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Using a population\u2010based sample of hrHPV positive women with cervical biopsies within 12\u2009months after cervical screening, the clinical value of the S5 methylation classifier (S5), HPV genotyping and cytology were compared as potential triage tests, for outcomes of cervical intraepithelial neoplasia (CIN) grade 3 or greater (CIN3+), CIN2+ and CIN2, and the area under the curve (AUC) calculated. S5 scores increased with histopathology severity (<jats:italic>P<\/jats:italic><jats:sub>trend<\/jats:sub>\u2009&lt;\u2009.001). For CIN3+, the AUC was 0.780 suggesting S5 provides good discrimination between &lt;CIN3 and CIN3+. AUCs were significant for all pairwise comparisons of &lt;CIN2, CIN2 and CIN3+ (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.001). The positive predictive value (PPV) of HPV16\/18 genotyping for women with any abnormal cytology was greater than S5 (25.36% vs 20.87%, <jats:italic>P<\/jats:italic>\u00a0=\u00a0.005) for CIN3+, while sensitivity was substantially greater for S5 (83.33% vs 59.28%, <jats:italic>P<\/jats:italic>\u2009&lt;\u2009.001). Restricting to women with abnormal cytology, but excluding those with high\u2010grade cytology, both S5 and HPV16\/18 provided CIN3+ PPVs high enough to recommend colposcopy. Triage with S5 also appeared useful for hrHPV positive women negative for HPV16\/18 (CIN3+ PPV: 7.33%, sensitivity: 57.52%). S5 provided increased sensitivity for CIN3+ compared to HPV16\/18 genotyping for hrHPV positive women, overall and when restricted to women with abnormal cytology, suggesting S5 may improve colposcopy referral. S5 also has the ability to distinguish between &lt;CIN2, CIN2 and CIN3+, a finding of importance for managing CIN2, given the complexity and uncertainty associated with this diagnosis.<\/jats:p>","DOI":"10.1002\/ijc.34050","type":"journal-article","created":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T04:47:23Z","timestamp":1651121243000},"page":"993-1004","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["<scp>DNA<\/scp> methylation testing with <scp>S5<\/scp> for triage of high\u2010risk <scp>HPV<\/scp> positive women"],"prefix":"10.1002","volume":"151","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2856-7108","authenticated-orcid":false,"given":"Rachael","family":"Adcock","sequence":"first","affiliation":[{"name":"Centre for Cancer Prevention, Wolfson Institute of Population Health Queen Mary University of London  London UK"},{"name":"Center for HPV Prevention University of New Mexico Comprehensive 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