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.