Field experience with the 8-HPV-type oncoprotein test for cervical cancer screening among HPV-positive women living with and without HIV in LMICs.

Overexpression of HPV-oncoproteins E6 and E7 is necessary for HPV-driven cervical carcinogenesis. Hence, these oncoproteins are promising disease-specific biomarkers. We assessed the technical and operational characteristics of the 8-HPV-type OncoE6/E7 Cervical Test in different laboratories using cervical samples from HPV-positive women living with (WLWH) and without HIV. The 8-HPV-type OncoE6/E7 Test (for short: "OncoE6/E7 test") was performed in 2833 HIV-negative women and 241 WLWH attending multicentric studies in Latin America (ESTAMPA study), and in Africa (CESTA study). Oncoprotein positivity were evaluated at each testing site, according to HIV status as well as type-specific agreement with HPV-DNA results. A feedback questionnaire was given to the operators performing the oncoprotein test to evaluate their impression and acceptability regarding the test. The OncoE6/E7 test revealed a high positivity rate heterogeneity across all testing sites (I2: 95.8%, p < .01) with significant lower positivity in WLWH compared to HIV-negative women (12% vs 25%, p < .01). A similar HPV-type distribution was found between HPV DNA genotyping and oncoprotein testing except for HPV31 and 33 (moderate agreement, k = 0.57). Twenty-one laboratory technicians were trained on oncoprotein testing. Despite operators' concerns about the time-consuming procedure and perceived need for moderate laboratory experience, they reported the OncoE6/E7 test as easy to perform and user-friendly for deployment in resource-limited settings. The high positivity rate variability found across studies and subjectivity in test outcome interpretation could potentially results in oncoprotein false positive/negative, and thus the need for further refinements before implementation of the oncoprotein testing in screen-triage-and-treat approaches is warranted.

Accuracy of HPV E6/E7 oncoprotein tests to detect high-grade cervical lesions: a systematic literature review and meta-analysis.

BACKGROUND: Cervical carcinogenesis is mediated by the HPV-E6 and E7 oncoproteins, considered as biomarkers usable in managing screen-positive women. METHODS: We conducted a systematic review and meta-analysis assessing the accuracy of HPV-E6/E7-oncoprotein tests to detect underlying cervical-precancer and cancer. We included studies reporting data on oncoprotein test accuracy detecting cervical intraepithelial neoplasia grade 3 or worse. Random effects logistic regression models were applied for pooling absolute and relative accuracy. RESULTS: Twenty-two studies were included. Sensitivity and specificity estimates ranged from 54.2% (95%CI: 45.2-63.0) to 69.5% (95%CI:60.8-76.9) and from 82.8% (95%CI: 50.4-95.8) to 99.1 (95%CI: 98.8-99.3), respectively in the population irrespective of HPV status. Higher sensitivity estimates ranging from 60.8% (95%CI: 49.6-70.9) to 75.5% (95%CI: 71.7-78.9) but lower specificity estimates ranging from 83.7% (95%CI: 76.1-89.3) to 92.1% (95%CI: 88.5-94.6) were observed in studies enrolling high-risk-HPV-positive women. Studies recruiting only HIV-positive women showed a pooled sensitivity of 46.9% (95%CI: 30.6-63.9) with a specificity of 98.0% (95%CI: 96.8-98.7). CONCLUSIONS: The high specificity of oncoprotein tests supports its use for triaging HPV-positive women. However, oncoprotein-negative women would not be recommended to undertake routine screening, requiring further follow-up. Large-scale and longitudinal studies are needed to further investigate the role of E6/E7-oncoprotein detection in predicting the risk of developing cervical pre-cancer and cancer.

Accuracy and effectiveness of HPV mRNA testing in cervical cancer screening: a systematic review and meta-analysis.

