Journal of Life Sciences 5 (2011) 503-508

Dynamics and Control of Infectious Diseases in Stochastic Metapopulation Models

Ariel Flix Gualtieri and Juan Pedro Hecht
Facultad de Odontologa, Universidad de Buenos Aires, 1122 Buenos Aires, Argentina Received: October 17, 2010 / Accepted: March 01, 2011 / Published: July 30, 2011. Abstract: The research on spatial epidemic models is a topic of considerable recent interest. In another hand, the advances in computer technology have stimulated the development of stochastic models. Metapopulation models are spatial designs that involve movements of individuals between distinct subpopulations. The purpose of the present work has been to develop stochastic models in order to study the transmission dynamics and control of infectious diseases in metapopulations. The authors studied Susceptible-Infected-Susceptible (SIS) and Susceptible-Infected-Recovered (SIR) epidemic schemes, using the Gillespie algorithm. Computational numerical simulations were carried in order to explore the models. The results obtained show how the dynamics of transmission and the application of control measures within each subpopulation may affect all subpopulations of the system. They also show how the distribution of control measures among subpopulations affects the efficacy of these strategies. The dynamics of the stochastic models developed in the current study follow the trends observed in the classic deterministic designs. Also, the present models exhibit fluctuating behavior. This work highlights the importance of the spatial distribution of the population in spread and control of infectious diseases. In addition, it shows how chance could play an important role in these scenarios. Key words: Epidemic dynamics and control, stochastic metapopulation models, SIS and SIR schemes.

1. Introduction
Mathematical models are useful frameworks to study the dynamics of spread of infectious diseases. They provide insight into essential aspects of host-parasite interactions. Simple models serve as a point of departure for adding realistic complications step by step, in an understandable way. In addition, they help to suggest what kinds of data need to be sought in order effectively to design and monitor programs of control [1]. An epidemic is a chain reaction of disease spread within a population. Defining an epidemic model therefore involves classifying the possible infection states of an individual and the processes or events causing movement between those states. The aim then is to predict changes through time in the proportions of
Corresponding author: Ariel Flix Gualtieri, Ph.D. candidate, research fields: applied mathematics, epidemiology. E-mail: agualtieri@odon.uba.ar.

the population in different infection states, and the incidence of disease-related events [2]. The choice of which states to include in a model depends on the characteristics of the particular disease being modeled and the purpose of the model. Acronyms for epidemiology models are often based on the flow patterns between the different states [3]. For example, in a SIR (Susceptible-Infected-Recovered) type model individuals can be in one of three states; they are susceptible (S) and can catch the disease, infected (I) and can spread the disease, or recovered and immune (R) [4, 5]. The SIS (Susceptible-Infected-Susceptible) type models deal with infection without immunity, where recovery is possible but recovered individuals are immediately susceptible [6, 7]. Both deterministic and stochastic models are used to describe the transmission dynamics of epidemics. Both model types are needed, and both have their advantages

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Dynamics and Control of Infectious Diseases in Stochastic Metapopulation Models

and weaknesses. The deterministic models, based in systems of differential equations, often lead to powerful qualitative results with important threshold behavior. They also lead to simpler mathematical problems than the stochastic ones. Work on deterministic models has therefore dominated strongly over work on stochastic models [8]. However, deterministic models are not appropriate when population size is small and stochastic factors play a major role [9]. There are a number of ways to allow the events in a model to be influenced by chance, but the most common and rigorous method is Monte Carlo simulation, where the set of possible next events is defined with a probability attached to each. A random number generator is then used to calculate when the next event will occur and which of the range of possible events it will be [10]. The Gillespie event algorithm is a variety of Monte Carlo method. It was developed by D.T. Gillespie in 1977 to the study of chemical dynamics [11]. However, this algorithm has been applied to several biological systems, including models of spread of epidemics [12-14]. Gillespie algorithm can simulate the dynamics of a stochastic system without setting up a master equation, which describes how the probability of being in each possible state evolves over the time. The master equation is hard to solve, both theoretically and numerically. With recent increases in the speed of computers, stochastic models have become more convenient and should have an important role in understanding the transmission and control of infectious diseases [10]. Classical epidemic models have tended to minimize geographic heterogeneity and related spatial aspects of spread of infectious diseases. However, rapid transportation and, in particular, air travel, has changed the way epidemics spread [15]. Thus, today, there is a growing interest in epidemiological models that include spatial elements and population mobility. Spatial models of infectious disease transmission provide the only plausible experimental system in

which knowledge of the location of hosts and their typical movement patterns can be combined with a quantitative description of the infection process and disease natural history to investigate observed patterns and to evaluate alternative intervention options [16]. There are different approaches that allow to consider the spatial distribution of population and mobility of individuals between different areas. Metapopulation models (also known as patch models) are one of these designs. A metapopulation model involves explicit movements of individuals between distinct locations [17]. These locations can be interpreted as different geographic regions [18, 19]. The development of models of spread of infectious diseases in metapopulations is relatively recent [15, 17]. In the current work, the aim has been to design stochastic models in discrete time, in order to study the transmission dynamics and control of infectious diseases in metapopulations. For this, the authors developed a computer program that allows to implement the Gillespie algorithm to represent epidemiological dynamics.

2. Materials and Methods

The input of the Gillespie algorithm, for application in chemical dynamics, consists of a set of reactions and the probability of occurrence for each of them. This probability is called stochastic reaction constant. In each cycle of the algorithm two pseudo-random numbers are generated. Then stochastic reaction constants and the pseudo-random numbers are used to select the next reaction and to calculate the time between two successive reactions (waiting time). The complete formulation of the algorithm, with the equations to calculate the next reaction and the waiting time, can be found in Ref. [11]. The dynamics of the models developed in this work are represented by the Gillespie algorithm. In this way, the system is defined by a set of events (reactions), and it is not attempted to solve a master equation. The different categories of individuals (e.g., susceptible,

Dynamics and Control of Infectious Diseases in Stochastic Metapopulation Models

505

infected, recovered) correspond to different chemical species of a molecular system. The processes of transition between these categories (such as infection: SI, or recovery with immunity: IR) are equivalent to the reactions of a chemical model. Thus, in the present epidemiological models, stochastic reaction constants are the parameters that govern the transition between these categories. The models consider a closed population system consisting of a set of subpopulations, linked by migration between them. Births and deaths are not considered. Two schemes were studied: SIS (Susceptible-Infected-Susceptible) and SIR (Susceptible-Infected-Recovered). In each subpopulation i the following events were represented: infection (SiIi) in both schemes, recovery without immunity (IiSi) in SIS scheme, and recovery with immunity (IiRi) and vaccination (SiRi) in SIR scheme. Displacements of individuals in state X (X = S, I or R), between different subpopulations i and j, were also considered (XiXj). The Gillespie algorithm was implemented in a computer program developed by the authors on Delphi 7.0 platform. For each simulation, the application allows to incorporate the initial number of individuals in each state and the values of stochastic reaction constants for each event. After each simulation run, the program provides a numerical record of the number of individuals in each state as a function of simulation time. The application executes the Gillespie algorithm according to the general syntax referenced above [11]. Pseudo-random numbers are generated by the internal engine of Delphi 7.0. A particular case of two subpopulations was explored (Table 1, Fig. 1). The developed program was run to study the general dynamics of the system and specific aspects of propagation and control. The authors explored the influence of infection (in SIS scheme) and vaccination (in SIR scheme) in a subpopulation on the propagation behavior in the other subpopulation of the system. Uniform reduction of

probability of infection in both subpopulations and localized reduction in only one of them were compared in SIS scheme. In analogy, uniform and localized vaccination were analyzed in SIR scheme. In order to perform simulations, arbitrary values were assigned to initial number of people and stochastic reaction constants. The time is quantified in adimensional units.
Table 1 Reactions for modeled SIS and SIR schemes in a system of two subpopulations. Stochastic reaction constant a b c d e f g h i j k l m n
(A)

