{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:45:37Z","timestamp":1792676737419,"version":"4.5.0"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Epithelial ovarian cancer has become the most frequent cause of deaths among gynecologic malignancies. Our study elucidates the diagnostic performance of Risk of Ovarian Malignancy Algorithm (ROMA), Human epididymis secretory protein 4 (HE4) and cancer antigen (CA125). To compare the diagnostic accuracy of ROMA, HE-4 and CA125 in the early diagnosis and screening of Epithelial Ovarian Cancer. Literature search in electronic databases such as Medicine: MEDLINE (through PUBMED interface), EMBASE, Google Scholar, Science Direct and Cochrane library from January 2011 to August 2020. Studies that evaluated the diagnostic measures of ROMA, HE4 and CA125 by using Chemilumincence immunoassay or electrochemiluminescence immunoassay (CLIA or ECLIA) as index tests. Using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2).\n We included 32 studies in our meta-analysis. We calculated AUC by SROC, pooled estimated like sensitivity, specificity, likelihood ratio, diagnostic odds ratio (DOR), Tau square, Cochran Q through random effect analysis and meta-regression. Data was retrieved from 32 studies. The number of studies included for HE4, CA125 and ROMA tests was 25, 26 and 22 respectively. The patients with EOC were taken as cases, and women with benign ovarian mass were taken as control, which was 2233\/5682, 2315\/5875 and 2281\/5068 respectively for the markers or algorithm.\n The pooled estimates of the markers or algorithm were sensitivity: ROMA (postmenopausal) (0.88, 95% CI 0.86\u20130.89)\u2009&gt;\u2009ROMA (premenopausal) 0.80, 95% CI 0.78\u20130.83\u2009&gt;\u2009CA-125(0.84, 95% CI 0.82\u20130.85)\u2009&gt;\u2009HE4 (0.73, 95% CI 0.71\u20130.75) specificity: HE4 (0.90, 95% CI 0.89\u20130.91)\u2009&gt;\u2009ROMA (postmenopausal) (0.83, 95% CI 0.81\u20130.84)\u2009&gt;\u2009ROMA (premenopausal) (0.80, 95% CI 0.79\u20130.82)\u2009&gt;\u2009CA125 (0.73, 95%CI 0.72\u20130.74), Diagnostic odd\u2019s ratio ROMA (postmenopausal) 44.04, 95% CI 31.27\u201362.03, ROMA (premenopausal)-18.93, 95% CI 13.04\u201327.48, CA-125-13.44, 95% CI 9.97\u201318.13, HE4-41.03, 95% CI 27.96\u201360.21 AUC(SE): ROMA (postmenopausal) 0.94(0.01), ROMA (premenopausal)-0.88(0.01), HE4 0.91(0.01), CA125-0.86(0.02) through bivariate random effects model considering the heterogeneity. Our study found ROMA as the best marker to differentiate EOC from benign ovarian masses with greater diagnostic accuracy as compared to HE4 and CA125 in postmenopausal women. In premenopausal women, HE4 is a promising predictor of Epithelial ovarian cancer; however, its utilisation requires further exploration.\n Our study elucidates the diagnostic performance of ROMA, HE4 and CA125 in EOC. ROMA is a promising diagnostic marker of Epithelial ovarian cancers in postmenopausal women, while HE4 is the best diagnostic predictor of EOC in the premenopausal group. Our study had only EOC patients as cases and those with benign ovarian masses as controls. Further, we considered the studies estimated using the markers by the same index test: CLIA or ECLIA. The good number of studies with strict inclusion criteria reduced bias because of the pooling of studies with different analytical methods, especially for HE4. We did not consider the studies published in foreign languages. Since a few studies were available for HE4 and CA125 in the premenopausal and postmenopausal group separately, data were inadequate for sub-group analysis. Further, we did not assess these markers' diagnostic efficiency stratified by the stage and type of tumour due to insufficient studies.