BACKGROUND: Cervical cancer screening tests that identify DNA of the main causal agent, high-risk human papillomavirus (HPV) types, are more protective than cervical cytology. We systematically reviewed the literature to assess whether tests targeting high-risk HPV (hrHPV) mRNA are as accurate and effective as HPV DNA-based screening tests. METHODS: We did a systematic review to assess the cross-sectional clinical accuracy to detect cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or 3 or worse (CIN3+) of hrHPV mRNA versus DNA testing in primary cervical cancer screening; the longitudinal clinical performance of cervical cancer screening using hrHPV mRNA versus DNA assays; and the clinical accuracy of hrHPV mRNA testing on self-collected versus clinician-collected samples. We identified relevant studies published before Aug 1, 2021, through a search of Medline (PubMed), Embase, and CENTRAL. Eligible studies had to contain comparative data addressing one of our three clinical questions. Aggregated data were extracted from selected reports or requested from study authors if necessary. QUADAS and ROBINS-1 tools were used to assess the quality of diagnostic test accuracy studies and cohort studies. To assess cross-sectional clinical accuracy of mRNA testing versus DNA testing and clinical accuracy of hrHPV mRNA testing on self-collected versus clinician collected samples, we applied meta-analytical methods for comparison of diagnostic tests. To assess the longitudinal clinical performance of cervical cancer screening using hrHPV mRNA versus DNA assays, we compared the longitudinal sensitivity of mRNA tests and validated DNA tests for CIN3+ and the relative detection of CIN3+ among women who screened negative for hrHPV mRNA or DNA (both used as measures of safety) at baseline and pooled estimates by years of follow-up. A random-effect model for pooling ratios of proportions or risks was used to summarise longitudinal performance. FINDINGS: For the hrHPV mRNA testing with APTIMA HPV Test (APTIMA), the cross-sectional accuracy could be compared with DNA assays on clinician-collected samples in eight studies; longitudinal performance was compared in four studies; and accuracy on self-samples was assessed in five studies. Few reports were retrieved for other mRNA assays, precluding their evaluation in meta-analyses. Compared with validated DNA assays, APTIMA was similarly sensitive (relative sensitivity 0·98 [95% CI 0·95-1·01]) and slightly more specific (1·03 [1·02-1·04]) for CIN2+. The relative sensitivity for CIN3+ was 0·98 (95% CI 0·95-1·01). The longitudinal relative sensitivity for CIN3+ of APTIMA compared with DNA assays assessed over 4-7 years ranged at the study level from 0·91 to 1·05 and in the pooled analysis between 0·95 and 0·98, depending on timepoint, with CIs including or close to unity. The detection rate ratios between 4 and 10 years after baseline negative mRNA versus negative DNA screening were imprecise and heterogeneous among studies, but summary ratios did not differ from unity. In self-collected samples, APTIMA was less sensitive for CIN2+ (relative cross-sectional sensitivity 0·84 [0·74-0·96]) but similarly specific (relative specificity 0·96 [0·91-1·01]) compared with clinician-collected samples. INTERPRETATION: HrHPV RNA testing with APTIMA had similar cross-sectional sensitivity for CIN2+ and CIN3+ and slightly higher specificity than DNA tests. Four studies with 4-7 years of follow-up showed heterogeneous safety outcomes. One study with up to 10 years of follow-up showed no differences in cumulative detection of CIN3+ after negative mRNA versus DNA screening. APTIMA could be accepted for primary cervical cancer screening on clinician-collected cervical samples at intervals of around 5 years. APTIMA is less sensitive on self-collected samples than clinician-collected samples. FUNDING: Horizon 2020 Framework Programme for Research and Innovation of the European Commission, through the RISCC Network, WHO, Haute Autorité de la Santé, European Society of Gynaecological Oncology, and the National Institute of Public Health and the Environment.

Trends in bednet ownership and usage, and the effect of bednets on malaria hospitalization in the Kilifi Health and Demographic Surveillance System (KHDSS): 2008-2015.

