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Mathematical Biosciences & Engineering
2016 , Volume 13 , Issue 1
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2016, 13(1): 1-18
doi: 10.3934/mbe.2016.13.1
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Abstract:
We consider a two-strain pathogen model described by a system of reaction-diffusion equations. We define a basic reproduction number $R_0$ and show that when the model parameters are constant (spatially homogeneous), if $R_0 >1$ then one strain will outcompete the other strain and drive it to extinction, but if $R_0 \le 1$ then the disease-free equilibrium is globally attractive. When we assume that the diffusion rates are equal while the transmission and recovery rates are heterogeneous, then there are two possible outcomes under the condition $R_0 >1$: 1) Competitive exclusion where one strain dies out. 2) Coexistence between the two strains. Thus, spatial heterogeneity promotes coexistence.
We consider a two-strain pathogen model described by a system of reaction-diffusion equations. We define a basic reproduction number $R_0$ and show that when the model parameters are constant (spatially homogeneous), if $R_0 >1$ then one strain will outcompete the other strain and drive it to extinction, but if $R_0 \le 1$ then the disease-free equilibrium is globally attractive. When we assume that the diffusion rates are equal while the transmission and recovery rates are heterogeneous, then there are two possible outcomes under the condition $R_0 >1$: 1) Competitive exclusion where one strain dies out. 2) Coexistence between the two strains. Thus, spatial heterogeneity promotes coexistence.
2016, 13(1): 19-41
doi: 10.3934/mbe.2016.13.19
+[Abstract](2230)
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Abstract:
The growth of a population subject to maturation delay is modeled by using either a discrete delay or a delay continuously distributed over the population. The occurrence of stability switches (stable-unstable-stable) of the positive equilibrium as the delay increases is investigated in both cases. Necessary and sufficient conditions are provided by analyzing the relevant characteristic equations. It is shown that for any choice of parameter values for which the discrete delay model presents stability switches there exists a maximum delay variance beyond which no switch occurs for the continuous delay model: the delay variance has a stabilizing effect. Moreover, it is illustrated how, in the presence of switches, the unstable delay domain is as larger as lower is the ratio between the juveniles and the adults mortality rates.
The growth of a population subject to maturation delay is modeled by using either a discrete delay or a delay continuously distributed over the population. The occurrence of stability switches (stable-unstable-stable) of the positive equilibrium as the delay increases is investigated in both cases. Necessary and sufficient conditions are provided by analyzing the relevant characteristic equations. It is shown that for any choice of parameter values for which the discrete delay model presents stability switches there exists a maximum delay variance beyond which no switch occurs for the continuous delay model: the delay variance has a stabilizing effect. Moreover, it is illustrated how, in the presence of switches, the unstable delay domain is as larger as lower is the ratio between the juveniles and the adults mortality rates.
2016, 13(1): 43-65
doi: 10.3934/mbe.2016.13.43
+[Abstract](2499)
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Abstract:
A spatial-temporal transmission model of 2009 A/H1N1 pandemic influenza across Chile, a country that spans a large latitudinal range, is developed to characterize the spatial variation in peak timing of that pandemic as a function of local transmission rates, spatial connectivity assumptions for Chilean regions, and the putative location of introduction of the novel virus into the country. Specifically, a metapopulation SEIR (susceptible-exposed-infected-removed) compartmental model that tracks the transmission dynamics of influenza in 15 Chilean regions is calibrated. The model incorporates population mobility among neighboring regions and indirect mobility to and from other regions via the metropolitan central region (``hub region''). The stability of the disease-free equilibrium of this model is analyzed and compared with the corresponding stability in each region, concluding that stability may occur even with some regions having basic reproduction numbers above 1. The transmission model is used along with epidemiological data to explore potential factors that could have driven the spatial-temporal progression of the pandemic. Simulations and sensitivity analyses indicate that this relatively simple model is sufficient to characterize the south-north gradient in peak timing observed during the pandemic, and suggest that south Chile observed the initial spread of the pandemic virus, which is in line with a retrospective epidemiological study. The ``hub region'' in our model significantly enhanced population mixing in a short time scale.
