Matejka Rebolj

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.

HPValidate—human papillomavirus testing with DNA and mRNA assays on self-collected samples in cervical screening: comparison of test characteristics on three self-sampling devices

Abstract Background Relative test accuracy of human papillomavirus (HPV) testing on self vs. clinician-collected samples may depend on the specific combination of a self-sampling device and HPV assay. Methods Five self-sampling workflows were studied within the routine English cervical screening programme; the cobas HPV DNA and APTIMA HPV mRNA assays with the Evalyn brush, Self Vaginal FLOQSwabs (FLOQSwabs) and the Multitest kit. To study test sensitivity, women were recruited at routine colposcopy appointments; to study test specificity, women were recruited at routine screening appointments. Results The estimated conditional relative sensitivity for high-grade cervical intraepithelial neoplasia (CIN2+) was 0.90 (90% CI: 0.84–0.94) for the Evalyn + cobas workflow, 0.94 (0.90–0.97) for FLOQSwabs + cobas, 0.77 (0.69–0.83) for Evalyn + APTIMA, 0.92 (0.85–0.96) for FLOQSwabs+APTIMA and 0.92 (0.86–0.96) for Multitest+APTIMA. The estimates of the relative specificity were 0.96 (0.95-0.98), 0.91 (0.90-0.93), 0.99 (0.97–1.01), 0.89 (0.87–0.92) and 0.87 (0.85–0.89), respectively. The specificity estimates were sensitive to the inclusion of certain subgroups of women. HPV detection rates were higher for all self-sample than clinician-sample workflows. Conclusions The relative test sensitivity of four self-sampling workflows including both DNA and mRNA HPV assays was relatively close to that associated with clinician-collected samples.

Outcomes associated with large loop excision of the cervical transformation zone in women 60–64 years of age: A population‐based register study from Denmark

AbstractIntroductionFor women treated for cervical dysplasia at 60–64 years in Denmark, we reported the frequency of abnormalities before and after treatment of cervix uteri (most frequently performed as large loop excision of the cervical transformation zone, LLETZ) using population‐based real‐world data.Material and MethodsWe conducted a retrospective cohort study based on national data from the Danish Pathology Data Bank and identified women who underwent a LLETZ in 2010–2016 at the age of 60–64. Women were managed according to nationwide evidence‐based recommendations proposed by the Danish professional organizations. We retrieved information on all LLETZ specimens, cervical histology, cytology, and human papillomavirus (HPV) tests in the period of 2 years prior to the procedure to 2 years thereafter. We reported the frequencies of abnormalities before, at, or after the procedure.ResultsOf the 1014 women who had a LLETZ during the study period, 660 (65%) showed cervical intraepithelial neoplasia grade 1 or worse (CIN1+, including CIN1, CIN2, CIN3, cervical cancer, and CIN not otherwise specified) in their LLETZ specimen, with free resection margins in 255 (39%). Of the 1014 women, 551 (54%) had CIN2+ in a biopsy preceding the LLETZ and in 567 (56%) CIN2+ was found in their LLETZ specimen. In 37 (4%) women, the specimen showed cervical cancer; whereas in the pre‐LLETZ biopsies of these 37 women, cancer was detected in only 7 (1%). After LLETZ, 818 (81%) women underwent test‐of‐cure follow‐up which was positive in 406 women (40%). Furthermore, 408 (40%) women had new histological samples registered after LLETZ. These showed CIN2+ in 134 (13%) women, whereas a new cancer was diagnosed in 11 (1%) women.ConclusionsDue to persistent abnormal tests after LLETZ, an extended follow‐up is still required for a large proportion of the women in this age group.

Predictable changes in the accuracy of human papillomavirus tests after vaccination: review with implications for performance monitoring in cervical screening

AbstractVaccination against human papillomavirus (HPV) is changing the performance of cytology as a cervical screening test, but its effect on HPV testing is unclear. We review the effect of HPV16/18 vaccination on the epidemiology and the detection of HPV infections and high-grade cervical lesions (CIN2+) to evaluate the likely direction of changes in HPV test accuracy. The reduction in HPV16/18 infections and cross-protection against certain non-16/18 high-risk genotypes, most notably 31, 33, and/or 45, will likely increase the test’s specificity but decrease its positive predictive value (PPV) for CIN2+. Post-vaccination viral unmasking of non-16/18 genotypes due to fewer HPV16 co-infections might reduce the specificity and the PPV for CIN2+. Post-vaccination clinical unmasking exposing a higher frequency of CIN2+ related to non-16/18 high-risk genotypes is likely to increase the specificity and the PPV of HPV tests. The effect of HPV16/18 vaccination on HPV test sensitivity is difficult to predict based on these changes alone. Programmes relying on HPV detection for primary screening should monitor the frequency of false-positive and false-negative tests in vaccinated (younger) vs. unvaccinated (older) cohorts, to assess the outcomes and performance of their service.

