{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:34:10Z","timestamp":1787020450790,"version":"build-2736575974"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T00:00:00Z","timestamp":1630627200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T00:00:00Z","timestamp":1630627200000},"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":["81272337"],"award-info":[{"award-number":["81272337"]}],"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":["81973136"],"award-info":[{"award-number":["81973136"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Current methods for cervical cancer screening result in an increased number of referrals and unnecessary diagnostic procedures. This study aimed to develop and evaluate a more accurate model for cervical cancer screening.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Multiple predictors including age, cytology, high-risk human papillomavirus (hrHPV) DNA\/mRNA, E6 oncoprotein, HPV genotyping, and p16\/Ki-67 were used for model construction in a cross-sectional population including women with normal cervix (\n                      <jats:italic>N<\/jats:italic>\n                      = 1085), cervical intraepithelial neoplasia (CIN,\n                      <jats:italic>N<\/jats:italic>\n                      = 279), and cervical cancer (\n                      <jats:italic>N<\/jats:italic>\n                      = 551) to predict CIN2+ or CIN3+. A base model using age, cytology, and hrHPV was calculated, and extended versions with additional biomarkers were considered. External validations in two screening cohorts with 3-year follow-up were further conducted (\n                      <jats:italic>N<\/jats:italic>\n                      <jats:sub>Cohort-I<\/jats:sub>\n                      = 3179,\n                      <jats:italic>N<\/jats:italic>\n                      <jats:sub>Cohort-II<\/jats:sub>\n                      = 3082).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The base model increased the area under the curve (AUC, 0.91, 95% confidence interval [CI] = 0.88\u20130.93) and reduced colposcopy referral rates (42.76%, 95% CI = 38.67\u201346.92) compared to hrHPV and cytology co-testing in the cross-sectional population (AUC 0.80, 95% CI = 0.79\u20130.82, referrals rates 61.62, 95% CI = 59.4\u201363.8) to predict CIN2+. The AUC further improved when HPV genotyping and\/or E6 oncoprotein were included in the base model. External validation in two screening cohorts further demonstrated that our models had better clinical performances than routine screening methods, yielded AUCs of 0.92 (95% CI = 0.91\u20130.93) and 0.94 (95% CI = 0.91\u20130.97) to predict CIN2+ and referrals rates of 17.55% (95% CI = 16.24\u201318.92) and 7.40% (95% CI = 6.50\u20138.38) in screening cohort I and II, respectively. Similar results were observed for CIN3+ prediction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Compared to routine screening methods, our model using current cervical screening indicators can improve the clinical performance and reduce referral rates.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12916-021-02078-2","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T08:18:26Z","timestamp":1630657106000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Development of models for cervical cancer screening: construction in a cross-sectional population and validation in two screening cohorts in China"],"prefix":"10.1186","volume":"19","author":[{"given":"Zeni","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongli","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyue","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinjing","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youlin","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,3]]},"reference":[{"issue":"6","key":"2078_CR1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394\u2013424. https:\/\/doi.org\/10.3322\/caac.21492.","journal-title":"CA Cancer J Clin"},{"issue":"3","key":"2078_CR2","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1002\/(sici)1097-0215(20000501)86:3<429::aid-ijc20>3.0.co;2-d","volume":"86","author":"AP Vizcaino","year":"2000","unstructured":"Vizcaino AP, Moreno V, Bosch FX, Munoz N, Barros-Dios XM, Borras J, et al. International trends in incidence of cervical cancer: II. Squamous-cell carcinoma. Int J Cancer. 