Peer-reviewed publications

  • Interferon-gamma release assay for the diagnosis of latent tuberculosis infection: A latent-class analysis.
    Doan TN, Eisen DP, Rose MT, Slack A, Stearnes G, McBryde ES.
    PLoS One. 2017 Nov 28;12(11):e0188631. doi: 10.1371/journal.pone.0188631. eCollection 2017.

    BACKGROUND:

    Accurate diagnosis and subsequent treatment of latent tuberculosis infection (LTBI) is essential for TB elimination. However, the absence of a gold standard test for diagnosing LTBI makes assessment of the true prevalence of LTBI and the accuracy of diagnostic tests challenging. Bayesian latent class models can be used to make inferences about disease prevalence and the sensitivity and specificity of diagnostic tests using data on the concordance between tests. We performed the largest meta-analysis to date aiming to evaluate the performance of tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) for LTBI diagnosis in various patient populations using Bayesian latent class modelling.

    METHODS:

    Systematic search of PubMeb, Embase and African Index Medicus was conducted without date and language restrictions on September 11, 2017 to identify studies that compared the performance of TST and IGRAs for LTBI diagnosis. Two IGRA methods were considered: QuantiFERON-TB Gold In Tube (QFT-GIT) and T-SPOT.TB. Studies were included if they reported 2x2 agreement data between TST and QFT-GIT or T-SPOT.TB. A Bayesian latent class model was developed to estimate the sensitivity and specificity of TST and IGRAs in various populations, including immune-competent adults, immune-compromised adults and children. A TST cut-off value of 10 mm was used for immune-competent subjects and 5 mm for immune-compromised individuals.

    FINDINGS:

    A total of 157 studies were included in the analysis. In immune-competent adults, the sensitivity of TST and QFT-GIT were estimated to be 84% (95% credible interval [CrI] 82-85%) and 52% (50-53%), respectively. The specificity of QFT-GIT was 97% (96-97%) in non-BCG-vaccinated and 93% (92-94%) in BCG-vaccinated immune-competent adults. The estimated figures for TST were 100% (99-100%) and 79% (76-82%), respectively. T-SPOT.TB has comparable specificity (97% for both tests) and better sensitivity (68% versus 52%) than QFT-GIT in immune-competent adults. In immune-compromised adults, both TST and QFT-GIT display low sensitivity but high specificity. QFT-GIT and TST are equally specific (98% for both tests) in non-BCG-vaccinated children; however, QFT-GIT is more specific than TST (98% versus 82%) in BCG-vaccinated group. TST is more sensitive than QFT-GIT (82% versus 73%) in children.

    CONCLUSIONS:

    This study is the first to assess the utility of TST and IGRAs for LTBI diagnosis in different population groups using all available data with Bayesian latent class modelling. Our results challenge the current beliefs about the performance of LTBI screening tests, and have important implications for LTBI screening policy and practice. We estimated that the performance of IGRAs is not as reliable as previously measured in the general population. However, IGRAs are not or minimally affected by BCG and should be the preferred tests in this setting. Adoption of IGRAs in settings where BCG is widely administered will allow for a more accurate identification and treatment of LTBI.

  • Modular programming for tuberculosis control, the "AuTuMN" platform.
    Trauer JM, Ragonnet R, Doan TN, McBryde ES.
    BMC Infect Dis. 2017 Aug 7;17(1):546. doi: 10.1186/s12879-017-2648-6.

    BACKGROUND:

    Tuberculosis (TB) is now the world's leading infectious killer and major programmatic advances will be needed if we are to meet the ambitious new End TB Targets. Although mathematical models are powerful tools for TB control, such models must be flexible enough to capture the complexity and heterogeneity of the global TB epidemic. This includes simulating a disease that affects age groups and other risk groups differently, has varying levels of infectiousness depending upon the organ involved and varying outcomes from treatment depending on the drug resistance pattern of the infecting strain.