<\/jats:p>","DOI":"10.1038\/s41598-021-96552-9","type":"journal-article","created":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T10:03:36Z","timestamp":1630058616000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Diagnostic measures comparison for ovarian malignancy risk in Epithelial ovarian cancer patients: a meta-analysis"],"prefix":"10.1038","volume":"11","author":[{"given":"Arpita","family":"Suri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanamail","family":"Perumal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prajwal","family":"Ammalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varsha","family":"Suryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjiv Kumar","family":"Bansal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,27]]},"reference":[{"key":"96552_CR1","unstructured":"Cancer today [Internet]. 2019 [cited 2019 Jan 30]. http:\/\/gco.iarc.fr\/today\/home."},{"issue":"6","key":"96552_CR2","doi-asserted-by":"publisher","first-page":"2541","DOI":"10.18203\/2320-1770.ijrcog20172348","volume":"6","author":"D Jindal","year":"2017","unstructured":"Jindal, D., Sahasrabhojanee, M., Jindal, M. & D\u2019Souza, J. Epidemiology of epithelial ovarian cancer: A tertiary hospital based study in Goa, India. Int. J. Reprod. Contracept. Obstet. Gynecol. 6(6), 2541. https:\/\/doi.org\/10.18203\/2320-1770.ijrcog20172348 (2017).","journal-title":"Int. J. Reprod. Contracept. Obstet. Gynecol."},{"key":"96552_CR3","doi-asserted-by":"publisher","first-page":"20","DOI":"10.4103\/2278-0513.172078","volume":"5","author":"SK Saini","year":"2016","unstructured":"Saini, S. K., Srivastava, S., Singh, Y., Dixit, A. K. & Prasad, S. N. Epidemiology of epithelial ovarian cancer, a single institution-based study in India. Clin. Cancer Investig. J. 5, 20\u201324. https:\/\/doi.org\/10.4103\/2278-0513.172078 (2016).","journal-title":"Clin. Cancer Investig. J."},{"issue":"1","key":"96552_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/oxfordjournals.humrep.a136832","volume":"4","author":"I Jacobs","year":"1989","unstructured":"Jacobs, I. & Bast, R. C. The CA 125 tumour-associated antigen: A review of the literature. Hum. Reprod. 4(1), 1\u201312. https:\/\/doi.org\/10.1093\/oxfordjournals.humrep.a136832 (1989).","journal-title":"Hum. Reprod."},{"issue":"2","key":"96552_CR5","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.ultras.2013.05.014","volume":"54","author":"D Peng","year":"2014","unstructured":"Peng, D., Xu, T., Mason, T. J. & Wu, W. A study of ovarian cancer biomarker amplification using ultrasound for early stage detection. Ultrasonics 54(2), 451\u2013454. https:\/\/doi.org\/10.1016\/j.ultras.2013.05.014 (2014).","journal-title":"Ultrasonics"},{"issue":"3","key":"96552_CR6","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.ygyno.2015.03.044","volume":"137","author":"JB Liao","year":"2015","unstructured":"Liao, J. B. et al. Detection of the HE4 protein in urine as a biomarker for ovarian neoplasms: Clinical correlates. Gynecol. Oncol. 137(3), 430\u2013435. https:\/\/doi.org\/10.1016\/j.ygyno.2015.03.044 (2015).","journal-title":"Gynecol. Oncol."},{"key":"96552_CR7","unstructured":"Ovarian Cancer\u2014AACC.org [Internet]. [cited 2019 Jan 30]. https:\/\/www.aacc.org\/publications\/cln\/articles\/2013\/march\/ovarian-cancer."},{"issue":"2","key":"96552_CR8","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/S1470-2045(06)70579-4","volume":"7","author":"D Bouchard","year":"2006","unstructured":"Bouchard, D., Morisset, D., Bourbonnais, Y. & Tremblay, G. M. Proteins with whey-acidic-protein motifs and cancer. Lancet Oncol. 