{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T15:48:18Z","timestamp":1773157698871,"version":"3.50.1"},"reference-count":23,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009228","name":"Region \u00c3\u2013rebro l\u00c3\u00a4n","doi-asserted-by":"publisher","award":["OLL-982781"],"award-info":[{"award-number":["OLL-982781"]}],"id":[{"id":"10.13039\/501100009228","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009228","name":"Region \u00c3\u2013rebro l\u00c3\u00a4n","doi-asserted-by":"publisher","award":["OLL-978099"],"award-info":[{"award-number":["OLL-978099"]}],"id":[{"id":"10.13039\/501100009228","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006736","name":"Universitetssjukhuset \u00c3\u2013rebro","doi-asserted-by":"publisher","award":["OLL-972849"],"award-info":[{"award-number":["OLL-972849"]}],"id":[{"id":"10.13039\/501100006736","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003509","name":"\u00c3\u2013rebro Universitet","doi-asserted-by":"publisher","award":["open access funding"],"award-info":[{"award-number":["open access funding"]}],"id":[{"id":"10.13039\/501100003509","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objective<\/jats:title>\n<jats:p>To improve human papilloma virus (HPV) screening, more effective triage methods for HPV-positive samples need development and validation. Cytology, the most common triage method today, is subjective and can only be applied to professionally collected samples. Methylation status has been shown to be informative, as genes are highly methylated in HPV-induced cervical dysplasia and cancer. This study aimed to assess whether triaging HPV-positive samples using molecular methods, such as methylation and genotyping for high-risk HPV types, could be as effective as cytology in cervical screening.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>A retrospective biobank study was conducted on HPV-positive samples collected in 2017\u20132018, analyzing FAM19A4\/MiR-124-2 hypermethylation and HPV genotyping for types 16, 18, 31, 33, 45, 52, and\/or 59, comparing these results to cytology triage for detecting histologically confirmed high-grade squamous intraepithelial lesions (HSIL) and cancer.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Results from 1915 positive screening samples were analyzed, including 1052 follow-up biopsies with 402 HSIL or cancer cases. Genotyping showed slightly higher sensitivity than cytology but lower specificity, while methylation had higher specificity but much lower sensitivity. Cytology\u2019s positive predictive value (PPV) was 36%, with lower PPVs for the molecular methods. Combining molecular methods increased the PPV but significantly reduced sensitivity.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Based on these findings with molecular methods reducing sensitivity, we do not recommend adopting the molecular triage methods evaluated in this study in the Swedish setting. The trade-off between sensitivity and specificity does not support a change from the current cytology-based triage approach.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0333539","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T17:21:46Z","timestamp":1760376106000},"page":"e0333539","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular triage on HPV-positive samples in a cervical screening setting"],"prefix":"10.1371","volume":"20","author":[{"given":"Gabriella Lillsunde","family":"Larsson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Carlsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gisela","family":"Helenius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1458-1542","authenticated-orcid":true,"given":"Lovisa","family":"Bergengren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"pone.0333539.ref001","unstructured":"World Health Organization. Cancer tomorrow, internation agency for research on cancer. 2024 [cited 2024 January 24]. https:\/\/gco.iarc.fr\/tomorrow\/en\/dataviz\/bubbles?years=2030&types=0&mode=population&group_populations=1&multiple_cancers=0&multiple_populations=1&single_unit=500000&sexes=1_2&cancers=23"},{"issue":"5","key":"pone.0333539.ref002","article-title":"Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer","volume":"30","author":"M Arbyn","year":"2012","journal-title":"Vaccine"},{"issue":"3","key":"pone.0333539.ref003","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S1470-2045(09)70360-2","article-title":"Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial","volume":"11","author":"G Ronco","year":"2010","journal-title":"Lancet Oncol"},{"issue":"9916","key":"pone.0333539.ref004","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/S0140-6736(13)62218-7","article-title":"Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials","volume":"383","author":"G Ronco","year":"2014","journal-title":"Lancet"},{"issue":"3","key":"pone.0333539.ref005","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1002\/ijgo.12538","article-title":"Comparison between professional sampling and self-sampling for HPV-based cervical cancer screening among postmenopausal women","volume":"142","author":"L Bergengren","year":"2018","journal-title":"Int J Gynaecol Obstet"},{"issue":"1","key":"pone.0333539.ref006","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1186\/s12916-019-1460-0","article-title":"Introduction of primary screening using high-risk HPV DNA detection in the Dutch cervical cancer screening programme: a population-based cohort study","volume":"17","author":"CA Aitken","year":"2019","journal-title":"BMC Med"},{"key":"pone.0333539.ref007","article-title":"The biology and life-cycle of human papillomaviruses","author":"J Doorbar","year":"2012","journal-title":"Vaccine"},{"key":"pone.0333539.ref008","article-title":"How distressing is referral to colposcopy in cervical cancer screening? A prospective quality of life study","author":"IJ Korfage","year":"2023","journal-title":"Qual Life Res"},{"key":"pone.0333539.ref009","unstructured":"Centre RC. National cervical cancer prevention guidelines. 