Introducing human papillomavirus (HPV) primary testing in the age of HPV vaccination: projected impact on colposcopy services in Wales

ObjectiveTo determine the demand for colposcopy in the Cervical Screening Wales programme after the introduction of human papillomavirus (HPV) cervical screening, which coincided with the start of screening of women vaccinated against HPV types 16/18.DesignThe study used a computational model that assigns screening and screening‐related colposcopy events to birth cohorts in individual calendar years.SettingCervical Screening Wales.PopulationWomen aged 25–64 years from birth cohorts 1953–2007.Methods and main outcome measuresWe estimated the numbers of colposcopies and high‐grade cervical intraepithelial lesions (CIN2+) within Cervical Screening Wales in 2018–32, using official population projections for Wales and published estimates of the effects of HPV screening and vaccination.ResultsVaccination will reduce the number of colposcopies by 10% within the first 3–4 years after the national roll‐out of HPV screening, and by about 20% thereafter. The number of screening colposcopies is estimated to increase from 6100 in 2018 and peak at 8000 (+31%) in 2021, assuming current screening intervals are maintained. The numbers of CIN2+ lesions follow similar patterns, stabilising at around 1000 diagnoses per year by 2026, approximately 60% lower than at present. Extending the screening intervals to 5 years for all women shows similar trends but introduces peaks and troughs over the years.ConclusionsVaccination will not fully prevent an increase in colposcopies and detected CIN2+ lesions during the first 2–3 years of HPV‐based screening but the numbers are expected to decrease substantially after 5–6 years.Tweetable abstractHPV‐based cervical screening will initially increase colposcopy referral. In 6 years, this increase will be reversed, partly by HPV vaccination.

Attendance at early recall and colposcopy in routine cervical screening with human papillomavirus testing

AbstractAttendance at early recall and colposcopy is crucial to attaining the benefits of primary high‐risk human papillomavirus (HR‐HPV)‐based screening. Within the English HPV pilot, we analysed deprivation‐ and age‐related patterns of attendance at colposcopy and 12‐ and 24‐month early recall of HR‐HPV positive women screened in 2013 to 2015 (N = 36 466). We fitted logistic regression models for adjusted odds ratios (OR). Despite high overall attendance, area deprivation had a small but significant impact at both early recalls, for example, attendance at 24 months was 86.3% and 83.0% in less vs more deprived areas, respectively (ORadj: 0.76; 95% CI: 0.67‐0.87). Older women (≥30 years) were more likely to attend early recall than younger women (<30 years), for example, attendance at 24 months was 86.1% vs 82.3%, respectively (ORadj: 1.32, 95% CI: 1.16‐1.51). Most women attended colposcopy following a baseline referral, with 96.9% attendance among more deprived and 97.8% among less deprived areas (ORadj: 0.70; 95% CI: 0.55‐0.88). Differences in colposcopy attendance by deprivation level at 12 and 24 months were of approximately the same magnitude. In conclusion, attendance at early recall and colposcopy was reassuringly high. Although there were statistically significant differences by deprivation and age group, these were small in absolute terms.

Concurrent participation in screening for cervical, breast, and bowel cancer in England

Objectives To determine how many women participate in all three recommended cancer screening programmes (breast, cervical, and bowel). During their early 60s, English women receive an invitation from all the three programmes. Methods For 3060 women aged 60–65 included in an England-wide breast screening case–control study, we investigated the number of screening programmes they participated in during the last invitation round. Additionally, using the Fingertips database curated by Public Health England, we explored area-level correlations between participation in the three cancer screening programmes and various population characteristics for all 7014 English general practices with complete data. Results Of the 3060 women, 1086 (35%) participated in all three programmes, 1142 (37%) in two, 526 (17%) in one, and 306 (10%) in none. Participation in all three did not appear to be a random event ( p < 0.001). General practices from areas with less deprivation, with more patients who are carers or have chronic illnesses themselves, and with more patients satisfied with the provided service were significantly more likely to attain high coverage rates in all programmes. Conclusions Only a minority of English women is concurrently protected through all recommended cancer screening programmes. Future studies should consider why most women participate in some but not all recommended screening.

