towards understanding tuberculosis on the...

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Towards Understanding Tuberculosis on the

Multi-scale Jane Heffernan

Modelling Infection and Immunity Lab Centre for Disease Modelling

Mathematics & Statistics York University

http://immune.math.yorku.ca/jmheffer

http://immune.math.yorku.ca/jmheffer

Canada Capital: Ottawa Population: 35 million (2012) Population by Province (million)

Ont: 13.5 Que: 8 BC: 4.6 Alb: 4 Man: 1 Sas: 1

NS: 1 NB 0.7 NFL: 0.5 PEI: 0.1 Terr: 0.1

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In 2011, 76% Canadian-born non-Aboriginals, 4% Aboriginal Peoples 20% was comprised of immigrants

TB in Canada

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Halverson, Jessica, et al. "Epidemiology of tuberculosis in Canada." Canadian Tuberculosis Standards (2014): 7.

TB in Canada


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Distribution of active TB cases by origin across provinces and

territories: 2000 - 2010


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Reported foreign-born TB cases in Canada, 2000-2010: Time from Arrival

in Canada to Diagnosis in Years

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Years from arrival in Canada to diagnosis

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Distribution of reported foreign-born active TB cases in Canada by

country of birth: 2000-2010

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Percentage of tuberculosis cases by age group and origin - Canada: 2010

Age group

Perc

enta

ge

0%

20%

40%

60%

80%

100%

Canadian-born non-Aboriginal 2 8 6 21 17 14 26 31 22 36

Foreign-born 0 4 10 115 207 190 145 108 99 162

Canadian-born Aboriginal 7 17 23 64 57 62 35 30 21 14

< 1 1-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75+


Drug resistance by origin group: All cases 2000 - 2010

Resistance to one or more first-line anti-tb drug (n= 1,162)

Resistant to at least INH and RMP, MDR-TB (n=155)


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Distribution of cases by origin: Aboriginal and Foreign-born: 2000 - 2010

Foreign-born Aboriginal

Courtesy of PHAC

Ontario TB stats

• 2010 • Canada – 1577 new cases • Ontario – 633 new cases • Toronto – 300-350 cases/yr

– 1/6 first-line drug resistance – MDR and XDR have been documented – 4% of cases HIV+ve – 2-3% homeless – 1% aboriginal

http://www.on.lung.ca/document.doc?id=1644 http://www.bc.lung.ca/association_and_services/documents/1-ELIZABETHREA.4.18.13.pdf

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Want to understand Pathogenesis of TB in-host Granuloma formation, Complications with other diseases

i.e. HIV Transmission of TB How this links to pathogenesis in-host AND population

demographics/characteristics Treatment of TB In-host, evolution of resistance, public health

Public Health Resources How to mobilize public health resources efficiently i.e.

urban vs. rural(remote); new vs. latent infection;

MULTI-SCALE!! 13

More vs. More

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Biology Incorporated in Model

New

Kno

wle

dge

from

Res

ults

Infected cell Antigen Naïve B-cell

Memory B-cell

Plasma cell

Antibodies Effector CTL

Memory CD8

Memory CD4

Naïve CD8

Naïve CD4 Th0 CD4 Th1

CD4 Th2

Antigen Presenting Cell

Type 2 cytokines

Type 1 cytokines

In-host Modelling: General

In-host Pathogenesis M. tuberculosis mainly targets macrophages Macrophages ‘kill’ bacteria Cytotoxic T-lymphocytes (CTLs) ‘kill’ infected

cells Granuloma: limit the spread of bacteria and

facilitate interactions between immune cells 4 disease outcomes Primary TB, latent TB, clearance, reactivation

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TB Pathogenesis

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Healthy Macrophage

Infected Macrophage

Bacteria Activated CD8 T-cells (CTL)

Birth

Birth

Death

Infection

Production Killing Killing

Proliferation

Death

Birth

Death

Key Parameters Changes in

disease outcomes are affected by these parameters We need to focus

on these to help patients

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Granuloma Spatial distribution of cells Cellular Automaton model

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Compartments

Can also include treated classes, resistance

S*

E* I*

infection birth

death

L*

death death death

R* V*

death death

progression latency

recovery

vaccination re-infection

relapse

Coupling between and in-host dynamics

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Screening and Treatment of Immigrants?

What should Canada’s optimal policy be? Mathematical model

Progression of LTBI among new immigrants, by country of origin, age groups, and time since landing

Data from Immigration Canada and Canadian TB Reporting System were used to calibrate and validate the baseline model without the screening program.

Cost-effectiveness of different screening programs were evaluated using the model.

Results show that the most cost-effective screening is to screen and treat LTBI in new immigrants from countries of birth with TB incidence rate higher than 50.

(Mary Varughese et al, Int J Tuberc Lung Dis. 2014 Apr;18(4):405-12.)

22 Years from arrival in Canada to diagnosis

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Aboriginal Health Understanding the mechanism of TB transmission in these communities

Complex due to the role of social and economic determinants of health such as overcrowding, lack of access to health care, substance abuse, HIV-TB co-infection, diabetes, and general poor socioeconomic conditions.

Health Canada’s new strategy to reduce TB for First Nations on-Reserve aims for community based control strategies that targets social and economic determinants of health.

Evaluate the cost-effectiveness of these types of TB intervention strategies using mathematical models and statistical models and data

Will answer questions such as: How many TB cases can be prevented in a ten-year period if a chest x-ray machine

was made available in a high incidence community? or if housing conditions are improved to a certain level?

Cost-effectiveness analysis will inform Health Canada’s new TB strategy.

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Michael Li, U Alberta

Drug Resistance Development of drug resistance Probability

Transmission of drug resistance strains Fitness

Agent-based Modelling

24 ESPíNDOLA, AQUINO L., ALEXANDRE SOUTO MARTINEZ, and Seyed M. Moghadas. "An Agent-Based Modelling Framework for Tuberculosis Infection with Drug-Resistance."

Resistance With and without relapse

25 ESPíNDOLA, AQUINO L., ALEXANDRE SOUTO MARTINEZ, and Seyed M. Moghadas. "An Agent-Based Modelling Framework for Tuberculosis Infection with Drug-Resistance."

Meta-population

What can we include? Demographics Workplaces, schools, shopping malls, etc. Schedules Household characteristics Health risk factors Behavioural traits – game theory, decision

making Relationships Disease Model

Nitric Oxide Treatment Size of unit Mobilization of resources Reaching those that most need it

28 Mobile devices: how many devices, how to arrange the schedules

Mobile devices

towards understanding tuberculosis on the...

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