    RESULTS:

    We adopted sound basic principles of software engineering to develop a modular software platform for simulation of TB control interventions ("AuTuMN"). These included object-oriented programming, logical linkage between modules and consistency of code syntax and variable naming. The underlying transmission dynamic model incorporates optional stratification by age, risk group, strain and organ involvement, while our approach to simulating time-variant programmatic parameters better captures the historical progression of the epidemic. An economic model is overlaid upon this epidemiological model which facilitates comparison between new and existing technologies. A "Model runner" module allows for predictions of future disease burden trajectories under alternative scenario situations, as well as uncertainty, automatic calibration, cost-effectiveness and optimisation. The model has now been used to guide TB control strategies across a range of settings and countries, with our modular approach enabling repeated application of the tool without the need for extensive modification for each application.

    CONCLUSIONS:

    The modular construction of the platform minimises errors, enhances readability and collaboration between multiple programmers and enables rapid adaptation to answer questions in a broad range of contexts without the need for extensive re-programming. Such features are particularly important in simulating an epidemic as complex and diverse as TB.

    KEYWORDS:

    Disease transmission, infectious; Global health; Models, biological; Software; Tuberculosis; Tuberculosis, multidrug-resistant

  • Optimally capturing latency dynamics in models of tuberculosis transmission.
    Ragonnet R, Trauer JM, Scott N, Meehan MT, Denholm JT, McBryde ES.
    Epidemics. 2017 Jun 16. pii: S1755-4365(17)30017-8. doi: 10.1016/j.epidem.2017.06.002. [Epub ahead of print]

    Although different structures are used in modern tuberculosis (TB) models to simulate TB latency, it remains unclear whether they are all capable of reproducing the particular activation dynamics empirically observed. We aimed to determine which of these structures replicate the dynamics of progression accurately. We reviewed 88 TB-modelling articles and classified them according to the latency structure employed. We then fitted these different models to the activation dynamics observed from 1352 infected contacts diagnosed in Victoria (Australia) and Amsterdam (Netherlands) to obtain parameter estimates. Six different model structures were identified, of which only those incorporating two latency compartments were capable of reproducing the activation dynamics empirically observed. We found important differences in parameter estimates by age. We also observed marked differences between our estimates and the parameter values used in many previous models. In particular, when two successive latency phases are considered, the first period should have a duration that is much shorter than that used in previous studies. In conclusion, structures incorporating two latency compartments and age-stratification should be employed to accurately replicate the dynamics of TB latency. We provide a catalogue of parameter values and an approach to parameter estimation from empiric data for calibration of future TB-models.

    KEYWORDS:

    Mathematical modelling; Parameter estimation; Risk of disease activation; Tuberculosis latency

  • A user-friendly mathematical modelling web interface to assist local decision making in the fight against drug-resistant tuberculosis.
    Ragonnet R, Trauer JM, Denholm JT, Marais BJ, McBryde ES.
    BMC Infect Dis. 2017 May 30;17(1):374. doi: 10.1186/s12879-017-2478-6.

    Multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) represent an important challenge for global tuberculosis (TB) control. The high rates of MDR/RR-TB observed among re-treatment cases can arise from diverse pathways: de novo amplification during initial treatment, inappropriate treatment of undiagnosed MDR/RR-TB, relapse despite appropriate treatment, or reinfection with MDR/RR-TB. Mathematical modelling allows quantification of the contribution made by these pathways in different settings. This information provides valuable insights for TB policy-makers, allowing better contextualised solutions. However, mathematical modelling outputs need to consider local data and be easily accessible to decision makers in order to improve their usefulness. We present a user-friendly web-based modelling interface, which can be used by people without technical knowledge. Users can input their own parameter values and produce estimates for their specific setting. This innovative tool provides easy access to mathematical modelling outputs that are highly relevant to national TB control programs. In future, the same approach could be applied to a variety of modelling applications, enhancing local decision making.

    KEYWORDS:

    Causal pathway; Decision making; Misdiagnosis; Multidrug-resistant tuberculosis; Re-treatment; Tuberculosis; User Interface

  • The risk of global epidemic replacement with drug resistant M. tuberculosis strains.
    McBryde ES, Meehan MT, Doan TN, Ragonnet R, Marais BJ, Guernier V, Trauer JM.
    Int J Infect Dis. 2017 Feb 2. pii: S1201-9712(17)30034-6. doi: 10.1016/j.ijid.2017.01.031. [Epub ahead of print]

    OBJECTIVES:

    Multi-drug resistant tuberculosis (MDR-TB) is a threat to TB control. To guide TB control, it is essential to understand the extent to which and the circumstances in which MDR-TB will replace drug-susceptible TB (DS-TB) as the dominant phenotype. We examined the issue by presenting evidence from genomics, pharmacokinetics and epidemiology studies. We then synthesised this evidence into a mathematical model.

    METHODS:

    Our model consider two TB strains, one with and one without MDR phenotype. We allowed that intrinsic transmissibility may be different between the two strains, as may the control response including detection rate, treatment failure and default rates. We explored the outcomes in terms of incidence of MDR-TB and time until MDR-TB surpasses DS-TB as the dominant strain.

    RESULTS AND CONCLUSIONS:

    The ability of MDR-TB to dominate DS-TB was highly sensitive to the relative transmissibility of the resistant strain; however, MDR-TB could dominate even when its transmissibility was modestly reduced (to between 50% and 100% as transmissible as DS-TB strain). Our model suggest that it may take decades or more for strain replacement to occur. We also found that while amplification of resistance is the early cause of MDR-TB, this will rapidly give way to person-to-person transmission.

    KEYWORDS:

    antibiotic resistance; communicable disease control; mathematical modelling; tuberculosis

  • High rates of multidrug-resistant and rifampicin-resistant tuberculosis among re-treatment cases: where do they come from?
    Ragonnet R, Trauer JM, Denholm JT, Marais BJ, McBryde ES.
    BMC Infect Dis. 2017 Jan 6;17(1):36. doi: 10.1186/s12879-016-2171-1.

    BACKGROUND:

    Globally 3.9% of new and 21% of re-treatment tuberculosis (TB) cases are multidrug-resistant or rifampicin-resistant (MDR/RR), which is often interpreted as evidence that drug resistance results mainly from poor treatment adherence. This study aims to assess the respective contributions of the different causal pathways leading to MDR/RR-TB at re-treatment.

    METHODS:

    We use a simple mathematical model to simulate progression between the different stages of disease and treatment for patients diagnosed with TB. The model is parameterised using region and country-specific TB disease burden data reported by the World Health Organization (WHO). The contributions of four separate causal pathways to MDR/RR-TB among re-treatment cases are estimated: I) initial drug-susceptible TB with resistance amplification during treatment; II) initial MDR/RR-TB inappropriately treated as drug-susceptible TB; III) MDR/RR-TB relapse despite appropriate treatment; and IV) re-infection with MDR/RR-TB.

    RESULTS:

    At the global level, Pathways I, II, III and IV contribute 38% (28-49, 95% Simulation Interval), 44% (36-52, 95% SI), 6% (5-7, 95% SI) and 12% (7-19, 95% SI) respectively to the burden of MDR/RR-TB among re-treatment cases. Pathway II is dominant in the Western Pacific (74%; 67-80 95% SI), Eastern Mediterranean (68%; 60-74 95% SI) and European (53%; 48-59 95% SI) regions, while Pathway I makes the greatest contribution in the American (53%; 40-66 95% SI), African (43%; 28-61 95% SI) and South-East Asian (50%; 40-59 95% SI) regions.

    CONCLUSIONS:

    Globally, failure to diagnose MDR/RR-TB at first presentation is the leading cause of the high proportion of MDR/RR-TB among re-treatment cases. These findings highlight the need for contextualised solutions to limit the impact and spread of MDR/RR-TB.

    KEYWORDS:

    Causal pathway; Drug resistance amplification; Inappropriate therapy; Misdiagnosis; Multidrug-resistant tuberculosis; Re-treatment; Tuberculosis

  • Is IPT more effective in high-burden settings? Modelling the effect of tuberculosis incidence on IPT impact.
    Ragonnet R, Trauer JM, McBryde ES, Houben RM, Denholm JT, Handel A, Sumner T.
    Int J Tuberc Lung Dis. 2017 Jan 1;21(1):60-66. doi: 10.5588/ijtld.16.0297.

    SETTING:

    Isoniazid preventive therapy (IPT) is effective for preventing active tuberculosis (TB), although its mechanism of action is poorly understood and the optimal disease burden for IPT use has not been defined.

    OBJECTIVE:

    To describe the relationship between TB incidence and IPT effectiveness.

    METHODS:

    We constructed a model of TB transmission dynamics to investigate IPT effectiveness under various epidemiological settings. The model structure was intended to be highly adaptable to uncertainty in both input parameters and the mechanism of action of IPT. To determine the optimal setting for IPT use, we identified the lowest number needed to treat (NNT) with IPT to prevent one case of active TB.

    RESULTS:

    We found that the NNT as a function of TB incidence shows a 'U-shape', whereby IPT impact is greatest at an intermediate incidence and attenuated at both lower and higher incidence levels. This U-shape was observed over a broad range of parameter values; the optimal TB incidence was between 500 and 900 cases per 100 000 per year.

    CONCLUSIONS:

    TB burden is a critical factor to consider when making decisions about communitywide implementation of IPT. We believe that the total disease burden should not preclude programmatic application of IPT.

  • Modelling the effect of short-course multidrug-resistant tuberculosis treatment in Karakalpakstan, Uzbekistan.
    Trauer JM, Achar J, Parpieva N, Khamraev A, Denholm JT, Falzon D, Jaramillo E, Mesic A, du Cros P, McBryde ES.
    BMC Med. 2016 Nov 18;14(1):187.

    BACKGROUND:

    Multidrug-resistant tuberculosis (MDR-TB) is a major threat to global TB control. MDR-TB treatment regimens typically have a high pill burden, last 20 months or more and often lead to unsatisfactory outcomes. A 9-11 month regimen with seven antibiotics has shown high success rates among selected MDR-TB patients in different settings and is conditionally recommended by the World Health Organization.

    METHODS:

    We construct a transmission-dynamic model of TB to estimate the likely impact of a shorter MDR-TB regimen when applied in a low HIV prevalence region of Uzbekistan (Karakalpakstan) with high rates of drug resistance, good access to diagnostics and a well-established community-based MDR-TB treatment programme providing treatment to around 400 patients. The model incorporates acquisition of additional drug resistance and incorrect regimen assignment. It is calibrated to local epidemiology and used to compare the impact of shorter treatment against four alternative programmatic interventions.

    RESULTS:

    Based on empirical outcomes among MDR-TB patients and assuming no improvement in treatment success rates, the shorter regimen reduced MDR-TB incidence from 15.2 to 9.7 cases per 100,000 population per year and MDR-TB mortality from 3.0 to 1.7 deaths per 100,000 per year, achieving comparable or greater gains than the alternative interventions. No significant increase in the burden of higher levels of resistance was predicted. Effects are probably conservative given that the regimen is likely to improve success rates.

    CONCLUSIONS:

    In addition to benefits to individual patients, we find that shorter MDR-TB treatment regimens also have the potential to reduce transmission of resistant strains. These findings are in the epidemiological setting of treatment availability being an important bottleneck due to high numbers of patients being eligible for treatment, and may differ in other contexts. The high proportion of MDR-TB with additional antibiotic resistance simulated was not exacerbated by programmatic responses and greater gains may be possible in contexts where the regimen is more widely applicable.

