The predicted impact of tuberculosis preventive therapy: the importance of disease progression assumptions.

BACKGROUND: Following infection with Mycobacterium tuberculosis (M.tb), individuals may rapidly develop tuberculosis (TB) disease or enter a "latent" infection state with a low risk of progression to disease. Mathematical models use a variety of structures and parameterisations to represent this process. The effect of these different assumptions on the predicted impact of TB interventions has not been assessed. METHODS: We explored how the assumptions made about progression from infection to disease affect the predicted impact of TB preventive therapy. We compared the predictions using three commonly used model structures, and parameters derived from two different data sources. RESULTS: The predicted impact of preventive therapy depended on both the model structure and parameterisation. At a baseline annual TB incidence of 500/100,000, there was a greater than 2.5-fold difference in the predicted reduction in incidence due to preventive therapy (ranging from 6 to 16%), and the number needed to treat to avert one TB case varied between 67 and 157. The relative importance of structure and parameters depended on baseline TB incidence and assumptions about the efficacy of preventive therapy, with the choice of structure becoming more important at higher incidence. CONCLUSIONS: The assumptions use to represent progression to disease in models are likely to influence the predicted impact of preventive therapy and other TB interventions. Modelling estimates of TB preventive therapy should consider routinely incorporating structural uncertainty, particularly in higher burden settings. Not doing so may lead to inaccurate and over confident conclusions, and sub-optimal evidence for decision making

Modelling the impact of tuberculosis preventive therapy: the importance of disease progression assumptions

AbstractBackgroundFollowing infection with Mycobacterium tuberculosis (M.tb) individuals may rapidly develop tuberculosis (TB) disease or enter “latent” infection state with a low risk of progression to disease. The mechanisms underlying this process are incompletely known. Mathematical models use a variety of structures and parameterisations to represent this progression from infection with M.tb to disease. This structural and parametric uncertainty may affect the predicted impact of interventions leading to incorrect conclusions and decision making.MethodsWe used a simple dynamic transmission model to explore the effect of uncertainty in model structure and parameterisation on the predicted impact of scaling up preventive therapy. We compared three commonly used model structures and used parameter values from two different data sources. Models 1 and 2 are equally consistent with observations of the time from infection to disease. Model 3, produces a worse fit to the data, but is widely used in published modelling studies. We simulated treatment of 5% of all M.tb infected individuals per year in a population of 10,000 and calculated the reduction in TB incidence and number needed to treat to avert one TB case over 10 years.ResultsThe predicted impact of the preventive therapy intervention depended on both the model structure and the parameterisation of that structure. For example, at a baseline annual TB incidence of 500/100,000, the impact ranged from 11% to 27% and the number needed to treat to avert one TB case varied between 38 and 124. The relative importance of structure and parameters varied depending on the baseline incidence of TB.DiscussionOur analysis shows that the choice of model structure and the parameterisation can influence the predicted impact of interventions. Modelling studies should consider incorporating structural uncertainty in their analysis. Not doing so may lead to incorrect conclusions on the impact of interventions.</jats:sec

Variance-based sensitivity analysis of tuberculosis transmission models

Mathematical models are widely used to provide evidence to inform policies for tuberculosis (TB) control. These models contain many sources of input uncertainty including the choice of model structure, parameter values and input data. Quantifying the role of these different sources of input uncertainty on the model outputs is important for understanding model dynamics and improving evidence for policy making. In this paper, we applied the Sobol sensitivity analysis method to a TB transmission model used to simulate the effects of a hypothetical population-wide screening strategy. We demonstrated how the method can be used to quantify the importance of both model parameters and model structure and how the analysis can be conducted on groups of inputs. Uncertainty in the model outputs was dominated by uncertainty in the intervention parameters. The important inputs were context dependent, depending on the setting, time horizon and outcome measure considered. In particular, the choice of model structure had an increasing effect on output uncertainty in high TB incidence settings. Grouping inputs identified the same influential inputs. Wider use of the Sobol method could inform ongoing development of infectious disease models and improve the use of modelling evidence in decision making