2000;86(3):429\u201335. https:\/\/doi.org\/10.1002\/(sici)1097-0215(20000501)86:3<429::aid-ijc20>3.0.co;2-d.","journal-title":"Int J Cancer"},{"issue":"1","key":"2078_CR3","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1002\/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F","volume":"189","author":"JM Walboomers","year":"1999","unstructured":"Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12\u20139. https:\/\/doi.org\/10.1002\/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F.","journal-title":"J Pathol"},{"issue":"4","key":"2078_CR4","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1309\/AJCPTGD94EVRSJCG","volume":"137","author":"D Saslow","year":"2012","unstructured":"Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain J, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 2012;137(4):516\u201342. https:\/\/doi.org\/10.1309\/AJCPTGD94EVRSJCG.","journal-title":"Am J Clin Pathol"},{"issue":"16","key":"2078_CR5","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1056\/NEJMoa071430","volume":"357","author":"MH Mayrand","year":"2007","unstructured":"Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, et al. Canadian Cervical Cancer Screening Trial Study G: Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357(16):1579\u201388. https:\/\/doi.org\/10.1056\/NEJMoa071430.","journal-title":"N Engl J Med"},{"issue":"7","key":"2078_CR6","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1093\/jnci\/djn065","volume":"100","author":"G Ronco","year":"2008","unstructured":"Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, et al. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test. J Natl Cancer Inst. 2008;100(7):492\u2013501. https:\/\/doi.org\/10.1093\/jnci\/djn065.","journal-title":"J Natl Cancer Inst"},{"key":"2078_CR7","unstructured":"WHO. In: WHO Guidelines for Screening and Treatment of Precancerous Lesions for Cervical Cancer Prevention. edn. Geneva; 2013."},{"issue":"11","key":"2078_CR8","doi-asserted-by":"publisher","first-page":"2606","DOI":"10.1002\/ijc.30375","volume":"139","author":"M Schiffman","year":"2016","unstructured":"Schiffman M, Hyun N, Raine-Bennett TR, Katki H, Fetterman B, Gage JC, et al. A cohort study of cervical screening using partial HPV typing and cytology triage. Int J Cancer. 2016;139(11):2606\u201315. https:\/\/doi.org\/10.1002\/ijc.30375.","journal-title":"Int J Cancer"},{"issue":"9","key":"2078_CR9","doi-asserted-by":"publisher","first-page":"2267","DOI":"10.1128\/JCM.00508-16","volume":"54","author":"D Ejegod","year":"2016","unstructured":"Ejegod D, Bottari F, Pedersen H, Sandri MT, Bonde J. The BD Onclarity HPV Assay on Samples Collected in SurePath Medium Meets the International Guidelines for Human Papillomavirus Test Requirements for Cervical Screening. J Clin Microbiol. 2016;54(9):2267\u201372. https:\/\/doi.org\/10.1128\/JCM.00508-16.","journal-title":"J Clin Microbiol"},{"issue":"4","key":"2078_CR10","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1002\/ijc.31368","volume":"143","author":"L Yu","year":"2018","unstructured":"Yu L, Jiang M, Qu P, Wu Z, Sun P, Xi M, et al. Clinical evaluation of human papillomavirus 16\/18 oncoprotein test for cervical cancer screening and HPV positive women triage. Int J Cancer. 