A spatial-temporal transmission model of 2009 A/H1N1 pandemic influenza across Chile, a country that spans a large latitudinal range, is developed to characterize the spatial variation in peak timing of that pandemic as a function of local transmission rates, spatial connectivity assumptions for Chilean regions, and the putative location of introduction of the novel virus into the country. Specifically, a metapopulation SEIR (susceptible-exposed-infected-removed) compartmental model that tracks the transmission dynamics of influenza in 15 Chilean regions is calibrated. The model incorporates population mobility among neighboring regions and indirect mobility to and from other regions via the metropolitan central region (``hub region''). The stability of the disease-free equilibrium of this model is analyzed and compared with the corresponding stability in each region, concluding that stability may occur even with some regions having basic reproduction numbers above 1. The transmission model is used along with epidemiological data to explore potential factors that could have driven the spatial-temporal progression of the pandemic. Simulations and sensitivity analyses indicate that this relatively simple model is sufficient to characterize the south-north gradient in peak timing observed during the pandemic, and suggest that south Chile observed the initial spread of the pandemic virus, which is in line with a retrospective epidemiological study. The ``hub region'' in our model significantly enhanced population mixing in a short time scale.
2016, 13(1): 67-82
doi: 10.3934/mbe.2016.13.67
+[Abstract](1665)
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Abstract:
The body mass growth of organisms is usually represented in terms of what is known as ontogenetic growth models, which represent the relation of dependence between the mass of the body and time. The paper is concerned with a problem of finding an optimal experimental design for discriminating between two competing mass growth models applied to a beef farm. T-optimality was first introduced for discrimination between models but in this paper, KL-optimality based on the Kullback-Leibler distance is used to deal with correlated obsevations since, in this case, observations on a particular animal are not independent.
The body mass growth of organisms is usually represented in terms of what is known as ontogenetic growth models, which represent the relation of dependence between the mass of the body and time. The paper is concerned with a problem of finding an optimal experimental design for discriminating between two competing mass growth models applied to a beef farm. T-optimality was first introduced for discrimination between models but in this paper, KL-optimality based on the Kullback-Leibler distance is used to deal with correlated obsevations since, in this case, observations on a particular animal are not independent.
2016, 13(1): 83-99
doi: 10.3934/mbe.2016.13.83
+[Abstract](2720)
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Abstract:
Diabetes affects millions of Americans, and the correct identification of individuals afflicted with this disease, especially of those in early stages or in progression towards diabetes, remains an active area of research. The minimal model is a simplified mathematical construct for understanding glucose-insulin interactions. Developed by Bergman, Cobelli, and colleagues over three decades ago [7,8], this system of coupled ordinary differential equations prevails as an important tool for interpreting data collected during an intravenous glucose tolerance test (IVGTT). In this study we present an explicit solution to the minimal model which allows for separating the glucose and insulin dynamics of the minimal model and for identifying patient-specific parameters of glucose trajectories from IVGTT. As illustrated with patient data, our approach seems to have an edge over more complicated methods currently used. Additionally, we also present an application of our method to prediction of the time to baseline recovery and calculation of insulin sensitivity and glucose effectiveness, two quantities regarded as significant in diabetes diagnostics.
Diabetes affects millions of Americans, and the correct identification of individuals afflicted with this disease, especially of those in early stages or in progression towards diabetes, remains an active area of research. The minimal model is a simplified mathematical construct for understanding glucose-insulin interactions. Developed by Bergman, Cobelli, and colleagues over three decades ago [7,8], this system of coupled ordinary differential equations prevails as an important tool for interpreting data collected during an intravenous glucose tolerance test (IVGTT). In this study we present an explicit solution to the minimal model which allows for separating the glucose and insulin dynamics of the minimal model and for identifying patient-specific parameters of glucose trajectories from IVGTT. As illustrated with patient data, our approach seems to have an edge over more complicated methods currently used. Additionally, we also present an application of our method to prediction of the time to baseline recovery and calculation of insulin sensitivity and glucose effectiveness, two quantities regarded as significant in diabetes diagnostics.
2016, 13(1): 101-118
doi: 10.3934/mbe.2016.13.101
+[Abstract](1875)
+[PDF](374.7KB)
Abstract:
We analyze the dynamics of three models of mutualism, establishing the global stability of coexisting equilibria by means of Lyapunov's second method. This further establishes the usefulness of certain Lyapunov functionals of an abstract nature introduced in an earlier paper. As a consequence, it is seen that the use of higher order self-limiting terms cures the shortcomings of Lotka-Volterra mutualisms, preventing unbounded growth and promoting global stability.
