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      Fitting dynamic models to epidemic outbreaks with quantified uncertainty: A primer for parameter uncertainty, identifiability, and forecasts

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          Abstract

          Mathematical models provide a quantitative framework with which scientists can assess hypotheses on the potential underlying mechanisms that explain patterns in observed data at different spatial and temporal scales, generate estimates of key kinetic parameters, assess the impact of interventions, optimize the impact of control strategies, and generate forecasts. We review and illustrate a simple data assimilation framework for calibrating mathematical models based on ordinary differential equation models using time series data describing the temporal progression of case counts relating, for instance, to population growth or infectious disease transmission dynamics. In contrast to Bayesian estimation approaches that always raise the question of how to set priors for the parameters, this frequentist approach relies on modeling the error structure in the data. We discuss issues related to parameter identifiability, uncertainty quantification and propagation as well as model performance and forecasts along examples based on phenomenological and mechanistic models parameterized using simulated and real datasets.

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          Most cited references23

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          Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood.

          Mathematical description of biological reaction networks by differential equations leads to large models whose parameters are calibrated in order to optimally explain experimental data. Often only parts of the model can be observed directly. Given a model that sufficiently describes the measured data, it is important to infer how well model parameters are determined by the amount and quality of experimental data. This knowledge is essential for further investigation of model predictions. For this reason a major topic in modeling is identifiability analysis. We suggest an approach that exploits the profile likelihood. It enables to detect structural non-identifiabilities, which manifest in functionally related model parameters. Furthermore, practical non-identifiabilities are detected, that might arise due to limited amount and quality of experimental data. Last but not least confidence intervals can be derived. The results are easy to interpret and can be used for experimental planning and for model reduction. An implementation is freely available for MATLAB and the PottersWheel modeling toolbox at http://web.me.com/andreas.raue/profile/software.html. Supplementary data are available at Bioinformatics online.
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            Using Bayesian Model Averaging to Calibrate Forecast Ensembles

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              Comparative estimation of the reproduction number for pandemic influenza from daily case notification data.

              The reproduction number, R, defined as the average number of secondary cases generated by a primary case, is a crucial quantity for identifying the intensity of interventions required to control an epidemic. Current estimates of the reproduction number for seasonal influenza show wide variation and, in particular, uncertainty bounds for R for the pandemic strain from 1918 to 1919 have been obtained only in a few recent studies and are yet to be fully clarified. Here, we estimate R using daily case notifications during the autumn wave of the influenza pandemic (Spanish flu) in the city of San Francisco, California, from 1918 to 1919. In order to elucidate the effects from adopting different estimation approaches, four different methods are used: estimation of R using the early exponential-growth rate (Method 1), a simple susceptible-exposed-infectious-recovered (SEIR) model (Method 2), a more complex SEIR-type model that accounts for asymptomatic and hospitalized cases (Method 3), and a stochastic susceptible-infectious-removed (SIR) with Bayesian estimation (Method 4) that determines the effective reproduction number Rt at a given time t. The first three methods fit the initial exponential-growth phase of the epidemic, which was explicitly determined by the goodness-of-fit test. Moreover, Method 3 was also fitted to the whole epidemic curve. Whereas the values of R obtained using the first three methods based on the initial growth phase were estimated to be 2.98 (95% confidence interval (CI): 2.73, 3.25), 2.38 (2.16, 2.60) and 2.20 (1.55, 2.84), the third method with the entire epidemic curve yielded a value of 3.53 (3.45, 3.62). This larger value could be an overestimate since the goodness-of-fit to the initial exponential phase worsened when we fitted the model to the entire epidemic curve, and because the model is established as an autonomous system without time-varying assumptions. These estimates were shown to be robust to parameter uncertainties, but the theoretical exponential-growth approximation (Method 1) shows wide uncertainty. Method 4 provided a maximum-likelihood effective reproduction number 2.10 (1.21, 2.95) using the first 17 epidemic days, which is consistent with estimates obtained from the other methods and an estimate of 2.36 (2.07, 2.65) for the entire autumn wave. We conclude that the reproduction number for pandemic influenza (Spanish flu) at the city level can be robustly assessed to lie in the range of 2.0-3.0, in broad agreement with previous estimates using distinct data.
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                Author and article information

                Contributors
                Journal
                Infect Dis Model
                Infect Dis Model
                Infectious Disease Modelling
                KeAi Publishing
                2468-2152
                2468-0427
                12 August 2017
                August 2017
                12 August 2017
                : 2
                : 3
                : 379-398
                Affiliations
                [a ]Division of Epidemiology & Biostatistics, School of Public Health, Georgia State University, Atlanta, GA, USA
                [b ]Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, MD, USA
                Author notes
                []School of Public Health, Georgia State University, Atlanta, GA, USA. gchowell@ 123456gsu.edu
                Article
                S2468-0427(17)30023-4
                10.1016/j.idm.2017.08.001
                5726591
                29250607
                ddc7097a-9681-495b-a8f1-9e95026b542b
                © 2017 The Authors. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 4 June 2017
                : 8 August 2017
                Categories
                Article

                parameter estimation,uncertainty quantification,bootstrap,parameter identifiability,model performance,forecasts,uncertainty propagation

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