{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:34:54Z","timestamp":1788363294112,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2025,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    High\u2010risk HPV (hrHPV)\u2010based screening has led to many unnecessary colposcopy referrals, mainly because of direct referral after low\u2010grade cytology (ASC\u2010US\/LSIL). DNA methylation and genotyping tests on ASC\u2010US\/LSIL samples have the potential to significantly improve the efficiency of screening. In this study, 12 triage strategies were constructed from\n                    <jats:italic>FAM19A4\/miR124\u20102<\/jats:italic>\n                    or\n                    <jats:italic>ASCL1\/LHX8<\/jats:italic>\n                    methylation, HPV16\/18 or HPV16\/18\/31\/33\/45 genotyping and 1\u2010year repeat cytology. The performance was evaluated on 215 hrHPV\u2010positive ASC\u2010US\/LSIL samples from the IMPROVE trial (NTR5078). Performance was measured by colposcopy referral rate, positive predictive value (PPV) for detecting precancer (CIN3), and negative predictive value (NPV). To evaluate efficiency, strategies were ordered by the cumulative colposcopy referral rate after 1\u2010year cytology and compared by the marginal PPV to detect one additional CIN3 (mPPV). The most conservative strategy (referral when HPV16\/18 and\n                    <jats:italic>FAM19A4\/miR124<\/jats:italic>\n                    methylation results are positive) had a direct referral rate of 5.2%, a cumulative referral rate after 1\u2010year cytology of 54.1%, and mPPV of 19.3%. Replacing HPV16\/18 by HPV16\/18\/31\/33\/45 increased the cumulative 1\u2010year referral rate to 54.6%, and yielded an mPPV of 10.0%. Similar results were obtained for strategies with\n                    <jats:italic>ASCL1\/LHX8<\/jats:italic>\n                    methylation. Of all strategies, referral after an HPV16\/18\/31\/33\/45 positive,\n                    <jats:italic>ASCL1\/LHX8<\/jats:italic>\n                    methylation\u2010positive, and\/or 1\u2010year cytology\u2010positive result yielded the highest direct and cumulative 1\u2010year colposcopy referral rates of 64.4% and 79.1%, respectively. The NPVs after 1\u2010year cytology varied between 98.1% and 99.4%, warranting a return to routine screening. Altogether, DNA methylation\u2010based triage strategies are recommended as they are discriminative for CIN3 and control the number of immediate colposcopy referrals.\n                  <\/jats:p>","DOI":"10.1002\/ijc.35289","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T01:05:27Z","timestamp":1734397527000},"page":"1065-1073","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Colposcopy referrals and\n                    <scp>CIN3<\/scp>\n                    detection after triage by host cell\n                    <scp>DNA<\/scp>\n                    methylation and\/or\n                    <scp>HPV<\/scp>\n                    genotyping in\n                    <scp>HPV<\/scp>\n                    positive women with low\u2010grade cytology from a population\u2010based Dutch primary\n                    <scp>HPV<\/scp>\n                    screening trial"],"prefix":"10.1002","volume":"156","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9877-0297","authenticated-orcid":false,"given":"Lisanne","family":"Verhoef","sequence":"first","affiliation":[{"name":"Amsterdam UMC, location Vrije Universiteit Amsterdam, Pathology  Amsterdam The Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaike C. G.","family":"Bleeker","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, location Vrije Universiteit Amsterdam, Pathology  Amsterdam The Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Polman","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, location Vrije Universiteit Amsterdam, Pathology  Amsterdam The Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7546-4410","authenticated-orcid":false,"given":"Kelsi R.","family":"Kroon","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, location Vrije Universiteit Amsterdam, Epidemiology and Data Science  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2327-9839","authenticated-orcid":false,"given":"Renske D. M.","family":"Steenbergen","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, location Vrije Universiteit Amsterdam, Pathology  Amsterdam The Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3422-5086","authenticated-orcid":false,"given":"Ren\u00e9e M. F.","family":"Ebisch","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center, Obstetrics and Gynecology  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem J. G.","family":"Melchers","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center, Medical Microbiology  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4577-8495","authenticated-orcid":false,"given":"Ruud L. M.","family":"Bekkers","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center, Obstetrics and Gynecology  Nijmegen The Netherlands"},{"name":"GROW School for Oncology and Reproduction, Maastricht University  Maastricht The Netherlands"},{"name":"Catharina Hospital  Eindhoven The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anco C.","family":"Molijn","sequence":"additional","affiliation":[{"name":"Eurofins NMDL\u2010LCPL  Rijswijk The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Folkert","family":"van Kemenade","sequence":"additional","affiliation":[{"name":"Erasmus MC University Medical Center, Department of Pathology  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J. L. 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