1. Epidemiology and Global Health
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A user-friendly, open-source tool to project impact and cost of diagnostic tests for tuberculosis

  1. David W Dowdy  Is a corresponding author
  2. Jason R Andrews
  3. Peter J Dodd
  4. Robert H Gilman
  1. Johns Hopkins Bloomberg School of Public Health, United States
  2. Johns Hopkins University, United States
  3. Massachusetts General Hospital, United States
  4. University of Sheffield, United Kingdom
Research Article
Cite this article as: eLife 2014;3:e02565 doi: 10.7554/eLife.02565
4 figures, 2 tables and 2 additional files

Figures

Overview of user-friendly model.

Users are asked, via open-source computer script or Web interface, to select one of the nine diagnostic strategies and to provide unit costs and three basic epidemiological parameters (TB incidence, MDR-TB prevalence among new cases, and adult HIV prevalence). The selected diagnostic strategy is used to populate a decision tree that calculates (a) the probability of missed diagnosis, unsuccessful treatment, and successful treatment, (b) costs, and (c) diagnostic delays. These outputs depend on patients' TB (yes/no, and drug susceptibility status), HIV, and TB treatment history status. The selected epidemiological parameters are then used to populate a dynamic transmission model, creating a steady-state population that reflects local TB epidemiology. The decision tree—which inputs user-defined unit costs—is then incorporated into the transmission model to project outcomes under the selected diagnostic scenario. Users can sequentially select multiple diagnostic scenarios for comparison, and the computer script (though not the Web interface) allows users to manipulate input parameters at their discretion.

https://doi.org/10.7554/eLife.02565.003
Transmission model of TB diagnosis.

Boxes represent sub-populations in the model, and arrows represent rates of movement between those sub-populations. Parallel structures exist for: (a) HIV-infected vs HIV-uninfected; (b) never-treated vs previously treated (for TB); and (c) among TB-infected individuals, drug-susceptible vs isoniazid-monoresistant vs rifampin-resistant (including MDR). ‘Pre-diagnostic’ TB refers to individuals who are infectious but have not yet begun to seek care. Mortality occurs from all sub-populations (not shown), and at a higher rate among those with HIV and active TB.

https://doi.org/10.7554/eLife.02565.004
Incremental 5-year cost and impact of TB diagnostic strategies, high-incidence setting.

Shown are cumulative projected 5-year costs and impact (averted TB cases [panel A] or MDR-TB cases [panel B]) of each diagnostic strategy described in the Introduction, incremental to the baseline strategy, per 100,000 population. Strategies with greater impact appear to the right on the x-axis; more costly strategies appear higher on the y-axis. The same-day smear strategy is cost-saving but shown at an incremental cost of $0 for simplicity.

https://doi.org/10.7554/eLife.02565.006
Relative impact of diagnostic strategies in emblematic settings.

Shown are projected changes in TB incidence, MDR-TB incidence, TB mortality, and costs (in Year 1 and Year 5 after immediate implementation), relative to baseline (Strategy 1) after implementing each of the diagnostic strategies described in the text. Epidemiological outcomes are measured at the end of Year 5. Panel A (high incidence) shows a setting with TB incidence of 250 per 100,000/year, stable MDR-TB prevalence of 3.7% among new cases, adult HIV prevalence of 0.83%, and cost of $500 to treat one case of TB with first-line therapy. In panel B (low incidence), the TB incidence is reduced to 8.3 per 100,000/year (implemented by gradual decline in incidence over 50 years). In panel C (high MDR), MDR-TB prevalence among new cases is set at 3.7% in the beginning of year 1, increasing to 10.7% by the end of year 5. In panel D (high HIV), adult HIV prevalence is set to 20% and TB incidence is set to 500 per 100,000/year.

