Analytical Exploration of Potential Pathways by which Diabetes Mellitus Impacts Tuberculosis Epidemiology

Abstract

We aimed to develop a conceptual framework of diabetes mellitus (DM) effects on tuberculosis (TB) natural history and treatment outcomes, and to assess the impact of these effects on TB-transmission dynamics. The model was calibrated using TB data for India. A conceptual framework was developed based on a literature review, and then translated into a mathematical model to assess the impact of the DM-on-TB effects. The impact was analyzed using TB-disease incidence hazard ratio (HR) and population attributable fraction (PAF) measures. Evidence was identified for 10 plausible DM-on-TB effects. Assuming a flat change of 300% (meaning an effect size of 3.0) for each DM-on-TB effect, the HR ranged between 1.0 (Effect 9-Recovery) and 2.7 (Effect 2-Fast progression); most effects did not have an impact on the HR. Meanwhile, TB-disease incidence attributed directly and indirectly to each effect ranged between -4.6% (Effect 7-TB mortality) and 34.5% (Effect 2-Fast progression). The second largest impact was for Effect 6-Disease infectiousness at 29.9%. In conclusion, DM can affect TB-transmission dynamics in multiple ways, most of which are poorly characterized and difficult to assess in epidemiologic studies. The indirect (e.g. onward transmission) impacts of some DM-on-TB effects are comparable in scale to the direct impacts. While the impact of several effects on the HR was limited, the impact on the PAF was substantial suggesting that DM could be impacting TB epidemiology to a larger extent than previously thought.

Figure 1

List of the key research questions assessed in this study along with the methods used to address them.

Figure 2

A conceptual framework for the TB-DM epidemiologic synergy. The black lines indicate the transitions within TB’s natural history and treatment states. The red lines indicate the 10 plausible effects of DM on TB natural history and treatment outcomes.

Figure 3

Epidemiological impact of the 10 plausible effects of diabetes mellitus (DM) on tuberculosis (TB) natural history and treatment outcomes, as measured by the incidence hazard ratio (HR) of TB disease among those with DM compared to those without DM. (A) Results of the impact of each of the effects individually. (B) Results of the impact of all possible combinations of the effects that individually had an HR >1.0. Each DM on TB effect had a standardized effect size (ES) of 3.0 if the expected ES (based on evidence) is ≥1, and (an inverse) ES of 1/3 if the expected ES is <1 (red line).

Figure 4

Assessment of varying the effect size of each of the diabetes mellitus (DM) on tuberculosis (TB) effects to yield the observed hazard ratio (HR) of 3.0. HR is defined as the ratio of TB disease incidence rate among those with DM compared to those without DM.

Figure 5

Proportion of tuberculosis (TB) disease incidence (A), prevalence (B), and mortality (C) attributed to each of the effects of diabetes mellitus (DM) on TB natural history and treatment outcomes. These population attributable fraction (PAF_True) measures were estimated as the proportional reduction in the measure in a comparison between the measure in a scenario where there is TB-DM epidemiologic synergy (that is some effect for DM on TB is active), compared to a counter-factual scenario where there is no TB-DM epidemiologic synergy. Each DM on TB effect had a standardized effect size (ES) of 3.0 if the expected ES (based on evidence) is ≥1, and (an inverse) ES of 1/3 if the expected ES is <1. The red bar (and line) in panel A is the estimated Levin’s formula population attributable fraction, assuming a relative risk (RR) of 3.0 for TB-disease incidence among DM versus non-DM individuals.