Thesis

DNA methylation for the triage of HPV-positive clinician-collected cervical samples 71 3 these classifiers and corresponding thresholds are applied. The diagnostic accuracy was evaluated and visualised by receiver operating characteristic (ROC) curves and evaluated by area under the curve (AUC). Estimates of cytology with threshold atypical squamous cells of undetermined significance (ASC-US, i.e., threshold BMD) and HPV16/18 genotyping were included in the ROC curve. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and relative risk (RR) were determined with Wald 95% CI for the following triage strategies: (I) cytology, (II) HPV16/18 genotyping, (III) methylation analysis, (IV) HPV16/18 genotyping combined with cytology, and (V) HPV16/18 genotyping combined with methylation Figure 3.1 Flowchart of the study cohort. Low-grade cytology: BMD equalling ASC-US/ASC-H/LSIL. High-grade cytology: >BMD equalling HSIL. Abbreviations: ASC-US, atypical squamous cells of undetermined significance; ASC-H: atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion; BMD, borderline or mild dyskaryosis; CIN, cervical intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial lesions; LSIL, low-grade squamous intraepithelial lesions; n, number of; NILM, negative for intraepithelial lesion or malignancy; CxCa, cancer Study population n = 715 Normal cytology (NILM) baseline n = 339 Abnormal cytology baseline n = 316 ASC-US/ASC-H/LSIL HSIL Repeat cytology n = 339 NILM ASC-US/ASC-H/LSIL HSIL No repeat cytology n = 40 Histology n = 339 No histology No dysplasia LSIL/CIN1 HSIL/CIN2 HSIL/CIN3 CxCa n = 215 n = 101 n = 281 n = 68 n = 10 n = 322 n = 25 n = 7 n = 15 n = 10 n = 339 Histology n = 316 No histology No dysplasia LSIL/CIN1 HSIL/CIN2 HSIL/CIN3 CxCa n = 25 n = 61 n = 92 n = 57 n = 78 n = 3

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