ISSN:

1551-0018

eISSN:

1547-1063

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## Mathematical Biosciences & Engineering

February 2018 , Volume 15 , Issue 1

Special issue on Erice ‘MathCompEpi 2015’ Proceedings

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*+*[Abstract](4021)

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**Abstract:**

A review is presented here of the research carried out, by a group including the authors, on the mathematical analysis of epidemic systems. Particular attention is paid to recent analysis of optimal control problems related to spatially structured epidemics driven by environmental pollution. A relevant problem, related to the possible eradication of the epidemic, is the so called zero stabilization. In a series of papers, necessary conditions, and sufficient conditions of stabilizability have been obtained. It has been proved that it is possible to diminish exponentially the epidemic process, in the whole habitat, just by reducing the concentration of the pollutant in a nonempty and sufficiently large subset of the spatial domain. The stabilizability with a feedback control of harvesting type is related to the magnitude of the principal eigenvalue of a certain operator. The problem of finding the optimal position (by translation) of the support of the feedback stabilizing control is faced, in order to minimize both the infected population and the pollutant at a certain finite time.

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**Abstract:**

We propose a new deterministic mathematical model for the transmission dynamics of Ebola Virus Disease (EVD) in a complex Ebola virus life ecology. Our model captures as much as possible the features and patterns of the disease evolution as a three cycle transmission process in the two ways below. Firstly it involves the synergy between the epizootic phase (during which the disease circulates periodically amongst non-human primates populations and decimates them), the enzootic phase (during which the disease always remains in fruit bats population) and the epidemic phase (during which the EVD threatens and decimates human populations). Secondly it takes into account the well-known, the probable/suspected and the hypothetical transmission mechanisms (including direct and indirect routes of contamination) between and within the three different types of populations consisting of humans, animals and fruit bats. The reproduction number $\mathcal R_0$ for the full model with the environmental contamination is derived and the global asymptotic stability of the disease free equilibrium is established when $\mathcal R_0 < 1$. It is conjectured that there exists a unique globally asymptotically stable endemic equilibrium for the full model when $\mathcal R_0>1$. The role of a contaminated environment is assessed by comparing the human infected component for the sub-model without the environment with that of the full model. Similarly, the sub-model without animals on the one hand and the sub-model without bats on the other hand are studied. It is shown that bats influence more the dynamics of EVD than the animals. Global sensitivity analysis shows that the effective contact rate between humans and fruit bats and the mortality rate for bats are the most influential parameters on the latent and infected human individuals. Numerical simulations, apart from supporting the theoretical results and the existence of a unique globally asymptotically stable endemic equilibrium for the full model, suggest further that: (1) fruit bats are more important in the transmission processes and the endemicity level of EVD than animals. This is in line with biological findings which identified bats as reservoir of Ebola viruses; (2) the indirect environmental contamination is detrimental to human beings, while it is almost insignificant for the transmission in bats.

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**Abstract:**

A new deterministic model for the population biology of immature and mature mosquitoes is designed and used to assess the impact of temperature and rainfall on the abundance of mosquitoes in a community. The trivial equilibrium of the model is globally-asymptotically stable when the associated *vectorial reproduction* number $({\mathcal R}_0)$ is less than unity. In the absence of density-dependence mortality in the larval stage, the autonomous version of the model has a unique and globally-asymptotically stable non-trivial equilibrium whenever $1 < {\mathcal R}_0 < {\mathcal R}_0^C$ (this equilibrium bifurcates into a limit cycle, *via* a Hopf bifurcation at ${\mathcal R}_0={\mathcal R}_0^C$). Numerical simulations of the weather-driven model, using temperature and rainfall data from three cities in Sub-Saharan Africa (Kwazulu Natal, South Africa; Lagos, Nigeria; and Nairobi, Kenya), show peak mosquito abundance occurring in the cities when the mean monthly temperature and rainfall values lie in the ranges $[22 -25]^{0}$C, $[98 -121]$ mm; $[24 -27]^{0}$C, $[113 -255]$ mm and $[20.5 -21.5]^{0}$C, $[70 -120]$ mm, respectively (thus, mosquito control efforts should be intensified in these cities during the periods when the respective suitable weather ranges are recorded).

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**Abstract:**

In this article we describe the transmission dynamics of hantavirus in rodents using a spatio-temporal susceptible-exposed-infective-recovered (SEIR) compartmental model that distinguishes between male and female subpopulations [L.J.S. Allen, R.K. McCormack and C.B. Jonsson, *Bull. Math. Biol.* **68** (2006), 511-524]. Both subpopulations are assumed to differ in their movement with respect to local variations in the densities of their own and the opposite gender group. Three alternative models for the movement of the male individuals are examined. In some cases the movement is not only directed by the gradient of a density (as in the standard diffusive case), but also by a non-local convolution of density values as proposed, in another context, in [R.M. Colombo and E. Rossi, *Commun. Math. Sci.*, **13** (2015), 369-400]. An efficient numerical method for the resulting convection-diffusion-reaction system of partial differential equations is proposed. This method involves techniques of weighted essentially non-oscillatory (WENO) reconstructions in combination with implicit-explicit Runge-Kutta (IMEX-RK) methods for time stepping. The numerical results demonstrate significant differences in the spatio-temporal behavior predicted by the different models, which suggest future research directions.

