DNA methylation for the triage of HPV-positive clinician-collected cervical samples 73 3 RESULTS STUDY COHORT A total of 739 women who participated in the IMPROVE study had an hrHPV-positive clinician-collected cervical sample available for methylation analysis. Twenty-four samples (24/739; 3.2%) with invalid results based on an ACTB Cq value above 30 were excluded, leaving 715 hrHPV-positive women in the final analysis. Median age was 40.0 years (IQR 34–49; range 29–60). Genotyping results were available for 650/715 (84.9%) women, of whom 183/650 (25.6%) were positive for HPV16 and 62/650 (8.7%) for HPV18. Threehundred sixteen (44.2%) women had abnormal cytology at baseline, of whom 81 (25.6%) women had CIN3+, including 1 adenocarcinoma and 2 squamous cell carcinomas, and ASCL1 LHX8 ST6GALNAC5 GHSR ZIC1 SST 0.884 0.833 0.761 0.756 0.725 0.720 (0.796-0.892) (0.780-0.880) (0.699-0.823) (0.704-0.808) (0.667-0.783) (0.662-0.779) AUC 95% CI Cytology HPV16/18 genotyping ASCL1/LHX8 methylation Trainingset10 AUC = 0.882 (95% CI 0.859-0.920) Validationset (n = 715) AUC = 0.853 (95% CI 0.810-0.897) CIN3+ (A) 0.0 0.0 0.2 0.2 0.4 0.4 0.6 0.6 0.8 0.8 1.0 1.0 1 − Specificity Sensitivity CIN3+ (B) 0.0 0.0 0.2 0.2 0.4 0.4 0.6 0.6 0.8 0.8 1.0 1.0 1 − Specificity Sensitivity Figure 3.3 Diagnostic accuracy. ROC curves and corresponding AUC for CIN3+ detection for (A) single marker classifiers ASCL1, LHX8, ST6GALNAC5, GHSR, ZIC1, SST; and (B) bi-marker panel ASCL1/LHX8 (solid line), including point estimates of cytology (darkest pink circle), HPV16/18 genotyping (middle pink circle) and bi-marker panel ASCL1/LHX8 with the predefined threshold calibrated at 70% clinical specificity (lightest pink circle). For comparison, the cross-validated ROC curve and corresponding AUC, as obtained in the hrHPV-positive training series is projected (dotted line) 10. Abbreviations: AUC, area under the curve; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; ROC, receiver operating characteristic; CI, confidence interval
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