Acceleration of cervical cancer diagnosis with human papillomavirus testing below age 30: Observational study

AbstractSeveral international cervical screening guidelines advise against using high‐risk human papillomavirus (HR‐HPV) testing in women younger than 30. The rationale for this in young women, lies in the potential for additional detection of both low‐grade and high‐grade cervical intraepithelial neoplasia (CIN) leading to unnecessary treatments without reducing the burden of cervical cancer. We studied 56 544 women screened at 24 to 29 with HR‐HPV testing and 116 858 screened with liquid‐based cytology (LBC) in the English HPV screening pilot. They were compared to 528 460 women screened at the age of 30 to 49. We studied the detection of cervical cancer and CIN2/3 across two consecutive screening rounds 3 years apart. At 24 to 29, a positive HR‐HPV test detected more cases of cervical cancer in the prevalence round than did a positive LBC test (1.36/1000 screened vs 0.82/1000, ORadj: 1.61, 95% CI: 1.18‐2.19). In women with a negative HR‐HPV test, cervical cancer was diagnosed before or at the incidence round in 0.07/1000. After a negative LBC test, cancer detection reached 0.47/1000 and 40% of these cases were diagnosed at FIGO stage IB+. HR‐HPV testing increased the detection of CIN2/3 diagnoses in two consecutive rounds combined by 30% (71.9/1000 vs 55.2/1000). The patterns of detection of cervical cancer and CIN2/3 were almost identical at older ages. These data support using HR‐HPV testing for screening of women younger than 30, which not only accelerates the diagnosis of cervical cancer but leads to a similar relative increase in CIN2/3 diagnosis to that found in women aged 30 to 49.

Adherence to follow‐up after the exit cervical cancer screening test at age 60–64: A nationwide register‐based study

AbstractBackgroundIn Denmark, human papillomavirus (HPV) testing has replaced cytology in primary cervical cancer screening for women aged 60–64; at this age, women are invited for the last (exit) screening test within the national organized program.AimWe investigated the adherence of these women to the recommended follow‐up after a non‐negative (positive or inadequate) HPV test and the overall resource use during that follow‐up.Materials & MethodsWe included all 2926 women aged 60–64 years with nonnegative HPV screening tests between March 2012 and December 2016. All relevant follow‐up tests and procedures were retrieved until the end of 2020 from the highly complete Danish administrative health registers, and the data were linked at the individual level. We determined the extent to which the adherence patterns followed the national recommendations for follow‐up and estimated the total numbers of tests and diagnostic procedures utilized during the entire process.ResultsIn total, only 26% of women had follow‐up in accordance with the recommendations; 4% had no follow‐up, 46% had insufficient follow‐up, and 24% had more follow‐up than recommended. We estimated that 17% of women remained in follow‐up for longer than 4 years. The average numbers of diagnostic tests and procedures used after positive HPV screening were higher than expected, even among women who had insufficient follow‐up, that is, those who received less invasive procedures than recommended, or experienced delays in receiving those procedures.ConclusionTo conclude, we found that the patterns of follow‐up of women with nonnegative primary HPV screening tests at 60–64 often diverged from the recommendations. Addressing these inconsistencies in follow‐up by providing evidence for optimal clinical management should help improve the quality of screening programs and secure an equal and reliable follow‐up care service for all women.

Supporting the implementation of new healthcare technologies by investigating generalisability of pilot studies using area-level statistics