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**Abstract:**

Three deterministic Kermack-McKendrick-type models for studying the transmission dynamics of an infection in a two-sex closed population are analyzed here. In each model it is assumed that infection can be transmitted through heterosexual contacts, and that there is a higher probability of transmission from one sex to the other than vice versa. The study is focused on understanding whether and how this bias in transmission reflects in sex differences in final attack ratios (i.e. the fraction of individuals of each sex that eventually gets infected). In the first model, where the other two transmission modes are not considered, the attack ratios (fractions of the population of each sex that will eventually be infected) can be obtained as solutions of a system of two nonlinear equations, that has a unique solution if the net reproduction number exceeds unity. It is also shown that the ratio of attack ratios depends solely on the ratio of gender-specific susceptibilities and on the basic reproductive number of the epidemic *ρ*). Quantitatively, the ratio of final attack ratios generally will not exceed 1.5, if non-sexual transmission accounts for most transmission events (*ρ* ≥ 0.6) and the ratio of gender-specific susceptibilities is not too large (say, 5 at most).

The third model considers vector-borne, instead of direct transmission. In this case, we were not able to find an analytical expression for the final attack ratios, but used instead numerical simulations. The results on final attack ratios are actually quite similar to those obtained with the second model. It is interesting to note that transient patterns can differ from final attack ratios, as new cases will tend to occur more often in the more susceptible sex, while later depletion of susceptibles may bias the ratio in the opposite direction.

The analysis of these simple models, despite their lack of realism, can help in providing insight into, and assessment of, the potential role of gender-specific transmission in infections with multiple modes of transmission, such as Zika virus (ZIKV), by gauging what can be expected to be seen from epidemiological reports of new cases, disease incidence and seroprevalence surveys.

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**Abstract:**

We present a method, known in control theory, to give set-membership estimates for the states of a population in which an infectious disease is spreading. An estimation is reasonable due to the fact that the parameters of the equations describing the dynamics of the disease are not known with certainty. We discuss the properties of the resulting estimations. These include the possibility to determine best-or worst-case-scenarios and identify under which circumstances they occur, as well as a method to calculate confidence intervals for disease trajectories under sparse data. We give numerical examples of the technique using data from the 2014 outbreak of the Ebola virus in Africa. We conclude that the method presented here can be used to extract additional information from epidemiological data.

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**Abstract:**

When mathematical models of infectious diseases are used to inform health policy, an important first step is often to calibrate a model to disease surveillance data for a specific setting (or multiple settings). It is increasingly common to also perform sensitivity analyses to demonstrate the robustness, or lack thereof, of the modeling results. Doing so requires the modeler to find multiple parameter sets for which the model produces behavior that is consistent with the surveillance data. While frequently overlooked, the calibration process is nontrivial at best and can be inefficient, poorly communicated and a major hurdle to the overall reproducibility of modeling results.

In this work, we describe a general approach to calibrating infectious disease models to surveillance data. The technique is able to match surveillance data to high accuracy in a very efficient manner as it is based on the Newton-Raphson method for solving nonlinear systems. To demonstrate its robustness, we use the calibration technique on multiple models for the interacting dynamics of HIV and HSV-2.

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**Abstract:**

In the present paper we propose a simple time-varying ODE model to describe the evolution of HIV epidemic in Italy. The model considers a single population of susceptibles, without distinction of high-risk groups within the general population, and accounts for the presence of immigration and emigration, modelling their effects on both the general demography and the dynamics of the infected subpopulations. To represent the intra-host disease progression, the untreated infected population is distributed over four compartments in cascade according to the CD4 counts. A further compartment is added to represent infected people under antiretroviral therapy. The per capita exit rate from treatment, due to voluntary interruption or failure of therapy, is assumed variable with time. The values of the model parameters not reported in the literature are assessed by fitting available epidemiological data over the decade

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**Abstract:**

This paper is dedicated to the application of two types of SEIR models to the influenza outbreak peak prediction in Russian cities. The first one is a continuous SEIR model described by a system of ordinary differential equations. The second one is a discrete model formulated as a set of difference equations, which was used in the Baroyan-Rvachev modeling framework for the influenza outbreak prediction in the Soviet Union. The outbreak peak day and height predictions were performed by calibrating both models to varied-size samples of long-term data on ARI incidence in Moscow, Saint Petersburg, and Novosibirsk. The accuracy of the modeling predictions on incomplete data was compared with a number of other peak forecasting methods tested on the same dataset. The drawbacks of the described prediction approach and possible ways to overcome them are discussed.

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**Abstract:**

Tuberculosis (TB) is returning to be a worldwide global public health threat. It is estimated that 9.6 million cases occurred in 2014, of which just two-thirds notified to public health authorities. The "missing cases" constitute a severe challenge for TB transmission control. TB is a severe disease in India, while, worldwide, the WHO estimates that one third of the entire world population is infected.

