An official website of the United States government
Understanding the epidemiology of emerging pathogens, such as Usutu virus (USUV) infections, requires systems investigation at each scale involved in the host–virus transmission cycle, from individual bird infections, to bird-to-vector transmissions, and to USUV incidence in bird and vector populations. For new pathogens field data are sparse, and predictions can be aided by the use of laboratory-type inoculation and transmission experiments combined with dynamical mathematical modelling. In this study, we investigated the dynamics of two strains of USUV by constructing mathematical models for the within-host scale, bird-to-vector transmission scale and vector-borne epidemiological scale. We used individual within-host infectious virus data and per cent mosquito infection data to predict USUV incidence in birds and mosquitoes. We addressed the dependence of predictions on model structure, data uncertainty and experimental design. We found that uncertainty in predictions at one scale change predicted results at another scale. We proposedin silicoexperiments that showed that sampling every 12 hours ensures practical identifiability of the within-host scale model. At the same time, we showed that practical identifiability of the transmission scale functions can only be improved under unrealistically high sampling regimes. Instead, we proposed optimal experimental designs and suggested the types of experiments that can ensure identifiability at the transmission scale and, hence, induce robustness in predictions at the epidemiological scale.
more »
« less
Minimally sufficient experimental design using identifiability analysis
Abstract Mathematical models are increasingly being developed and calibrated in tandem with data collection, empowering scientists to intervene in real time based on quantitative model predictions. Well-designed experiments can help augment the predictive power of a mathematical model but the question of when to collect data to maximize its utility for a model is non-trivial. Here we define data as model-informative if it results in a unique parametrization, assessed through the lens of practical identifiability. The framework we propose identifies an optimal experimental design (how much data to collect and when to collect it) that ensures parameter identifiability (permitting confidence in model predictions), while minimizing experimental time and costs. We demonstrate the power of the method by applying it to a modified version of a classic site-of-action pharmacokinetic/pharmacodynamic model that describes distribution of a drug into the tumor microenvironment (TME), where its efficacy is dependent on the level of target occupancy in the TME. In this context, we identify a minimal set of time points when data needs to be collected that robustly ensures practical identifiability of model parameters. The proposed methodology can be applied broadly to any mathematical model, allowing for the identification of a minimally sufficient experimental design that collects the most informative data.
more »
« less
- PAR ID:
- 10484567
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- npj Systems Biology and Applications
- Volume:
- 10
- Issue:
- 1
- ISSN:
- 2056-7189
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
This paper describes a geometric approach to parameter identifiability analysis in models of power systems dynamics. When a model of a power system is to be compared with measurements taken at discrete times, it can be interpreted as a mapping from parameter space into a data or prediction space. Generically, model mappings can be interpreted as manifolds with dimensionality equal to the number of structurally identifiable parameters. Empirically it is observed that model mappings often correspond to bounded manifolds. We propose a new definition of practical identifiability based the topological definition of a manifold with boundary. In many ways, our proposed definition extends the properties of structural identifiability. We construct numerical approximations to geodesics on the model manifold and use the results, combined with insights derived from the mathematical form of the equations, to identify combinations of practically identifiable and unidentifiable parameters. We give several examples of application to dynamic power systems models.more » « less
-
Identifiability of a mathematical model plays a crucial role in the parameterization of the model. In this study, we established the structural identifiability of a susceptible-exposed-infected-recovered (SEIR) model given different combinations of input data and investigated practical identifiability with respect to different observable data, data frequency, and noise distributions. The practical identifiability was explored by both Monte Carlo simulations and a correlation matrix approach. Our results showed that practical identifiability benefits from higher data frequency and data from the peak of an outbreak. The incidence data gave the best practical identifiability results compared to prevalence and cumulative data. In addition, we compared and distinguished the practical identifiability by Monte Carlo simulations and a correlation matrix approach, providing insights into when to use which method for other applications.more » « less
-
Abstract 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.more » « less
-
In this paper we develop a four compartment within-host model of nutrition and HIV. We show that the model has two equilibria: an infection-free equilibrium and infection equilibrium. The infection free equilibrium is locally asymptotically stable when the basic reproduction number $$ \mathcal{R}_0 < 1 $$, and unstable when $$ \mathcal{R}_0 > 1 $$. The infection equilibrium is locally asymptotically stable if $$ \mathcal{R}_0 > 1 $$ and an additional condition holds. We show that the within-host model of HIV and nutrition is structured to reveal its parameters from the observations of viral load, CD4 cell count and total protein data. We then estimate the model parameters for these 3 data sets. We have also studied the practical identifiability of the model parameters by performing Monte Carlo simulations, and found that the rate of clearance of the virus by immunoglobulins is practically unidentifiable, and that the rest of the model parameters are only weakly identifiable given the experimental data. Furthermore, we have studied how the data frequency impacts the practical identifiability of model parameters.more » « less
