DNA methylation for the triage of HPV-positive clinician-collected cervical samples 69 3 which was performed to evaluate the clinical accuracy of hrHPV testing on self-collected and clinician-collected samples within the setting of the Dutch cervical screening program. The IMPROVE study was approved by the Dutch Ministry of Health Welfare, and Sport (2014/32). A detailed description of the trial has been published before 11. In brief, 16,410 women were enrolled and randomised (1:1) to the intervention group (self-sampling) and the control group (clinician-based sampling). HrHPV-positive women (n = 1,020) were retested using the other collection method. In accordance with the current guidelines of the Dutch primary HPV screening programme, women with a positive hrHPV test were triaged by cytology. Cytology results were classified according to the CISOE-A (reporting on composition, inflammation, squamous, other and endometrium, and endocervical cylindrical epithelium, and adequacy) used in the Netherlands. In the IMPROVE trial, hrHPV-positive women with cytology triage result of borderline or mild dyskaryosis (BMD) or worse (>BMD) at baseline were immediately referred to the gynaecologist for colposcopy. HrHPV-positive women with normal cytology (i.e., negative for intraepithelial lesion of malignancy (NILM)) at baseline were advised to undergo repeat cytological testing after 6 months, and referred to colposcopy when repeat cytology was ≥BMD. For the present study, we included all women who had an hrHPV-positive cliniciancollected cervical sample and provided consent for follow-up research (n = 739; 72.5%). Data on cytology and hrHPV were retrieved from the study database 11. For analysis, the CISOE-A classification was translated into the Bethesda nomenclature 12. HPV genotype was categorised as HPV16, HPV18 or other hrHPV types (i.e., HPV31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, and -68). The current study was approved by the Medical Ethics Committee of Amsterdam UMC, Vrije Universiteit Amsterdam (Amsterdam, The Netherlands; METC 2018/09, TcB 2018.106). HISTOLOGY Original histology. The original histology results as reported during regular care were retrieved from the pathology laboratories through the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA) 13. Histology was categorised as normal (no dysplasia; CIN0), LSIL/CIN1, HSIL/CIN2, HSIL/CIN3 (further referred to as CIN1, CIN2, and CIN3, respectively), or invasive cervical cancer according to the latest WHO classifications 14. Adenocarcinoma in situ (AIS) and carcinoma in situ (CIS) were classified as CIN3. Revised histology. A revision diagnosis based on morphologic features combined with the interpretation of Ki-67 and p16INK4A immunostainings was rendered centrally by an expert
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