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

Attendance at cervical cancer screening and use of diagnostic and therapeutic procedures on the uterine cervix assessed from individual health insurance data (Belgium, 2002-2006)

Objective: To assess the coverage for cervical cancer screening as well as the use of cervical cytology, colposcopy and other diagnostic and therapeutic interventions on the uterine cervix in Belgium, using individual health insurance data. Methods: The Intermutualistic Agency compiled a database containing 14 million records from reimbursement claims for Pap smears, colposcopies, cervical biopsies and surgery, performed between 2002 and 2006. Cervical cancer screening coverage was defined as the proportion of women aged 25-64 that had a Pap smear within the last 3 years. Results: Cervical cancer screening coverage was 61% at national level, for the target population of women between 25 and 64 years old, in the period 2004-2006. Differences between the 3 regions were small, but varied more substantially between provinces. Coverage was 70% for 25-34 year old women, 67% for those aged 35-39 years, and decreased to 44% in the age group of 60-64 years. The median screening interval was 13 months. The screening coverage varied substantially by social category: 40% and 64%, in women categorised as beneficiary or not-beneficiary of increased reimbursement from social insurance, respectively. In the 3-year period 2004-2006, 3.2 million screen tests were done in the target group consisting of 2.8 million women. However, only 1.7 million women got one or more smears and 1.1 million women had no smears, corresponding to an average of 1.88 smears per woman in three years of time. Colposcopy was excessively used (number of Pap smears over colposcopies = 3.2). The proportion of women with a history of conisation or hysterectomy, before the age of 65, was 7% and 19%, respectively. Conclusion: The screening coverage increased slightly from 59% in 2000 to 61% in 2006. The screening intensity remained at a high level, and the number of cytological examinations was theoretically sufficient to cover more than the whole target population

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

Effectiveness of bivalent and quadrivalent human papillomavirus vaccination in Luxembourg

Background: In Luxembourg, the human papillomavirus (HPV) vaccination program introduced in 2008, provided either bivalent (BV) or quadrivalent (QV) vaccines to girls aged 12-17 years. Here, we estimate the effectiveness of BV and QV vaccines combined and separately in reducing type-specific HPV prevalence eight years after the introduction of the vaccination program. Methods: A cross-sectional prevalence study was conducted among women aged 18-29 years in 2015-2017. Seven hundred sixteen participants were recruited at family planning centres or private gynaecology practices in Luxembourg. Vaccination records were verified in the social security database. Cervical samples were tested using the Anyplex II HPV28 assay. Vaccine effectiveness was estimated using logistic regression. Results: In total, 363/716 (50.7%) participants were HPV positive with any HPV and 209/716 (29.2%) with carcinogenic HPV genotypes. HPV vaccination offered high protection against HPV16/18 (adjusted odds ratio (AOR) = 0.13; 95% CI 0.03-0.63), HPV6/11 (AOR = 0.16; 95% CI 0.05-0.48) and cross-protection against HPV31/33/45 (AOR = 0.41; 95% CI 0.18-0.94). The AORs were generally enhanced when only considering vaccination before sexual debut corresponding to AORs: 0.05 (95% CI 0.00-0.88), 0.08 (95% CI 0.02-0.36) and 0.20 (0.06-0.65) against HPV16/18, HPV6/11 and HPV31/33/45, respectively. We observed significant protection against carcinogenic genotypes included in nonavalent vaccine for BV (AOR = 0.29; 95% CI 0.13-0.67), but not for QV (AOR = 0.81; 95% CI 0.47-1.40) (heterogeneity Chi(2) P = 0.04). Conclusions: Our study suggests high effectiveness of HPV vaccination against HPV6/11, HPV16/18 and a crossprotection against HPV31/33/45. Vaccination effectiveness was slightly higher for women vaccinated before sexual debut