2018;143(4):813\u201322. https:\/\/doi.org\/10.1002\/ijc.31368.","journal-title":"Int J Cancer"},{"issue":"12","key":"2078_CR11","doi-asserted-by":"publisher","first-page":"djv257","DOI":"10.1093\/jnci\/djv257","volume":"107","author":"N Wentzensen","year":"2015","unstructured":"Wentzensen N, Fetterman B, Castle PE, Schiffman M, Wood SN, Stiemerling E, et al. p16\/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women. J Natl Cancer Inst. 2015;107(12):djv257.","journal-title":"J Natl Cancer Inst"},{"issue":"20","key":"2078_CR12","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.1161\/CIRCULATIONAHA.115.001593","volume":"132","author":"RC Deo","year":"2015","unstructured":"Deo RC. Machine Learning in Medicine. Circulation. 2015;132(20):1920\u201330. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.115.001593.","journal-title":"Circulation"},{"issue":"2","key":"2078_CR13","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1148\/rg.2017160130","volume":"37","author":"BJ Erickson","year":"2017","unstructured":"Erickson BJ, Korfiatis P, Akkus Z, Kline TL. Machine Learning for Medical Imaging. Radiographics. 2017;37(2):505\u201315. https:\/\/doi.org\/10.1148\/rg.2017160130.","journal-title":"Radiographics"},{"issue":"2","key":"2078_CR14","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.ajog.2004.02.065","volume":"191","author":"RG Pretorius","year":"2004","unstructured":"Pretorius RG, Zhang WH, Belinson JL, Huang MN, Wu LY, Zhang X, et al. Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse. Am J Obstet Gynecol. 2004;191(2):430\u20134. https:\/\/doi.org\/10.1016\/j.ajog.2004.02.065.","journal-title":"Am J Obstet Gynecol"},{"issue":"9","key":"2078_CR15","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1158\/1940-6207.CAPR-13-0091","volume":"6","author":"FH Zhao","year":"2013","unstructured":"Zhao FH, Jeronimo J, Qiao YL, Schweizer J, Chen W, Valdez M, et al. An evaluation of novel, lower-cost molecular screening tests for human papillomavirus in rural China. Cancer Prev Res (Phila). 2013;6(9):938\u201348. https:\/\/doi.org\/10.1158\/1940-6207.CAPR-13-0091.","journal-title":"Cancer Prev Res (Phila)"},{"key":"2078_CR16","doi-asserted-by":"publisher","first-page":"303192","DOI":"10.1155\/2012\/303192","volume":"2012","author":"P Karakitsos","year":"2012","unstructured":"Karakitsos P, Chrelias C, Pouliakis A, Koliopoulos G, Spathis A, Kyrgiou M, et al. Identification of women for referral to colposcopy by neural networks: a preliminary study based on LBC and molecular biomarkers. J Biomed Biotechnol. 2012;2012:303192.","journal-title":"J Biomed Biotechnol"},{"issue":"2","key":"2078_CR17","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1097\/PGP.0b013e318159cbc0","volume":"27","author":"M Branca","year":"2008","unstructured":"Branca M, Ciotti M, Giorgi C, Santini D, Di Bonito L, Costa S, et al. Predicting high-risk human papillomavirus infection, progression of cervical intraepithelial neoplasia, and prognosis of cervical cancer with a panel of 13 biomarkers tested in multivariate modeling. Int J Gynecol Pathol. 2008;27(2):265\u201373. https:\/\/doi.org\/10.1097\/PGP.0b013e318159cbc0.","journal-title":"Int J Gynecol Pathol"},{"issue":"4","key":"2078_CR18","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1177\/0300060515577846","volume":"43","author":"J Kahng","year":"2015","unstructured":"Kahng J, Kim EH, Kim HG, Lee W. Development of a cervical cancer progress prediction tool for human papillomavirus-positive Koreans: A support vector machine-based approach. J Int Med Res. 2015;43(4):518\u201325. https:\/\/doi.org\/10.1177\/0300060515577846.","journal-title":"J Int Med Res"},{"issue":"3","key":"2078_CR19","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1007\/s10552-018-1013-4","volume":"29","author":"MB Rothberg","year":"2018","unstructured":"Rothberg MB, Hu B, Lipold L, Schramm S, Jin XW, Sikon A, et al. A risk prediction model to allow personalized screening for cervical cancer. Cancer Causes Control. 2018;29(3):297\u2013304. https:\/\/doi.org\/10.1007\/s10552-018-1013-4.","journal-title":"Cancer Causes Control"},{"issue":"1 Suppl 1","key":"2078_CR20","doi-asserted-by":"publisher","first-page":"S163","DOI":"10.1016\/j.ygyno.2007.07.050","volume":"107","author":"ME Scheurer","year":"2007","unstructured":"Scheurer ME, Guillaud M, Tortolero-Luna G, Follen M, Adler-Storthz K. Epidemiologic modeling of cervical dysplasia with molecular and cytopathological markers. Gynecol Oncol. 