Reaction S1I1 S2I2 I1S1 I2S2 I1R1 I2R2 S1R1 S2R2 S1S2 S2S1 I1I2 I2I1 R1R2 R2R1

Type of event represented Infection Recovery without immunity Recovery with immunity Vaccination

Displacement

S1 c I1 a

i j b k l

S2 d I2

(B)

S1 a g

i j

S2 b

k I1 l e m R1 f I2 h

R2 n Fig. 1 Flow charts for a particular case of two subpopulations: (A) SIS scheme, (B) SIR scheme.

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Dynamics and Control of Infectious Diseases in Stochastic Metapopulation Models

3. Results and Discussion

The prevalence curves obtained from the models developed in the current work follow the expected trends for SIS (Susceptible-Infected-Susceptible) and SIR (Susceptible-Infected-Recovered) schemes. However, the dynamics exhibit fluctuating behavior. This demonstrates the capture of a stochastic dynamics, achieved by the Gillespie algorithm. Fig. 2 shows the proportion of infected individuals in the system as a function of time for specific examples of both schemes in a system of two subpopulations. In the SIS scheme the infected proportion increases to stabilize around a plateau. While in the SIR scheme is observed that the prevalence increases with exponential trend to higher values, and then begins to decline. The performed explorations show how the reduction of infection or the increase of vaccination in a subpopulation, modify the behavior of propagation in the other subpopulation of the system. Fig. 3 shows that the reduction of the probability of infection in the subpopulation 2 (by decreasing the value of the stochastic reaction constant b for the infection event) causes a reduction of the prevalence in the subpopulation 1 at long times, in SIS scheme. In addition, an increase in the vaccination of susceptible individuals in the subpopulation 2 (by increasing the stochastic reaction constant h for the vaccination event) causes a decrease in the maximum values of prevalence in the subpopulation 1, and a marked decline of prevalence in the subpopulation 1 at long times, in SIR scheme (Fig. 4). Fig. 5 shows the comparison between a uniform and a localized reduction of the infection probability in the system, in SIS scheme. It can be observed that the trends are different in the two cases. Thus, the represented localized strategy produces greater decrease in prevalence at long times than the uniform measure. The authors also found differences between the two represented vaccination strategies. The represented uniform vaccination produces a greater

reduction of peak prevalence than the simulated focalized vaccination (Fig. 6). These results show how the dynamics of transmission and the application of control measures within each subpopulation, which may affect all subpopulations of the metapopulation system. The authors also show how the distribution of control measures among subpopulations affects the efficacy of these strategies.
0.45 SIS

Proportion infected in the system

SIR 0.30

0.15

0.00
0 20 40 60 80 100 120

Time

Fig. 2 Typical spread dynamics of SIS and SIR models for two subpopulations. Initial number of people for the SIS scheme: S1 = 90; I1 = 10; S2 = 90; I2 = 10. Initial number of people for the SIR scheme: S1 = 90; I1 = 5; R1 = 5; S2 = 90; I2 = 5; R2 = 5. Stochastic reaction constants: a = b = 0.20; c = d = 0.30; e = f = 0.30; g = h = 0.00; i = j = k = l = m = n = 0.10. Time expressed in adimensional units.
0.48

Proportion infected in the subpopulation 1

0.24

b = 0.200 b = 0.100 b = 0.025

0.00
0 20 40 60 80 100

Time

Fig. 3 Influence of the infection probability in the subpopulation 2 on the propagation dynamics in the subpopulation 1, for a SIS scheme of two subpopulations. Initial number of people: S1 = 90; I1 = 10; S2 = 90; I2 = 10. Stochastic reaction constants: a = 0.20; c = d = 0.30; i = j = k = l = 0.10. b = {0.200; 0.100; 0.025}. b is the stochastic reaction constant for the infection event in the subpopulation 2. Time expressed in adimensional units.