BACKGROUND: Use of bednets reduces malaria morbidity and mortality. In Kilifi, Kenya, there was a mass distribution of free nets to children < 5 years in 2006. In 2009, a new policy was implemented to offer bednets to pregnant women and children < 5 years free of charge. Nets were again distributed to children and adults through national mass campaigns in 2012 and 2015. We aimed to evaluate trends in bednet ownership and usage, and the effect of bednets on the incidence of malaria hospitalization in children < 5 years within the Kilifi Health and Demographic Surveillance System (KHDSS). METHODS: Bednet ownership and usage were assessed during eight routine enumeration rounds of the KHDSS between 2008 and 2015. Malaria admissions (i.e. admissions to hospital with P. falciparum > 2500 parasitemia per µl) among children < 5 years were captured using a system of continuous vital registration that links admissions at Kilifi County Hospital to the KHDSS population register. Survival analysis was used to assess relative risk of hospitalization with malaria among children that reported using a bednet compared to those who did not. RESULTS: We observed 63% and 62% mean bednet ownership and usage, respectively, over the eight-survey period. Among children < 5 years, reported bednet ownership in October-December 2008 was 69% and in March-August 2009 was 73% (p < 0.001). An increase was also observed following the mass distribution campaigns in 2012 (62% in May-July 2012 vs 90% in May-October 2013, p < 0.001) and 2015 (68% in June-September 2015 vs 93% in October-November 2015, p < 0.001). Among children <5 years who reported using a net the night prior to the survey, the incidence of malaria hospitalization per 1000 child-years was 2.91 compared to 4.37 among those who did not (HR = 0.67, 95% CI: 0.52, 0.85 [p = 0.001]). CONCLUSION: On longitudinal surveillance, increasing bednet ownership and usage corresponded to mass distribution campaigns; however, this method of delivering bednets did not result in sustained improvements in coverage. Among children < 5 years old bednet use was associated with a 33% decreased incidence of malaria hospitalization.

Cytology versus HPV testing for cervical cancer screening in the general population.

BACKGROUND: Cervical cancer screening has traditionally been based on cervical cytology. Given the aetiological relationship between human papillomavirus (HPV) infection and cervical carcinogenesis, HPV testing has been proposed as an alternative screening test. OBJECTIVES: To determine the diagnostic accuracy of HPV testing for detecting histologically confirmed cervical intraepithelial neoplasias (CIN) of grade 2 or worse (CIN 2+), including adenocarcinoma in situ, in women participating in primary cervical cancer screening; and how it compares to the accuracy of cytological testing (liquid-based and conventional) at various thresholds. SEARCH METHODS: We performed a systematic literature search of articles in MEDLINE and Embase (1992 to November 2015) containing quantitative data and handsearched the reference lists of retrieved articles. SELECTION CRITERIA: We included comparative test accuracy studies if all women received both HPV testing and cervical cytology followed by verification of the disease status with the reference standard, if positive for at least one screening test. The studies had to include women participating in a cervical cancer screening programme who were not being followed up for previous cytological abnormalities. DATA COLLECTION AND ANALYSIS: We completed a 2 x 2 table with the number of true positives (TP), false positives (FP), true negatives (TN), and false negatives for each screening test (HPV test and cytology) used in each study. We calculated the absolute and relative sensitivities and the specificities of the tests for the detection of CIN 2+ and CIN 3+ at various thresholds and computed sensitivity (TP/(TP + TN) and specificity (TN/ (TN + FP) for each test separately. Relative sensitivity and specificity of one test compared to another test were defined as sensitivity of test-1 over sensitivity of test-2 and specificity of test-1 over specificity of test-2, respectively. To assess bias in the studies, we used the Quality Assessment of Diagnostic test Accuracy Studies (QUADAS) tool. We used a bivariate random-effects model for computing pooled accuracy estimates. This model takes into account the within- and between-study variability and the intrinsic correlation between sensitivity and specificity. MAIN RESULTS: We included a total of 40 studies in the review, with more than 140,000 women aged between 20 and 70 years old. Many studies were at low risk of bias. There were a sufficient number of included studies with adequate methodology to perform the following test comparisons: hybrid capture 2 (HC2) (1 pg/mL threshold) versus conventional cytology (CC) (atypical squamous cells of undetermined significance (ASCUS)+ and low-grade squamous intraepithelial lesions (LSIL)+ thresholds) or liquid-based cytology (LBC) (ASCUS+ and LSIL+ thresholds), other high-risk HPV tests versus conventional cytology (ASCUS+ and LSIL+ thresholds) or LBC (ASCUS+ and LSIL+ thresholds). For CIN 2+, pooled sensitivity estimates for HC2, CC and LBC (ASCUS+) were 89.9%, 62.5% and 72.9%, respectively, and pooled specificity estimates were 89.9%, 96.6%, and 90.3%, respectively. The results did not differ by age of women (less than or greater than 30 years old), or in studies with verification bias. Accuracy of HC2 was, however, greater in European countries compared to other countries. The results for the sensitivity of the tests were heterogeneous ranging from 52% to 94% for LBC, and 61% to 100% for HC2. Overall, the quality of the evidence for the sensitivity of the tests was moderate, and high for the specificity.The relative sensitivity of HC2 versus CC for CIN 2+ was 1.52 (95% CI: 1.24 to 1.86) and the relative specificity 0.94 (95% CI: 0.92 to 0.96), and versus LBC for CIN 2+ was 1.18 (95% CI: 1.10 to 1.26) and the relative specificity 0.96 (95% CI: 0.95 to 0.97). The relative sensitivity of HC2 versus CC for CIN 3+ was 1.46 (95% CI: 1.12 to 1.91) and the relative specificity 0.95 (95% CI: 0.93 to 0.97). The relative sensitivity of HC2 versus LBC for CIN 3+ was 1.17 (95% CI: 1.07 to 1.28) and the relative specificity 0.96 (95% CI: 0.95 to 0.97). AUTHORS' CONCLUSIONS: Whilst HPV tests are less likely to miss cases of CIN 2+ and CIN 3+, these tests do lead to more unnecessary referrals. However, a negative HPV test is more reassuring than a negative cytological test, as the cytological test has a greater chance of being falsely negative, which could lead to delays in receiving the appropriate treatment. Evidence from prospective longitudinal studies is needed to establish the relative clinical implications of these tests.

