{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:08:29Z","timestamp":1792793309927,"version":"4.5.0"},"reference-count":44,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T00:00:00Z","timestamp":1685923200000},"content-version":"unspecified","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013842","name":"Imperial Health Charity","doi-asserted-by":"publisher","award":["RFPR2223_27"],"award-info":[{"award-number":["RFPR2223_27"]}],"id":[{"id":"10.13039\/100013842","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["P77712"],"award-info":[{"award-number":["P77712"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2023,5,15]]},"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Human papillomavirus (HPV) is necessary but not sufficient for cervical cancer development. During cervical carcinogenesis, methylation levels increase across host and HPV DNA. DNA methylation has been proposed as a test to diagnose cervical intraepithelial neoplasia (CIN); we present a protocol to evaluate the accuracy of methylation markers to detect high-grade CIN and cervical cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>We will search electronic databases (Medline, Embase and Cochrane Library), from inception, to identify studies examining DNA methylation as a diagnostic marker for CIN or cervical cancer, in a cervical screening population. The primary outcome will be to assess the diagnostic test accuracy of host and HPV DNA methylation for high-grade CIN; the secondary outcomes will be to examine the accuracy of different methylation cut-off thresholds, and accuracy in high-risk HPV positive women. Our reference standard will be histology. We will perform meta-analyses using Cochrane guidelines for diagnostic test accuracy. We will use the number of true positives, false negatives, true negatives and false positives from individual studies. We will use the bivariate mixed effect model to estimate sensitivity and specificity with 95% CIs; we will employ different bivariate models to estimate sensitivity and specificity at different thresholds if sufficient data per threshold. For insufficient data, the hierarchical summary receiver operating curve model will be used to calculate a summary curve across thresholds. If there is interstudy and intrastudy variation in thresholds, we will use a linear mixed effects model to calculate the optimum threshold. If few studies are available, we will simplify models by assuming no correlation between sensitivity and specificity and perform univariate, random-effects meta-analysis. We will assess the quality of studies using QUADAS-2 and QUADAS-C.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>Ethical approval is not required. Results will be disseminated to academic beneficiaries, medical practitioners, patients and the public.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PROSPERO registration number<\/jats:title>\n                    <jats:p>CRD42022299760.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2022-071534","type":"journal-article","created":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T14:25:19Z","timestamp":1685975119000},"page":"e071534","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Protocol for a systematic review and meta-analysis of the diagnostic test accuracy of host and HPV DNA methylation in cervical cancer screening and management"],"prefix":"10.1136","volume":"13","author":[{"given":"Sarah J","family":"Bowden","sequence":"first","affiliation":[{"name":"Department of Surgery & Cancer, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"},{"name":"Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0639-785X","authenticated-orcid":false,"given":"Laura Burney","family":"Ellis","sequence":"additional","affiliation":[{"name":"Department of Surgery & Cancer, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"},{"name":"Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilkka","family":"Kalliala","sequence":"additional","affiliation":[{"name":"Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"},{"name":"Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Paraskevaidi","sequence":"additional","affiliation":[{"name":"Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Tighe","sequence":"additional","affiliation":[{"name":"Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos S","family":"Kechagias","sequence":"additional","affiliation":[{"name":"Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Triada","family":"Doulgeraki","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynaecology, Ioannina University Hospital, Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1859-261X","authenticated-orcid":false,"given":"Evangelos","family":"Paraskevaidis","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynaecology, University of Ioannina, Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Arbyn","sequence":"additional","affiliation":[{"name":"Unit of Cancer Epidemiology, Belgian Cancer