Title: Predicting the Risk of High-grade Precancerous Cervical Lesions Based on High-risk
HPV Typing in Changsha China
Version: 1 Date: 19 Dec 2024
Reviewer:  Sveinung Wergeland Sørbye
Reviewer's report:
The authors have addressed the reviewers' comments effectively in their revised manuscript. I
have no additional substantive comments as the revisions are satisfactory. However, there are
still some spelling errors that need correction.
Abstract:
"Background: Persistent infection with high-risk human papillomavirus (HPV) is a significant
risk factor for cervical cancer. HPV typing and cytology are conducted in women of appropriate
age to assess the risk of cervical lesions and to guide the need for further diagnostic procedures
such as colposcopy, cervical biopsy, or treatment. This article explores methods to predict the
risks of high-grade precancerous cervical lesions based on high-risk HPV typing.
Methods: We conducted a retrospective analysis of HPV typing data from 158,565 women,
including 19,707 who underwent ThinPrep cytologic testing (TCT), 7,539 who had colposcopy
examinations, and 4,762 who had biopsies. We evaluated the sensitivity, specificity, and risk
parameters of high-grade lesions associated with high-risk HPV types.
Results: (1) The overall prevalence of HPV infection was 17.89%, with the most prevalent types
being HPV52 (4.44%), HPV58 (2.10%), HPV53 (1.96%), HPV81 (1.85%), HPV42 (1.75%),
and HPV16 (1.44%). (2) The sensitivity and specificity of detecting high-grade lesions in TCT,
colposcopy, and biopsy, based on high-risk HPV typing, demonstrated a strong linear correlation
with the infection rate of each type. (3) HPV16 was confirmed to have a higher risk of CIN2+ in
biopsies using a self-defined risk parameter. (4) The top five HPV types with the highest PPVs
and pathogenicity risks in biopsies were HPV45, HPV16, HPV58, HPV33, and HPV18.
Conclusion: In Changsha, China, HPV52, HPV58, and HPV53 were the most prevalent and
contributed significantly to high-grade lesions. After adjusting for infection rates, a self-defined
risk parameter was proposed as a measure of the intrinsic risks of high-grade lesions associated
with high-risk HPV types. Focused monitoring of prevalent high-risk HPV types such as
HPV45, HPV16, HPV58, HPV33, and HPV18, which show the highest pathogenicity risks, is
recommended in our region."
Lines 187-193, "The self-defined pathogenicity risk demonstrated perfect correlation with PPV
for HSIL+ in TCT, high-grade lesions in colposcopy, and CIN2+ in biopsy, featuring a Pearson
correlation coefficient (r) greater than 0.999998 and a p-value less than 2.65E-40. However, the
pathogenicity risk for high-grade lesions observed in colposcopy correlated poorly with HSIL
+ in TCT and CIN2+ in biopsy, with Pearson correlation coefficients of -0.2303 and -0.2112,
respectively. In contrast, the pathogenicity risk for HSIL+ in TCT showed a good correlation
with CIN2+ in biopsy, with a Pearson correlation coefficient of 0.7545 and a p-value below
0.05."
Lines 194-204, "Figure 6 depicts the pathogenicity risks of high-grade lesions for high-risk
HPV types detected through TCT, colposcopy, and biopsy. The average risk of HSIL+ for the
16 non-16/18 HPV types identified by TCT was 1.12, with a 95% confidence interval (CI) of
0.81-1.44. For high-grade lesions identified by colposcopy, the average risk was 1.02, with a
95% CI of 0.96-1.07. The average risk of CIN2+ for the 18 high-risk HPV types was 0.91, with
a 95% CI of 0.70-1.12. For HPV types 16/18 detecting high-grade lesions in colposcopy, the
risk levels were 0.86 and 0.78, respectively, both falling below the 95% CI. In biopsies, the
risk levels for CIN2+ associated with HPV16/18 were 1.51 and 0.60, respectively, with HPV16
exceeding and HPV18 falling below the 95% CI.
Among the HPV types from biopsy results in Table 3 showing statistically significant results
(p-value < 0.05), the top five HPV types with the highest PPV and pathogenicity risks were
HPV45, HPV16, HPV58, HPV33, and HPV18."
Lines 228-242, "To mitigate the effect of infection rates, we assessed several parameters
including odds ratio (OR), positive predictive value (PPV), and self-defined pathogenicity risk.
A strong correlation was observed between OR and PPV in TCT and biopsy, with a Pearson
correlation coefficient (r) greater than 0.98. However, this correlation was weaker in colposcopy,
with a Pearson correlation of 0.67. The self-defined pathogenicity risk displayed perfect
correlation with PPV, achieving a Pearson correlation of 1.0 across all cases. Pathogenicity risk
provides a more effective scale for comparison than PPV across TCT, colposcopy, and biopsy.
Nonetheless, the pathogenicity risk in colposcopy did not align well with that in TCT or biopsy,
showing a Pearson correlation |r| of less than 0.23. In contrast, the pathogenicity risk in TCT
demonstrated a good correlation with that in biopsy, with a Pearson correlation greater than 0.75.
Variability was noted in the risk of high-grade lesions using different parameters across TCT,
colposcopy, and biopsy. Our study confirmed that HPV16 presents a higher risk of CIN2+ in
biopsy, exceeding the 95% confidence interval of the 18 high-risk HPV types. The top five
HPV types with the highest and statistically significant PPV and pathogenicity risks of CIN2+
in biopsy were HPV45, HPV16, HPV58, HPV33, and HPV18."
Lines 250-260, "The early detection of high-grade cervical lesions provides several preventative
options, including vaccination, surgery, and other therapeutic strategies. Numerous studies have
been conducted to identify the primary determinants of recurrence risk. The persistence of HPV
is strongly associated with a significantly increased risk of disease recurrence [23]. A multi-
center retrospective study supports the adoption of HPV vaccination in patients treated for HPV-
related diseases. Even in the absence of the uterine cervix, HPV vaccination could protect against
the development of lower genital tract dysplasia [24]. In our retrospective study, individuals
with a history of cervical cancer and other genital malignancies were excluded. It would be
valuable to conduct prospective studies on the recurrence of cervical malignancies to explore
any associations with specific high-risk HPV types and HPV vaccination."
Lines 263-268, "Our study demonstrates diverse risks of high-grade cervical lesions associated
with different HPV types, revealing a strong linear correlation between the sensitivity and
specificity of detection methods and the infection rates. Specifically, the most prevalent types,
HPV52, HPV58, and HPV53, accounted for a significant proportion of high-grade lesions in
Changsha. After adjusting for infection rates, HPV58, HPV45, HPV33, HPV18, and HPV16
emerged as having the highest risks. Therefore, we recommend focused monitoring of these
prevalent high-risk HPV types, which display the greatest pathogenicity risks in our region."