Nowadays, incidence estimation relies increasingly more on notifications of new cases from routine surveillance. There is an urgent need for better estimates of the load of TB, in high-burden settings. We developed a simple model of TB transmission dynamics, using a dynamical system model, consisting of six classes of individuals. It contains the current medical epidemiologists' understanding of the spread of the *Mycobacterium tuberculosis* in humans, which is substantiated by field observations at the district level in India. The model incorporates the treatment options provided by the public and private sectors in India. Mathematically, an interesting feature of the system is that it exhibits a backward, or subcritical, bifurcation.

One of the results of the investigation shows that the discrepancy between the diagnosis rates of the public and private sector does not seem to be the cause of the endemicity of the disease, and, unfortunately, even if they reached 100% of correct diagnosis, this would not be enough to achieve disease eradication.

Several other approaches have been attempted on the basis of this model to indicate possible strategies that may lead to disease eradication, but the rather sad conclusion is that they unfortunately do not appear viable in practice.

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**Abstract:**

Funds from various global organizations, such as, The Global Fund, The World Bank, etc. are not directly distributed to the targeted risk groups. Especially in the so-called third-world-countries, the major part of the fund in HIV prevention programs comes from these global funding organizations. The allocations of these funds usually pass through several levels of decision making bodies that have their own specific parameters to control and specific objectives to achieve. However, these decisions are made mostly in a heuristic manner and this may lead to a non-optimal allocation of the scarce resources. In this paper, a hierarchical mathematical optimization model is proposed to solve such a problem. Combining existing epidemiological models with the kind of interventions being on practice, a 3-level hierarchical decision making model in optimally allocating such resources has been developed and analyzed. When the impact of antiretroviral therapy (ART) is included in the model, it has been shown that the objective function of the lower level decision making structure is a non-convex minimization problem in the allocation variables even if all the production functions for the intervention programs are assumed to be linear.

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**Abstract:**

For an intervention against the spread of communicable diseases, the idealized situation is when individuals fully comply with the intervention and the exposure to the infectious agent is comparable across all individuals. Some level of non-compliance is likely where the intervention is widely implemented. The focus is on a more accurate view of its effects population-wide. A frailty model is applied. Qualitative analysis, in mathematical terms, reveals how large variability in compliance renders the intervention less effective. This finding sharpens our vague, intuitive and empirical notions. An effective reproduction number in the presence of frailty is defined and is shown to be invariant with respect to the time-scale of disease progression. This makes the results in this paper valid for a wide spectrum of acute and chronic infectious diseases. Quantitative analysis by comparing numerical results shows that they are also robust with respect to assumptions on disease progression structure and distributions, such as with or without the latent period and the assumed distributions of latent and infectious periods.

*+*[Abstract](9632)

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**Abstract:**

We extend here the game-theoretic investigation made by d'Onofrio et al (2012) on the interplay between private vaccination choices and actions of the public health system (PHS) to favor vaccine propensity in SIR-type diseases. We focus here on three important features. First, we consider a SEIR-type disease. Second, we focus on the role of seasonal fluctuations of the transmission rate. Third, by a simple population-biology approach we derive -with a didactic aim -the game theoretic equation ruling the dynamics of vaccine propensity, without employing 'economy-related' concepts such as the payoff. By means of analytical and analytical-approximate methods, we investigate the global stability of the of disease-free equilibria. We show that in the general case the stability critically depends on the 'shape' of the periodically varying transmission rate. In other words, the knowledge of the average transmission rate (ATR) is not enough to make inferences on the stability of the elimination equilibria, due to the presence of the class of latent subjects. In particular, we obtain that the amplitude of the oscillations favors the possible elimination of the disease by the action of the PHS, through a threshold condition. Indeed, for a given average value of the transmission rate, in absence of oscillations as well as for moderate oscillations, there is no disease elimination. On the contrary, if the amplitude exceeds a threshold value, the elimination of the disease is induced. We heuristically explain this apparently paradoxical phenomenon as a beneficial effect of the phase when the transmission rate is under its average value: the reduction of transmission rate (for example during holidays) under its annual average over-compensates its increase during periods of intense contacts. We also investigate the conditions for the persistence of the disease. Numerical simulations support the theoretical predictions. Finally, we briefly investigate the qualitative behavior of the non-autonomous system for SIR-type disease, by showing that the stability of the elimination equilibria are, in such a case, determined by the ATR.

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**Abstract:**

The recent measles outbreaks in US and Germany emphasize the importance of sustaining and increasing vaccination rates. In Slovakia, despite mandatory vaccination scheme, decrease in the vaccination rates against measles has been observed in recent years. Different kinds of intervention at the state level, like a law making vaccination a requirement for school entry or education and advertising seem to be the only strategies to improve vaccination coverage. This study aims to analyze the economic effectiveness of intervention in Slovakia. Using real options techniques we determine the level of vaccination rate at which it is optimal to perform intervention. We represent immunization rate of newborns as a stochastic process and intervention as a one-period jump of this process. Sensitivity analysis shows the importance of early intervention in the population with high initial average vaccination coverage. Furthermore, our numerical results demonstrate that the less certain we are about the future development of the immunization rate of newborns, the more valuable is the option to intervene.

2018
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