Dynamics and Control of Infectious Diseases in Stochastic Metapopulation Models

0.34 h = 0.00

507

0.32 g = h = 0.00 g = h = 0.20 g = 0.40, h = 0.00

Proportion infected in the subpopulation 1

h = 0.40

Proportion infected in the system

120

h = 0.80

0.17

0.16

0.00
0 20 40 60 80 100

0.00
0 20 40 60 80 100 120

Time

Time

Fig. 4 Influence of the vaccination probability in the subpopulation 2 on the propagation dynamics in the subpopulation 1, for a SIR scheme of two subpopulations. Initial number of people: S1 = 90; I1 = 5; R1 = 5; S2 = 90; I2 = 5; R2 = 5. Stochastic reaction constants: a = b = 0.20; e = f = 0.30; g = 0.00; i = j = k = l = m = n = 0.10. h = {0.00; 0.40; 0.80}. h is the stochastic reaction constant of the vaccination event in the subpopulation 2. Time expressed in adimensional units.
0.45

Fig. 6 Effect of the vaccination probability on the propagation dynamics in the system, for a SIR scheme of two subpopulations. Initial number of people: S1 = 90; I1 = 5; R1 = 5; S2 = 90; I2 = 5; R2 = 5. Stochastic reaction constants: a = b = 0.20; e = f = 0.30; i = j = k = l = m = n = 0.10. The dashed line represents the control case. The solid gray line represents a uniform implementation of vaccination in both subpopulations. The solid black line represents a localized implementation of vaccination in the subpopulation 1 only. Time expressed in adimensional units.

0.30

0.15 a = b = 0.20 a = b = 0.15 a = 0.10, b = 0.20

0.00
0 20 40 60 80

Time

Fig. 5 Effect of the infection probability on the propagation dynamics in the system, for a SIS scheme of two subpopulations. Initial number of people: S1 = 90; I1 = 10; S2 = 90, I2 = 10. Stochastic reaction constants: c = d = 0.30; i = j = k = l = 0.10. The dashed line represents the control case. The solid gray line represents a uniform reduction of the infection probability in both subpopulations. The solid black line represents a localized reduction of the infection probability in the subpopulation 1 only. Time expressed in arbitrary units.

The behavior of the models developed in this work is consistent with the general dynamics observed in SIR and SIS models represented by systems of differential equations [1]. However, the dynamics of the models presented here are altered by fluctuations. This coincides with the results obtained by other authors that also studied epidemiological models simulated by event-driven Monte Carlo procedures [13, 20]. The

existence of these fluctuations shows that the chance could influence the dynamics of propagation. The models designed in the current study represent general schemes and they have not been calibrated. The present work aims to provide a basis for the future development of more complex and complete models. However, other authors has shown how epidemiological models based on the Gillespie algorithm can increase the knowledge about the spread and control of specific diseases, such as meningococcal disease [12] and influenza [9, 13]. In addition, metapopulation models have been designed to represent real scenarios. For example, some years ago, a metapopulation model was developed in order to estimate the impact of migration on the spread of HIV in South Africa [21]. More recently, metapopulation techniques were employed to model global propagation of the new influenza A (H1N1) [22].

Proportion infected in the system

4. Conclusions
This work highlights the importance of the spatial distribution of the population in the spread and control of infectious diseases. It also shows how chance could play an important role in these scenarios.

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The objective of the present study was not to make precise quantitative projections in any given population. Instead, the authors wanted to design a simplified model that allows to gain a better understanding of the spread and control of epidemics in metapopulation systems influenced by chance. In future works, the aim of authors will be to complicate these simple designs in order to continue studying the spread of epidemics through the development and the exploration of spatial models.

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Acknowledgments
This work was supported by Universidad de Buenos Aires under grant UBACyT O405.
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