Methods for meta-analysis and meta-regression of binomial data: concepts and tutorial with Stata command metapreg.

BACKGROUND: Despite the widespread interest in meta-analysis of proportions, its rationale, certain theoretical and methodological concepts are poorly understood. The generalized linear models framework is well-established and provides a natural and optimal model for meta-analysis, network meta-analysis, and meta-regression of proportions. Nonetheless, generic methods for meta-analysis of proportions based on the approximation to the normal distribution continue to dominate. METHODS: We developed metapreg, a tool with advanced statistical procedures to perform a meta-analysis, network meta-analysis, and meta-regression of binomial proportions in Stata using binomial, logistic and logistic-normal models. First, we explain the rationale and concepts essential in understanding statistical methods for meta-analysis of binomial proportions and describe the models implemented in metapreg. We then describe and demonstrate the models in metapreg using data from seven published meta-analyses. We also conducted a simulation study to compare the performance of metapreg estimators with the existing estimators of the population-averaged proportion in metaprop and metan under a broad range of conditions including, high over-dispersion and small meta-analysis. CONCLUSION: metapreg is a flexible, robust and user-friendly tool employing a rigorous approach to evidence synthesis of binomial data that makes the most efficient use of all available data and does not require ad-hoc continuity correction or data imputation. We expect its use to yield higher-quality meta-analysis of binomial proportions.

Comparison and validation of metadta for meta-analysis of diagnostic test accuracy studies.

We developed metadta, a flexible, robust, and user-friendly statistical procedure that fuses established and innovative statistical methods for meta-analysis, meta-regression, and network meta-analysis of diagnostic test accuracy studies in Stata. Using data from published meta-analyses, we validate metadta by comparing and contrasting its features and output to popular procedures dedicated to the meta-analysis of diagnostic test accuracy studies; (midas [Stata], metandi [Stata], metaDTA [web application], mada [R], and MetaDAS [SAS]). We also demonstrate how to perform network meta-analysis with metadta, for which no alternative procedure is dedicated to network meta-analysis of diagnostic test accuracy data in the frequentist framework. metadta generated consistent estimates in simple and complex diagnostic test accuracy data sets. We expect its availability to stimulate better statistical practice in the evidence synthesis of diagnostic test accuracy studies.

Metadta: a Stata command for meta-analysis and meta-regression of diagnostic test accuracy data - a tutorial.