7(2), 167\u2013174. https:\/\/doi.org\/10.1016\/S1470-2045(06)70579-4 (2006).","journal-title":"Lancet Oncol."},{"issue":"6","key":"96552_CR9","first-page":"463","volume":"20","author":"N Abdalla","year":"2016","unstructured":"Abdalla, N. et al. Analysis of serum level of HE4 and CA125 considering selected risk factors among patients with endometrioid endometrial cancer. Contemp. Oncol. 20(6), 463\u2013467 (2016).","journal-title":"Contemp. Oncol."},{"key":"96552_CR10","first-page":"54","volume":"22","author":"XY Li","year":"2012","unstructured":"Li, X. Y. Application of chemiluminescence method to testing environmental samples. J. Environ. Coll. China 22, 54\u201356 (2012).","journal-title":"J. Environ. Coll. China"},{"key":"96552_CR11","doi-asserted-by":"publisher","first-page":"41","DOI":"10.3892\/br.2016.682","volume":"5","author":"S Wei","year":"2016","unstructured":"Wei, S., Li, H. & Zhang, B. The diagnostic value of serum HE4 and CA125 and ROMA index in ovarian cancer. Biomed. Rep. 5, 41\u201344 (2016).","journal-title":"Biomed. Rep."},{"issue":"2","key":"96552_CR12","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.ygyno.2007.10.017","volume":"108","author":"RG Moore","year":"2008","unstructured":"Moore, R. G. et al. The use of multiple novel tumour biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol. Oncol. 108(2), 402\u2013408. https:\/\/doi.org\/10.1016\/j.ygyno.2007.10.017 (2008).","journal-title":"Gynecol. Oncol."},{"issue":"3","key":"96552_CR13","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1515\/CCLM.2011.075","volume":"49","author":"M Montagnana","year":"2011","unstructured":"Montagnana, M. et al. The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: Is it really useful?. Clin. Chem. Lab. Med. 49(3), 521\u2013525. https:\/\/doi.org\/10.1515\/CCLM.2011.075 (2011).","journal-title":"Clin. Chem. Lab. Med."},{"key":"96552_CR14","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/1471-2288-6-31","volume":"6","author":"J Zamora","year":"2006","unstructured":"Zamora, J., Abraira, V., Muriel, A., Khan, K. & Coomarasamy, A. Meta-DiSc: A software for meta-analysis of test accuracy data. BMC Med. Res. Methodol. 6, 31. https:\/\/doi.org\/10.1186\/1471-2288-6-31 (2006).","journal-title":"BMC Med. Res. Methodol."},{"issue":"5","key":"96552_CR15","doi-asserted-by":"publisher","first-page":"3101","DOI":"10.3892\/ol.2016.5058","volume":"12","author":"A Chudecka-G\u0142az","year":"2016","unstructured":"Chudecka-G\u0142az, A., Cymbaluk-P\u0142oska, A., Luterek-Puszy\u0144ska, K. & Menkiszak, J. Diagnostic usefulness of the risk of ovarian malignancy algorithm using the electrochemiluminescence immunoassay for HE4 and the chemiluminescence micro particle immunoassay for CA125. Oncol. Lett. 12(5), 3101\u20133114. https:\/\/doi.org\/10.3892\/ol.2016.5058 (2016).","journal-title":"Oncol. Lett."},{"issue":"12","key":"96552_CR16","doi-asserted-by":"publisher","first-page":"2496","DOI":"10.1158\/1055-9965.EPI-11-0635","volume":"20","author":"E Bandiera","year":"2011","unstructured":"Bandiera, E. et al. Serum human epididymis protein 4 and risk for ovarian malignancy algorithm as new diagnostic and prognostic tools for epithelial ovarian cancer management. Cancer Epidemiol. Biomark. Prev. 20(12), 2496\u20132506. https:\/\/doi.org\/10.1158\/1055-9965.EPI-11-0635 (2011).","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"issue":"7","key":"96552_CR17","doi-asserted-by":"publisher","first-page":"7249","DOI":"10.1007\/s13277-014-1945-6","volume":"35","author":"B Ortiz-Mu\u00f1oz","year":"2014","unstructured":"Ortiz-Mu\u00f1oz, B. et al. HE4, Ca125 and ROMA algorithm for differential diagnosis between benign gynaecological diseases and ovarian cancer. Tumour Biol. 35(7), 7249\u20137258. https:\/\/doi.org\/10.1007\/s13277-014-1945-6 (2014).","journal-title":"Tumour Biol."},{"issue":"2","key":"96552_CR18","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.ygyno.2012.09.034","volume":"128","author":"KKL Chan","year":"2013","unstructured":"Chan, K. K. L. et al. The use of HE4 in the prediction of ovarian cancer in Asian women with a pelvic mass. Gynecol. Oncol. 128(2), 239\u2013244. https:\/\/doi.org\/10.1016\/j.ygyno.2012.09.034 (2013).","journal-title":"Gynecol. Oncol."},{"issue":"11","key":"96552_CR19","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1373\/clinchem.2010.157073","volume":"57","author":"JM Escudero","year":"2011","unstructured":"Escudero, J. M. et al. Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumour marker in patients with malignant and nonmalignant diseases. Clin. Chem. 57(11), 1534\u20131544. https:\/\/doi.org\/10.1373\/clinchem.2010.157073 (2011).","journal-title":"Clin. Chem."},{"key":"96552_CR20","doi-asserted-by":"publisher","DOI":"10.5812\/ircmj.17185","author":"F Farzaneh","year":"2014","unstructured":"Farzaneh, F. et al. Preoperative evaluation of risk of ovarian malignancy algorithm index in prediction of malignancy of adnexal masses. Iran. Red Crescent Med. J. https:\/\/doi.org\/10.5812\/ircmj.17185 (2014).","journal-title":"Iran. Red Crescent Med. J."},{"issue":"15\u201316","key":"96552_CR21","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1016\/j.cca.2011.04.028","volume":"412","author":"G Ruggeri","year":"2011","unstructured":"Ruggeri, G. et al. HE4 and epithelial ovarian cancer: Comparison and clinical evaluation of two immunoassays and a combination algorithm. Clin. Chim. Acta 412(15\u201316), 1447\u20131453. https:\/\/doi.org\/10.1016\/j.cca.2011.04.028 (2011).","journal-title":"Clin. Chim. Acta"},{"issue":"1","key":"96552_CR22","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/1746-1596-8-11","volume":"8","author":"EO Hamed","year":"2013","unstructured":"Hamed, E. O. et al. Significance of HE4 estimation in comparison with CA125 in diagnosis of ovarian cancer and assessment of treatment response. Diagn. Pathol. 8(1), 11. https:\/\/doi.org\/10.1186\/1746-1596-8-11 (2013).","journal-title":"Diagn. Pathol."},{"issue":"5","key":"96552_CR23","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.7314\/apjcp.2014.15.5.1949","volume":"15","author":"H Winarto","year":"2014","unstructured":"Winarto, H., Laihad, B. J. & Nuranna, L. Modification of cutoff values for HE4, CA125, the risk of malignancy index, and the risk of malignancy algorithm for ovarian cancer detection in Jakarta, Indonesia.  Asian Pac. J. Cancer Prev. 15(5), 1949\u20131953. https:\/\/doi.org\/10.7314\/apjcp.2014.15.5.1949 (2014).","journal-title":"Asian Pac. J. Cancer Prev."},{"issue":"4","key":"96552_CR24","doi-asserted-by":"publisher","first-page":"358.e1","DOI":"10.1016\/j.ajog.2011.05.017","volume":"205","author":"K Holcomb","year":"2011","unstructured":"Holcomb, K., Vucetic, Z., Miller, M. C. & Knapp, R. C. Human epididymis protein 4 offers superior specificity in the differentiation of benign and malignant adnexal masses in premenopausal women. Am. J. Obstet. Gynecol. 205(4), 358.e1-358.e6. https:\/\/doi.org\/10.1016\/j.ajog.2011.05.017 (2011).","journal-title":"Am. J. Obstet. Gynecol."},{"issue":"12","key":"96552_CR25","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.3346\/jkms.2015.30.12.1777","volume":"30","author":"HY Cho","year":"2015","unstructured":"Cho, H. Y. et al. Comparison of HE4, CA125, and risk of ovarian malignancy algorithm in the prediction of ovarian cancer in Korean women. J. Korean Med. Sci. 30(12), 1777. https:\/\/doi.org\/10.3346\/jkms.2015.30.12.1777 (2015).","journal-title":"J. Korean Med. Sci."