We analyze the dynamics of three models of mutualism, establishing the global stability of coexisting equilibria by means of Lyapunov's second method. This further establishes the usefulness of certain Lyapunov functionals of an abstract nature introduced in an earlier paper. As a consequence, it is seen that the use of higher order self-limiting terms cures the shortcomings of Lotka-Volterra mutualisms, preventing unbounded growth and promoting global stability.
2016, 13(1): 119-133
doi: 10.3934/mbe.2016.13.119
+[Abstract](2208)
+[PDF](482.6KB)
Abstract:
Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections, which is part of a broader class of antibiotics called carbapenem. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. A physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose. PBPK modeling incorporates known physiological parameters such as body weight, organ volumes, and blood flow rates in particular tissues. Furthermore, ertapenem is highly bound in human blood plasma; therefore, nonlinear binding is incorporated in the model since only the free portion of the drug can saturate tissues and, hence, is the only portion of the drug considered to be medicinally effective. Parameters in the model were estimated using a least squares inverse problem formulation with published data for blood concentrations of ertapenem for normal height, normal weight males. Finally, an uncertainty analysis of the parameter estimation and model predictions is presented.
Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections, which is part of a broader class of antibiotics called carbapenem. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. A physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose. PBPK modeling incorporates known physiological parameters such as body weight, organ volumes, and blood flow rates in particular tissues. Furthermore, ertapenem is highly bound in human blood plasma; therefore, nonlinear binding is incorporated in the model since only the free portion of the drug can saturate tissues and, hence, is the only portion of the drug considered to be medicinally effective. Parameters in the model were estimated using a least squares inverse problem formulation with published data for blood concentrations of ertapenem for normal height, normal weight males. Finally, an uncertainty analysis of the parameter estimation and model predictions is presented.
2016, 13(1): 135-157
doi: 10.3934/mbe.2016.13.135
+[Abstract](2437)
+[PDF](4821.9KB)
Abstract:
In this paper, we propose and analyze a delayed HIV-1 model with CTL immune response and virus waning. The two discrete delays stand for the time for infected cells to produce viruses after viral entry and for the time for CD$8^+$ T cell immune response to emerge to control viral replication. We obtain the positiveness and boundedness of solutions and find the basic reproduction number $R_0$. If $R_0<1$, then the infection-free steady state is globally asymptotically stable and the infection is cleared from the T-cell population; whereas if $R_0>1$, then the system is uniformly persistent and the viral concentration maintains at some constant level. The global dynamics when $R_0>1$ is complicated. We establish the local stability of the infected steady state and show that Hopf bifurcation can occur. Both analytical and numerical results indicate that if, in the initial infection stage, the effect of delays on HIV-1 infection is ignored, then the risk of HIV-1 infection (if persists) will be underestimated. Moreover, the viral load differs from that without virus waning. These results highlight the important role of delays and virus waning on HIV-1 infection.
In this paper, we propose and analyze a delayed HIV-1 model with CTL immune response and virus waning. The two discrete delays stand for the time for infected cells to produce viruses after viral entry and for the time for CD$8^+$ T cell immune response to emerge to control viral replication. We obtain the positiveness and boundedness of solutions and find the basic reproduction number $R_0$. If $R_0<1$, then the infection-free steady state is globally asymptotically stable and the infection is cleared from the T-cell population; whereas if $R_0>1$, then the system is uniformly persistent and the viral concentration maintains at some constant level. The global dynamics when $R_0>1$ is complicated. We establish the local stability of the infected steady state and show that Hopf bifurcation can occur. Both analytical and numerical results indicate that if, in the initial infection stage, the effect of delays on HIV-1 infection is ignored, then the risk of HIV-1 infection (if persists) will be underestimated. Moreover, the viral load differs from that without virus waning. These results highlight the important role of delays and virus waning on HIV-1 infection.
2016, 13(1): 159-170
doi: 10.3934/mbe.2016.13.159
+[Abstract](1650)
+[PDF](664.3KB)
Abstract:
Radiation therapy is one of the important treatment procedures of cancer. The day-to-day delivered dose to the tissue in radiation therapy often deviates from the planned fixed dose per fraction. This day-to-day variation of radiation dose is stochastic. Here, we have developed the mathematical formulation to represent the day-to-day stochastic dose variation effect in radiation therapy. Our analysis shows that that the fixed dose delivery approximation under-estimates the biological effective dose, even if the average delivered dose per fraction is equal to the planned dose per fraction. The magnitude of the under-estimation effect relies upon the day-to-day stochastic dose variation level, the dose fraction size and the values of the radiobiological parameters of the tissue. We have further explored the application of our mathematical formulation for adaptive dose calculation. Our analysis implies that, compared to the premise of the Linear Quadratic Linear (LQL) framework, the Linear Quadratic framework based analytical formulation under-estimates the required dose per fraction necessary to produce the same biological effective dose as originally planned. Our study provides analytical formulation to calculate iso-effect in adaptive radiation therapy considering day-to-day stochastic dose deviation from planned dose and also indicates the potential utility of LQL framework in this context.