BACKGROUND: Although statistical procedures for pooling of several epidemiological metrics are generally available in statistical packages, those for meta-analysis of diagnostic test accuracy studies including options for multivariate regression are lacking. Fitting regression models and the processing of the estimates often entails lengthy and tedious calculations. Therefore, packaging appropriate statistical procedures in a robust and user-friendly program is of great interest to the scientific community. METHODS: metadta is a statistical program for pooling of diagnostic accuracy test data in Stata. It implements both the bivariate random-effects and the fixed-effects model, allows for meta-regression, and presents the results in tables, a forest plot and/or summary receiver operating characteristic (SROC) plot. For a model without covariates, it quantifies the unexplained heterogeneity due to between-study variation using an I2 statistic that accounts for the mean-variance relationship and the correlation between sensitivity and specificity. To demonstrate metadta, we applied the program on two published meta-analyses on: 1) the sensitivity and specificity of cytology and other markers including telomerase for primary diagnosis of bladder cancer, and 2) the accuracy of human papillomavirus (HPV) testing on self-collected versus clinician-collected samples to detect cervical precancer. RESULTS: Without requiring a continuity correction, the pooled sensitivity and specificity generated by metadta of telomerase for the diagnosis of primary bladder cancer was 0.77 [95% CI, 0.70, 0.82] and 0.91 [95% CI, 0.75, 0.97] respectively. Metadta also allowed to assess the relative accuracy of HPV testing on self- versus clinician-taken specimens using data from comparative studies conducted in different clinical settings. The analysis showed that HPV testing with target-amplification assays on self-samples was as sensitive as on clinician-samples in detecting cervical pre-cancer irrespective of the clinical setting. CONCLUSION: The metadta program implements state of art statistical procedures in an attempt to close the gap between methodological statisticians and systematic reviewers. We expect the program to popularize the use of appropriate statistical methods for diagnostic meta-analysis further.

The Effect of Endogenous Cushing Syndrome on All-cause and Cause-specific Mortality.

OBJECTIVE: We aimed to perform a systematic review and meta-analysis of all-cause and cause-specific mortality of patients with benign endogenous Cushing syndrome (CS). METHODS: The protocol was registered in PROSPERO (CRD42017067530). PubMed, EMBASE, CINHAL, Web of Science, and Cochrane Central searches were undertaken from inception to January 2021. Outcomes were the standardized mortality ratio (SMR), proportion, and cause of deaths. The I2 test, subgroup analysis, and meta-regression were used to assess heterogeneity across studies. RESULTS: SMR was reported in 14 articles including 3691 patients (13 Cushing disease [CD] and 7 adrenal CS [ACS] cohorts). Overall SMR was 3.0 (95% CI, 2.3-3.9; I2 = 80.5%) for all CS, 2.8 (95% CI, 2.1-3.7; I2 = 81.2%) for CD and 3.3 (95% CI, 0.5-6.6; I2 = 77.9%) for ACS. Proportion of deaths, reported in 87 articles including 19 181 CS patients (53 CD, 24 ACS, and 20 combined CS cohorts), was 0.05 (95% CI, 0.03-0.06) for all CS subtypes with meta-regression analysis revealing no differences between CS subtypes (P = .052). The proportion of deaths was 0.1 (10%) in articles published before 2000 and 0.03 (3%) in 2000 until the last search for CS (P < .001), CD (P < .001), and ACS (P = .01). The causes of death were atherosclerotic diseases and thromboembolism (43.4%), infection (12.7%), malignancy (10.6%), active disease (3.5%), adrenal insufficiency (3.0%), and suicide (2.2%). Despite improved outcomes in recent years, increased mortality from CS persists. The causes of death highlight the need to prevent and manage comorbidities in addition to treating hypercortisolism.

Diagnostic value of α-synuclein seeding amplification assays in α-synucleinopathies: A systematic review and meta-analysis.

INTRODUCTION: Alpha-synuclein(αSyn) aggregates are definite pathological hallmarks of α-synucleinopathies. Seeding amplification assays (SAAs) have been developed to detect trace amounts of αSyn oligomers in vivo.. Herein, we assessed the diagnostic accuracy of the αSyn-SAAs across biospecimens, diagnostic references, methods, and subtypes. METHODS: A systematic literature search yielded 36 eligible studies for a meta-analysis of the sensitivity and specificity of αSyn-SAAs in patients with α-synucleinopathies(n = 2722) and controls(n = 2278). Pooled sensitivities and specificities with 95% confidence intervals (CIs) were calculated using bivariate random-effects models and a meta-regression analysis was performed. RESULTS: The summary sensitivity and specificity of αSyn-SAAs positivity for the diagnosis of α-synucleinopathies were 0.88(95% CIs = 0.84-0.91) and 0.95(0.93-0.97), respectively. Two covariates (biospecimen and diagnostic reference) were significant in fitting the meta-regression model (likelihood-ratio test for sensitivity and specificity, p < 0.01, p = 0.01, respectively). Skin αSyn-SAAs exhibited the highest sensitivity 0.92(0.87-0.95), which was not different from that of cerebrospinal fluid (CSF)(0.90(0.86-0.93), p = 0.39). Olfactory mucosa αSyn-SAAs exhibited a lower sensitivity 0.64(0.49-0.76) than those of the other two specimens(p = 0.02, 0.01, compared to CSF and skin, respectively). Application of pathological diagnostic standards were associated with a higher specificity of αSyn-SAAs compared to clinical diagnosis (p < 0.01). The diagnostic sensitivity and specificity of CSF αSyn-SAAs were 0.91(0.87-0.94) and 0.96(0.93-0.98) for Lewy body disease, 0.90(0.79-0.95) and 0.96(0.90-0.98) for prodromal α-synucleinopathies, and 0.63(0.24-0.90) and 0.97(0.93-0.99) for multiple system atrophy. CONCLUSIONS: αSyn-SAAs are promising in vivo detectors of abnormal αSyn aggregates and may aid the early diagnosis of α-synucleinopathies.