},{"issue":"2","key":"96552_CR26","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1016\/j.ygyno.2012.07.106","volume":"127","author":"MA Karlsen","year":"2012","unstructured":"Karlsen, M. A. et al. 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. Gynecol. Oncol. 127(2), 379\u2013383. https:\/\/doi.org\/10.1016\/j.ygyno.2012.07.106 (2012).","journal-title":"Gynecol. Oncol."},{"issue":"1","key":"96552_CR27","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s13048-016-0254-7","volume":"9","author":"KM Terlikowska","year":"2016","unstructured":"Terlikowska, K. M. et al. Preoperative HE4, CA125 and ROMA in the differential diagnosis of benign and malignant adnexal masses. J. Ovarian Res. 9(1), 43. https:\/\/doi.org\/10.1186\/s13048-016-0254-7 (2016).","journal-title":"J. Ovarian Res."},{"issue":"3","key":"96552_CR28","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/j.ygyno.2013.03.001","volume":"129","author":"S Kondalsamy-Chennakesavan","year":"2013","unstructured":"Kondalsamy-Chennakesavan, S., Hackethal, A., Bowtell, D. & Obermair, A. Differentiating stage 1 epithelial ovarian cancer from benign ovarian tumours using a combination of tumour markers HE4, CA125, and CEA and patient\u2019s age. Gynecol. Oncol. 129(3), 467\u2013471. https:\/\/doi.org\/10.1016\/j.ygyno.2013.03.001 (2013).","journal-title":"Gynecol. Oncol."},{"key":"96552_CR29","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.cca.2016.06.010","volume":"459","author":"L Li","year":"2016","unstructured":"Li, L. et al. Value of serum human epididymis secretory protein 4 as a marker for differential diagnosis of malignant and benign gynecological diseases of patients in southern China. Clin. Chim. Acta 459, 170\u2013176. https:\/\/doi.org\/10.1016\/j.cca.2016.06.010 (2016).","journal-title":"Clin. Chim. Acta"},{"issue":"1","key":"96552_CR30","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/1757-2215-6-45","volume":"6","author":"S \u0141awicki","year":"2013","unstructured":"\u0141awicki, S., B\u0119dkowska, G. E., Gacuta-Szumarska, E. & Szmitkowski, M. The plasma concentration of VEGF, HE4 and CA125 as a new biomarkers panel in different stages and sub-types of epithelial ovarian tumours. J. Ovarian Res. 6(1), 45. https:\/\/doi.org\/10.1186\/1757-2215-6-45 (2013).","journal-title":"J. Ovarian Res."},{"issue":"6","key":"96552_CR31","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1007\/s13277-011-0204-3","volume":"32","author":"R Molina","year":"2011","unstructured":"Molina, R. et al. HE4 a novel tumour marker for ovarian cancer: Comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases. Tumor Biol. 32(6), 1087\u20131095. https:\/\/doi.org\/10.1007\/s13277-011-0204-3 (2011).","journal-title":"Tumor Biol."},{"issue":"9","key":"96552_CR32","first-page":"4137","volume":"32","author":"Z Novotny","year":"2012","unstructured":"Novotny, Z. et al. HE4 and ROMA index in Czech postmenopausal women. Anticancer Res. 32(9), 4137\u20134140 (2012).","journal-title":"Anticancer Res."},{"issue":"10\u201311","key":"96552_CR33","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1016\/j.clinbiochem.2011.04.011","volume":"44","author":"Y Park","year":"2011","unstructured":"Park, Y., Lee, J. H., Hong, D. J., Lee, E. Y. & Kim, H. S. Diagnostic performances of HE4 and CA125 for the detection of ovarian cancer from patients with various gynecologic and non-gynecologic diseases. ClinBiochem 44(10\u201311), 884\u2013888. https:\/\/doi.org\/10.1016\/j.clinbiochem.2011.04.011 (2011).","journal-title":"ClinBiochem"},{"issue":"2","key":"96552_CR34","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.ygyno.2012.11.026","volume":"128","author":"MT Sandri","year":"2013","unstructured":"Sandri, M. T. et al. Comparison of HE4, CA125 and ROMA algorithm in women with a pelvic mass: Correlation with pathological outcome. Gynecol. Oncol. 