    KEYWORDS:

    Epidemiology; Extensively drug-resistant tuberculosis; Modelling; Multidrug-resistant tuberculosis; Public health; Treatment; Tuberculosis; Uzbekistan

  • Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models.
    Houben RM, Menzies NA, Sumner T, Huynh GH, Arinaminpathy N, Goldhaber-Fiebert JD, Lin HH, Wu CY, Mandal S, Pandey S, Suen SC, Bendavid E, Azman AS, Dowdy DW, Bacaër N, Rhines AS, Feldman MW, Handel A, Whalen CC, Chang ST, Wagner BG, Eckhoff PA, Trauer JM, Denholm JT, McBryde ES, Cohen T, Salomon JA, Pretorius C, Lalli M, Eaton JW, Boccia D, Hosseini M, Gomez GB, Sahu S, Daniels C, Ditiu L, Chin DP, Wang L, Chadha VK, Rade K, Dewan P, Hippner P, Charalambous S, Grant AD, Churchyard G, Pillay Y, Mametja LD, Kimerling ME, Vassall A, White RG.
    Lancet Glob Health. 2016 Nov;4(11):e806-e815. doi: 10.1016/S2214-109X(16)30199-1. Epub 2016 Oct 6.

    BACKGROUND:

    The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements.

    METHODS:

    11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy.

    FINDINGS:

    Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31-62%) and a 72% reduction in mortality (range 64-82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis.

    INTERPRETATION:

    Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level.

    FUNDING:

    Bill and Melinda Gates Foundation.

  • Cost-effectiveness and resource implications of aggressive action on tuberculosis in China, India, and South Africa: a combined analysis of nine models.
    Menzies NA, Gomez GB, Bozzani F, Chatterjee S, Foster N, Baena IG, Laurence YV, Qiang S, Siroka A, Sweeney S, Verguet S, Arinaminpathy N, Azman AS, Bendavid E, Chang ST, Cohen T, Denholm JT, Dowdy DW, Eckhoff PA, Goldhaber-Fiebert JD, Handel A, Huynh GH, Lalli M, Lin HH, Mandal S, McBryde ES, Pandey S, Salomon JA, Suen SC, Sumner T, Trauer JM, Wagner BG, Whalen CC, Wu CY, Boccia D, Chadha VK, Charalambous S, Chin DP, Churchyard G, Daniels C, Dewan P, Ditiu L, Eaton JW, Grant AD, Hippner P, Hosseini M, Mametja D, Pretorius C, Pillay Y, Rade K, Sahu S, Wang L, Houben RM, Kimerling ME, White RG, Vassall A.
    Lancet Glob Health. 2016 Nov;4(11):e816-e826. doi: 10.1016/S2214-109X(16)30265-0. Epub 2016 Oct 6.

    BACKGROUND:

    The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa.

    METHODS:

    We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016-35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice.

    FINDINGS:

    Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective.

    INTERPRETATION:

    Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary.

    FUNDING:

    Bill & Melinda Gates Foundation.

  • Controlled fire use in early humans might have triggered the evolutionary emergence of tuberculosis.
    Chisholm RH, Trauer JM, Curnoe D, Tanaka MM.
    PNAS. 2016 Jul 25. pii: 201603224. [Epub ahead of print]

    Tuberculosis (TB) is caused by the Mycobacterium tuberculosis complex (MTBC), a wildly successful group of organisms and the leading cause of death resulting from a single bacterial pathogen worldwide. It is generally accepted that MTBC established itself in human populations in Africa and that animal-infecting strains diverged from human strains. However, the precise causal factors of TB emergence remain unknown. Here, we propose that the advent of controlled fire use in early humans created the ideal conditions for the emergence of TB as a transmissible disease. This hypothesis is supported by mathematical modeling together with a synthesis of evidence from epidemiology, evolutionary genetics, and paleoanthropology.

    KEYWORDS:

    cultural evolution; epidemiology; mathematical modeling; pathogen evolution; tuberculosis

  • Scenario Analysis for Programmatic Tuberculosis Control in Western Province, Papua New Guinea.
    Trauer JM, Denholm JT, Waseem S, Ragonnet R, McBryde ES.
    Am J Epidemiol. 2016 May 19. pii: kwv323.

