Title: Validation of New Technologies for Diagnostic Evaluation of Tuberculosis (VANTDET)
Funder: Department of Health (England)

Abstract: Background: Despite the long-standing national and global burden of tuberculosis (TB) we still lack a rapid test of high diagnostic sensitivity and specificity. Current microbiological tests lack sensitivity; while immunological tests such as interferon-gamma release-assays (IGRA) lack specificity. A rapid test of high sensitivity and specificity for active TB i.e. a test that could distinguish active TB from non-TB illnesses or latent TB infection would transform management of TB by shortening time to treatment lessening morbidity and mortality and curtailing spread of infection. A test of very high sensitivity for TB infection even without distinguishing active from latent TB infection would be clinically very useful as it would provide a rapid ‘rule-out’ test. Given the inadequacy of the current TB diagnostic toolkit and the growing burden and spread of TB in the UK rigorous clinical validation of promising new tools could deliver a step-change in NHS practice. Hypotheses: 1. Recently identified gene expression proteomic and cellular immunological signatures accurately differentiate active TB from other diseases and latent TB in routine clinical practice;2. Our novel chemokine gene expression assay provides sufficient diagnostic sensitivity to reliably exclude the diagnosis of active TBAims: We will prospectively validate the role of novel tests in diagnostic evaluation of TB in routine NHS clinical practice. Our specific aims are:1. To validate the role of previously identified whole blood gene-expression signatures in diagnostic evaluation of active TB using gene-expression microarray and RT-PCR; 2. To validate the role of previously identified serum proteomic signatures in diagnostic evaluation of active TB using mass spectrometry;3. To validate our recently established cellular immunological signature in diagnostic evaluation of active TB using flow cytometry; 4. To validate our recently established antigen-stimulated whole blood chemokine-based RT PCR assay for rapid exclusion of suspected TB; 5. To establish optimal diagnostic algorithms that define the role of these new tests in the routine diagnostic assessment of patients with suspected active TB;6. To assess the cost effectiveness and overall health economic impact from an NHS perspective of the novel tests and diagnostic algorithms defined in this proposal.Outcomes: Novel tests will be validated in patients (n=1012) with a final diagnosis of TB compared to patients in whom active TB has been excluded. Patients were previously recruited for the NIHR-funded longitudinal cohort study ‘IGRAs in diagnostic Evaluation of Active TB’ (IDEA). Test performance will be assessed for the two subgroups diagnosed with TB (culture-positive and culture-negative TB) as well as for both groups combined (all TB). Our rigorous case definitions are based on robust established criteria that we previously validated in routine NHS practice (Dosanjh 2008). The new tests will be compared to currently available diagnostic tests including IGRA microscopy and Mtb culture.Output: We will validate the role of new diagnostic tests for TB in routine NHS practice delivering blood tests that can rapidly rule-in and rule-out a diagnosis of TB. Test performance characteristics will be generalisable thanks to the study design and the real-life prospectively recruited IDEA patient population. Optimal diagnostic assessment algorithms incorporating the new tests in routine practice will be determined. Health economic analysis will quantify the cost effectiveness of the novel tests from an NHS perspective.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION