A Priori Identifiability Analysis of Cardiovascular Models.
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ABSTRACT:
SUBMITTER: Kirk JA
PROVIDER: S-EPMC4696755 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
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Project description:A priori identifiability of mathematical models assures that for a given input/output experiment, the parameter set has one unique solution within a defined space, independent of the experimental design. Many biologic therapeutics exhibit target-mediated drug disposition (TMDD), and use of the full compartmental model describing this system is well documented. In practice, estimation of the full parameter set for TMDD models, given real-world clinical data, is characterized by convergence difficulties and unstable solutions. Still, the formal assessment of the a priori identifiability of these systems has yet to be reported. The exact arithmetic rank (EAR) approach was used to test the a priori identifiability of a TMDD model as well as model approximations. The full TMDD and quasi-equilibrium/rapid binding (QE/RB), quasi-steady state (QSS), and Michaelis-Menten (MM) approximations were fully identifiable, a priori, regardless of whether observations were taken from a single or multiple compartments. The results of these identifiability analyses indicated that the difficulty with TMDD model convergence, a posteriori, lies in the experimental design, not in the mathematical identifiability in the lack of samples from several compartments. Experiments can be tailored to resolve these structurally non-identifiable parameters, notwithstanding practical implementation challenges. This work highlights the importance of identifiability analyses, specifically how they can influence experimental design and selection of the appropriate model structure to describe a dynamic biological system.
| S-EPMC4540726 | biostudies-literature
Project description:Mathematical models are routinely calibrated to experimental data, with goals ranging from building predictive models to quantifying parameters that cannot be measured. Whether or not reliable parameter estimates are obtainable from the available data can easily be overlooked. Such issues of parameter identifiability have important ramifications for both the predictive power of a model, and the mechanistic insight that can be obtained. Identifiability analysis is well-established for deterministic, ordinary differential equation (ODE) models, but there are no commonly adopted methods for analysing identifiability in stochastic models. We provide an accessible introduction to identifiability analysis and demonstrate how existing ideas for analysis of ODE models can be applied to stochastic differential equation (SDE) models through four practical case studies. To assess structural identifiability, we study ODEs that describe the statistical moments of the stochastic process using open-source software tools. Using practically motivated synthetic data and Markov chain Monte Carlo methods, we assess parameter identifiability in the context of available data. Our analysis shows that SDE models can often extract more information about parameters than deterministic descriptions. All code used to perform the analysis is available on Github.
| S-EPMC7811582 | biostudies-literature
Project description:Motivation:Mathematical modeling using ordinary differential equations is used in systems biology to improve the understanding of dynamic biological processes. The parameters of ordinary differential equation models are usually estimated from experimental data. To analyze a priori the uniqueness of the solution of the estimation problem, structural identifiability analysis methods have been developed. Results:We introduce GenSSI 2.0, an advancement of the software toolbox GenSSI (Generating Series for testing Structural Identifiability). GenSSI 2.0 is the first toolbox for structural identifiability analysis to implement Systems Biology Markup Language import, state/parameter transformations and multi-experiment structural identifiability analysis. In addition, GenSSI 2.0 supports a range of MATLAB versions and is computationally more efficient than its previous version, enabling the analysis of more complex models. Availability and implementation:GenSSI 2.0 is an open-source MATLAB toolbox and available at https://github.com/genssi-developer/GenSSI. Contact:thomas.ligon@physik.uni-muenchen.de or jan.hasenauer@helmholtz-muenchen.de. Supplementary information:Supplementary data are available at Bioinformatics online.
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Project description:Mechanistic models are a powerful tool to gain insights into biological processes. The parameters of such models, e.g. kinetic rate constants, usually cannot be measured directly but need to be inferred from experimental data. In this article, we study dynamical models of the translation kinetics after mRNA transfection and analyze their parameter identifiability. That is, whether parameters can be uniquely determined from perfect or realistic data in theory and practice. Previous studies have considered ordinary differential equation (ODE) models of the process, and here we formulate a stochastic differential equation (SDE) model. For both model types, we consider structural identifiability based on the model equations and practical identifiability based on simulated as well as experimental data and find that the SDE model provides better parameter identifiability than the ODE model. Moreover, our analysis shows that even for those parameters of the ODE model that are considered to be identifiable, the obtained estimates are sometimes unreliable. Overall, our study clearly demonstrates the relevance of considering different modeling approaches and that stochastic models can provide more reliable and informative results.
| S-EPMC9110294 | biostudies-literature
Project description:Issues of parameter identifiability of routinely used pharmacodynamics models are considered in this paper. The structural identifiability of 16 commonly applied pharmacodynamic model structures was analyzed analytically, using the input-output approach. Both fixed-effects versions (non-population, no between-subject variability) and mixed-effects versions (population, including between-subject variability) of each model structure were analyzed. All models were found to be structurally globally identifiable under conditions of fixing either one of two particular parameters. Furthermore, an example was constructed to illustrate the importance of sufficient data quality and show that structural identifiability is a prerequisite, but not a guarantee, for successful parameter estimation and practical parameter identifiability. This analysis was performed by generating artificial data of varying quality to a structurally identifiable model with known true parameter values, followed by re-estimation of the parameter values. In addition, to show the benefit of including structural identifiability as part of model development, a case study was performed applying an unidentifiable model to real experimental data. This case study shows how performing such an analysis prior to parameter estimation can improve the parameter estimation process and model performance. Finally, an unidentifiable model was fitted to simulated data using multiple initial parameter values, resulting in highly different estimated uncertainties. This example shows that although the standard errors of the parameter estimates often indicate a structural identifiability issue, reasonably "good" standard errors may sometimes mask unidentifiability issues.
| S-EPMC5136565 | biostudies-literature
Project description:BackgroundKinetic models of biochemical systems usually consist of ordinary differential equations that have many unknown parameters. Some of these parameters are often practically unidentifiable, that is, their values cannot be uniquely determined from the available data. Possible causes are lack of influence on the measured outputs, interdependence among parameters, and poor data quality. Uncorrelated parameters can be seen as the key tuning knobs of a predictive model. Therefore, before attempting to perform parameter estimation (model calibration) it is important to characterize the subset(s) of identifiable parameters and their interplay. Once this is achieved, it is still necessary to perform parameter estimation, which poses additional challenges.MethodsWe present a methodology that (i) detects high-order relationships among parameters, and (ii) visualizes the results to facilitate further analysis. We use a collinearity index to quantify the correlation between parameters in a group in a computationally efficient way. Then we apply integer optimization to find the largest groups of uncorrelated parameters. We also use the collinearity index to identify small groups of highly correlated parameters. The results files can be visualized using Cytoscape, showing the identifiable and non-identifiable groups of parameters together with the model structure in the same graph.ResultsOur contributions alleviate the difficulties that appear at different stages of the identifiability analysis and parameter estimation process. We show how to combine global optimization and regularization techniques for calibrating medium and large scale biological models with moderate computation times. Then we evaluate the practical identifiability of the estimated parameters using the proposed methodology. The identifiability analysis techniques are implemented as a MATLAB toolbox called VisId, which is freely available as open source from GitHub ( https://github.com/gabora/visid ).ConclusionsOur approach is geared towards scalability. It enables the practical identifiability analysis of dynamic models of large size, and accelerates their calibration. The visualization tool allows modellers to detect parts that are problematic and need refinement or reformulation, and provides experimentalists with information that can be helpful in the design of new experiments.