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 (Rutter and Gatsonis 2001) and the bivariate random-effects meta-analysis model (BRMA; Reitsma et al. 2005; Arends et al. 2008; Chu and Cole 2006; Riley et al. 2007b). 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 (Riley et al. 2007a). This tutorial on advanced statistical methods for meta-analysis of diagnostic accuracy studies discusses and demonstrates Bayesian modeling using the R package CopulaDTA (Nyaga 2017) to fit different models to obtain the meta-analytic parameter estimates. The focus is on the joint modeling of sensitivity and specificity using a copula based bivariate beta distribution. Essentially, we extend the work of Nikoloulopoulos (2015) by: (i) presenting the Bayesian approach which offers the flexibility and ability to perform complex statistical modeling 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-analyzing data of two published meta-analyses. Modeling sensitivity and specificity using the bivariate beta distribution provides marginal as well as study-specific parameter estimates as opposed to using the bivariate normal distribution (e.g., in BRMA) which only yields study-specific parameter estimates. Moreover, copula based models offer greater flexibility in modeling different correlation structures in contrast to the normal distribution which allows for only one correlation structure

Accuracy of genotyping for HPV16 and 18 to triage women with low-grade squamous intraepithelial lesions: a pooled analysis of VALGENT studies

Background: Genotyping for the most carcinogenic human papillomavirus (HPV) types (HPV16/HPV18) can identify high risk of underlying cervical precancer and guide further management.Research design and methods: A pooled analysis was performed of the clinical accuracy of high-risk HPV (hrHPV) testing and HPV16/18 genotyping in triage of women with low-grade squamous intraepithelial lesions (LSIL). Data regarding 24 assays evaluated in four VALGENT validation panels were used.Results: In women with LSIL, hrHPV had a pooled sensitivity for CIN2+ of 95.5% (95% CI: 91.0-97.8%) and a specificity of 25.3% (95% CI: 22.2-28.6%). HPV16/18 genotyping had a sensitivity and specificity for CIN2+ of 52.9% (95% CI: 48.4-57.4%) and 83.5% (95% CI: 79.9-86.5%), respectively. The average risk of CIN2+ was 46.1% when HPV16/18-positive, 15.5% in women who were HPV16/18-negative but positive for other hrHPV types and 4.3% for hrHPV-negative women.Conclusions: Triage of women with LSIL with HPV16/18 genotyping increases the positive predictive value compared to hrHPV testing but at the expense of lower sensitivity. Arguably, women testing positive for HPV16/18 need further clinical work-up. Whether colposcopy referral or further surveillance is recommended for women with other hrHPV types may depend on the post-test risk of precancer and the local risk-based decision thresholds

Triage of Women with Low-Grade Cervical Lesions - HPV mRNA Testing versus Repeat Cytology

BACKGROUND: In Norway, women with low-grade squamous intraepithelial lesions (LSIL) are followed up after six months in order to decide whether they should undergo further follow-up or be referred back to the screening interval of three years. A high specificity and positive predictive value (PPV) of the triage test is important to avoid unnecessary diagnostic and therapeutic procedures. MATERIALS AND METHODS: At the University Hospital of North Norway, repeat cytology and the HPV mRNA test PreTect HPV-Proofer, detecting E6/E7 mRNA from HPV types 16, 18, 31, 33 and 45, are used in triage of women with ASC-US and LSIL. In this study, women with LSIL cytology in the period 2005-2008 were included (n = 522). Two triage methods were evaluated in two separate groups: repeat cytology only (n = 225) and HPV mRNA testing in addition to repeat cytology (n = 297). Histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) was used as the study endpoint. RESULTS: Of 522 women with LSIL, 207 had biopsies and 125 of them had CIN2+. The sensitivity and specificity of repeat cytology (ASC-US or worse) were 85.7% (95% confidence interval (CI): 72.1, 92.2) and 54.4 % (95% CI: 46.9, 61.9), respectively. The sensitivity and specificity of the HPV mRNA test were 94.2% (95% CI: 88.7, 99.7) and 86.0% (95% CI: 81.5, 90.5), respectively. The PPV of repeat cytology was 38.4% (95% CI: 29.9, 46.9) compared to 67.0% (95% CI: 57.7, 76.4) of the HPV mRNA test. CONCLUSION: HPV mRNA testing was more sensitive and specific than repeat cytology in triage of women with LSIL cytology. In addition, the HPV mRNA test showed higher PPV. These data indicate that the HPV mRNA test is a better triage test for women with LSIL than repeat cytology

Complete genome sequence of a novel human gammapapillomavirus isolated from a cervical swab in Luxembourg

A novel human papillomavirus genotype was detected in a cervical swab specimen by next-generation sequencing after rolling circular amplification. It was fully cloned and characterized. The L1 open reading frame showed 77% nucleotide similarity with the closest genotype, HPV101, belonging to the gamma-6 species