2007;107(1 Suppl 1):S163\u20139. https:\/\/doi.org\/10.1016\/j.ygyno.2007.07.050.","journal-title":"Gynecol Oncol"},{"issue":"1","key":"2078_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11262-009-0412-8","volume":"40","author":"R Ghittoni","year":"2010","unstructured":"Ghittoni R, Accardi R, Hasan U, Gheit T, Sylla B, Tommasino M. The biological properties of E6 and E7 oncoproteins from human papillomaviruses. Virus Genes. 2010;40(1):1\u201313. https:\/\/doi.org\/10.1007\/s11262-009-0412-8.","journal-title":"Virus Genes"},{"issue":"7","key":"2078_CR22","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1158\/1055-9965.EPI-15-1057","volume":"25","author":"LL Yu","year":"2016","unstructured":"Yu LL, Kang LN, Zhao FH, Lei XQ, Qin Y, Wu ZN, et al. Elevated Expression of Human Papillomavirus-16\/18 E6 Oncoprotein Associates with Persistence of Viral Infection: A 3-Year Prospective Study in China. Cancer Epidemiol Biomark Prev. 2016;25(7):1167\u201374. https:\/\/doi.org\/10.1158\/1055-9965.EPI-15-1057.","journal-title":"Cancer Epidemiol Biomark Prev"},{"issue":"6","key":"2078_CR23","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1002\/ijc.30807","volume":"141","author":"Q Zhang","year":"2017","unstructured":"Zhang Q, Dong L, Hu S, Feng R, Zhang X, Pan Q, et al. Risk stratification and long-term risk prediction of E6 oncoprotein in a prospective screening cohort in China. Int J Cancer. 2017;141(6):1110\u20139. https:\/\/doi.org\/10.1002\/ijc.30807.","journal-title":"Int J Cancer"},{"key":"2078_CR24","first-page":"CD008587","volume":"8","author":"G Koliopoulos","year":"2017","unstructured":"Koliopoulos G, Nyaga VN, Santesso N, Bryant A, Martin-Hirsch PP, Mustafa RA, et al. Cytology versus HPV testing for cervical cancer screening in the general population. Cochrane Database Syst Rev. 2017;8:CD008587.","journal-title":"Cochrane Database Syst Rev"},{"issue":"9","key":"2078_CR25","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1002\/cncy.21297","volume":"121","author":"QJ Pan","year":"2013","unstructured":"Pan QJ, Hu SY, Zhang X, Ci PW, Zhang WH, Guo HQ, et al. Pooled analysis of the performance of liquid-based cytology in population-based cervical cancer screening studies in China. Cancer Cytopathol. 2013;121(9):473\u201382. https:\/\/doi.org\/10.1002\/cncy.21297.","journal-title":"Cancer Cytopathol"}],"container-title":["BMC Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-021-02078-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12916-021-02078-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-021-02078-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T08:18:35Z","timestamp":1630657115000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedicine.biomedcentral.com\/articles\/10.1186\/s12916-021-02078-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,3]]},"references-count":25,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2078"],"URL":"https:\/\/doi.org\/10.1186\/s12916-021-02078-2","relation":{},"ISSN":["1741-7015"],"issn-type":[{"value":"1741-7015","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,3]]},"assertion":[{"value":"2 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Institutional review board (IRB) approval was provided by the Ethics Committee from Cancer Hospital, Chinese Academy of Medical Sciences. The ethical permission numbers are 13-104\/780, 16-111\/1190, and 15-118\/1045 for the cross-sectional study, screening cohort I, and screening cohort II, respectively. All participants have agreed on the study protocol and provided informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"YQ has received fund from Qiagen, Roche, Hologic, and Daltonbio for registration trials of HPV test kits. WC has received consulting fees and payment for lectures from Roche, Hologic, and BD Diagnostics. The other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"197"}}