128(2), 233\u2013238. https:\/\/doi.org\/10.1016\/j.ygyno.2012.11.026 (2013).","journal-title":"Gynecol. Oncol."},{"issue":"3","key":"96552_CR35","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1016\/j.ygyno.2014.01.005","volume":"132","author":"A Stiekema","year":"2014","unstructured":"Stiekema, A. et al. A predictive model combining human epididymal protein 4 and radiologic features for the diagnosis of ovarian cancer. Gynecol. Oncol. 132(3), 573\u2013577. https:\/\/doi.org\/10.1016\/j.ygyno.2014.01.005 (2014).","journal-title":"Gynecol. Oncol."},{"issue":"1","key":"96552_CR36","doi-asserted-by":"publisher","first-page":"101","DOI":"10.7314\/apjcp.2014.15.1.101","volume":"15","author":"WT Chen","year":"2014","unstructured":"Chen, W. T. et al. HE4 as a serum biomarker for ROMA prediction and prognosis of epithelial ovarian cancer. Asian Pac. J. Cancer Prev. 15(1), 101\u2013105. https:\/\/doi.org\/10.7314\/apjcp.2014.15.1.101 (2014).","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"96552_CR37","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.cca.2014.11.013","volume":"440","author":"X Chen","year":"2015","unstructured":"Chen, X. et al. Development of a multimarker assay for differential diagnosis of benign and malignant pelvic masses. Clin. Chim. Acta 440, 57\u201363. https:\/\/doi.org\/10.1016\/j.cca.2014.11.013 (2015).","journal-title":"Clin. Chim. Acta"},{"issue":"1\u20132","key":"96552_CR38","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.clinbiochem.2015.07.029","volume":"49","author":"Y Xu","year":"2016","unstructured":"Xu, Y. et al. Modification of cutoff values for HE4, CA125 and the ROMA algorithm for early-stage epithelial ovarian cancer detection: Results from 1021 cases in South China. Clin. Biochem. 49(1\u20132), 32\u201340. https:\/\/doi.org\/10.1016\/j.clinbiochem.2015.07.029 (2016).","journal-title":"Clin. Biochem."},{"issue":"12","key":"96552_CR39","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.12122\/j.issn.1673-4254.2019.12.02","volume":"39","author":"G Shipeng","year":"2019","unstructured":"Shipeng, G., Yongning, C., Yadi, Z., Chanyuan, L. I. & Qifan, J. Nan Fang Yi Ke Da Xue Xue Bao 39(12), 1393\u20131401. https:\/\/doi.org\/10.12122\/j.issn.1673-4254.2019.12.02 (2019).","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao"},{"issue":"12","key":"96552_CR40","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1111\/jog.13466","volume":"43","author":"T Nikolova","year":"2017","unstructured":"Nikolova, T. et al. Diagnostic performance of human epididymis protein 4 compared to a combination of biophysical and biochemical markers to differentiate ovarian endometriosis from epithelial ovarian cancer in premenopausal women. J. Obstet. Gynaecol. Res. 43(12), 1870\u20131879. https:\/\/doi.org\/10.1111\/jog.13466 (2017).","journal-title":"J. Obstet. Gynaecol. Res."},{"issue":"1","key":"96552_CR41","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1007\/s11596-020-2163-7","volume":"40","author":"YN Chen","year":"2020","unstructured":"Chen, Y. N. et al. Ultrasound features improve diagnostic performance of ovarian cancer predictors in distinguishing benign and malignant ovarian tumors. Curr. Med. Sci. 40(1), 184\u2013191. https:\/\/doi.org\/10.1007\/s11596-020-2163-7 (2020).","journal-title":"Curr. Med. Sci."