A 275–425-GHz Tunerless Waveguide Receiver Based on AlN-Barrier SIS Technology

We report on a 275–425-GHz tunerless waveguide receiver with a 3.5–8-GHz IF. As the mixing element, we employ a high-current-density Nb–AlN–Nb superconducting–insulating– superconducting (SIS) tunnel junction. Thanks to the combined use of AlN-barrier SIS technology and a broad bandwidth waveguide to thin-film microstrip transition, we are able to achieve an unprecedented 43% instantaneous bandwidth, limited by the receiver's corrugated feedhorn. The measured double-sideband (DSB) receiver noise temperature, uncorrected for optics loss, ranges from 55 K at 275 GHz, 48 K at 345 GHz, to 72 K at 425 GHz. In this frequency range, the mixer has a DSB conversion loss of 2.3 1 dB. The intrinsic mixer noise is found to vary between 17–19 K, of which 9 K is attributed to shot noise associated with leakage current below the gap. To improve reliability, the IF circuit and bias injection are entirely planar by design. The instrument was successfully installed at the Caltech Submillimeter Observatory (CSO), Mauna Kea, HI, in October 2006

Guest Editorial

A novel blood test for tuberculosis prevention and treatmen

Potential impact of tuberculosis vaccines in China, South Africa, and India.

More effective tuberculosis vaccines are needed to help reach World Health Organization tuberculosis elimination goals. Insufficient evidence exists on the potential impact of future tuberculosis vaccines with varying characteristics and in different epidemiological settings. To inform vaccine development decision making, we modeled the impact of hypothetical tuberculosis vaccines in three high-burden countries. We calibrated Mycobacterium tuberculosis (M.tb) transmission models to age-stratified demographic and epidemiological data from China, South Africa, and India. We varied vaccine efficacy to prevent infection or disease, effective in persons M.tb uninfected or infected, and duration of protection. We modeled routine early-adolescent vaccination and 10-yearly mass campaigns from 2025. We estimated median percentage population-level tuberculosis incidence rate reduction (IRR) in 2050 compared to a no new vaccine scenario. In all settings, results suggested vaccines preventing disease in M.tb-infected populations would have greatest impact by 2050 (10-year, 70% efficacy against disease, IRR 51%, 52%, and 54% in China, South Africa, and India, respectively). Vaccines preventing reinfection delivered lower potential impact (IRR 1, 12, and 17%). Intermediate impact was predicted for vaccines effective only in uninfected populations, if preventing infection (IRR 21, 37, and 50%) or disease (IRR 19, 36, and 51%), with greater impact in higher-transmission settings. Tuberculosis vaccines have the potential to deliver substantial population-level impact. For prioritizing impact by 2050, vaccine development should focus on preventing disease in M.tb-infected populations. Preventing infection or disease in uninfected populations may be useful in higher transmission settings. As vaccine impact depended on epidemiology, different development strategies may be required

Informing Balanced Investment in Services and Health Systems: A Case Study of Priority Setting for Tuberculosis Interventions in South Africa.

OBJECTIVES: Health systems face nonfinancial constraints that can influence the opportunity cost of interventions. Empirical methods to explore their impact, however, are underdeveloped. We develop a conceptual framework for defining health system constraints and empirical estimation methods that rely on routine data. We then present an empirical approach for incorporating nonfinancial constraints in cost-effectiveness models of health benefit packages for the health sector. METHODS: We illustrate the application of this approach through a case study of defining a package of services for tuberculosis case-finding in South Africa. An economic model combining transmission model outputs with unit costs was developed to examine the cost-effectiveness of alternative screening and diagnostic algorithms. Constraints were operationalized as restrictions on achievable coverage based on: (1) financial resources; (2) human resources; and (3) policy constraints around diagnostics purchasing. Cost-effectiveness of the interventions was assessed under one "unconstrained" and several "constrained" scenarios. For the unconstrained scenario, incremental cost-effectiveness ratios were estimated with and without the costs of "relaxing" constraints. RESULTS: We find substantial differences in incremental cost-effectiveness ratios across scenarios, leading to variations in the decision rules for prioritizing interventions. In constrained scenarios, the limiting factor for most interventions was not financial, but rather the availability of human resources. CONCLUSIONS: We find that optimal prioritization among different tuberculosis control strategies in South Africa is influenced by whether and how constraints are taken into consideration. We thus demonstrate both the importance and feasibility of considering nonfinancial constraints in health sector resource allocation models

