Thesis

Triage strategies and colposcopy referrals in HPV-positive women with low-grade cytology 135 6 referral rate of 29.4% (95% CI 23.0-35.8%). A particularly conservative strategy, with HPV16/18 genotyping OR ASCL1/LHX8 methylation (strategy VIII) yields an PPV for CIN3+ of 18.3% (95% CI 10.8-25.7%), a high NPV of 96.7% (95% CI 93.0-100.4%) together with a colposcopy referral rate of 53.6% (95% CI 46.6-60.6%). Collectively, these strategies underscore the heterogeneous approaches employed in triaging women for further evaluation. The incremental analysis is displayed in Figure 6.1. HPV16/18 genotyping (strategy III), HPV16/18/31/33/45 genotyping (strategy IV), HPV16/18/31/33/45 genotyping OR FAM19A4/miR124-2 methylation (strategy X), and HPV16/18/31/33/45 genotyping OR ASCL1/LHX8 methylation (strategy XII) are clearly dominated because they lie below the efficient frontier. HPV16/18 genotyping OR FAM19A4/miR124-2 methylation (strategy VI) and HPV16/18 genotyping OR ASCL1/LHX8 methylation (strategy VIII) are not dominated, but their mPPV values are substantially lower than the Dutch threshold of 20% 25. Number of CIN3+ detected 0 25 50 75 100 125 5 0 10 15 20 Number of colposcopy referrals Dominated Extended Dominated Efficient Frontier V mPPV: 50% VII XI III VI IV X XII IX mPPV: 33.3% I mPPV: 20% II mPPV: 17.2% VIII mPPV: 10.6% Figure 6.1 Number of CIN3+ cases and number of direct colposcopy referrals of strategies I-XII. The pink line is the efficient frontier. Strategies from low to high mPPV: (VIII) HPV16/18 genotyping OR ASCL1/LHX8 methylation; (II) ASCL1/LHX8 methylation; (I) FAM19A4/miR124-2 methylation; (IX) HPV16/18/31/33/45 genotyping AND FAM19A4/miR124-2 methylation; and (V) HPV16/18 genotyping AND FAM19A4/miR124-2 methylation. Abbreviations: CIN3+, cervical intraepithelial neoplasia grade 3 or worse; mPPV, marginal positive predictive value

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