{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:09:28Z","timestamp":1792112968436,"version":"4.4.0"},"reference-count":38,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2019,10,5]],"date-time":"2019-10-05T00:00:00Z","timestamp":1570233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Knowledge Economy, Science and Technology","award":["N0000425"],"award-info":[{"award-number":["N0000425"]}]},{"name":"Ministry for Health, Welfare and Family affairs, Republic of Korea","award":["0920010"],"award-info":[{"award-number":["0920010"]}]},{"name":"the Korea Health Industry Development Institute (KHIDI)","award":["HI06C0868"],"award-info":[{"award-number":["HI06C0868"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study was designed to analyze urinary proteins associated with ovarian cancer (OC) and investigate the potential urinary biomarker panel to predict malignancy in women with pelvic masses. We analyzed 23 biomarkers in urine samples obtained from 295 patients with pelvic masses scheduled for surgery. The concentration of urinary biomarkers was quantitatively assessed by the xMAP bead-based multiplexed immunoassay. To identify the performance of each biomarker in predicting cancer over benign tumors, we used a repeated leave-group-out cross-validation strategy. The prediction models using multimarkers were evaluated to develop a urinary ovarian cancer panel. After the exclusion of 12 borderline tumors, the urinary concentration of 17 biomarkers exhibited significant differences between 158 OCs and 125 benign tumors. Human epididymis protein 4 (HE4), vascular cell adhesion molecule (VCAM), and transthyretin (TTR) were the top three biomarkers representing a higher concentration in OC. HE4 demonstrated the highest performance in all samples withOC(mean area under the receiver operating characteristic curve (AUC) 0.822, 95% CI: 0.772\u20130.869), whereas TTR showed the highest efficacy in early-stage OC (AUC 0.789, 95% CI: 0.714\u20130.856). Overall, HE4 was the most informative biomarker, followed by creatinine, carcinoembryonic antigen (CEA), neural cell adhesion molecule (NCAM), and TTR using the least absolute shrinkage and selection operator (LASSO) regression models. A multimarker panel consisting of HE4, creatinine, CEA, and TTR presented the best performance with 93.7% sensitivity (SN) at 70.6% specificity (SP) to predict OC over the benign tumor. This panel performed well regardless of disease status and demonstrated an improved performance by including menopausal status. In conclusion, the urinary biomarker panel with HE4, creatinine, CEA, and TTR provided promising efficacy in predicting OC over benign tumors in women with pelvic masses. It was also a non-invasive and easily available diagnostic tool.<\/jats:p>","DOI":"10.3390\/ijms20194938","type":"journal-article","created":{"date-parts":[[2019,10,7]],"date-time":"2019-10-07T03:34:01Z","timestamp":1570419241000},"page":"4938","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["An Improved Prediction Model for Ovarian Cancer Using Urinary Biomarkers and a Novel Validation Strategy"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5088-1905","authenticated-orcid":false,"given":"Shin-Wha","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Obstetrics &amp; Gynecology, University of Ulsan, ASAN Medical Center, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha-Young","family":"Lee","sequence":"additional","affiliation":[{"name":"ASAN Institute for Life Science, ASAN Medical Center, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo Joo","family":"Bang","sequence":"additional","affiliation":[{"name":"Ahngook Pharmaceutical Co., Ltd., Seoul 07445, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye-Jeong","family":"Song","sequence":"additional","affiliation":[{"name":"Bio-IT Research Center, Hallym University, Chuncheon, Gangwon-do 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sek Won","family":"Kong","sequence":"additional","affiliation":[{"name":"Computational Health Informatics Program, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Man","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Obstetrics &amp; Gynecology, University of Ulsan, ASAN Medical Center, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E359","DOI":"10.1002\/ijc.29210","article-title":"Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"286","DOI":"10.4331\/wjbc.v5.i3.286","article-title":"In 2014, can we do better than CA125 in the early detection of ovarian cancer?","volume":"5","author":"Cohen","year":"2014","journal-title":"World J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3322\/caac.21254","article-title":"Cancer statistics, 2015","volume":"65","author":"Siegel","year":"2015","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","unstructured":"Howlader, N., Noone, A.M., Krapcho, M., Garshell, J., Neyman, N., Altekruse, S.F., Kosary, C.L., Yu, M., Ruhl, J., and Tatalovich, Z. (2017, December 01). SEER Cancer Statistics Review, 1975\u20132010, Available online: https:\/\/seer.cancer.gov\/archive\/csr\/1975_2010\/."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists Committee on Gynecologic Practice (2011). Committee Opinion No. 477: the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer. Obstet. Gynecol., 117, 742\u2013746.","DOI":"10.1097\/AOG.0b013e31821477db"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1097\/01.AOG.0000265207.27755.28","article-title":"Influence of the gynecologic oncologist on the survival of ovarian cancer patients","volume":"109","author":"Chan","year":"2007","journal-title":"Obstet. Gynecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/S0140-6736(15)01224-6","article-title":"Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomised controlled trial","volume":"387","author":"Jacobs","year":"2016","journal-title":"Lancet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1111\/j.1471-0528.1990.tb02448.x","article-title":"A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer","volume":"97","author":"Jacobs","year":"1990","journal-title":"Br. J. Obstet. Gynaecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ygyno.2008.08.031","article-title":"A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass","volume":"112","author":"Moore","year":"2009","journal-title":"Gynecol. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5882","DOI":"10.1158\/0008-5472.CAN-04-0746","article-title":"Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer","volume":"64","author":"Zhang","year":"2004","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1097\/AOG.0b013e31821b5118","article-title":"Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors","volume":"117","author":"Ueland","year":"2011","journal-title":"Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1158\/1078-0432.CCR-05-0461","article-title":"Proteomic-based discovery and characterization of glycosylated eosinophil-derived neurotoxin and COOH-terminal osteopontin fragments for ovarian cancer in urine","volume":"12","author":"Ye","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.ygyno.2007.04.022","article-title":"Urinary mesothelin provides greater sensitivity for early stage ovarian cancer than serum mesothelin, urinary hCG free beta subunit and urinary hCG beta core fragment","volume":"106","author":"Badgwell","year":"2007","journal-title":"Gynecol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.ygyno.2008.09.037","article-title":"Urinary levels of Bcl-2 are elevated in ovarian cancer patients","volume":"112","author":"Anderson","year":"2009","journal-title":"Gynecol. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.ygyno.2015.03.044","article-title":"Detection of the HE4 protein in urine as a biomarker for ovarian neoplasms: Clinical correlates","volume":"137","author":"Liao","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1200\/JCO.2008.19.2484","article-title":"Development of a multimarker assay for early detection of ovarian cancer","volume":"28","author":"Yurkovetsky","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Amonkar, S.D., Bertenshaw, G.P., Chen, T.H., Bergstrom, K.J., Zhao, J., Seshaiah, P., Yip, P., and Mansfield, B.C. (2009). Development and preliminary evaluation of a multivariate index assay for ovarian cancer. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004599"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.cll.2009.02.001","article-title":"Development and validation of a protein-based signature for the detection of ovarian cancer","volume":"29","author":"Kim","year":"2009","journal-title":"Clin. Lab. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kim, Y.W., Bae, S.M., Lim, H., Kim, Y.J., and Ahn, W.S. (2012). Development of multiplexed bead-based immunoassays for the detection of early stage ovarian cancer using a combination of serum biomarkers. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044960"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s40291-013-0027-6","article-title":"Biomarker testing for ovarian cancer: Clinical utility of multiplex assays","volume":"17","author":"Nolen","year":"2013","journal-title":"Mol. Diagn. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1158\/1078-0432.CCR-05-2563","article-title":"Ovarian cancer biomarkers in urine","volume":"12","author":"Chambers","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.canlet.2010.03.013","article-title":"Detection of the HE4 protein in urine as a biomarker for ovarian neoplasms","volume":"296","author":"Hellstrom","year":"2010","journal-title":"Cancer Lett."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Nolen, B.M., Orlichenko, L.S., Marrangoni, A., Velikokhatnaya, L., Prosser, D., Grizzle, W.E., Ho, K., Jenkins, F.J., Bovbjerg, D.H., and Lokshin, A.E. (2013). An extensive targeted proteomic analysis of disease-related protein biomarkers in urine from healthy donors. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063368"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1158\/1940-6207.CAPR-14-0210","article-title":"Urinary protein biomarkers in the early detection of lung cancer","volume":"8","author":"Nolen","year":"2015","journal-title":"Cancer Prev. Res (Phila)."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1097\/00001703-200102000-00009","article-title":"Ovarian cancer screening in the general population","volume":"13","author":"Menon","year":"2001","journal-title":"Curr. Opin. Obstet. Gynecol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1074\/mcp.R400006-MCP200","article-title":"Progress and challenges in screening for early detection of ovarian cancer","volume":"3","author":"Jacobs","year":"2004","journal-title":"Mol. Cell. Proteomics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"228.e1","DOI":"10.1016\/j.ajog.2010.03.043","article-title":"Comparison of a novel multiple marker assay vs the Risk of Malignancy Index for the prediction of epithelial ovarian cancer in patients with a pelvic mass","volume":"203","author":"Moore","year":"2010","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ygyno.2012.07.106","article-title":"Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass","volume":"127","author":"Karlsen","year":"2012","journal-title":"Gynecol. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.cca.2014.09.028","article-title":"Clinical performance of two multi-marker blood tests for predicting malignancy in women with an adnexal mass","volume":"438","author":"Grenache","year":"2015","journal-title":"Clin. Chim. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ygyno.2012.11.022","article-title":"Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay","volume":"128","author":"Bristow","year":"2013","journal-title":"Gynecol. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Efron, B., and Tibshirani, R. (1993). An Introduction to the Bootstrap, Chapman and Hall.","DOI":"10.1007\/978-1-4899-4541-9"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1214\/ss\/1063994968","article-title":"Second Thoughts on the Bootstrap","volume":"18","author":"Efron","year":"2003","journal-title":"Statist. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cccn.2005.04.002","article-title":"The bootstrap: A technique for data-driven statistics. Using computer-intensive analyses to explore experimental data","volume":"359","author":"Henderson","year":"2005","journal-title":"Clin. Chim. Acta"},{"key":"ref_34","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_35","doi-asserted-by":"crossref","unstructured":"Musoro, J.Z., Zwinderman, A.H., Puhan, M.A., ter Riet, G., and Geskus, R.B. (2014). Validation of prediction models based on lasso regression with multiply imputed data. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-116"},{"key":"ref_36","unstructured":"(2017, December 01). UPCI Luminex Core Facility. Available online: http:\/\/www.upci.upmc.edu\/luminex\/index.cfm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"R45","DOI":"10.1186\/bcr2096","article-title":"Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer","volume":"10","author":"Nolen","year":"2008","journal-title":"Breast Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kong, S.W., Collins, C.D., Shimizu-Motohashi, Y., Holm, I.A., Campbell, M.G., Lee, I.H., Brewster, S.J., Hanson, E., Harris, H.K., and Lowe, K.R. (2012). Characteristics and predictive value of blood transcriptome signature in males with autism spectrum disorders. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049475"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/19\/4938\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:27:51Z","timestamp":1760189271000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/19\/4938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,5]]},"references-count":38,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["ijms20194938"],"URL":"https:\/\/doi.org\/10.3390\/ijms20194938","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,5]]}}}