Abstract Background Implementation of new technologies into national health care systems requires careful capacity planning. This is sometimes informed by data from pilot studies that implement the technology on a small scale in selected areas. A critical consideration when using implementation pilot studies for capacity planning in the wider system is generalisability. We studied the feasibility of using publicly available national statistics to determine the degree to which results from a pilot might generalise for non-pilot areas, using the English human papillomavirus (HPV) cervical screening pilot as an exemplar. Methods From a publicly available source on population indicators in England (“Public Health Profiles”), we selected seven area-level indicators associated with cervical cancer incidence, to produce a framework for post-hoc pilot generalisability analysis. We supplemented these data by those from publicly available English Office for National Statistics modules. We compared pilot to non-pilot areas, and pilot regimens (pilot areas using the previous standard of care (cytology) vs. the new screening test (HPV)). For typical process indicators that inform real-world capacity planning in cancer screening, we used standardisation to re-weight the values directly observed in the pilot, to better reflect the wider population. A non-parametric quantile bootstrap was used to calculate 95% confidence intervals (CI) for differences in area-weighted means for indicators. Results The range of area-level statistics in pilot areas covered most of the spectrum observed in the wider population. Pilot areas were on average more deprived than non-pilot areas (average index of multiple deprivation 24.8 vs. 21.3; difference: 3.4, 95% CI: 0.2–6.6). Participants in HPV pilot areas were less deprived than those in cytology pilot areas, matching area-level statistics. Differences in average values of the other six indicators were less pronounced. The observed screening process indicators showed minimal change after standardisation for deprivation. Conclusions National statistical sources can be helpful in establishing the degree to which the types of areas outside pilot studies are represented, and the extent to which they match selected characteristics of the rest of the health care system ex-post. Our analysis lends support to extrapolation of process indicators from the HPV screening pilot across England.

Widening the offer of human papillomavirus self‐sampling to all women eligible for cervical screening: Make haste slowly

AbstractSelf‐collection of samples for human papillomavirus (HPV) testing has the potential to increase the uptake of cervical screening among underscreened women and will likely form a crucial part of the WHO's strategy to eliminate cervical cancer by 2030. In high‐income countries with long‐standing, organised cervical screening programmes, self‐collection is increasingly becoming available as a routine offer for women regardless of their screening histories, including under‐ and well‐screened women. For these contexts, a validated microsimulation model determined that adding self‐collection to clinician collection is likely to be cost‐effective on the condition that it meets specific thresholds relating to (1) uptake and (2) sensitivity for the detection of high‐grade cervical intraepithelial neoplasia (CIN2+). We used these thresholds to review the ‘early‐adopter’ programme‐level evidence with a mind to determine how well and how consistently they were being met. The available evidence suggested some risk to overall programme performance in the situation where low uptake among underscreened women was accompanied by a high rate of substituting clinician sampling with self‐collection among well‐screened women. Risk was further compounded in a situation where the slightly reduced sensitivity of self‐sampling vs clinician sampling for the detection of CIN2+ was accompanied with lack of adherence to a follow‐up triage test that required a clinician sample. To support real‐world programmes on their pathways toward implementation and to avoid HPV self‐collection being introduced as a screening measure in good faith but with counterproductive consequences, we conclude by identifying a range of mitigations and areas worthy of research prioritisation.

A model-based analysis of the health impacts of COVID-19 disruptions to primary cervical screening by time since last screen for current and future disruptions

We evaluated how temporary disruptions to primary cervical cancer (CC) screening services may differentially impact women due to heterogeneity in their screening history and test modality. We used three CC models to project the short- and long-term health impacts assuming an underlying primary screening frequency (i.e., 1, 3, 5, or 10 yearly) under three alternative COVID-19-related screening disruption scenarios (i.e., 1-, 2-, or 5-year delay) versus no delay in the context of both cytology-based and human papillomavirus (HPV)-based screening. Models projected a relative increase in symptomatically detected cancer cases during a 1-year delay period that was 38% higher (Policy1-Cervix), 80% higher (Harvard), and 170% higher (MISCAN-Cervix) for underscreened women whose last cytology screen was 5 years prior to the disruption period compared with guidelines-compliant women (i.e., last screen 3 years prior to disruption). Over a woman’s lifetime, temporary COVID-19-related delays had less impact on lifetime risk of developing CC than screening frequency and test modality; however, CC risks increased disproportionately the longer time had elapsed since a woman’s last screen at the time of the disruption. Excess risks for a given delay period were generally lower for HPV-based screeners than for cytology-based screeners. Our independent models predicted that the main drivers of CC risk were screening frequency and screening modality, and the overall impact of disruptions from the pandemic on CC outcomes may be small. However, screening disruptions disproportionately affect underscreened women, underpinning the importance of reaching such women as a critical area of focus, regardless of temporary disruptions.

