174 Chapter 8 1.45) and specificity (ratio 1.04, 95% CI 0.94-1.12). A recent systematic review and metaanalysis included both cohort and referral population-based studies and evaluated DNA methylation in hrHPV-positive women with histologically confirmed HSIL as endpoint. These studies encompassed a range of methylation markers, i.e., CADM1, MAL, FAM19A4, miR124-2, EPB41L3, HPV16 (L1/L2), HPV18 (L2), HPV31 (L1), HPV33 (L2), C13orf18, JAM3, TERT, ANKRD18CP, SOX1, ZCAN1, SLIT2, DLX1, ITGA4, RXFP3, SOX17, ZNF671, ASTN1, ZNF582 and PAX1 66. The meta-analysis resulted in a pooled sensitivity for HSIL detection of 78% (95% CI 74-82%) and specificity of 74% (95% CI 69-78%). Several studies have shown that self-sampling is a feasible and well-accepted approach to reach women who otherwise would not participate in clinician-based screening, and has potential for use as a primary screening test for all invited women 67-69. In the Dutch cervical screening program, as of the July 2023, the self-sampling kit is offered as an equivalent to clinician-collection 57. The broader use of self-sampling for screening underlines the importance of the search for triage methods which are directly applicable to this sample type. A direct strategy has an advantage over cytology triage as it integrates high adherence to triage given that no recall for a clinician-collected cervical sample is needed. In the Netherlands, about 18% of women with an HPV-positive self-collected sample do not show up for cytology triage 56. In Chapter 4, we assessed the performance of ASCL1/LHX8 methylation markers as a direct triage method using self-collected samples from primary HPV-based screening. This study demonstrated a CIN3+ sensitivity for ASCL1/LHX8 methylation of 73.3% (95% CI 63.9-82.6%) with a specificity of 61.1% (95% CI 56.9-65.4%). The triage performance of ASCL1/LHX8 methylation analysis on self-collected samples was somewhat lower than that on clinician-collected cervical samples (relative sensitivity for CIN3 + detection 0.95, 95% CI 0.82–1.10 and relative specificity 0.82, 95% CI 0.75–0.90). The performance of the bi-marker panel ASCL1/LHX8 on self-samples did not differ from that of HPV16/18 genotyping. HPV16/18 genotyping and ASCL1/LHX8 methylation analysis were however complementary in the sense that HPV16/18 genotyping in combination with the bimarker panel ASCL1/LHX8 reached a higher CIN3+ sensitivity than that reached by each triage test separately. These results are in line with the results in Chapter 3 as well as with previous studies evaluating methylation marker analysis and HPV16/18 genotyping in HPV-positive self-sampled specimens 70. A recent study using hrHPV-positive self-collected samples collected within the Dutch population-based screening program also reported on ASCL1 and LHX8. De Waard et al.,
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