Figure Legends:
Figure 1. Flowchart of the study showing the numbers of women in each step. All the included participants with abnormal results between HPV and cytology were divided into two groups, women with HPV16/18+ and/or ≥(TCT)HSIL result of cytology at first visiting time were divided into receive immediate colposcopy group (IC group; n=602), women with (“abnormal results between HPV positive except and cytology; meanwhile HPV16/18-” and “abnormal cytology results except ≥(TCT)HSIL” result of cytology) were divided into repeat follow-up group (RF group; n=1644).
Figure 2. Boxplot distribution of S5 score according to the histological diagnosis: NEG, LSIL, HSIL, and cervical cancer (CC). The median and interquartile ranges are depicted by boxes. Cuzick test for trend was significant (P < 0.001). The upper whisker extends to the largest point of the inter-quartile range from the upper quartile. The lower whisker extends to the smallest point of the inter-quartile range from the lower quartile.
Abbreviation: NEG, histologically negative without squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion; CC, cervical cancer.
Figure 3. Boxplot distribution of EPB41L3 score according to the histological diagnosis: NEG, LSIL, HSIL, and cervical cancer (CC). The median and interquartile ranges are depicted by boxes. Cuzick test for trend was significant (P < 0.001). In the box plot, it contains six data expressions. Arrange a set of data from the maximum (upper edge), upper quartile Q3, median (darkest black line), lower quartile Q1, minimum (lower edge), and outlier. The upper whisker extends to the largest point of the inter-quartile range from the upper quartile. The lower whisker extends to the smallest point of the inter-quartile range from the lower quartile. Abbreviation: NEG, histologically negative without squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion; CC, cervical cancer.
Figure 4. Percentage distribution of EPB41L3 methylation by hrHPV positive and SIL status in patients with abnormal results between HPV and cytology. Of particular interest was a methylation cut-off point for EPB41L3 when a sample was not positive for HPV 16, 18, 31 or 33; or unmethylated if positive, which was simple calculated at the predefined cutoff for S5 classifier as S5 = 2.85/30.9 ≈ 9.2%.
Figure 5. Receiver operating characteristic (ROC) of S5 classifier for detecting HSIL+. The red circle denotes the sensitivity and specificity of S5 at cutoff of 0.8 for HSIL+. The yellow triangle denotes the sensitivity and specificity of S5 at cutoff of 3.7 for HSIL+. Cytology (first ≥ HSIL result of cytology, or ≥ HSIL result of cytology at 6 or 12 months after first time), HPV16/18 and cytology plus HPV16/18 are depicted. In the ROC (receiver operator characteristic curve), AUC (Area Under Curve) is defined as the area under the ROC curve enclosed by the coordinate axis, the larger the AUC, the better the credibility. The y-coordinate value of yellow triangle indicates the sensitivity of S5 at 2.85 cutoff, is 0.761. The x-coordinate value of the yellow triangle indicates the (1-specificity) of S5 at 2.85 cutoff, is 0.201, which means the specificity of S5 at 2.85 cutoff is 0.799. HSIL+, high-grade squamous intraepithelial lesion or worse; (TCT)HSIL+, cytological high-grade squamous intraepithelial lesion or worse for TCT result.
Figure 6. Receiver operating characteristic (ROC) curves of S5 and EPB41L3 methylation site for detecting HSIL+. The blue curve denotes the S5 for detecting HSIL+. The red curve denotes the EPB41L3 for HSIL+. HSIL+, (histological) high-grade squamous intraepithelial lesion or worse.
Figure 7. Cumulative proportions of women who progressed to ≥(his)HSIL+ by time since the first visiting with “HPV positive except HPV16/18” and “abnormal cytology results except ≥(TCT)HSIL”. In this analysis, <(his)HSIL although following-up repeated (“HPV positive except HPV16/18” and “abnormal cytology results except ≥(TCT)HSIL”) were regarded as non-progressions. Among this population, the graph shows the distribution by time (in months) of women S5≥2.85 (solid line) vs S5 classifier <2.85 (dashed line). There was a significant difference between these predictors (Likehood-ratio [LR] test P = 0.02).
Figure 8. Potential modified screening strategy for triaging women with abnormal screening results. Firstly, for negative for HPV and/or cytology population, giving priority to routine screening for S5 positive women. Secondly, for women with HPV16/18 positive or cytology ≥ (TCT)HSIL+ or repeated abnormal result among HPV and cytology, giving priority to colposcopy inspection for S5 positive women. In addition, for women with “HPV positive except HPV16/18” and/or “abnormal cytology results except ≥(TCT)HSIL”, giving priority to repeated following-up in more strict internals for S5 positive women.