Methodology and preliminary results of a systematic literature review of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis.

A systematic review was conducted to identify studies with data for statistical meta-analyses of sensitivity (Se) and specificity (Sp) of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis (bTB) in cattle. Members of a working group (WG) developed and tested search criteria and developed a standardised two-stage review process, to identify primary studies with numerator and denominator data for test performance and an agreed range of covariate data. No limits were applied to year, language, region or type of test in initial searches of electronic databases. In stage 1, titles and available abstracts were reviewed. References that complied with stage 1 selection criteria were reviewed in entirety and agreed data were extracted from references that complied with stage 2 selection criteria. At stage 1, 9782 references were reviewed and 261 (2.6%) passed through to stage 2 where 215 English language references were each randomly allocated to two of 18 WG reviewers and 46 references in other languages were allocated to native speakers. Agreement regarding eligibility between reviewers of the same reference at stage 2 was moderate (Kappa statistic = 0.51) and a resolution procedure was conducted. Only 119 references (published 1934-2009) were identified with eligible performance estimates for one or more of 14 different diagnostic test types; despite a comprehensive search strategy and the global impact of bTB. Searches of electronic databases for diagnostic test performance data were found to be nonspecific with regard to identifying references with diagnostic test Se or Sp data. Guidelines for the content of abstracts to research papers reporting diagnostic test performance are presented. The results of meta-analyses of the sensitivity and specificity of the tests, and of an evaluation of the methodological quality of the source references, are presented in accompanying papers (Nuñez-Garcia et al., 2017; Downs et al., 2017).

Evaluation of the methodological quality of studies of the performance of diagnostic tests for bovine tuberculosis using QUADAS.

There has been little assessment of the methodological quality of studies measuring the performance (sensitivity and/or specificity) of diagnostic tests for animal diseases. In a systematic review, 190 studies of tests for bovine tuberculosis (bTB) in cattle (published 1934-2009) were assessed by at least one of 18 reviewers using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) checklist adapted for animal disease tests. VETQUADAS (VQ) included items measuring clarity in reporting (n = 3), internal validity (n = 9) and external validity (n = 2). A similar pattern for compliance was observed in studies of different diagnostic test types. Compliance significantly improved with year of publication for all items measuring clarity in reporting and external validity but only improved in four of the nine items measuring internal validity (p < 0.05). 107 references, of which 83 had performance data eligible for inclusion in a meta-analysis were reviewed by two reviewers. In these references, agreement between reviewers' responses was 71% for compliance, 32% for unsure and 29% for non-compliance. Mean compliance with reporting items was 2, 5.2 for internal validity and 1.5 for external validity. The index test result was described in sufficient detail in 80.1% of studies and was interpreted without knowledge of the reference standard test result in only 33.1%. Loss to follow-up was adequately explained in only 31.1% of studies. The prevalence of deficiencies observed may be due to inadequate reporting but may also reflect lack of attention to methodological issues that could bias the results of diagnostic test performance estimates. QUADAS was a useful tool for assessing and comparing the quality of studies measuring the performance of diagnostic tests but might be improved further by including explicit assessment of population sampling strategy.

Meta-analyses of the sensitivity and specificity of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis in the UK and Ireland.

Bovine Tuberculosis (bTB) in cattle is a global health problem and eradication of the disease requires accurate estimates of diagnostic test performance to optimize their efficiency. The objective of this study was, through statistical meta-analyses, to obtain estimates of sensitivity (Se) and specificity (Sp), for 14 different ante-mortem and post-mortem diagnostic tests for bTB in cattle. Using data from a systematic review of the scientific literature (published 1934-2009) diagnostic Se and Sp were estimated using Bayesian logistic regression models adjusting for confounding factors. Random effect terms were used to account for unexplained heterogeneity. Parameters in the models were implemented using Markov Chain Monte Carlo (MCMC), and posterior distributions for the diagnostic parameters with adjustment for covariates (confounding factors) were obtained using the inverse logit function. Estimates for Se and/or Sp of the tuberculin skin tests and the IFN-γ blood test were compared with estimates published 2010-2015. Median Se for the single intradermal comparative cervical tuberculin skin (SICCT) test (standard interpretation) was 0.50 and Bayesian credible intervals (CrI) were wide (95% CrI 0.26, 0.78). Median Sp for the SICCT test was 1.00 (95% CrI 0.99, 1.00). Estimates for the IFN-γ blood test Bovine Purified Protein Derivative (PPD)-Avian PPD and Early Secreted Antigen target 6 and Culture Filtrate Protein 10 (ESAT-6/CFP10) ESAT6/CFP10 were 0.67 (95% CrI 0.49, 0.82) and 0.78 (95% CrI 0.60, 0.90) respectively for Se, and 0.98 (95% CrI 0.96, 0.99) and 0.99 (95% CrI 0.99, 1.00) for Sp. The study provides an overview of the accuracy of a range of contemporary diagnostic tests for bTB in cattle. Better understanding of diagnostic test performance is essential for the design of effective control strategies and their evaluation.

Assessing the effects of the first 2 years of industry-led badger culling in England on the incidence of bovine tuberculosis in cattle in 2013-2015.