    Tuberculosis (TB) and multidrug-resistant TB (MDR-TB) are major health problems in Western Province, Papua New Guinea. While comprehensive expansion of TB control programs is desirable, logistical challenges are considerable, and there is substantial uncertainty regarding the true disease burden. We parameterized our previously described mathematical model of Mycobacterium tuberculosis dynamics in Western Province, following an epidemiologic assessment. Five hypothetical scenarios representing alternative programmatic approaches during the period from 2013 to 2023 were developed with local staff. Bayesian uncertainty analyses were undertaken to explicitly acknowledge the uncertainty around key epidemiologic parameters, and an economic evaluation was performed. With continuation of existing programmatic strategies, overall TB incidence remained stable at 555 cases per 100,000 population per year (95% simulation interval (SI): 420, 807), but the proportion of incident cases attributable to MDR-TB increased from 16% to 35%. Comprehensive, provincewide strengthening of existing programs reduced incidence to 353 cases per 100,000 population per year (95% SI: 246, 558), with 46% being cases of MDR-TB, while incorporating programmatic management of MDR-TB into these programs reduced incidence to 233 cases per 100,000 population per year (95% SI: 198, 269) with 14% MDR-TB. Most economic costs were due to hospitalization during the intensive treatment phase. Broad scale-up of TB control activities in Western Province with incorporation of programmatic management of MDR-TB is vital if control is to be achieved. Community-based treatment approaches are important to reduce the associated economic costs.

    © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

    KEYWORDS:

    Bayesian probability; Papua New Guinea; models, biological; tuberculosis; tuberculosis, multidrug-resistant

  • Multidrug-resistant tuberculosis in Australia and our region
    Trauer JM, Cheng AC.
    Med J Aust.2016; 204 (7): 251-253. doi: 10.5694/mja16.00012
    In a commissioned editorial and linked podcast in the Medical Journal of Australia, AuTuMN's James Trauer and the Alfred Hospital's Allen Cheng discuss the importance of multidrug-resistant TB to Australia and the Asia-Pacific Region. They note that MDR-TB threatens control programs in Australia's region and will not diminish without concerted efforts.
  • Risk of Active Tuberculosis in the Five Years Following Infection . . . 15%?
    Trauer JM, Moyo N, Tay EL, Dale K, Ragonnet R, McBryde ES, Denholm JT.
    Chest. 2016 Feb;149(2):516-25. doi: 10.1016/j.chest.2015.11.017.

    BACKGROUND:

    It is often stated that the lifetime risk of developing active TB after an index infection is 5% to 10%, one-half of which accrues in the 2 to 5 years following infection. The goal of this study was to determine whether such estimates are consistent with local programmatic data.

    METHODS:

    This study included close contacts of individuals with active pulmonary TB notified in the Australian state of Victoria from January 1, 2005, to December 31, 2013, who we deemed to have been infected as a result of their exposure. Survival analysis was first performed on the assumption of complete follow-up through to the end of the study period. The analysis was then repeated with imputation of censorship for migration, death, and preventive treatment, using local mortality and migration data combined with programmatic data on the administration of preventive therapy.

    RESULTS:

    Of 613 infected close contacts, 67 (10.9%) developed active TB during the study period. Assuming complete follow-up, the 1,650-day cumulative hazard was 11.5% (95% CI, 8.9-14.1). With imputation of censorship for death, migration, and preventive therapy, the median 1,650-day cumulative hazard over 10,000 simulations was 14.5% (95% CI, 11.1-17.9). Most risk accrued in the first 5 months after infection, and risk was greatest in the group aged < 5 years, reaching 56.0% with imputation, but it was also elevated in older children (27.6% in the group aged 5-14 years).

    CONCLUSIONS:

    The risk of active TB following infection is several-fold higher than traditionally accepted estimates, and it is particularly high immediately following infection and in children.

    Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

    KEYWORDS:

    TB; TB prevention; epidemiology

  • Vaccination Programs for Endemic Infections: Modelling Real versus Apparent Impacts of Vaccine and Infection Characteristics.
    Ragonnet R, Trauer JM, Denholm JT, Geard NL, Hellard M, McBryde ES.
    Sci Rep. 2015 Oct 20;5:15468. doi: 10.1038/srep15468.

