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Here, we compared the clinical performance of <jats:italic>FAM19A4<\/jats:italic> methylation analysis to cytology and HPV16\/18 genotyping, separately and in combination, for \u2265CIN3 detection in hrHPV\u2010positive women participating in a prospective observational multi\u2010center cohort study. The study population comprised hrHPV\u2010positive women aged 18\u201366 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy\u2010directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for <jats:italic>FAM19A4<\/jats:italic> gene promoter methylation, cytology and HPV16\/18 genotyping. Methylation analysis was performed by quantitative methylation\u2010specific PCR (qMSP). Sensitivities and specificities for \u2265CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV\u2010positive women, the sensitivities for \u2265CIN3 of cytology, <jats:italic>FAM19A4<\/jats:italic> methylation analysis, and cytology combined with HPV16\/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of <jats:italic>FAM19A4<\/jats:italic> methylation analysis were associated with age (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.001 each). In women \u226530 years (<jats:italic>n<\/jats:italic>\u2009=\u2009287), \u2265CIN3 sensitivity of <jats:italic>FAM19A4<\/jats:italic> methylation analysis was 88.3% (95%CI: 80.2\u201396.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0\u201394.0)], at a significantly higher specificity [62.1% (95%CI: 55.8\u201368.4) compared to 47.6% (95%CI: 41.1\u201354.1)]. In conclusion, among hrHPV\u2010positive women from an outpatient population aged \u226530 years, methylation analysis of <jats:italic>FAM19A4<\/jats:italic> is an attractive marker for the identification of women with \u2265CIN3.<\/jats:p>","DOI":"10.1002\/ijc.29824","type":"journal-article","created":{"date-parts":[[2015,8,28]],"date-time":"2015-08-28T23:03:08Z","timestamp":1440802988000},"page":"992-1002","source":"Crossref","is-referenced-by-count":71,"title":["Comparing the performance of <i>FAM19A4<\/i> methylation analysis, cytology and HPV16\/18 genotyping for the detection of cervical (pre)cancer in high\u2010risk HPV\u2010positive women of a gynecologic outpatient population (COMETH study)"],"prefix":"10.1002","volume":"138","author":[{"given":"Roosmarijn","family":"Luttmer","sequence":"first","affiliation":[{"name":"Department of Pathology VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise M.A.","family":"De Strooper","sequence":"additional","affiliation":[{"name":"Department of Pathology VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Berkhof","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics VU University Medical Center Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.F.","family":"Snijders","sequence":"additional","affiliation":[{"name":"Department of Pathology VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaike G.","family":"Dijkstra","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology VU University Medical Center Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot H.","family":"Uijterwaal","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Flevo Hospital Almere The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renske D.M.","family":"Steenbergen","sequence":"additional","affiliation":[{"name":"Department of Pathology VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Folkert J.","family":"van Kemenade","sequence":"additional","affiliation":[{"name":"Department of Pathology Erasmus Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Rozendaal","sequence":"additional","affiliation":[{"name":"Department of Pathology VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo J.M.","family":"Helmerhorst","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Erasmus MC University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene H.M.","family":"Verheijen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Abraham","family":"Ter Harmsel","sequence":"additional","affiliation":[{"name":"Department of Gynecology Roosevelt Clinic Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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