Radiation therapy is one of the important treatment procedures of cancer. The day-to-day delivered dose to the tissue in radiation therapy often deviates from the planned fixed dose per fraction. This day-to-day variation of radiation dose is stochastic. Here, we have developed the mathematical formulation to represent the day-to-day stochastic dose variation effect in radiation therapy. Our analysis shows that that the fixed dose delivery approximation under-estimates the biological effective dose, even if the average delivered dose per fraction is equal to the planned dose per fraction. The magnitude of the under-estimation effect relies upon the day-to-day stochastic dose variation level, the dose fraction size and the values of the radiobiological parameters of the tissue. We have further explored the application of our mathematical formulation for adaptive dose calculation. Our analysis implies that, compared to the premise of the Linear Quadratic Linear (LQL) framework, the Linear Quadratic framework based analytical formulation under-estimates the required dose per fraction necessary to produce the same biological effective dose as originally planned. Our study provides analytical formulation to calculate iso-effect in adaptive radiation therapy considering day-to-day stochastic dose deviation from planned dose and also indicates the potential utility of LQL framework in this context.
2016, 13(1): 171-191
doi: 10.3934/mbe.2016.13.171
+[Abstract](2130)
+[PDF](903.6KB)
Abstract:
Superinfection, a phenomenon that an individual infected by one HIV strain is re-infected by the second heterologous HIV strain, occurs in HIV infection. A mathematical model is formulated to examine how superinfection affects transmission dynamics of drug sensitive/resistant strains. Three reproduction numbers are defined: reproduction numbers $R_r$ and $R_s$ for drug-resistant and drug-sensitive strains, respectively, and the invasion reproduction number $R_s^r$. The disease-free equilibrium always exists and is locally stable when the larger of $R_s$ and $R_r$ is less than one. The drug resistant strain-only equilibrium is locally stable when $R_r>1$ and $R_s^r<1$. Numerical studies show that as the superinfection coefficient of the sensitive strain increases the system may (1) change to bistable states of disease-free equilibrium and the coexistence state from the stable disease-free equilibrium under no superinfection; (2) experience the stable resistant-strain only equilibrium, the bistable states of resistant-strain only equilibrium and the coexistence state, and the stable coexistence state in turn. This implies that superinfection of the sensitive strain is beneficial for two strains to coexist. While superinfection of the resistant strain makes resistant strain more likely to be sustained. The findings suggest that superinfection induces the complicated dynamics, and brings more difficulties in antiretroviral therapy.
Superinfection, a phenomenon that an individual infected by one HIV strain is re-infected by the second heterologous HIV strain, occurs in HIV infection. A mathematical model is formulated to examine how superinfection affects transmission dynamics of drug sensitive/resistant strains. Three reproduction numbers are defined: reproduction numbers $R_r$ and $R_s$ for drug-resistant and drug-sensitive strains, respectively, and the invasion reproduction number $R_s^r$. The disease-free equilibrium always exists and is locally stable when the larger of $R_s$ and $R_r$ is less than one. The drug resistant strain-only equilibrium is locally stable when $R_r>1$ and $R_s^r<1$. Numerical studies show that as the superinfection coefficient of the sensitive strain increases the system may (1) change to bistable states of disease-free equilibrium and the coexistence state from the stable disease-free equilibrium under no superinfection; (2) experience the stable resistant-strain only equilibrium, the bistable states of resistant-strain only equilibrium and the coexistence state, and the stable coexistence state in turn. This implies that superinfection of the sensitive strain is beneficial for two strains to coexist. While superinfection of the resistant strain makes resistant strain more likely to be sustained. The findings suggest that superinfection induces the complicated dynamics, and brings more difficulties in antiretroviral therapy.