https://doi.org/10.7554/eLife.02565.007

Tables

Table 1

Model input parameters*

https://doi.org/10.7554/eLife.02565.005
ParameterValueReference(s)/Rationale
TB and HIV Transmission
Transmission rate, per smear-positive/highly infectious person-yearCalibrated to user-defined TB incidence
Proportional reduction in per-case transmission rate, MDR-TBCalibrated to user-defined MDR-TB prevalence
Proportional reduction in fitness, isoniazid-monoresistant TB25% of MDR-TB reductionAssumption
HIV incidence rate, per yearCalibrated to user-defined HIV prevalence
Relative transmission rate from smear-negative/less infectious TB0.22(Behr et al., 1999)
Proportion of pulmonary TB that is smear-positive/highly infectious
 HIV-negative0.63(Steingart et al., 2006a; Steingart et al., 2006b)
 HIV-infected0.50(Getahun et al., 2007)
TB Progression
Endogenous reactivation rate
 HIV-negative0.0005/year(Horsburgh et al., 2010)
 HIV-infected0.05/year(Antonucci et al., 1995)
Proportion of recent infections resulting in rapid progression
 HIV-negative0.14(Vynnycky and Fine, 1997; Dye et al., 1998)
 HIV-infected0.470.75 without ART, (Daley et al., 1992)
75% reduction if on ART, (Williams et al., 2010) 50% ART coverage
Reduction in TB rapid progression probability due to latent TB infection (HIV-negative only)0.79(Andrews et al., 2012)
TB Mortality and Resolution
Life expectancy at age 1555 years(World Bank, 2012)
Annual mortality from HIV0.05/year(UNAIDS, 2012)
Annual mortality from TB
 HIV-negative, smear-positive/highly infectious0.23/year(Tiemersma et al., 2011)
 HIV-negative, smear-negative/less infectious0.07/year(Tiemersma et al., 2011)
 HIV-infected1.0/year(Corbett et al., 2003; Corbett et al., 2007; Wood et al., 2007)
Rate of spontaneous TB resolution (HIV-negative only)
 Smear-positive/highly infectious0.1/year(Tiemersma et al., 2011)
 Smear-negative/less infectious0.27/year(Tiemersma et al., 2011)
TB Treatment Outcomes and Emergence of Drug Resistance
Probability of failure or relapse (within 1 year)
 Drug-susceptible0.04(World Health Organization, 2012)
 INH-monoresistant, first-line therapy0.21(Menzies et al., 2009b)
 INH-monoresistant, retreatment or 2nd-line0.16(Menzies et al., 2009b)
 MDR-TB, first-line or retreatment0.50(Espinal et al., 2000)
 MDR-TB, second-line therapy0.30(World Health Organization, 2010)
Proportion of one-year recurrence due to failure
 Drug-susceptible0.14(Lew et al., 2008)
 INH-monoresistant0.33
 MDR-TB0.56
Probability of acquired drug resistance (per treatment course)
 Susceptible becoming INH-monoresistant0.001(Menzies et al., 2009a; Menzies et al., 2009b)
 Susceptible becoming MDR-TB0.002
 INH-monoresistant becoming MDR-TB0.045
 If treated with 2 effective drugs for >6 mos0.017
Behavioral Parameters
Infectious months before starting to seek care
 HIV-negative9 months(Dowdy et al., 2013)
 HIV-infected1 month(Corbett et al., 2004)
Diagnostic frequency while seeking care5.0/year(Storla et al., 2008; Sreeramareddy et al., 2009)
Probability of treatment in a TB patient whose microbiological test is negative0.25(Wilkinson et al., 2000; Dowdy et al., 2008)
Loss to follow-up between diagnostic presentation and treatment initiation
 Sputum smear or GXP (not same-day)0.15(MacPherson et al., 2014)
 Culture (microcolony or commercial liquid)0.25(Dowdy et al., 2008)
 Same-day diagnosis0Assumption
Diagnostic Accuracy
Sensitivity for smear-negative/less-infectious TB
 Sputum smear microscopy0
 Xpert MTB/RIF0.72(Brownell et al., 2012)
 Culture (microcolony or commercial liquid)0.85(Cruciani et al., 2004; Leung et al., 2012)
Specificity for TB(Steingart et al., 2006; Boehme et al., 2011; Leung et al., 2012)
 Sputum smear microscopy0.98
 Xpert MTB/RIF0.98
 Microcolony culture0.98
Sensitivity for drug resistance (if TB detected)
 Microcolony culture (rifampin and isoniazid)0.98(Minion et al., 2010)
 Xpert MTB/RIF (rifampin only)0.94(Boehme et al., 2011)
Specificity for drug resistance (if TB detected)
 Microcolony culture (isoniazid)0.96(Minion et al., 2010)
 Microcolony culture (rifampin)0.99(Minion et al., 2010)
 Xpert MTB/RIF (rifampin)0.98(Boehme et al., 2011)
Diagnostic Delay and non-TB Care-Seeking
Days from presentation to treatment initiation
 Sputum smear or Xpert MTB/RIF7 daysAssume 1 week
 Microcolony or commercial liquid culture30 days(Boehme et al., 2011)
Months of therapy before a failing regimen will be changed, or before default and recurrence6 monthsAssumption
Annual rate of diagnostic evaluation for TB, among people who do not have active TB0.01/year10% of suspects have TB, high-incidence setting
Cost Parameters (user-defined; values below for comparison purposes only)
Per-patient cost of TB therapy
 First-lineUS$500User-defined
 RetreatmentUS$1000(Vassall et al., 2011)
 Second-line/MDRUS$5000(Vassall et al., 2011)
 Outpatient visit (diagnosis or follow-up)US$10(Vassall et al., 2011)
Per-test cost:
 Sputum smearUS$2(Vassall et al., 2011)
 Same-day sputum smearUS$10Assumption
 Xpert MTB/RIFUS$15(Vassall et al., 2011)
 Same-day Xpert MTB/RIFUS$30Assumption
 Microcolony culture (with DST)US$5(Solari et al., 2011)
 Commercial liquid-media cultureUS$20(Vassall et al., 2011)
 Commercial liquid-media culture + DSTUS$40(Vassall et al., 2011)
  1. *