The EMPCAN study: protocol of a population-based cohort study on the evolution of the socio-economic position of workers with cancer.

BACKGROUND: The improvements in cancer control led to an increase in the number of cancer survivors, notably, in the working age population (16-64 years). There is a strong need to assess and understand their reintegration on the labour market, which underlines and ensures their social integration and quality of life. The objectives of the EMPCAN study is therefore to measure the scale of return-to-work after cancer and to identify the determining factors, allowing for the implementation of an adequate socio-professional support. METHODS: We requested data from the Belgian Cancer Registry and the Crossroad Bank for Social Security. We included all socially insured Belgian workers diagnosed between 2004 and 2011 with colorectal, breast, head & neck, prostate, testis, lung and corpus uteri cancer. The end of (administrative) follow-up was 31st December 2012. We include demographic, health-related and work-related factors in the analysis and observed how these factors interplay to determine the working status. After having solved legal, ethical and technical issues for the coupling, we will perform survival analysis with competing risks using the Fine and Gray model; we will also perform a multistate model using transitions probabilities; and finally, a group-based modeling for longitudinal data using the 'proc traj' package in SAS. DISCUSSION: The results of the EMPCAN study will allow the provision of an evidence-based support to professional reintegration policies. It will also bring some key features for the prediction of the cancer-related social security needs. Besides the raise of awareness among health professionals and policy makers, this study could lead to a better planning and organization of vocational rehabilitation programs.

Group B Streptococcus in surgical site and non-invasive bacterial infections worldwide: A systematic review and meta-analysis.

OBJECTIVES: The epidemiology of disease caused by group B Streptococcus (GBS; Streptococcus agalactiae) outside pregnancy and the neonatal period is poorly characterized. The aim of this study was to quantify the role of GBS as a cause of surgical site and non-invasive infections at all ages. METHODS: A systematic review (PROSPERO CRD42017068914) and meta-analysis of GBS as a proportion (%) of bacterial isolates from surgical site infection (SSI), skin/soft tissue infection (SSTI), urinary tract infection (UTI), and respiratory tract infection (RTI) was conducted. RESULTS: Seventy-four studies and data sources were included, covering 67 countries. In orthopaedic surgery, GBS accounted for 0.37% (95% confidence interval (CI) 0.08-1.68%), 0.87% (95% CI 0.33-2.28%), and 1.46% (95% CI 0.49-4.29%) of superficial, deep, and organ/space SSI, respectively. GBS played a more significant role as a cause of post-caesarean section SSI, detected in 2.92% (95% CI 1.51-5.55%), 1.93% (95% CI 0.97-3.81%), and 9.69% (95% CI 6.72-13.8%) of superficial, deep, and organ/space SSI. Of the SSTI isolates, 1.89% (95% CI 1.16-3.05%) were GBS. The prevalence of GBS in community and hospital UTI isolates was 1.61% (1.13-2.30%) and 0.73% (0.43-1.23%), respectively. GBS was uncommonly associated with RTI, accounting for 0.35% (95% CI 0.19-0.63%) of community and 0.27% (95% CI 0.15-0.48%) of hospital RTI isolates. CONCLUSIONS: GBS is implicated in a small proportion of surgical site and non-invasive infections, but a substantial proportion of invasive SSI post-caesarean section.

Beta-binomial analysis of variance model for network meta-analysis of diagnostic test accuracy data.

