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We compared S5 to HPV16\/18 and cytology to detect cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) and CIN3+ in hrHPV+ women selected from a randomized pragmatic trial of 2661 Colombian women with an earlier\u2010borderline abnormal cytology. We included all hrHPV+ CIN2 and CIN3+ cases (n = 183) age matched to 183 &lt;CIN2 hrHPV+. Baseline specimens were HPV\u2010genotyped and tested by S5\u2010methylation, blinded to cytology, histology and initial HPV results. We evaluated the test performance of predefined S5\u2010classifier (cut\u2010point 0.8) and a post hoc classifier at a different cut\u2010point (3.1). S5 sensitivity for CIN2+ was 82% (95% confidence interval [CI] 76.4\u201087.5) and for CIN3+ 77.08% (95% CI 65.19\u201088.97). S5 sensitivity was higher than HPV16\/18 sensitivity (48.1%, 95% CI 40.85\u201055.33) or cytology (31.21%, 95% CI 24.50\u201037.93) but with lower specificity (35%, 95% CI 28.1\u201042). At cut\u2010point 3.1, S5 sensitivity for CIN2+ (55.2%, 95% CI 48\u201062.4) or CIN3+ (64.6%, 95% CI 51.0\u201078.1) was also superior to HPV16\/18 (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.05) or cytology (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.0001). At this cut\u2010point S5 specificity (76%, 95% CI 69.8\u201082.1 for &lt;CIN2) was higher than HPV16\/18 (67.21%, 95% CI 60.41\u201074.01, <jats:italic>P<\/jats:italic> = .0062) and similar to cytology (75.57%, 95% CI 69.34\u201081.79, <jats:italic>P<\/jats:italic> = 1). HPV16\/18 plus cytology sensitivity was similar to S5 for CIN3+, however, false\u2010positive rate was higher (50.27% vs. 24.04%). High sensitivity is crucial in LMICs, S5\u2010methylation exceeded HPV16\/18 or cytology sensitivity with comparable specificity for CIN2+ and CIN3+ in hrHPV\u2010positive Colombian women. Furthermore, S5 triage had comparable sensitivity and significantly fewer false positives than cytology and HPV16\/18 combination.<\/jats:p>","DOI":"10.1002\/ijc.33314","type":"journal-article","created":{"date-parts":[[2020,10,2]],"date-time":"2020-10-02T09:59:16Z","timestamp":1601632756000},"page":"1383-1393","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Effective methylation triage of <scp>HPV<\/scp> positive women with abnormal cytology in a middle\u2010income country"],"prefix":"10.1002","volume":"148","author":[{"given":"Arianis Tatiana","family":"Ram\u00edrez","sequence":"first","affiliation":[{"name":"Infection and Cancer Group, School of Medicine and Corporaci\u00f3n Acad\u00e9mica para el Estudio de Patolog\u00edas Tropicales Universidad de Antioquia  Medell\u00edn Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria In\u00e9s","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Infection and Cancer Group, School of Medicine and Corporaci\u00f3n Acad\u00e9mica para el Estudio de Patolog\u00edas Tropicales Universidad de Antioquia  Medell\u00edn Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda","family":"Nedjai","sequence":"additional","affiliation":[{"name":"Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Cecilia","family":"Agudelo","sequence":"additional","affiliation":[{"name":"Infection and Cancer Group, School of Medicine and Corporaci\u00f3n Acad\u00e9mica para el Estudio de Patolog\u00edas Tropicales Universidad de Antioquia  Medell\u00edn Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6327-4357","authenticated-orcid":false,"given":"Adam R.","family":"Brentnall","sequence":"additional","affiliation":[{"name":"Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2604-3928","authenticated-orcid":false,"given":"Kate","family":"Cuschieri","sequence":"additional","affiliation":[{"name":"Queen's Medical Research Institute of The University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly Melisa","family":"Casta\u00f1eda","sequence":"additional","affiliation":[{"name":"Infection and Cancer Group, School of Medicine and Corporaci\u00f3n Acad\u00e9mica para el Estudio de Patolog\u00edas Tropicales Universidad de Antioquia  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