CopulaDTA: An R Package for Copula Based Bivariate Beta-Binomial Models for Diagnostic Test Accuracy Studies in a Bayesian Framework

The current statistical procedures implemented in statistical software packages for pooling of diagnostic test accuracy data include hSROC regression and the bivariate random-effects meta-analysis model (BRMA). However, these models do not report the overall mean but rather the mean for a central study with random-effect equal to zero and have difficulties estimating the correlation between sensitivity and specificity when the number of studies in the meta-analysis is small and/or when the between-study variance is relatively large. This tutorial on advanced statistical methods for meta-analysis of diagnostic accuracy studies discusses and demonstrates Bayesian modeling using CopulaDTA package in R to fit different models to obtain the meta-analytic parameter estimates. The focus is on the joint modelling of sensitivity and specificity using copula based bivariate beta distribution. Essentially, we extend the work of Nikoloulopoulos by: i) presenting the Bayesian approach which offers flexibility and ability to perform complex statistical modelling even with small data sets and ii) including covariate information, and iii) providing an easy to use code. The statistical methods are illustrated by re-analysing data of two published meta-analyses. Modelling sensitivity and specificity using the bivariate beta distribution provides marginal as well as study-specific parameter estimates as opposed to using bivariate normal distribution (e.g., in BRMA) which only yields study-specific parameter estimates. Moreover, copula based models offer greater flexibility in modelling different correlation structures in contrast to the normal distribution which allows for only one correlation structure.Comment: 26 pages, 5 figure

Human papillomavirus vaccination coverage in Luxembourg : implications of lowering and restricting target age groups

Background: In Luxembourg, a national Human Papillomavirus (HPV) vaccination programme was introduced in 2008, targeting 12-17 year old girls offering a choice of bivalent or quadrivalent vaccine free of charge. In 2015, the programme was changed offering the bivalent vaccine only to 11-13 year old girls. The aim of this study was to evaluate the HPV vaccination coverage, to assess the impact of age target changes and compare vaccination coverage to other European countries. Methods: Anonymous HPV vaccination records consisting of individual vaccine doses obtained free of charge in pharmacies between 2008 and 2016 were extracted from the Luxembourgish Social Security database. Additional aggregate tables by nationality and municipality were analysed. Results: Of the target cohort of 39,610 girls born between 1991 and 2003 residing in Luxembourg, 24,550 (62.0%) subjects obtained at least one dose, 22,082 (55.7%) obtained at least two doses, and 17,197 (43.4%) obtained three doses of HPV vaccine. The mean age at first dose was 13.7 years during 200814 and 12.7 years in 2016 after the age target change. Coverage varied significantly by nationality (p < 0.0001): Portuguese (80%), former Yugoslays (74%), Luxembourgish (54%), Belgian (52%), German (47%), French (39%) and other, nationalities (51%). Coverage varied also by geographical region, with lower rates (<50%) noted in some Northern and Central areas of Luxembourg (range: 38% to 78%). Conclusion: Overall HPV vaccination coverage in Luxembourg is moderate and varied by nationality and region. The policy changes in 2015 did not have a substantial impact except lowering age at initiating vaccination. Options to improve coverage deserve further investigation

European Guidelines for Quality Assurance in Cervical Cancer Screening. Second Edition—Summary Document

European Guidelines for Quality Assurance in Cervical Cancer Screening have been initiated in the Europe Against Cancer Programme. The first edition established the principles of organised population-based screening and stimulated numerous pilot projects. The second multidisciplinary edition was published in 2008 and comprises ∼250 pages divided into seven chapters prepared by 48 authors and contributors. Considerable attention has been devoted to organised, population-based programme policies which minimise adverse effects and maximise benefits of screening. It is hoped that this expanded guidelines edition will have a greater impact on countries in which screening programmes are still lacking and in which opportunistic screening has been preferred in the past. Other methodological aspects such as future prospects of human papillomavirus testing and vaccination in cervical cancer control have also been examined in the second edition; recommendations for integration of the latter technologies into European guidelines are currently under development in a related project supported by the European Union Health Programme. An overview of the fundamental points and principles that should support any quality-assured screening programme and key performance indicators are presented here in a summary document of the second guidelines edition in order to make these principles and standards known to a wider scientific community

The detection of cervical intraepithelial neoplasia by electrical impedance spectroscopy: The effects of acetic acid and tissue homogeneity