Culling badgers to control the transmission of bovine tuberculosis (TB) between this wildlife reservoir and cattle has been widely debated. Industry-led culling began in Somerset and Gloucestershire between August and November 2013 to reduce local badger populations. Industry-led culling is not designed to be a randomized and controlled trial of the impact of culling on cattle incidence. Nevertheless, it is important to monitor the effects of the culling and, taking the study limitations into account, perform a cautious evaluation of the impacts. A standardized method for selecting areas matched to culling areas in factors found to affect cattle TB risk has been developed to evaluate the impact of badger culling on cattle TB incidence. The association between cattle TB incidence and badger culling in the first 2 years has been assessed. Descriptive analyses without controlling for confounding showed no association between culling and TB incidence for Somerset, or for either of the buffer areas for the first 2 years since culling began. A weak association was observed in Gloucestershire for Year 1 only. Multivariable analysis adjusting for confounding factors showed that reductions in TB incidence were associated with culling in the first 2 years in both the Somerset and Gloucestershire intervention areas when compared to areas with no culling (incidence rate ratio (IRR): 0.79, 95% CI: 0.72-0.87, p < .001 and IRR: 0.42, 95% CI: 0.34-0.51, p < .001, respectively). An increase in incidence was associated with culling in the 2-km buffer surrounding the Somerset intervention area (IRR: 1.38, 95% CI: 1.09-1.75, p = .008), but not in Gloucestershire (IRR: 0.91, 95% CI: 0.77-1.07, p = .243). As only 2 intervention areas with 2 years of data are available for analysis, and the biological cause-effect relationship behind the statistical associations is difficult to determine, it would be unwise to use these findings to develop generalizable inferences about the effectiveness of the policy at present.

Estimating the hidden burden of bovine tuberculosis in Great Britain.

The number of cattle herds placed under movement restrictions in Great Britain (GB) due to the suspected presence of bovine tuberculosis (bTB) has progressively increased over the past 25 years despite an intensive and costly test-and-slaughter control program. Around 38% of herds that clear movement restrictions experience a recurrent incident (breakdown) within 24 months, suggesting that infection may be persisting within herds. Reactivity to tuberculin, the basis of diagnostic testing, is dependent on the time from infection. Thus, testing efficiency varies between outbreaks, depending on weight of transmission and cannot be directly estimated. In this paper, we use Approximate Bayesian Computation (ABC) to parameterize two within-herd transmission models within a rigorous inferential framework. Previous within-herd models of bTB have relied on ad-hoc methods of parameterization and used a single model structure (SORI) where animals are assumed to become detectable by testing before they become infectious. We study such a conventional within-herd model of bTB and an alternative model, motivated by recent animal challenge studies, where there is no period of epidemiological latency before animals become infectious (SOR). Under both models we estimate that cattle-to-cattle transmission rates are non-linearly density dependent. The basic reproductive ratio for our conventional within-herd model, estimated for scenarios with no statutory controls, increases from 1.5 (0.26-4.9; 95% CI) in a herd of 30 cattle up to 4.9 (0.99-14.0) in a herd of 400. Under this model we estimate that 50% (33-67) of recurrent breakdowns in Britain can be attributed to infection missed by tuberculin testing. However this figure falls to 24% (11-42) of recurrent breakdowns under our alternative model. Under both models the estimated extrinsic force of infection increases with the burden of missed infection. Hence, improved herd-level testing is unlikely to reduce recurrence unless this extrinsic infectious pressure is simultaneously addressed.

Estimation of the relative sensitivity of the comparative tuberculin skin test in tuberculous cattle herds subjected to depopulation.

Bovine tuberculosis (bTB) is one of the most serious economic animal health problems affecting the cattle industry in Great Britain (GB), with incidence in cattle herds increasing since the mid-1980s. The single intradermal comparative cervical tuberculin (SICCT) test is the primary screening test in the bTB surveillance and control programme in GB and Ireland. The sensitivity (ability to detect infected cattle) of this test is central to the efficacy of the current testing regime, but most previous studies that have estimated test sensitivity (relative to the number of slaughtered cattle with visible lesions [VL] and/or positive culture results) lacked post-mortem data for SICCT test-negative cattle. The slaughter of entire herds ("whole herd slaughters" or "depopulations") that are infected by bTB are occasionally conducted in GB as a last-resort control measure to resolve intractable bTB herd breakdowns. These provide additional post-mortem data for SICCT test-negative cattle, allowing a rare opportunity to calculate the animal-level sensitivity of the test relative to the total number of SICCT test-positive and negative VL animals identified post-mortem (rSe). In this study, data were analysed from 16 whole herd slaughters (748 SICCT test-positive and 1031 SICCT test-negative cattle) conducted in GB between 1988 and 2010, using a bayesian hierarchical model. The overall rSe estimate of the SICCT test at the severe interpretation was 85% (95% credible interval [CI]: 78-91%), and at standard interpretation was 81% (95% CI: 70-89%). These estimates are more robust than those previously reported in GB due to inclusion of post-mortem data from SICCT test-negative cattle.