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The successful application of epidemic models hinges on our ability to estimate model parameters from limited observations reliably. An often-overlooked step before estimating model parameters consists of ensuring that the model parameters are structurally identifiable from the observed states of the system. In this tutorial-based primer, intended for a diverse audience, including students training in dynamic systems, we review and provide detailed guidance for conducting structural identifiability analysis of differential equation epidemic models based on a differential algebra approach using differential algebra for identifiability of systems (DAISY) and Mathematica (Wolfram Research). This approach aims to uncover any existing parameter correlations that preclude their estimation from the observed variables. We demonstrate this approach through examples, including tutorial videos of compartmental epidemic models previously employed to study transmission dynamics and control. We show that the lack of structural identifiability may be remedied by incorporating additional observations from different model states, assuming that the system’s initial conditions are known, using prior information to fix some parameters involved in parameter correlations, or modifying the model based on existing parameter correlations. We also underscore how the results of structural identifiability analysis can help enrich compartmental diagrams of differential-equation models by indicating the observed state variables and the results of the structural identifiability analysis. [ABSTRACT FROM AUTHOR]

Determining accurate estimates for the characteristics of the severe acute respiratory syndrome coronavirus 2 in the upper and lower respiratory tracts, by fitting mathematical models to data, is made difficult by the lack of measurements early in the infection. To determine the sensitivity of the parameter estimates to the noise in the data, we developed a novel two-patch within-host mathematical model that considered the infection of both respiratory tracts and assumed that the viral load in the lower respiratory tract decays in a density dependent manner and investigated its ability to match population level data. We proposed several approaches that can improve practical identifiability of parameters, including an optimal experimental approach, and found that availability of viral data early in the infection is of essence for improving the accuracy of the estimates. Our findings can be useful for designing interventions. [ABSTRACT FROM AUTHOR]

Sensitivity Analysis (SA) is a useful tool to measure the impact of changes in model parameters on the infection dynamics, particularly to quantify the expected efficacy of disease control strategies. SA has only been applied to epidemic models at the population level, ignoring the effect of within-host virus-with-immune-system interactions on the disease spread. Connecting the scales from individual to population can help inform drug and vaccine development. Thus the value of understanding the impact of immunological parameters on epidemiological quantities. Here we consider an age-since-infection structured vector-host model, in which epidemiological parameters are formulated as functions of within-host virus and antibody densities, governed by an ODE system. We then use SA for these immuno-epidemiological models to investigate the impact of immunological parameters on population-level disease dynamics such as basic reproduction number, final size of the epidemic or the infectiousness at different phases of an outbreak. As a case study, we consider Rift Valley Fever Disease utilizing parameter estimations from prior studies. SA indicates that 1 % increase in within-host pathogen growth rate can lead up to 8 % increase in R 0 , up to 1 % increase in steady-state infected host abundance, and up to 4 % increase in infectiousness of hosts when the reproduction number R 0 is larger than one. These significant increases in population-scale disease quantities suggest that control strategies that reduce the within-host pathogen growth can be important in reducing disease prevalence. [ABSTRACT FROM AUTHOR]

In this paper we formulate a multi-scale nested immuno-epidemiological model of HIV on complex networks. The system is described by ordinary differential equations coupled with a partial differential equation. First, we prove the existence and uniqueness of the immunological model and then establish the well-posedness of the multi-scale model. We derive an explicit expression of the basic reproduction number R 0 of the immuno-epidemiological model. The system has a disease-free equilibrium and an endemic equilibrium. The disease-free equilibrium is globally stable when R 0 < 1 and unstable when R 0 > 1 . Numerical simulations suggest that R 0 increases as the number of nodes in the network increases. Further, we find that for a scale-free network the number of infected individuals at equilibrium is a hump-like function of the within-host reproduction number; however, the dependence becomes monotone if the network has predominantly low connectivity nodes or high connectivity nodes. [ABSTRACT FROM AUTHOR]

Traditionally, the monolayer (two-dimensional) cell cultures are used for initial evaluation of the effectiveness of anticancer drugs. In particular, these experiments provide the IC 50 curves that determine drug concentration that can inhibit growth of a tumor colony by half when compared to the cells grown with no exposure to the drug. Low IC 50 value means that the drug is effective at low concentrations, and thus will show lower systemic toxicity when administered to the patient. However, in these experiments cells are grown in a monolayer, all well exposed to the drug, while in vivo tumors expand as three-dimensional multicellular masses, where inner cells have a limited access to the drug. Therefore, we performed computational studies to compare the IC 50 curves for cells grown as a two-dimensional monolayer and a cross section through a three-dimensional spheroid. Our results identified conditions (drug diffusivity, drug action mechanisms and cell proliferation capabilities) under which these IC 50 curves differ significantly. This will help experimentalists to better determine drug dosage for future in vivo experiments and clinical trials. [ABSTRACT FROM AUTHOR]