Objective. To evaluate the efficacy of an electrical impedance probe (Epitheliometer) in the diagnosis of high grade cervical intraepithelial neoplasia (CIN) in women referred with cervical smear abnormalities and to assess the effect of acetic acid (AA) and tissue boundaries on the measurements. Methods. A prospective observational study was undertaken in the colposcopy clinic. One hundred and sixty-five women, either with a clinical indication or abnormal cervical cytology, were recruited into the study. A pencil type probe was used to record impedance spectra from 12 points on the cervix before and after the application of 5% AA. Spectra were also recorded from tissue boundaries. Colposcopic examinations, including probe positioning, were video recorded to allow for correlations between histopathological diagnosis of colposcopically directed biopsies, colposcopic impression and the diagnosis based on impedance measurements. Results. Receiver operating characteristic (ROC) curves were derived. The areas under the curves (AUCs) to discriminate original squamous from high grade CIN were 0.80 (pre AA) and 0.79 (post AA). Comparison of these curves showed no significant difference, indicating that application of AA does not produce a large change in spectra. The probe Could distinguish tissue boundaries from homogeneous tissue points. Conclusion. The Epitheliometer has the potential to be used as an adjunct to colposcopy in the diagnosis of high grade CIN. It has the advantage of real time results, decreasing the need for diagnostic cervical biopsies, and facilitates a wider use of the 'see and treat' policy without the risk of overtreatment. (C) 2009 Elsevier Inc. All rights reserved

Does lowering the screening age for cervical cancer in The Netherlands make sense?\ud

Recommendations for the age to initiate cervical cancer screening should be directed towards maximum detection of early cervical cancer. However, the screening programme should do more good than harm. The aim of this analysis was to determine whether the target age for cervical cancer screening should be lowered in view of apparent increases in new cases of invasive cancer below age 30 and in age group 30–44 years in The Netherlands. Therefore, all cervical cancer cases diagnosed between January 1, 1989 and December 31, 2003 were selected from the nationwide population-based Netherlands Cancer Registry. For age group 25–39 years, incidence data were also available for 2004 and 2005. To describe trends, the estimated annual percentage of change and joinpoint analysis were used. Between ages 25 and 28 years, the absolute number of new cases of cervical cancer annually has varied between 0 and 9 per age. Significantly decreasing trends in incidence were observed for age groups 35–39 and 45–49 (p < 0.0001 and p = 0.01, respectively). The annual number of deaths fluctuated with a decreasing trend for age groups 30–34 and 35–39 years (p = 0.01 and p = 0.03, respectively). Because the incidence and mortality rates for cervical cancer among women younger than 30 are low and not increasing, lowering the age for cervical cancer screening is not useful at this time. Although the number of years of life gained is high for every case of cervical cancer prevented, the disadvantages of lowering the screening age would be very large and even become disproportionate compared to the potential advantage

Triage of women with equivocal or low-grade cervical cytology results: a meta-analysis of the HPV test positivity rate

Introduction Methods Results Discussion Conclusion Abstract Consistent evidence underlines the utility of human papillomavirus (HPV) DNA testing in the management of women with equivocal cervical cytological abnormalities, but not in case of low-grade lesions. We performed a meta-analysis including studies where the high-risk probe of the Hybrid Capture-II is used to triage these two cytological categories. The triage test-positivity rate reflects the colposcopy referral workload.Data were pooled on the HPV test positivity rate in women with atypical squamous cells of undetermined significance (ASCUS/ASC-US) or low-grade squamous intraepithelial lesions (LSIL), derived from different cytological classification systems. The meta-analysis was restricted to studies, published between 1991 and 2007. A random-effect model was applied for meta-analytical pooling and the influence of covariates on the HPV positivity rate was analyzed by meta-regression. The variation by age was assessed within individual studies since age strata were not defined uniformly. On an average, 43% (95% CI: 40-46%) of women with ASCUS/ASC-US were high-risk HPV positive (range 23-74%). In women with LSIL, the pooled positivity rate was 76% (95% CI: 71-81%; range 55-89%). In spite of considerable inter-study heterogeneity, the difference in HPV positivity between the two triage groups was large and highly significant: 32% (95% CI: 27-38%). HPV rates dropped tremendously as age and cutoffs of test positivity increased. Other factors (cytological classification system, country, continent, collection method and year of publication) had no statistically significant impact, except in LSIL triage where HPV positivity was significantly lower in European compared to American studies. Women with LSIL, especially younger women, have high HPV positivity rates suggesting limited utility of reflex HPV triaging these cases. Research is needed to identify more specific methods to triage women with low-grade squamous cervical lesions

