https:\/\/doi.org\/10.3390\/s26185907","relation":{},"ISSN":["1424-8220"],"issn-type":[{"value":"1424-8220","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,18]]}}}