132 Chapter 6 Direct colposcopy referral rate, PPV and NPV were estimated together with Wald 95% confidence intervals (95% CI). The direct referral percentage was calculated as the percentage of triage positives from each screening strategy. To compare the efficiency of the different strategies, we utilised the incremental cost-effectiveness framework originally developed for health technology assessments 24. In our situation, cost is set equal to the number of direct colposcopy referrals and effect is set equal to the number of detected CIN3+. To identify strategies that strike an optimal balance between cost and effects in a cost-effectiveness study, strategies are compared by means of the incremental cost-effectiveness ratio (ICER). In our setting, the inverse of the ICER is the marginal PPV (mPPV), that quantifies the relationship between the additional number of CIN3+ cases and additional colposcopy referrals. The mPPV of a strategy is the PPV for end-point CIN3+ of the extra colposcopy referrals compared to the adjacent less aggressive, non-dominated strategy (i.e., with a lower number of colposcopy referrals). In the incremental cost-effectiveness framework, a strategy is called non-dominated when there does not exist another strategy that yields a higher number of CIN3+ against the same number of referrals. The curve connecting adjacent non-dominated strategies is the efficient frontier. To select strategies from the efficient frontier, we used a Dutch mPPV threshold of 20% 25, which is based on the PPV of abnormal cytology for CIN3+ in the previous cytology-based program which was 20-30% 26. This threshold equates to a one-in-five chance of identifying high-grade CIN among women referred for further evaluation. All statistical analysis were performed with SPSS Statistics (version 28, IBM Corp, Armonk, NY, USA). RESULTS A total of 215 hrHPV-positive women with ASC-US/LSIL cytology were identified in the IMPROVE study and were available for HPV genotyping and methylation analysis. Six samples (6/215; 2.3%) with invalid methylation results were excluded from further analysis. Additionally, fifteen samples (15/215; 7.0%) lacked genotyping results and were also excluded from further analysis, resulting in a total of 194 hrHPV-positive women for the final analysis. Among these, 22 (11.3%) were diagnosed with CIN3, 30 (15.5%) with CIN2 and 142 (73.2%) had no evidence of CIN2+, including 67 with CIN1 and 52 CIN0 and 23 women with two consecutive normal cytology results. The median age of the women included in the study was 39 years (range: 29-60 years). Out of the 194 women, 28 (14.4%) women tested positive for FAM19A4/miR124-2 methylation, 57 (29.4%) women tested positive for ASCL1/LHX8 methylation, 71 (36.6%) women tested positive for HPV16/18 and
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