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Cytology as triage for colposcopy referral suffers from several shortcomings. HPV testing overcomes some of these but lacks specificity in women under 30. Here, we aimed to develop and validate an automatable triage test that is highly sensitive\u00a0and\u00a0specific independently of age and sample heterogeneity, and predicts progression to CIN3+\u00a0in HPV+\u2009patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The WID\u2122-qCIN, assessing three regions in human genes<jats:italic>DPP6<\/jats:italic>,<jats:italic>RALYL<\/jats:italic>, and<jats:italic>GSX1,<\/jats:italic>was validated in both a diagnostic (case\u2013control) and predictive setting (nested case\u2013control), in a total of 761 samples. Using a predefined threshold, the sensitivity of the WID\u2122-qCIN test was 100% and 78% to detect invasive cancer and CIN3, respectively. Sensitivity to detect CIN3+\u00a0was 65% and 83% for women\u2009&lt;\u2009and\u2009\u2265\u200930\u00a0years of age. The specificity was 90%. Importantly, the WID\u2122-qCIN test identified 52% of\u2009\u2265\u200930-year-old women with a cytology negative (cyt\u2212) index sample who were diagnosed with CIN3 1\u20134\u00a0years after sample donation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified suitable DNAme regions in an epigenome-wide discovery using HPV+\u2009controls and CIN3+\u2009cases and established the WID\u2122-qCIN, a PCR-based DNAme test. The WID\u2122-qCIN test has a high sensitivity and specificity that may outperform conventional cervical triage tests and can in an objective, cheap, and scalable fashion identify most women with and at risk of (pre-)invasive cervical cancer. However, evaluation was limited to case\u2013control settings and future studies will assess performance and generalisability in a randomised controlled trial.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13148-022-01353-0","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:12:06Z","timestamp":1669162326000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["DNA methylation-based detection and prediction of cervical intraepithelial neoplasia grade 3 and invasive cervical cancer with the WID\u2122-qCIN test"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1572-498X","authenticated-orcid":false,"given":"Chiara","family":"Herzog","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Sundstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iona","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangrong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Redl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Schreiberhuber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Costas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Paytubi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Dostalek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Zikan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Cibula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaby","family":"Sroczynski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Siebert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joakim","family":"Dillner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7778-8380","authenticated-orcid":false,"given":"Martin","family":"Widschwendter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"1353_CR1","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/S1470-2045(20)30729-4","volume":"22","author":"M Das","year":"2020","unstructured":"Das M. 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Briefly, liquid-based cytology samples processed in the capital region of Stockholm in Sweden are biobanked through a state-of-the-art platform at the Karolinska University Laboratory, Karolinska University Hospital. Collection of samples is based on an opt-out system, with samples biobanked by default unless opted out. Ethical approval for use of samples and linked disease status information in the current study was granted by the Karolinska Ethical Committee (Dnr 2014\/1242-31\/4).","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":"J.E.B., A.J., I.E., and M.W. are named as inventors on a patent (submitted by UCLB, UCL\u2019s technology transfer organisation) which partly covers aspects described in this paper. C.H., J.E.B., and M.W. are shareholders in Sola Diagnostics GmbH, which holds an exclusive licence to the intellectual property that protects the commercialisation of the WID\u2122-qCIN test. L.C. received supplies from Integrated DNA Technologies\u2014IDT\u2014and Roche Diagnostics at 50% discount for a pilot study (includes 13 self-samples of this study) and has received speakers\u2019 honoraria from Roche.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"150"}}