2016, 13(1): 193-207
doi: 10.3934/mbe.2016.13.193
+[Abstract](1874)
+[PDF](376.2KB)
Abstract:
This work studies a general reaction-diffusion model for acid-mediated tumor invasion, where tumor cells produce excess acid that primarily kills healthy cells, and thereby invade the microenvironment. The acid diffuses and could be cleared by vasculature, and the healthy and tumor cells are viewed as two species following logistic growth with mutual competition. A key feature of this model is the density-limited diffusion for tumor cells, reflecting that a healthy tissue will spatially constrain a tumor unless shrunk. Under appropriate assumptions on model parameters and on initial data, it is shown that the unique heterogeneous state is nonlinearly stable, which implies a long-term coexistence of the healthy and tumor cells in certain parameter space. Our theoretical result suggests that acidity may play a significant role in heterogeneous tumor progression.
This work studies a general reaction-diffusion model for acid-mediated tumor invasion, where tumor cells produce excess acid that primarily kills healthy cells, and thereby invade the microenvironment. The acid diffuses and could be cleared by vasculature, and the healthy and tumor cells are viewed as two species following logistic growth with mutual competition. A key feature of this model is the density-limited diffusion for tumor cells, reflecting that a healthy tissue will spatially constrain a tumor unless shrunk. Under appropriate assumptions on model parameters and on initial data, it is shown that the unique heterogeneous state is nonlinearly stable, which implies a long-term coexistence of the healthy and tumor cells in certain parameter space. Our theoretical result suggests that acidity may play a significant role in heterogeneous tumor progression.
2016, 13(1): 209-225
doi: 10.3934/mbe.2016.13.209
+[Abstract](2055)
+[PDF](523.1KB)
Abstract:
In this paper, we investigate the global dynamics of a multi-group SEIR epidemic model, allowing heterogeneity of the host population, delay in latency and delay due to relapse distribution for the human population. Our results indicate that when certain restrictions on nonlinear growth rate and incidence are fulfilled, the basic reproduction number $\mathfrak{R}_0$ plays the key role of a global threshold parameter in the sense that the long-time behaviors of the model depend only on $\mathfrak{R}_0$. The proofs of the main results utilize the persistence theory in dynamical systems, Lyapunov functionals guided by graph-theoretical approach.
In this paper, we investigate the global dynamics of a multi-group SEIR epidemic model, allowing heterogeneity of the host population, delay in latency and delay due to relapse distribution for the human population. Our results indicate that when certain restrictions on nonlinear growth rate and incidence are fulfilled, the basic reproduction number $\mathfrak{R}_0$ plays the key role of a global threshold parameter in the sense that the long-time behaviors of the model depend only on $\mathfrak{R}_0$. The proofs of the main results utilize the persistence theory in dynamical systems, Lyapunov functionals guided by graph-theoretical approach.
2016, 13(1): 227-247
doi: 10.3934/mbe.2016.13.227
+[Abstract](2241)
+[PDF](440.9KB)
Abstract:
A recent paper [F. Brauer, Z. Shuai and P. van den Driessche, Dynamics of an age-of-infection cholera model, Math. Biosci. Eng., 10, 2013, 1335--1349.] presented a model for the dynamics of cholera transmission. The model is incorporated with both the infection age of infectious individuals and biological age of pathogen in the environment. The basic reproduction number is proved to be a sharp threshold determining whether or not cholera dies out. The global stability for disease-free equilibrium and endemic equilibrium is proved by constructing suitable Lyapunov functionals. However, for the proof of the global stability of endemic equilibrium, we have to show first the relative compactness of the orbit generated by model in order to make use of the invariance principle. Furthermore, uniform persistence of system must be shown since the Lyapunov functional is possible to be infinite if $i(a, t)/i^* (a) =0$ on some age interval. In this note, we give a supplement to above paper with necessary mathematical arguments.
A recent paper [F. Brauer, Z. Shuai and P. van den Driessche, Dynamics of an age-of-infection cholera model, Math. Biosci. Eng., 10, 2013, 1335--1349.] presented a model for the dynamics of cholera transmission. The model is incorporated with both the infection age of infectious individuals and biological age of pathogen in the environment. The basic reproduction number is proved to be a sharp threshold determining whether or not cholera dies out. The global stability for disease-free equilibrium and endemic equilibrium is proved by constructing suitable Lyapunov functionals. However, for the proof of the global stability of endemic equilibrium, we have to show first the relative compactness of the orbit generated by model in order to make use of the invariance principle. Furthermore, uniform persistence of system must be shown since the Lyapunov functional is possible to be infinite if $i(a, t)/i^* (a) =0$ on some age interval. In this note, we give a supplement to above paper with necessary mathematical arguments.
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