The Zika virus (ZIKV) epidemic has caused an ongoing threat to global health security and spurred new investigations of the virus. Use of epidemiological models for arbovirus diseases can be a powerful tool to assist in prevention and control of the emerging disease. In this article, we introduce six models of ZIKV, beginning with a general vector-borne model and gradually including different transmission routes of ZIKV. These epidemiological models use various combinations of disease transmission (vector and direct) and infectious classes (asymptomatic and pregnant), with addition to loss of immunity being included. The disease-induced death rate is omitted from the models. We test the structural and practical identifiability of the models to find whether unknown model parameters can uniquely be determined. The models were fit to obtain time-series data of cumulative incidences and pregnant infections from the Florida Department of Health Daily Zika Update Reports. The average relative estimation errors (AREs) were computed from the Monte Carlo simulations to further analyze the identifiability of the models. We show that direct transmission rates are not practically identifiable; however, fixed recovery rates improve identifiability overall. We found ARE is low for each model (only slightly higher for those that account for a pregnant class) and help to confirm a reproduction number greater than one at the start of the Florida epidemic. Basic reproduction number, R0, is an epidemiologically important threshold value which gives the number of secondary cases generated by one infected individual in a totally susceptible population in duration of infectiousness. Elasticity of the reproduction numbers suggests that the mosquito-to-human ratio, mosquito life span and biting rate have the greatest potential for reducing the reproduction number of Zika, and therefore, corresponding control measures need to be focused on. [ABSTRACT FROM AUTHOR]

In this paper, the spatiotemporal patterns of a reaction-diffusion substrate-inhibition chemical Seelig model are considered. We first prove that this parabolic Seelig model has an invariant rectangle in the phase plane which attracts all the solutions of the model regardless of the initial values. Then, we consider the long time behaviors of the solutions in the invariant rectangle. In particular, we prove that, under suitable 'lumped parameter assumption' conditions, these solutions either converge exponentially to the unique positive constant steady states or to the spatially homogeneous periodic solutions. Finally, we study the existence and non-existence of Turing patterns. To find parameter ranges where system does not exhibit Turing patterns, we use the properties of non-constant steady states, including obtaining several useful estimates. To seek the parameter ranges where system possesses Turing patterns, we use the techniques of global bifurcation theory. These two different parameter ranges are distinguished in a delicate bifurcation diagram. Moreover, numerical experiments are also presented to support and strengthen our analytical analysis. [ABSTRACT FROM AUTHOR]

Vector-borne disease transmission is a common dissemination mode used by many pathogens to spread in a host population. Similar to directly transmitted diseases, the within-host interaction of a vector-borne pathogen and a host's immune system influences the pathogen's transmission potential between hosts via vectors. Yet there are few theoretical studies on virulence-transmission trade-offs and evolution in vector-borne pathogen-host systems. Here, we consider an immuno-epidemiological model that links the within-host dynamics to between-host circulation of a vector-borne disease. On the immunological scale, the model mimics antibody-pathogen dynamics for arbovirus diseases, such as Rift Valley fever and West Nile virus. The within-host dynamics govern transmission and host mortality and recovery in an age-since-infection structured host-vector-borne pathogen epidemic model. By considering multiple pathogen strains and multiple competing host populations differing in their within-host replication rate and immune response parameters, respectively, we derive evolutionary optimization principles for both pathogen and host. Invasion analysis shows that the $${\mathcal {R}}_0$$ maximization principle holds for the vector-borne pathogen. For the host, we prove that evolution favors minimizing case fatality ratio (CFR). These results are utilized to compute host and pathogen evolutionary trajectories and to determine how model parameters affect evolution outcomes. We find that increasing the vector inoculum size increases the pathogen $${\mathcal {R}}_0$$ , but can either increase or decrease the pathogen virulence (the host CFR), suggesting that vector inoculum size can contribute to virulence of vector-borne diseases in distinct ways. [ABSTRACT FROM AUTHOR]

In this article, we discuss the structural and practical identifiability of a nested immuno-epidemiological model of arbovirus diseases, where host-vector transmission rate, host recovery, and disease-induced death rates are governed by the within-host immune system. We incorporate the newest ideas and the most up-to-date features of numerical methods to fit multi-scale models to multi-scale data. For an immunological model, we use Rift Valley Fever Virus (RVFV) time-series data obtained from livestock under laboratory experiments, and for an epidemiological model we incorporate a human compartment to the nested model and use the number of human RVFV cases reported by the CDC during the 2006-2007 Kenya outbreak. We show that the immunological model is not structurally identifiable for the measurements of time-series viremia concentrations in the host. Thus, we study the non-dimensionalized and scaled versions of the immunological model and prove that both are structurally globally identifiable. After fixing estimated parameter values for the immunological model derived from the scaled model, we develop a numerical method to fit observable RVFV epidemiological data to the nested model for the remaining parameter values of the multi-scale system. For the given (CDC) data set, Monte Carlo simulations indicate that only three parameters of the epidemiological model are practically identifiable when the immune model parameters are fixed. Alternatively, we fit the multi-scale data to the multi-scale model simultaneously. Monte Carlo simulations for the simultaneous fitting suggest that the parameters of the immunological model and the parameters of the immuno-epidemiological model are practically identifiable. We suggest that analytic approaches for studying the structural identifiability of nested models are a necessity, so that identifiable parameter combinations can be derived to reparameterize the nested model to obtain an identifiable one. This is a crucial step in developing multi-scale models which explain multi-scale data. [ABSTRACT FROM AUTHOR]