Adam R. Brentnall

Indicators to identify cancer screening providers with suboptimal case detection: A scoping review

Abstract Several international guidelines consider sensitivity (of test, episode, or programme) and related measures of the detection of prevalent cases of target disease to be among key performance indicators for quality control of routine cancer screening programmes and use them to identify suboptimal providers. We aimed to describe the variability encountered in real‐world settings around the measurement of these quantities in cervical and colorectal cancer screening, where the target for disease detection includes preinvasive disease. We performed a scoping review of grey literature, including international guidelines, annual statistical reports, and other official documents from European cervical and colorectal screening programmes. From the reviewed material, we extracted information on 20 measures used for this purpose. Some measures have been adopted in several programmes, but none have been used in all, not even within the same cancer type. While many of the methods might appear plausible for the intended use, our analysis showed that when applied to routinely collected data they may provide misleading or uninterpretable estimates of the ability of individual providers and the service as a whole to detect prevalent cases. Screening programmes should be cautious in their choice and interpretation of these measures. Further methodological development is required to better support policymakers and quality control managers in prioritising measures that are fit for purpose in routine cancer screening programmes.

Long‐term prediction by DNA methylation of high‐grade cervical intraepithelial neoplasia: Results of the ARTISTIC cohort

AbstractMethylation markers have shown potential for triaging high‐risk HPV‐positive (hrHPV+) women to identify those at increased risk of invasive cervical cancer (ICC). Our aim was to assess the performance of the S5 DNA methylation classifier for predicting incident high‐grade cervical intraepithelial neoplasia (CIN) and ICC among hrHPV+ women in the ARTISTIC screening trial cohort. The S5 classifier, comprising target regions of tumour suppressor gene EPB41L3 and L1 and L2 regions of HPV16, HPV18, HPV31, and HPV33, was assayed by pyrosequencing in archived hrHPV+ liquid‐based samples from 343 women with high‐grade disease (139 CIN2, 186 CIN3, and 18 ICC) compared to 800 hrHPV+ controls. S5 DNA methylation correlated directly with increasing severity of disease and inversely with lead time to diagnosis. S5 could discriminate between hrHPV+ women who developed CIN3 or ICC and hrHPV+ controls (p <.0001) using samples taken on average 5 years before diagnosis. This relationship was independent of cytology at baseline. The S5 test showed much higher sensitivity than HPV16/18 genotyping for identifying prevalent CIN3 (93% vs. 61%, p = .01) but lower specificity (50% vs. 66%, p <.0001). The S5 classifier identified most women at high risk of developing precancer and missed very few prevalent advanced lesions thus appearing to be an objective test for triage of hrHPV+ women. The combination of methylation of host and HPV genes enables S5 to combine the predictive power of methylation with HPV genotyping to identify hrHPV‐positive women who are at highest risk of developing CIN3 and ICC in the future.

Effective methylation triage of HPV positive women with abnormal cytology in a middle‐income country

AbstractThe S5‐methylation test, an alternative to cytology and HPV16/18 genotyping to triage high‐risk HPV‐positive (hrHPV+) women, has not been widely validated in low‐middle‐income countries (LMICs). We compared S5 to HPV16/18 and cytology to detect cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) and CIN3+ in hrHPV+ women selected from a randomized pragmatic trial of 2661 Colombian women with an earlier‐borderline abnormal cytology. We included all hrHPV+ CIN2 and CIN3+ cases (n = 183) age matched to 183 <CIN2 hrHPV+. Baseline specimens were HPV‐genotyped and tested by S5‐methylation, blinded to cytology, histology and initial HPV results. We evaluated the test performance of predefined S5‐classifier (cut‐point 0.8) and a post hoc classifier at a different cut‐point (3.1). S5 sensitivity for CIN2+ was 82% (95% confidence interval [CI] 76.4‐87.5) and for CIN3+ 77.08% (95% CI 65.19‐88.97). S5 sensitivity was higher than HPV16/18 sensitivity (48.1%, 95% CI 40.85‐55.33) or cytology (31.21%, 95% CI 24.50‐37.93) but with lower specificity (35%, 95% CI 28.1‐42). At cut‐point 3.1, S5 sensitivity for CIN2+ (55.2%, 95% CI 48‐62.4) or CIN3+ (64.6%, 95% CI 51.0‐78.1) was also superior to HPV16/18 (P < .05) or cytology (P < .0001). At this cut‐point S5 specificity (76%, 95% CI 69.8‐82.1 for <CIN2) was higher than HPV16/18 (67.21%, 95% CI 60.41‐74.01, P = .0062) and similar to cytology (75.57%, 95% CI 69.34‐81.79, P = 1). HPV16/18 plus cytology sensitivity was similar to S5 for CIN3+, however, false‐positive rate was higher (50.27% vs. 24.04%). High sensitivity is crucial in LMICs, S5‐methylation exceeded HPV16/18 or cytology sensitivity with comparable specificity for CIN2+ and CIN3+ in hrHPV‐positive Colombian women. Furthermore, S5 triage had comparable sensitivity and significantly fewer false positives than cytology and HPV16/18 combination.

Comments on: “Meta‐analysis of agreement/concordance statistics in studies comparing self‐ vs clinician‐collected samples for HPV testing in cervical cancer screening”

Staged design recommendations for validating relative sensitivity of self-sample human papillomavirus tests for cervical screening

To ensure that the emerging methods for human papillomavirus (HPV) testing on self-collected samples in cervical screening are evaluated robustly. We assess paired study designs for relative sensitivity of self-collected vs. traditional clinician-collected samples in detection of high-grade cervical intraepithelial neoplasia. Designs considered are (D1) both samples at screening, with clinical actions triggered by HPV positivity; (D2) offering a self-sample test to clinician-collected HPV-positive women; (D3) as D2 but using a repeat clinician-sample as comparator; (D4) offering a choice of self- vs. clinician-sampling, and the alternative test in HPV-positive women; (D5) paired samples at referral appointment. D1 is simple to analyze but requires the largest sample size and referral of self-sample positive, clinician-sample negative women. D2 requires a much smaller sample size, and no change to clinical practice, and could be used to rule-in a test because estimates are conservative (against self-sampling). D3 mitigates this bias but requires a second clinician sample. D4 is only manageable where self-sampling already occurs. The liberal D5 might be used to rule-out a self-sampling test. A universal recommendation for an optimal study design is challenging. Staged validation might be useful with D5 as a gatekeeper for D1-D4.