},{"issue":"1","key":"96552_CR42","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s13048-020-00643-6","volume":"13","author":"A Hada","year":"2020","unstructured":"Hada, A. et al. Comparison of the predictive performance of risk of malignancy indexes 1\u20134, HE4 and risk of malignancy algorithm in the triage of adnexal masses. J. Ovarian Res. 13(1), 46. https:\/\/doi.org\/10.1186\/s13048-020-00643-6 (2020).","journal-title":"J. Ovarian Res."},{"issue":"8","key":"96552_CR43","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1080\/01443615.2018.1457632","volume":"38","author":"\u00c2 Melo","year":"2018","unstructured":"Melo, \u00c2., Ver\u00edssimo, R., Farinha, M., Martins, N. N. & Martins, F. N. Discriminative value of CA-125, HE4, Risk of Malignancy Index II (RMI-II) and risk of malignancy algorithm (ROMA) in the differential diagnosis of pelvic masses: Conclusions from a referral Centre in Portugal. J. Obstet. Gynaecol. 38(8), 1140\u20131145. https:\/\/doi.org\/10.1080\/01443615.2018.1457632 (2018).","journal-title":"J. Obstet. Gynaecol."},{"issue":"1","key":"96552_CR44","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.ygyno.2018.08.025","volume":"151","author":"M Lycke","year":"2018","unstructured":"Lycke, M., Kristjansdottir, B. & Sundfeldt, K. A multicenter clinical trial validating the performance of HE4, CA125, risk of ovarian malignancy algorithm and risk of malignancy index. Gynecol. Oncol. 151(1), 159\u2013165. https:\/\/doi.org\/10.1016\/j.ygyno.2018.08.025 (2018).","journal-title":"Gynecol. Oncol."},{"key":"96552_CR45","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.gore.2018.07.002","volume":"25","author":"NVQ Huy","year":"2018","unstructured":"Huy, N. V. Q. et al. Standard and optimal cutoff values of serum ca-125, HE4 and ROMA in preoperative prediction of ovarian cancer in Vietnam. Gynecol. Oncol. Rep. 25, 110\u2013114. https:\/\/doi.org\/10.1016\/j.gore.2018.07.002 (2018).","journal-title":"Gynecol. Oncol. Rep."},{"key":"96552_CR46","first-page":"40","volume":"20","author":"HJ Choi","year":"2019","unstructured":"Choi, H. J. et al. Comparison of CA 125 alone and risk of ovarian malignancy algorithm (ROMA) in patients with adnexal mass: A multicenter study. Curr. Probl. Cancer 20, 40 (2019).","journal-title":"Curr. Probl. Cancer"},{"issue":"8","key":"96552_CR47","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1016\/j.clinbiochem.2015.07.029","volume":"50","author":"S Yu","year":"2012","unstructured":"Yu, S., Yang, H. J., Xie, S. Q. & Bao, Y. X. Diagnostic value of HE4 for ovarian cancer: A meta-analysis. Clin. Chem. Lab. Med. 50(8), 1439\u20131446. https:\/\/doi.org\/10.1016\/j.clinbiochem.2015.07.029 (2012).","journal-title":"Clin. Chem. Lab. Med."},{"key":"96552_CR48","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1186\/1471-2407-12-258","volume":"12","author":"F Li","year":"2012","unstructured":"Li, F. et al. Does risk for ovarian malignancy algorithm excel human epididymis protein 4 and CA125 in predicting epithelial ovarian cancer: A meta-analysis. BMC Cancer 12, 258. https:\/\/doi.org\/10.1186\/1471-2407-12-258 (2012).","journal-title":"BMC Cancer"},{"issue":"6","key":"96552_CR49","doi-asserted-by":"publisher","first-page":"6127","DOI":"10.1007\/s13277-014-1811-6","volume":"35","author":"J Wang","year":"2014","unstructured":"Wang, J. et al. Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: A meta-analysis. Tumour Biol. 35(6), 6127\u20136138. https:\/\/doi.org\/10.1007\/s13277-014-1811-6 (2014).","journal-title":"Tumour Biol."