    Vaccine effect, as measured in clinical trials, may not accurately reflect population-level impact. Furthermore, little is known about how sensitive apparent or real vaccine impacts are to factors such as the risk of re-infection or the mechanism of protection. We present a dynamic compartmental model to simulate vaccination for endemic infections. Several measures of effectiveness are calculated to compare the real and apparent impact of vaccination, and assess the effect of a range of infection and vaccine characteristics on these measures. Although broadly correlated, measures of real and apparent vaccine effectiveness can differ widely. Vaccine impact is markedly underestimated when primary infection provides partial natural immunity, when coverage is high and when post-vaccination infectiousness is reduced. Despite equivalent efficacy, 'all or nothing' vaccines are more effective than 'leaky' vaccines, particularly in settings with high risk of re-infection and transmissibility. Latent periods result in greater real impacts when risk of re-infection is high, but this effect diminishes if partial natural immunity is assumed. Assessments of population-level vaccine effects against endemic infections from clinical trials may be significantly biased, and vaccine and infection characteristics should be considered when modelling outcomes of vaccination programs, as their impact may be dramatic.

  • Construction of a mathematical model for tuberculosis transmission in highly endemic regions of the Asia-Pacific.
    Trauer JM, Denholm JT, McBryde ES.
    J Theor Biol. 2014 Oct 7;358:74-84. doi: 10.1016/j.jtbi.2014.05.023. Epub 2014 May 27.

    We present a mathematical model to simulate tuberculosis (TB) transmission in highly endemic regions of the Asia-Pacific, where epidemiology does not appear to be primarily driven by HIV-coinfection. The ten-compartment deterministic model captures many of the observed phenomena important to disease dynamics, including partial and temporary vaccine efficacy, declining risk of active disease following infection, the possibility of reinfection both during the infection latent period and after treatment, multidrug resistant TB (MDR-TB) and de novo resistance during treatment. We found that the model could not be calibrated to the estimated incidence rate without allowing for reinfection during latency, and that even in the presence of a moderate fitness cost and a lower value of R0, MDR-TB becomes the dominant strain at equilibrium. Of the modifiable programmatic parameters, the rate of detection and treatment commencement was the most important determinant of disease rates with each respective strain, while vaccination rates were less important. Improved treatment of drug-susceptible TB did not result in decreased rates of MDR-TB through prevention of de novo resistance, but rather resulted in a modest increase in MDR-TB through strain replacement. This was due to the considerably greater relative contribution of community transmission to MDR-TB incidence, by comparison to de novo amplification of resistance in previously susceptible strains.

    Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

    KEYWORDS:

    BCG vaccine; Disease Transmission—Infectious; Latent tuberculosis; Models—Theoretical; Tuberculosis—Multidrug Resistant

  • Can Australia eliminate TB? Modelling immigration strategies for reaching MDG targets in a low-transmission setting.
    Denholm JT, McBryde ES.
    Aust N Z J Public Health. 2014 Feb;38(1):78-82. doi: 10.1111/1753-6405.12161.

    BACKGROUND:

    The 2050 Millennium Development Goals (MDG) for tuberculosis (TB) aim for elimination of TB as a public health issue. We used a mathematical modelling approach to evaluate the feasibility of this target in a low-prevalence setting with immigration-related strategies directed at latent tuberculosis.

    METHODS:

    We used a stochastic individual-based model to simulate tuberculosis disease among immigrants to Victoria, Australia; a representative low-transmission setting. A variety of screening and treatment approaches aimed at preventing reactivation of latent infection were applied to evaluate overall tuberculosis incidence reduction and rates of multidrug resistant disease.

    RESULTS:

    Without additional intervention, tuberculosis incidence was predicted to reach 34.5 cases/million by 2050. Strategies involving the introduction of an available screening/treatment combination reduced TB incidence to between 16.9-23.8 cases/million, and required screening of 136-427 new arrivals for each case of TB prevented. Limiting screening to higher incidence regions of origin was less effective but more efficient.

    CONCLUSIONS:

    Public health strategies targeting latent tuberculosis infection in immigrants may substantially reduce tuberculosis incidence in a low prevalence region. However, immigration-focused strategies cannot achieve the 2050 MDG and alternative or complementary approaches are required.