Extension of cervical screening intervals with primary human papillomavirus testing: observational study of English screening pilot data

Abstract Objectives To provide updated evidence about the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and cervical cancer after a negative human papillomavirus (HPV) test in primary cervical screening, by age group and test assay. Design Observational study. Setting Real world data from the English HPV screening pilot’s first and second rounds (2013-16, follow-up to end of 2019). Participants 1 341 584 women. Interventions Cervical screening with HPV testing or liquid based cytological testing (cytology or smear tests). Women screened with cytology were referred to colposcopy after high grade cytological abnormalities or after borderline or low grade abnormalities combined with a positive HPV triage test. Women screened with HPV testing who were positive were referred at baseline if their cytology triage test showed at least borderline abnormalities or after a retest (early recall) at 12 and 24 months if they had persistent abnormalities. Main outcome measures Detection of CIN3+ and cervical cancer after a negative HPV test. Results For women younger than 50 years, second round detection of CIN3+ in this study was significantly lower after a negative HPV screen in the first round than after cytology testing (1.21/1000 v 4.52/1000 women screened, adjusted odds ratio 0.26, 95% confidence interval 0.23 to 0.30), as was the risk of interval cervical cancer (1.31/100 000 v 2.90/100 000 woman years, adjusted hazard ratio 0.44, 0.23 to 0.84). Risk of an incident CIN3+ detected at the second screening round in the pilot five years after a negative HPV test was even lower in women older than 50 years, than in three years in women younger than 50 years (0.57/1000 v 1.21/1000 women screened, adjusted odds ratio 0.46, 0.27 to 0.79). Women with negative HPV tests at early recall after a positive HPV screening test without cytological abnormalities had a higher detection rate of CIN3+ at the second routine recall than women who initially tested HPV negative (5.39/1000 v 1.21/1000 women screened, adjusted odds ratio 3.27, 95% confidence interval 2.21 to 4.84). Detection after a negative result on a clinically validated APTIMA mRNA HPV test was similar to that after clinically validated cobas and RealTime DNA tests (for CIN3+ at the second round 1.32/1000 v 1.14/1000 women screened, adjusted odds ratio 1.05, 0.73 to 1.50). Conclusions These data support an extension of the screening intervals, regardless of the test assay used: to five years after a negative HPV test in women aged 25-49 years, and even longer for women aged 50 years and older. The screening interval for HPV positive women who have negative HPV tests at early recall should be kept at three years.

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

Cytology interpretation after a change to HPV testing in primary cervical screening: Observational study from the English pilot

BACKGROUNDOvercalling of abnormalities has been a concern for using cytology triage after positive high‐risk human papillomavirus (HPV) tests in cervical screening.METHODSThe authors studied the detection of cytological and histological abnormalities at age 24 to 64 years, using data from the English HPV pilot. The pilot compared routine implementation of primary cervical screening based on cytology (N = 931,539), where HPV test results were not available before cytology reporting, with that based on HPV testing (N = 403,269), where cytology was only required after positive HPV tests.RESULTSRevealed HPV positivity was associated with a higher direct referral to colposcopy after any abnormality (adjusted odds ratio [ORadj], 1.16; 95% confidence interval [CI], 1.14‐1.18). Laboratories with higher direct referral referred fewer persistently HPV‐positive women after early recall. The detection of high‐grade cervical intraepithelial neoplasia (CIN2+) after direct referral increased with an ORadj of 1.17 (95% CI, 1.13‐1.20) for informed versus uninformed cytology. Generally, the positive predictive value (PPV) of colposcopy for CIN2+ remained comparable under both conditions of interpreting cytology. In women 50 to 64 years old with high‐grade dyskaryosis, however, the PPV increased from 71% to 83% after revealing HPV positivity (ORadj, 2.05; 95% CI, 1.43‐2.93).CONCLUSIONSQuality‐controlled cervical screening programs can avoid inappropriate overgrading of HPV‐positive cytology.;