Centre, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4955-1383","authenticated-orcid":false,"given":"James","family":"Flanagan","sequence":"additional","affiliation":[{"name":"Department of Surgery & Cancer, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Areti","family":"Veroniki","sequence":"additional","affiliation":[{"name":"Institute of Health Policy Management and Evaluation, St Michael's Hospital Toronto, Toronto, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kyrgiou","sequence":"additional","affiliation":[{"name":"Department of Surgery & Cancer, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"},{"name":"Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,6,5]]},"reference":[{"key":"2025121603392583000_13.6.e071534.1","unstructured":"World Health Organization . Cervical cancer. n.d. Available: https:\/\/www.who.int\/health-topics\/cervical-cancer#tab=tab_1"},{"key":"2025121603392583000_13.6.e071534.2","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(19)30482-6"},{"key":"2025121603392583000_13.6.e071534.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(09)70096-8"},{"key":"2025121603392583000_13.6.e071534.4","unstructured":"Institute . HPV and cancer. n.d. Available: https:\/\/www.cancer.gov\/about-cancer\/causes-prevention\/risk\/infectious-agents\/hpv-and-cancer"},{"key":"2025121603392583000_13.6.e071534.5","doi-asserted-by":"publisher","DOI":"10.1097\/OLQ.0000000000000193"},{"key":"2025121603392583000_13.6.e071534.6","doi-asserted-by":"crossref","DOI":"10.3390\/v9080229","article-title":"Targeting persistent human papillomavirus infection","volume":"9","author":"Shanmugasundaram","year":"2017","journal-title":"Viruses"},{"key":"2025121603392583000_13.6.e071534.7","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.ejca.2019.12.013","article-title":"Effect of organised cervical cancer screening on cervical cancer mortality in Europe: a systematic review","volume":"127","author":"Jansen","year":"2020","journal-title":"Eur J Cancer"},{"key":"2025121603392583000_13.6.e071534.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2006.05.113"},{"key":"2025121603392583000_13.6.e071534.9","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1016\/S2468-2667(17)30007-5","article-title":"Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National cervical screening program","volume":"2","author":"Lew","year":"2017","journal-title":"Lancet Public Health"},{"key":"2025121603392583000_13.6.e071534.10","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.28514"},{"key":"2025121603392583000_13.6.e071534.11","article-title":"Cytology versus HPV testing for Cervical cancer screening in the general population","volume":"8","author":"Koliopoulos","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"2025121603392583000_13.6.e071534.12","unstructured":"Public Health England . Cervical screening: programme overview, 2021."},{"key":"2025121603392583000_13.6.e071534.13","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62218-7"},{"key":"2025121603392583000_13.6.e071534.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2012.06.095"},{"key":"2025121603392583000_13.6.e071534.15","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.l240","article-title":"Primary Cervical screening with high risk human Papillomavirus testing: observational study","volume":"364","author":"Rebolj","year":"2019","journal-title":"BMJ"},{"key":"2025121603392583000_13.6.e071534.16","unstructured":"Public Health England . Cervical screening: programme and Colposcopy management. n.d. Available: https:\/\/www.gov.uk\/government\/publications\/cervical-screening-programme-and-colposcopy-management"},{"key":"2025121603392583000_13.6.e071534.17","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1097\/PPO.0000000000000279","article-title":"The roles of DNA methylation in the stages of cancer","volume":"23","author":"McMahon","year":"2017","journal-title":"Cancer J"},{"key":"2025121603392583000_13.6.e071534.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.09.082"},{"key":"2025121603392583000_13.6.e071534.19","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiw645"},{"key":"2025121603392583000_13.6.e071534.20","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ebiom.2019.10.053","article-title":"The use of human papillomavirus DNA methylation in cervical intraepithelial neoplasia: a systematic review and meta-analysis","volume":"50","author":"Bowden","year":"2019","journal-title":"EBioMedicine"},{"key":"2025121603392583000_13.6.e071534.21","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1111\/1471-0528.16395","article-title":"The use of host cell DNA methylation analysis in the detection and management of women with advanced Cervical intraepithelial Neoplasia: a review","volume":"128","author":"Kremer","year":"2021","journal-title":"BJOG"},{"key":"2025121603392583000_13.6.e071534.22","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31261"},{"key":"2025121603392583000_13.6.e071534.23","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1159\/000450595","article-title":"Virtues and weaknesses of DNA methylation as a test for cervical cancer prevention","volume":"60","author":"Lorincz","year":"2016","journal-title":"Acta Cytol"},{"key":"2025121603392583000_13.6.e071534.