    In the actual model program (Supplementary file 1), users can change any parameter based on local values.

  2. For reference, the transmission rate (in infections per person-year during diagnosis-seeking active TB) is 36.9 in the reference scenario, 14.0 in the low-incidence scenario, 25.4 in the high MDR scenario, and 12.9 in the high HIV scenario. Corresponding proportional reductions in MDR-TB transmission rate are 0.23, 0.23, 0.21, and 0.19; and HIV incidence estimates (per 1000 adult person-years) are 0.7, 0.6, 0.6, and 18.9.

Table 2

Model parameters and symbolic representations

https://doi.org/10.7554/eLife.02565.008
ParameterRepresentationBaseline value (see Table 1)
Transmission rate (transmission events per highly infectious person-year)βCalibrated to TB incidence
Proportional reduction in per-case transmission rate
 Drug-susceptible TBφ01.0
 Isoniazid-monoresistant TBφ125%* of φ2
 MDR-TBφ2Calibrated
HIV incidence rate, per yearθCalibrated to HIV prevalence
Relative transmission rate from smear-negative/less infectious TBζ0.22
Proportion of pulmonary TB that is smear-positive/highly infectious
 HIV-negativeψ00.63
 HIV-infectedψ10.50
Endogenous reactivation rate, per year
 HIV-negativeε00.005
 HIV-infectedε10.05
Proportion of recent infections resulting in rapid progression
 HIV-negativeπ00.14
 HIV-infectedπ10.47
Reduction in TB rapid progression probability due to latent TB infection
 HIV-negativeι0.79
 HIV-infectedNot included0
Baseline mortality rate, per yearμbl1/55 = 0.018
Additional HIV-related mortality rate, per yearμh0.05
Additional untreated TB-related mortality rate, per year
 HIV-negative, smear-positive/highly infectiousμt10.23
 HIV-negative, smear-negative/less infectiousμt00.07
 HIV-infectedμth1.0
Rate of spontaneous TB resolution, per year
 Smear-positive/highly infectiousν10.1
 Smear-negative/less infectiousν00.27
 HIV-infectedNot included0
Rate of starting diagnosis-seeking in active TB, per year
 HIV-negativeδe01.33 (9 months)
 HIV-infectedδe112 (1/month)
Rate of progression: ineffective therapy to repeat therapy (failure) or active TB (relapse), per yearδf6/12 = 0.5
Rate of diagnostic evaluation for TB, per year
 Late active TBInput into decision tree5.0
 No active TBτ00.01
Decision tree outputs (in addition to unit costs):Vary by intervention
 Successful diagnosis rate of late active TB, per yearσhdip
 Rate of movement from successful diagnosis to treatment (1/diagnostic delay), per yearρhdip
 Ineffective diagnosis rate of late active TB, per yearκhdip
 Rate of diagnosis and treatment leading to new resistance, per year
 susceptible to INH-monoresistantαsihip
 susceptible to MDRαsmhip
 INH-monoresistant to MDRαimhip
  1. *

    Calculated such that (1−φ1) = 0.25*(1−φ2).

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