COVID-19 disruption to cervical cancer screening in England

Introduction In England, routine invitations for cervical screening were reduced between April 2020 and June 2020 due to the COVID-19 pandemic. We quantify the impact of COVID-19 disruptions on attendance and excess diagnoses of cervical cancer (CC). Methods Using Public Health England CC screening data on laboratory samples received in 2018 as a baseline we quantify the reduction in screening attendances due to the COVID-19 pandemic between April 2020 and March 2021 for women aged 25–64. We model the impact on excess CC diagnoses assuming once invitations resume 87.5% of women attend within 12 months and 12.5% delay screening for 3 or 5 years (depending on age). Results The number of samples received at laboratories was 91% lower than expected during April, 85% during May and 43% during June 2020 compared to the same period in 2018. Although on average laboratories received 12.6% more samples between August 2020 and April 2021 than over the same months in 2018, by April 2021 there was a short fall of 200,949 samples (6.4% fewer than in 2018). An excess of 41 CC (4.0 per 100,000 women with a maximum screening delay of 12 months) are predicted to occur among the estimated 1,024,794 women attending this screening round with a delay. An excess of 60 CC (41.0 per 100,000 women) are predicted to occur among the estimated 146,391 women who do not attend this screening round. Conclusion Prompt restoration of cervical screening services limited the impact on excess CC diagnoses. However, in 2020 a 6.4% shortfall of screening samples was observed. Every effort should be made to reassure these women that services are open and safe to attend.

The impact of catch-up bivalent human papillomavirus vaccination on cervical screening outcomes: an observational study from the English HPV primary screening pilot

Abstract Background In England, bivalent vaccination (Cervarix) against high-risk human papillomavirus (HR-HPV) genotypes 16/18 was offered in a population-based catch-up campaign in 2008–2010 to girls aged 14–17 years. These women are now entering the national cervical screening programme. We determined the impact of catch-up bivalent vaccination on their screening outcomes. Methods We studied the overall and genotype-specific screening outcomes in 108,138 women aged 24–25 (offered vaccination) and 26–29 years (not offered vaccination) included in the English HPV screening pilot between 2013 and 2018. Results At 24–25 years, the detection of high-grade cervical intraepithelial neoplasia (CIN2+) associated with HPV16/18 decreased from 3 to 1% (p < 0.001), with estimated vaccine effectiveness of 87% (95% CI: 82–91%). The detection of any CIN2+ halved from 6 to 3% (p < 0.001), with an estimated vaccine effectiveness of 72% (95% CI: 66–77%). The positive predictive value of a colposcopy for CIN2+ decreased for both low-grade (p < 0.001) and high-grade (p = 0.02) abnormalities on triage cytology. The decreases in screen-detected abnormalities at age 26-29 were of a substantially smaller magnitude. Conclusions These data confirm high effectiveness of bivalent HPV vaccination delivered through a population-based catch-up campaign in England. These findings add to the rationale for extending screening intervals for vaccinated cohorts.

Age‐specific outcomes from the first round of HPV screening in unvaccinated women: Observational study from the English cervical screening pilot

AbstractObjectiveTo report detailed age‐specific outcomes from the first round of an English pilot studying the implementation of high‐risk human papillomavirus (HR‐HPV) testing in primary cervical screening.DesignObservational study with screening in 2013–2016, followed by two early recalls and/or colposcopy until the end of 2019.SettingSix NHS laboratory sites.PopulationA total of 1 341 584 women undergoing screening with HR‐HPV testing or liquid‐based cytology (LBC).MethodsEarly recall tests and colposcopies were recommended, depending on the nature of the screening‐detected abnormality.Main outcome measuresWe reported standard screening process indicators, e.g. proportions with an abnormality, including high‐grade cervical intraepithelial neoplasia (CIN2+) or cancer, and the positive predictive value (PPV) of colposcopy for CIN2+, by screening test and age group.ResultsAmong unvaccinated women screened with HR‐HPV testing at age 24–29 years, 26.9% had a positive test and 10.4% were directly referred to colposcopy following cytology triage, with a PPV for CIN2+ of 47%. At 50–64 years of age, these proportions were much lower: 5.3%, 1.2% and 27%, respectively. The proportions of women testing positive for HR‐HPV without cytological abnormalities, whose early recall HR‐HPV tests returned negative results, were similar across the age spans: 54% at 24–29 years and 55% at 50–64 years. Two‐thirds of infections at any age were linked to non‐16/18 genotypes. Among women with CIN2, CIN3 or cervical cancer, however, the proportion of non‐16/18 infections increased with age. As expected, the detection of abnormalities was lower following screening with LBC.ConclusionsThese data provide a reliable reference for future epidemiological studies, including those concerning the effectiveness of HPV vaccination.Tweetable abstractData from the English pilot study provide a comprehensive overview of abnormalities detected through HPV 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.