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-019-0593-4"},{"key":"2025121603392583000_13.6.e071534.25","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.g7647","article-title":"Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation","volume":"350","author":"Shamseer","year":"2015","journal-title":"BMJ"},{"key":"2025121603392583000_13.6.e071534.26","unstructured":"Bock C , Halbritter F , Carmona FJ , et al . Quantitative comparison of DNA methylation assays for biomarker development and clinical applications. 2016."},{"key":"2025121603392583000_13.6.e071534.27","unstructured":"Public Health England . Cervical screening: Laboratories providing HPV testing and Cytology services in the NHS Cervical screening programme. n.d. Available: https:\/\/www.gov.uk\/government\/publications\/cervical-screening-laboratory-hpv-testing-and-cytology-services\/cervical-screening-guidance-for-laboratories-providing-hpv-testing-and-cytology-services-in-the-nhs-cervical-screening-programme#reporting-and-classification-of-cervical-cytology"},{"key":"2025121603392583000_13.6.e071534.28","unstructured":"de H , Eisinga A , Riphagen I . Chapter 7: searching for studies. In: Cochrane handbook for systematic reviews of diagnostic test accuracy."},{"key":"2025121603392583000_13.6.e071534.29","unstructured":"Team TE . EndNote 20. Philadelphia, PA: Clarivate, 2013."},{"key":"2025121603392583000_13.6.e071534.30","unstructured":"Maintainer BP . liftOver: changing genomic coordinate systems with Rtracklayer: liftOver 2023."},{"key":"2025121603392583000_13.6.e071534.31","unstructured":"Public Health England . Colposcopic diagnosis, treatment and follow up. n.d. Available: https:\/\/www.gov.uk\/government\/publications\/cervical-screening-programme-and-colposcopy-management\/3-colposcopic-diagnosis-treatment-and-follow-up#CIN"},{"key":"2025121603392583000_13.6.e071534.32","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(13)70570-9"},{"key":"2025121603392583000_13.6.e071534.33","doi-asserted-by":"publisher","DOI":"10.1059\/0003-4819-155-8-201110180-00009"},{"key":"2025121603392583000_13.6.e071534.34","unstructured":"Deeks J , Wisniewski S , Davenport C . Chapter 4: guide to the contents of a Cochrane diagnostic test accuracy protocol. In: Deeks JJ , Bossuyt PM , Gatsonis C , eds. Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy Version 1.0.0, 2013."},{"key":"2025121603392583000_13.6.e071534.35","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.7326\/M21-2234","article-title":"QUADAS-C: a tool for assessing risk of bias in comparative diagnostic accuracy studies","volume":"174","author":"Yang","year":"2021","journal-title":"Ann Intern Med"},{"key":"2025121603392583000_13.6.e071534.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2005.02.022"},{"key":"2025121603392583000_13.6.e071534.37","doi-asserted-by":"publisher","DOI":"10.1002\/sim.942"},{"key":"2025121603392583000_13.6.e071534.38","doi-asserted-by":"crossref","DOI":"10.1186\/s12874-016-0196-1","article-title":"Modelling multiple thresholds in meta-analysis of diagnostic test accuracy studies","volume":"16","author":"Steinhauser","year":"2016","journal-title":"BMC Med Res Methodol"},{"key":"2025121603392583000_13.6.e071534.39","doi-asserted-by":"crossref","unstructured":"Bates D , Maechler M , Bolker B , et al . Fitting linear mixed-effects models using Lme4. 2015;67:1\u201348. doi:10.18637\/jss.v067.i01","DOI":"10.18637\/jss.v067.i01"},{"key":"2025121603392583000_13.6.e071534.40","doi-asserted-by":"crossref","DOI":"10.1186\/s13690-022-00953-9","article-title":"Metadta: a STATA command for meta-analysis and meta-regression of diagnostic test accuracy data \u2013 a Tutorial","volume":"80","author":"Nyaga","year":"2022","journal-title":"Arch Public Health"},{"key":"2025121603392583000_13.6.e071534.41","doi-asserted-by":"publisher","DOI":"10.1136\/ebmental-2019-300117"},{"key":"2025121603392583000_13.6.e071534.42","doi-asserted-by":"publisher","DOI":"10.1177\/0962280215592269"},{"key":"2025121603392583000_13.6.e071534.43","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-158-7-201304020-00006"},{"key":"2025121603392583000_13.6.e071534.44","unstructured":"What is GRADE? n.d. Available: https:\/\/bestpractice.bmj.com\/info\/toolkit\/learn-ebm\/what-is-grade\/"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2022-071534","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T11:39:37Z","timestamp":1765885177000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2022-071534"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6,5]]},"published-print":{"date-parts":[[2023,6]]}},"alternative-id":["10.1136\/bmjopen-2022-071534"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2022-071534","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6]]}}}