Fertility and early pregnancy outcomes after treatment for cervical intraepithelial neoplasia: systematic review and meta-analysis

OBJECTIVE: To determine the impact of cervical excision for cervical intraepithelial neoplasia on fertility and early pregnancy outcomes. DESIGN: Systematic review and meta-analysis of cohort studies. DATA SOURCES: Medline and Embase. ELIGIBILITY CRITERIA: Studies assessing fertility and early pregnancy outcomes in women with a history of treatment for cervical intraepithelial neoplasia versus untreated women. We classified the included studies according to treatment type and fertility or early pregnancy endpoint. ANALYSIS: Pooled relative risks and 95% confidence intervals using a random effect model, and interstudy heterogeneity with I(2) statistics. RESULTS: 15 studies fulfilled the inclusion criteria and were included. The meta-analysis did not provide any evidence that treatment for cervical intraepithelial neoplasia adversely affected the chances of conception. The overall pregnancy rate was higher for treated women than for untreated women (four studies; 43% v 38%, pooled relative risk 1.29, 95% confidence interval 1.02 to 1.64), although the heterogeneity between studies was high (P<0.0001). Pregnancy rates did not differ between women with an intention to conceive (two studies; 88% v 95%, 0.93, 0.80 to 1.08) and the number requiring more than 12 months to conceive (three studies, 15% v 9%, 1.45, 0.89 to 2.37). Although the rates for total miscarriages (10 studies; 4.6% v 2.8%, 1.04, 0.90 to 1.21) and miscarriage in the first trimester (four studies; 9.8% v 8.4%, 1.16, 0.80 to 1.69) was similar for treated and untreated women, cervical treatment was associated with a significantly increased risk of miscarriage in the second trimester. The rate was higher for treated women than for untreated women (eight studies; 1.6% v 0.4%, 16,558 women; 2.60, 1.45 to 4.67). The number of ectopic pregnancies (1.6% v 0.8%; 1.89, 1.50 to 2.39) and terminations (12.2% v 7.4%; 1.71, 1.31 to 2.22) was also higher for treated women. CONCLUSION: There is no evidence suggesting that treatment for cervical intraepithelial neoplasia adversely affects fertility, although treatment was associated with a significantly increased risk of miscarriages in the second trimester. Research should explore mechanisms that may explain this increase in risk and stratify the impact that treatment may have on fertility and early pregnancy outcomes by the size of excision and treatment method used

Using the VALGENT-3 framework to assess the clinical and analytical performance of the RIATOL qPCR HPV genotyping assay

Background and objective: The VALGENT framework is developed to assess the clinical performance of HPV tests that offer genotyping capability. Samples from the VALGENT-3 panel are used to identify an optimal viral concentration threshold for the RIATOL qPCR HPV genotyping assay (RIATOL qPCR) to assure non-inferior accuracy to detect high-grade cervical intraepithelial neoplasia (CIN), compared to Qiagen Hybrid Capture 2 (HC2), a standard comparator test validated for cervical cancer screening. Study design: The VALGENT-3 panel comprised 1300 samples from women participating in the Slovenian cervical cancer screening programme, enriched with 300 samples from women with abnormal cytology. In follow-up, 126 women were diagnosed with CIN2+ (defined as diseased) and 1167 women had two consecutive negative Pap smears (defined as non-diseased). All 1600 samples were analyzed with the RIATOL qPCR. Viral concentration was expressed as viral log10 of the number of copies/ml. A zone of viral concentration cut-offs was defined by relative ROC analysis where the sensitivity and specificity were not inferior to HC2. Results: The RIATOL qPCR had a sensitivity and specificity for CIN2+ of 97.6% (CI: 93.2-99.5%) and 85.1% (CI: 82.9-87.1%), respectively, when the analytical cut off was used. At a cut off of 6.5, RIATOL qPCR had a sensitivity of 96.0% (CI: 91.0-98.7%) and a specificity of 89.5% (87.6-91.2%). At optimized cut off, accuracy of the qPCR was non-inferior to the HC2 with a relative sensitivity of 1.00 [CI: 0.95-1.05 (p= 0.006)] and relative specificity of 1.00 [CI: 0.98-1.01 (p= 0.0069)]. Conclusions: The RIATOL qPCR has a high sensitivity and specificity for the detection of CIN2+. By using a fixed cut-off based on viral concentration, the test is non-inferior to HC2. HPV tests that provide viral concentration measurements or other quantifiable signals allow flexibility to optimize accuracy required for cervical cancer screening

Longterm prediction of failure after treatment of cervical precancer

Non peer reviewe