2022 [cited 2024 January 23]. https:\/\/kunskapsbanken.cancercentrum.se\/diagnoser\/livmoderhalscancerprevention\/vardprogram\/"},{"issue":"1","key":"pone.0333539.ref010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/LGT.0000000000000494","article-title":"Clinical Utility of Human Papillomavirus Genotyping in Cervical Cancer Screening: A Systematic Review","volume":"24","author":"JH Bonde","year":"2020","journal-title":"J Low Genit Tract Dis"},{"issue":"1","key":"pone.0333539.ref011","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.jcv.2014.02.002","article-title":"Individual detection of 14 high risk human papilloma virus genotypes by the PapType test for the prediction of high grade cervical lesions","volume":"60","author":"J Cuzick","year":"2014","journal-title":"J Clin Virol"},{"key":"pone.0333539.ref012","article-title":"How many human papillomavirus types do we need to screen for?","author":"K Sundstr\u00f6m","year":"2020","journal-title":"J Infect Dis"},{"issue":"6","key":"pone.0333539.ref013","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/nrc3728","article-title":"Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions","volume":"14","author":"RDM Steenbergen","year":"2014","journal-title":"Nat Rev Cancer"},{"issue":"12","key":"pone.0333539.ref014","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1158\/1940-6207.CAPR-14-0237","article-title":"Methylation analysis of the FAM19A4 gene in cervical scrapes is highly efficient in detecting cervical carcinomas and advanced CIN2\/3 lesions","volume":"7","author":"LMA De Strooper","year":"2014","journal-title":"Cancer Prev Res (Phila)"},{"key":"pone.0333539.ref015","article-title":"FAM19A4\/miR124-2 methylation analysis as a triage test for HPV-positive women: cross-sectional and longitudinal data from a Dutch screening cohort","author":"FJ Vink","year":"2020","journal-title":"Clin Microbiol Infect"},{"issue":"16","key":"pone.0333539.ref016","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1001\/jama.287.16.2114","article-title":"The 2001 Bethesda System: terminology for reporting results of cervical cytology","volume":"287","author":"D Solomon","year":"2002","journal-title":"JAMA"},{"issue":"1","key":"pone.0333539.ref017","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1089\/bio.2012.0036","article-title":"The Swedish cervical cytology biobank: sample handling and storage process","volume":"11","author":"N Perskvist","year":"2013","journal-title":"Biopreserv Biobank"},{"key":"pone.0333539.ref018","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jviromet.2016.05.015","article-title":"HPV Genotyping from the high risk mRNA Aptima assay- a direct approach using DNA from Aptima sample tubes","volume":"235","author":"G Lillsunde Larsson","year":"2016","journal-title":"J Virol Methods"},{"issue":"1","key":"pone.0333539.ref019","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/ijc.34685","article-title":"Performance of the HPV E6\/E7 mRNA Aptima HPV assay combined with partial genotyping compared with the HPV DNA Cobas 4800 HPV test for use in primary screening: Results from the CERVIVA HPV primary screening study in Ireland","volume":"154","author":"C White","year":"2024","journal-title":"Int J Cancer"},{"issue":"2","key":"pone.0333539.ref020","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1002\/ijc.33320","article-title":"Methylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women: A large European multicenter study","volume":"148","author":"J Bonde","year":"2021","journal-title":"Int J Cancer"},{"issue":"4","key":"pone.0333539.ref021","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1002\/ijc.29824","article-title":"Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16\/18 genotyping for the detection of cervical (pre)cancer in high-risk HPV-positive women of a gynecologic outpatient population (COMETH study)","volume":"138","author":"R Luttmer","year":"2016","journal-title":"Int J Cancer"},{"issue":"9","key":"pone.0333539.ref022","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0274825","article-title":"Full genotyping and FAM19A4\/miR124-2 methylation analysis in high-risk human papillomavirus-positive samples from women over 30 years participating in cervical cancer screening in \u00d6rebro, Sweden","volume":"17","author":"M Kaliff","year":"2022","journal-title":"PLoS One"},{"key":"pone.0333539.ref023","first-page":"1527","article-title":"Clinical regression of high-grade cervical intraepithelial neoplasia is associated with absence of FAM19A4\/miR124-2 DNA methylation (CONCERVE Study)","author":"WW Kremer","year":"2023","journal-title":"Clin Cancer Res"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0333539","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T17:21:57Z","timestamp":1760376117000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0333539"}},"subtitle":[],"editor":[{"given":"Mehmet","family":"Demirci","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":23,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0333539","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,13]]}}}