136 Chapter 6 Strategies with an mPPV close to 20% are FAM19A4/miR124-2 methylation (strategy I), ASCL1/LHX8 methylation (strategy II), HPV16/18 genotyping AND ASCL1/LHX8 methylation (strategy VII) AND HPV16/18/31/33/45 genotyping AND ASCL1/LHX8 methylation (strategy XI). The two strategies with the highest mPPV are HPV16/18/31/33/45 AND FAM19A4/ miR124-2 methylation (strategy IX) and HPV16/18 AND FAM19A4/miR124-2 methylation (strategy V). DISCUSSION In this study, we evaluated different molecular triage methods for the detection of CIN3+ in hrHPV-positive women with ASC-US/LSIL cytology in cervical cancer screening. The primary objective of this study was to address the challenge of the relatively low rate of CIN3+ lesions in hrHPV-positive women with ASC-US/LSIL cytology. In the context of cervical cancer screening, where the goal is to accurately identify women at a higher risk of CIN3+ lesions, optimising PPV becomes crucial. By prioritising mPPV, we aim to enhance the accuracy of identifying cases that truly warrant further investigation and intervention, thereby minimising unnecessary colposcopy referrals. Among the single triage strategies, FAM19A4/miR124-2 methylation (strategy I) and ASCL1/ LHX8 methylation (strategy II) demonstrated superior performance in terms of colposcopy referral rate compared to HPV16/18 genotyping (strategy III). FAM19A4/miR124-2 exhibited excellent PPV (32.1%) and NPV (92.2%), with the lowest colposcopy referral rate (14.4%). This highlights its efficacy in reducing unnecessary colposcopy in primary HPV screening. Notably, HPV16/18 genotyping AND FAM19A4/miR124-2 methylation (strategy V) emerges as a strong contender with a PPV of 50.0%, NPV of 90.8% and a low referral rate of 5.2%. This strategy shows promise in detecting CIN3+ lesions while minimising unwarranted referrals. While striving for efficiency, these strategies underscore the challenge of balancing efficiency and the potential risk of missing a significant percentage of CIN3+. In comparison, genotyping and abnormal cytology have shown higher NPVs, often exceeding 90% 27. Transitioning from cytology to molecular triage is a logical step forward, but the potential trade-off of missing high-grade cervical abnormalities must be considered. Achieving the right balance between efficiency and effectiveness remains a challenge in cervical cancer screening. As previously published, FAM19A4/miR124-2 and ASCL1/LHX8 methylation have demonstrated remarkable sensitivity for cervical cancer and advanced CIN2/3 lesions,
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