Saccadic compensation for reflexive optokinetic nystagmus just as good as compensation for volitional pursuit

The natural viewing behavior of moving observers ideally requires target-selecting saccades to be coordinated with automatic gaze-stabilizing eye movements such as optokinetic nystagmus. However, it is unknown whether saccade plans can compensate for reflexive movement of the eye during the variable saccade latency period, and it is unclear whether reflexive nystagmus is even accompanied by extraretinal signals carrying the eye movement information that could potentially underpin such compensation. We show that saccades do partially compensate for optokinetic nystagmus that displaces the eye during the saccade latency period. Moreover, this compensation is as good as for displacements due to voluntary smooth pursuit. In other words, the saccade system appears to be as well coordinated with reflexive nystagmus as it is with volitional pursuit, which in turn implies that extraretinal signals accompany nystagmus and are just as informative as those accompanying pursuit

An evaluation of tuberculosis contact investigations against national standards.

BACKGROUND: Contact tracing is a key element in England's 2015 collaborative TB strategy, although proposed indicators of successful contact tracing remain undescribed. METHODS: We conducted descriptive and multivariable analyses of contact tracing of TB cases in London between 1 July 2012 and 31 December 2015 using cohort review data from London's TB Register, identifying characteristics associated with improved indicators and yield. RESULTS: Of the pulmonary TB cases notified, 60% (2716/4561) had sufficient information for inclusion. Of these, 91% (2481/2716) had at least 1 contact (median: 4/case (IQR: 2-6)) identified, with 86% (10 251/11 981) of these contacts evaluated. 4.1% (177/4328), 1.3% (45/3421) and 0.70% (51/7264) of evaluated contacts of pulmonary smear-positive, pulmonary smear-negative and non-pulmonary cases, respectively, had active disease. Cases who were former prisoners or male were less likely to have at least one contact identified than those never imprisoned or female, respectively. Cases diagnosed at clinics with more directly observed therapy or social workers were more likely to have one or more contacts identified. Contacts screened at a different clinic to their index case or of male index cases were less likely to be evaluated than those screened at the same clinic or of women, respectively; yield of active disease was similar by sex. 10% (490/4850) of evaluated child contacts had latent TB infection. CONCLUSIONS: These are the first London-wide estimates of TB contact tracing indicators which are important for monitoring the strategy's success and informing risk assessment of index cases. Understanding why differences in indicators occur between groups could improve contact tracing outcomes

Should NICE reconsider the 2016 UK guidelines on TB contact tracing? A cost-effectiveness analysis of contact investigations in London.

BACKGROUND: In January 2016, clinical TB guidance in the UK changed to no longer recommend screening contacts of non-pulmonary, non-laryngeal (ETB) index cases. However, no new evidence was cited for this change, and there is evidence that screening these contacts may be worthwhile. The objective of this study was to estimate the cost-effectiveness of screening contacts of adult ETB cases and adult pulmonary or laryngeal TB (PTB) cases in London, UK. METHODS: We carried out a cross-sectional analysis of data collected on TB index cases and contacts in the London TB register and an economic evaluation using a static model describing contact tracing outcomes. Incremental cost-effectiveness ratios (ICERs) were calculated using no screening as the baseline comparator. All adult TB cases (≥15 years old) in London from 2012 to 2015, and their contacts, were eligible (2465/5084 PTB and 2559/6090 ETB index cases were included). RESULTS: Assuming each contact with PTB infects one person/month, the ICER of screening contacts of ETB cases was £78 000/quality-adjusted life-years (QALY) (95% CI 39 000 to 140 000), and screening contacts of PTB cases was £30 000/QALY (95% CI 18 000 to 50 000). The ICER of screening contacts of ETB cases was £30 000/QALY if each contact with PTB infects 3.4 people/month. Limitations of this study include the use of self-reported symptomatic periods and lack of knowledge about onward transmission from PTB contacts. CONCLUSIONS: Screening contacts of ETB cases in London was almost certainly not cost-effective at any conventional willingness-to-pay threshold in England, supporting recent changes to National Institute for Health and Care Excellence national guidelines