},{"issue":"7","key":"96552_CR50","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1097\/IGC.0000000000000192","volume":"24","author":"ACL Macedo","year":"2014","unstructured":"Macedo, A. C. L., da Rosa, M. I., Lumertz, S. & Medeiros, L. R. Accuracy of serum human epididymis protein 4 in ovarian cancer diagnosis: A systematic review and meta-analysis. Int. J. Gynecol. Cancer 24(7), 1222\u20131231. https:\/\/doi.org\/10.1097\/IGC.0000000000000192 (2014).","journal-title":"Int. J. Gynecol. Cancer"},{"key":"96552_CR51","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.ejogrb.2020.07.015","volume":"252","author":"J Liu","year":"2020","unstructured":"Liu, J., Han, L., Sun, Q., Li, Y. & Niyazi, M. Meta-analysis of the diagnostic accuracy of HE4 for endometrial carcinoma. Eur. J. Obstet. Gynecol. Reprod. Biol. 252, 404\u2013411. https:\/\/doi.org\/10.1016\/j.ejogrb.2020.07.015 (2020).","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"96552_CR52","doi-asserted-by":"publisher","DOI":"10.1111\/ajo.13302","author":"N Rajadevan","year":"2021","unstructured":"Rajadevan, N., McNally, O., Neesham, D., Richards, A. & Naaman, Y. Prognostic value of serum HE4 level in the management of endometrial cancer: A pilot study. Aust. N. Z. J. Obstet. Gynaecol. https:\/\/doi.org\/10.1111\/ajo.13302 (2021).","journal-title":"Aust. N. Z. J. Obstet. Gynaecol."},{"key":"96552_CR53","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cca.2020.12.029","volume":"515","author":"M Degez","year":"2021","unstructured":"Degez, M. et al. Endometrial cancer: A systematic review of HE4, REM and REM-B. Clin. Chim. Acta. 515, 27\u201336. https:\/\/doi.org\/10.1016\/j.cca.2020.12.029 (2021).","journal-title":"Clin. Chim. Acta."},{"issue":"9","key":"96552_CR54","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1097\/IGC.0000000000000804","volume":"26","author":"F Dayyani","year":"2016","unstructured":"Dayyani, F. et al. Diagnostic performance of risk of ovarian malignancy algorithm against CA125 and HE4 in connection with ovarian cancer: A meta-analysis. Int. J. Gynecol. Cancer 26(9), 1586\u20131593. https:\/\/doi.org\/10.1097\/IGC.0000000000000804 (2016).","journal-title":"Int. J. Gynecol. Cancer"},{"key":"96552_CR55","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1111\/j.1447-0756.2008.00869.x","volume":"35","author":"CA Enakpene","year":"2009","unstructured":"Enakpene, C. A. et al. Preoperative evaluationand triage of women with suspicious adnexal masses using risk ofmalignancy index. J. Obstet. Gynaecol. Res. 35, 131\u2013138 (2009).","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"96552_CR56","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s13048-017-0315-6","volume":"10","author":"RT Fortner","year":"2017","unstructured":"Fortner, R. T. et al. Correlates of circulating ovarian cancerearly detection markers and their contribution to discrimination of earlydetection models: results from the EPIC cohort. J. Ovarian Res. 10, 20 (2017).","journal-title":"J. Ovarian Res."},{"key":"96552_CR57","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.cca.2014.08.020","volume":"438","author":"S Ferraro","year":"2015","unstructured":"Ferraro, S., Schiumarini, D. & Panteghini, M. Human epididymis protein 4: Factors of variation. Clin. Chim. Acta. 438, 171\u2013177 (2015).","journal-title":"Clin. Chim. Acta."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96552-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96552-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96552-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T13:12:33Z","timestamp":1670073153000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96552-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,27]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["96552"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-96552-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,27]]},"assertion":[{"value":"19 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17308"}}