Systematic review, meta-analysis and economic modelling of molecular diagnostic tests for antibiotic resistance in tuberculosis.

BACKGROUND: Drug-resistant tuberculosis (TB), especially multidrug-resistant (MDR, resistance to rifampicin and isoniazid) disease, is associated with a worse patient outcome. Drug resistance diagnosed using microbiological culture takes days to weeks, as TB bacteria grow slowly. Rapid molecular tests for drug resistance detection (1 day) are commercially available and may promote faster initiation of appropriate treatment. OBJECTIVES: To (1) conduct a systematic review of evidence regarding diagnostic accuracy of molecular genetic tests for drug resistance, (2) conduct a health-economic evaluation of screening and diagnostic strategies, including comparison of alternative models of service provision and assessment of the value of targeting rapid testing at high-risk subgroups, and (3) construct a transmission-dynamic mathematical model that translates the estimates of diagnostic accuracy into estimates of clinical impact. REVIEW METHODS AND DATA SOURCES: A standardised search strategy identified relevant studies from EMBASE, PubMed, MEDLINE, Bioscience Information Service (BIOSIS), System for Information on Grey Literature in Europe Social Policy & Practice (SIGLE) and Web of Science, published between 1 January 2000 and 15 August 2013. Additional 'grey' sources were included. Quality was assessed using quality assessment of diagnostic accuracy studies version 2 (QUADAS-2). For each diagnostic strategy and population subgroup, a care pathway was constructed to specify which medical treatments and health services that individuals would receive from presentation to the point where they either did or did not complete TB treatment successfully. A total cost was estimated from a health service perspective for each care pathway, and the health impact was estimated in terms of the mean discounted quality-adjusted life-years (QALYs) lost as a result of disease and treatment. Costs and QALYs were both discounted at 3.5% per year. An integrated transmission-dynamic and economic model was used to evaluate the cost-effectiveness of introducing rapid molecular testing (in addition to culture and drug sensitivity testing). Probabilistic sensitivity analysis was performed to evaluate the impact on cost-effectiveness of diagnostic and treatment time delays, diagnosis and treatment costs, and associated QALYs. RESULTS: A total of 8922 titles and abstracts were identified, with 557 papers being potentially eligible. Of these, 56 studies contained sufficient test information for analysis. All three commercial tests performed well when detecting drug resistance in clinical samples, although with evidence of heterogeneity between studies. Pooled sensitivity for GenoType® MTBDRplus (Hain Lifescience, Nehren, Germany) (isoniazid and rifampicin resistance), INNO-LiPA Rif.TB® (Fujirebio Europe, Ghent, Belgium) (rifampicin resistance) and Xpert® MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) (rifampicin resistance) was 83.4%, 94.6%, 95.4% and 96.8%, respectively; equivalent pooled specificity was 99.6%, 98.2%, 99.7% and 98.4%, respectively. Results of the transmission model suggest that all of the rapid assays considered here, if added to the current diagnostic pathway, would be cost-saving and achieve a reduction in expected QALY loss compared with current practice. GenoType MTBDRplus appeared to be the most cost-effective of the rapid tests in the South Asian population, although results were similar for GeneXpert. In all other scenarios GeneXpert appeared to be the most cost-effective strategy. CONCLUSIONS: Rapid molecular tests for rifampicin and isoniazid resistance were sensitive and specific. They may also be cost-effective when added to culture drug susceptibility testing in the UK. There is global interest in point-of-care testing and further work is needed to review the performance of emerging tests and the wider health-economic impact of decentralised testing in clinics and primary care, as well as non-health-care settings, such as shelters and prisons. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001537. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Noninvasive assessment of endothelial dysfunction by brachial artery flow-mediated dilatation in prediction of coronary artery disease in Indian subjects.

BACKGROUND: A noninvasive technique for testing endothelial function by ultrasound measurement of flow-mediated dilatation has recently generated considerable interest as a marker of atherosclerosis, and in the prediction of clinical coronary events and coronary artery disease. METHODS AND RESULTS: We measured the flow-mediated dilatation of the brachial artery (endothelium-dependent vasodilatation) in 136 subjects, with or without evidence of coronary artery disease. Endothelial dysfunction was diagnosed if flow-mediated dilatation was less than 4.5%. Of the 136 subjects (age group 40-70 years) recruited for the study, 94 were males and 42 females. Sixty-eight subjects had evidence of coronary artery disease as diagnosed by documented hospitalization due to myocardial infarction or acute coronary syndrome, proved by coronary angiography when feasible or noninvasive cardiac evaluation. Endothelial dysfunction was detected in 90 subjects (66.2%). Prevalence of coronary artery disease was higher among subjects with endothelial dysfunction compared to those without (57.5% v. 34.7%, p=0.013). Prevalence of endothelial dysfunction was significantly higher among subjects with coronary artery disease as compared to those without coronary artery disease (76.4% v. 55.8%, p=0.012). The present study showed a sensitivity of 76%, specificity of 44%, positive predictive value of 58% and negative predictive value of 65% for endothelial dysfunction in the prediction of coronary artery disease. Multiple regression analysis using coronary artery disease as a dependent variable revealed a statistically significant association with endothelial dysfunction (p=0.033) even after the inclusion of traditional risk factors into the model. CONCLUSIONS: We conclude that endothelial dysfunction shows a strong association with coronary artery disease and can be a useful noninvasive tool for the evaluation of coronary artery disease.