There are several generalized linear mixed models to combine direct and indirect evidence on several diagnostic tests from related but independent diagnostic studies simultaneously also known as network meta-analysis. The popularity of these models is due to the attractive features of the normal distribution and the availability of statistical software to obtain parameter estimates. However, modeling the latent sensitivity and specificity using the normal distribution after transformation is neither natural nor computationally convenient. In this article, we develop a meta-analytic model based on the bivariate beta distribution, allowing to obtain improved and direct estimates for the global sensitivities and specificities of all tests involved, and taking into account simultaneously the intrinsic correlation between sensitivity and specificity and the overdispersion due to repeated measures. Using the beta distribution in regression has the following advantages, that the probabilities are modeled in their proper scale rather than a monotonic transform of the probabilities. Secondly, the model is flexible as it allows for asymmetry often present in the distribution of bounded variables such as proportions, which is the case with sparse data common in meta-analysis. Thirdly, the model provides parameters with direct meaningful interpretation since further integration is not necessary to obtain the meta-analytic estimates.

ANOVA model for network meta-analysis of diagnostic test accuracy data.

Procedures combining and summarising direct and indirect evidence from independent studies assessing the diagnostic accuracy of different tests for the same disease are referred to network meta-analysis. Network meta-analysis provides a unified inference framework and uses the data more efficiently. Nonetheless, handling the inherent correlation between sensitivity and specificity continues to be a statistical challenge. We developed an arm-based hierarchical model which expresses the logit transformed sensitivity and specificity as the sum of fixed effects for test, correlated study-effects to model the inherent correlation between sensitivity and specificity and a random error associated with various tests evaluated in a given study. We present the accuracy of 11 tests used to triage women with minor cervical lesions to detect cervical precancer. Finally, we compare the results with those from a contrast-based model which expresses the linear predictor as a contrast to a comparator test. The proposed arm-based model is more appealing than the contrast-based model since the former permits more straightforward interpretation of the parameters, makes use of all available data yielding shorter credible intervals, and models more natural variance-covariance matrix structures.

Metaprop: a Stata command to perform meta-analysis of binomial data.

BACKGROUND: Meta-analyses have become an essential tool in synthesizing evidence on clinical and epidemiological questions derived from a multitude of similar studies assessing the particular issue. Appropriate and accessible statistical software is needed to produce the summary statistic of interest. METHODS: Metaprop is a statistical program implemented to perform meta-analyses of proportions in Stata. It builds further on the existing Stata procedure metan which is typically used to pool effects (risk ratios, odds ratios, differences of risks or means) but which is also used to pool proportions. Metaprop implements procedures which are specific to binomial data and allows computation of exact binomial and score test-based confidence intervals. It provides appropriate methods for dealing with proportions close to or at the margins where the normal approximation procedures often break down, by use of the binomial distribution to model the within-study variability or by allowing Freeman-Tukey double arcsine transformation to stabilize the variances. Metaprop was applied on two published meta-analyses: 1) prevalence of HPV-infection in women with a Pap smear showing ASC-US; 2) cure rate after treatment for cervical precancer using cold coagulation. RESULTS: The first meta-analysis showed a pooled HPV-prevalence of 43% (95% CI: 38%-48%). In the second meta-analysis, the pooled percentage of cured women was 94% (95% CI: 86%-97%). CONCLUSION: By using metaprop, no studies with 0% or 100% proportions were excluded from the meta-analysis. Furthermore, study specific and pooled confidence intervals always were within admissible values, contrary to the original publication, where metan was used.

Plasmodium falciparum infection patterns since birth and risk of severe malaria: a nested case-control study in children on the coast of Kenya.

Children in malaria endemic areas acquire immunity to severe malaria faster than to mild malaria. Only a minority of children suffers from severe malaria and it is not known what determines this. The aim of this study was to establish how P. falciparum infections during the first years of life affect the risk of severe malaria. A matched case-control study was nested within a large birth cohort set up to study the immunoepidemiology of pneumococci on the Kenyan coast. Infection patterns in three-monthly blood samples in cohort children admitted to hospital with severe malaria were compared to controls matched on age, residential location and time of sampling. P. falciparum detected at least once from birth conferred an increased risk of severe malaria and particularly if multiclonal infections, as characterized by genotyping of a polymorphic antigen gene, were ever detected. The results show for the first time that children with severe malaria have more infections early in life compared to community controls. These findings provide important insights on the immunity to severe disease, knowledge essential for the development of a vaccine against severe malaria.