130 Chapter 6 LSIL 13, 15, 19. These studies, which included participants from the POBASCAM trial and the VUSA-screen trial, indicated that by incorporating FAM19A4/miR124-2 methylation testing, a substantial 58.8% reduction in direct colposcopy referrals can be achieved, while maintaining a high sensitivity of 70.2% for detecting CIN3+ 19. Similar results were reported by Bonde et al. 15, showing a 66% reduction in colposcopy referrals for hrHPVpositive women with ASC-US/LSIL cytology using FAM19A4/miR124-2 methylation testing. These findings underscore the potential of DNA methylation biomarkers in cervical cancer screening programs to improve the efficiency of screening by reducing colposcopy referral, while retaining high sensitivity. While reducing colposcopy referrals is valuable, it is crucial to remember that high-grade CIN is heterogeneous. Nonetheless, a negative methylation test indicates a low cancer risk. In light of these developments, our study aims to assess the effectiveness, particularly in terms of positive predictive value (PPV), negative predictive value (NPV) and marginal PPV (mPPV), of various molecular triage methods, including FAM19A4/miR124-2 methylation, ASCL1/LHX8 methylation, HPV16/18 genotyping, extended genotyping with HPV16/18/31/33/45, and combinations thereof, in hrHPV-positive women with ASC-US/ LSIL cytology within a population-based Dutch primary HPV screening trial (IMPROVE study 21). METHODS CLINICAL SPECIMENS This study involved a post hoc analysis of the IMPROVE trial (the Netherlands Trial Register NTR5078). The IMPROVE study was designed as a randomised non-inferiority trial to assess the clinical accuracy of HPV testing on self-collected samples compared to cliniciancollected cervical samples within the Dutch cervical cancer screening program. Approval for the IMPROVE study was obtained from the Ministry of Public Health (The Hague, The Netherlands; IMPROVE VWS no. 2014/32). A total of 16,410 women participated in the trial and were randomly assigned in a 1:1 ratio to either the intervention group (self-sampling) or the control group (clinician-based sampling). All 1,020 hrHPV-positive women underwent re-testing using the other collection method. Detailed information about the IMPROVE study can be found in a previous publication by Polman et al. 21. For the purpose of this study, we included all 215 women with an hrHPV-positive cliniciancollected cervical sample with an ASC-US/LSIL cytology result. According to the latest classifications of the World Health Organisation (WHO), histology was categorised into
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