    © 2014 The Authors. ANZJPH © 2014 Public Health Association of Australia.

    KEYWORDS:

    immigration; latent tuberculosis infection; mathematical model; public health; screening



Other publications

  • The world’s most lethal infectious disease threatens a comeback
    Cheng AC, Trauer JM
    Croakey April 19, 2016.
    While over 11,000 people have died from Ebola virus disease during the most recent epidemic in West Africa, 1.5 million people die from tuberculosis (TB) each year. And now, estimates of TB burden are greater than ever before. While there have been some successful drug treatments for TB in the past, drug-resistant Tuberculosis is becoming more common and is poised to derail global control efforts.

    In this piece, authors from today’s Medical Journal of Australia article on multi-drug resistant tuberculosis explain why this highly contagious disease should be on everyone’s radar, and why Australia should be taking a leadership role on this issue.
  • The world’s most lethal infectious disease threatens a comeback
    Trauer JM
    Policy Forum July 21, 2017.
    A resurgent TB epidemic is a problem for the developing and developed world alike. The international community will need an expanded, cooperative, and holistic response to tuberculosis if it is to eliminate the ancient disease, James Trauer writes.

Talks

  • Using epidemic and economic models for tuberculosis for national decision support
    Emma McBryde, James Trauer, Tan Doan, Romain Ragonnet
    Union Asia Pacific Region Conference. Workshop.
    22 Mar 2017
    Tokyo, Japan
  • Is isoniazid preventive therapy more effective in high-burden settings? Modelling the effect of TB incidence on IPT impact
    Romain Ragonnet
    Union World Conference on Lung Health 2016
    26 Oct 2016
    Liverpool, UK
  • Optimising tuberculosis control by integrating transmission dynamic, health economic modelling and minimisation routine – the AuTuMN framework
    Tan Doan
    Modelling Emerging Infections and Neglected Tropical Diseases. PRISM2 Workshop
    22-23 Sep 2016
    Brisbane, Australia
  • Dynamics of progression to active TB: Which model structure to best replicate them?
    Romain Ragonnet
    Modelling Emerging Infections and Neglected Tropical Diseases. PRISM2 Workshop
    22-23 Sep 2016
    Brisbane, Australia
  • Mathematical modelling to inform TB control in our region
    Emma McBryde
    International Congress for Tropical Medicine and Malaria 2016
    21 Sep 2016
    Brisbane, Australia
  • Tuberculosis model as a decision support tool to inform TB National Program choices
    Emma McBryde
    5th Tuberculosis control symposium, TB-CRE
    18-19 May 2016
    Sydney, Australia
  • Spatial epidemiology of tuberculosis
    Tan Doan
    PRISM2 Centre of Research Excellence in Infectious Diseases Modelling to Inform Public Health Policy Annual Workshop
    2-4 May 2016
    Melbourne, Australia
  • AuTuMN to enhance decision making and efficiency of National Tuberculosis Control Programme
    Tan Doan
    Workshop on AuTuMN application in the Philippines to support National Tuberculosis Control Programme strategic planning
    16-18 February 2016
    Manila, Philippines
  • An introduction to the AuTuMN model of tuberculosis transmission dynamics
    Tan Doan
    Workshop on AuTuMN application in the Philippines to support National Tuberculosis Control Programme strategic planning
    16-18 February 2016
    Manila, Philippines
  • Mathematical modelling to understand tuberculosis transmission dynamics and optimise tuberculosis programmes
    Tan Doan
    Workshop on AuTuMN application in the Philippines to support National Tuberculosis Control Programme strategic planning
    16-18 February 2016
    Manila, Philippines
  • Optima TB with the AuTuMN transmission dynamic model
    Tan Doan
    Conference on improving efficiency in health
    3-4 February 2016
    Washington DC, USA
  • An introduction to the AuTuMN model
    James Trauer & Emma McBryde
    The 46th Union World Conference on Lung Health
    2-6 December 2015
    Cape Town, South Africa