| S-EPMC5420165 | biostudies-literature
Project description:The concept of dynamical compensation has been recently introduced to describe the ability of a biological system to keep its output dynamics unchanged in the face of varying parameters. However, the original definition of dynamical compensation amounts to lack of structural identifiability. This is relevant if model parameters need to be estimated, as is often the case in biological modelling. Care should we taken when using an unidentifiable model to extract biological insight: the estimated values of structurally unidentifiable parameters are meaningless, and model predictions about unmeasured state variables can be wrong. Taking this into account, we explore alternative definitions of dynamical compensation that do not necessarily imply structural unidentifiability. Accordingly, we show different ways in which a model can be made identifiable while exhibiting dynamical compensation. Our analyses enable the use of the new concept of dynamical compensation in the context of parameter identification, and reconcile it with the desirable property of structural identifiability.
| S-EPMC5724898 | biostudies-literature
Project description:A powerful way of gaining insight into biological systems is by creating a nonlinear differential equation model, which usually contains many unknown parameters. Such a model is called structurally identifiable if it is possible to determine the values of its parameters from measurements of the model outputs. Structural identifiability is a prerequisite for parameter estimation, and should be assessed before exploiting a model. However, this analysis is seldom performed due to the high computational cost involved in the necessary symbolic calculations, which quickly becomes prohibitive as the problem size increases. In this paper we show how to analyse the structural identifiability of a very general class of nonlinear models by extending methods originally developed for studying observability. We present results about models whose identifiability had not been previously determined, report unidentifiabilities that had not been found before, and show how to modify those unidentifiable models to make them identifiable. This method helps prevent problems caused by lack of identifiability analysis, which can compromise the success of tasks such as experiment design, parameter estimation, and model-based optimization. The procedure is called STRIKE-GOLDD (STRuctural Identifiability taKen as Extended-Generalized Observability with Lie Derivatives and Decomposition), and it is implemented in a MATLAB toolbox which is available as open source software. The broad applicability of this approach facilitates the analysis of the increasingly complex models used in systems biology and other areas.
| S-EPMC5085250 | biostudies-literature
Project description:ObjectiveOur aim is to analyze the identifiability of three commonly used control-oriented models for glucose control in patients with type 1 diabetes (T1D).MethodsStructural and practical identifiability analysis were performed on three published control-oriented models for glucose control in patients with type 1 diabetes (T1D): the subcutaneous oral glucose minimal model (SOGMM), the intensive control insulin-nutrition-glucose (ICING) model, and the minimal model control-oriented (MMC). Structural identifiability was addressed with a combination of the generating series (GS) approach and identifiability tableaus whereas practical identifiability was studied by means of (1) global ranking of parameters via sensitivity analysis together with the Latin hypercube sampling method (LHS) and (2) collinearity analysis among parameters. For practical identifiability and model identification, continuous glucose monitor (CGM), insulin pump, and meal records were selected from a set of patients (n = 5) on continuous subcutaneous insulin infusion (CSII) that underwent a clinical trial in an outpatient setting. The performance of the identified models was analyzed by means of the root mean square (RMS) criterion.ResultsA reliable set of identifiable parameters was found for every studied model after analyzing the possible identifiability issues of the original parameter sets. According to an importance factor ([Formula: see text]), it was shown that insulin sensitivity is not the most influential parameter from the dynamical point of view, that is, is not the parameter impacting the outputs the most of the three models, contrary to what is assumed in the literature. For the test data, the models demonstrated similar performance with most RMS values around 20 mg/dl (min: 15.64 mg/dl, max: 51.32 mg/dl). However, MMC failed to identify the model for patient 4. Also, considering the three models, the MMC model showed the higher parameter variability when reidentified every 6 hours.ConclusionThis study shows that both structural and practical identifiability analysis need to be considered prior to the model identification/individualization in patients with T1D. It was shown that all the studied models are able to represent the CGM data, yet their usefulness in a hypothetical artificial pancreas could be a matter of debate. In spite that the three models do not capture all the dynamics and metabolic effects as a maximal model (ie, our FDA-accepted UVa/Padova simulator), SOGMM and ICING appear to be more appealing than MMC regarding both the performance and parameter variability after reidentification. Although the model predictions of ICING are comparable to the ones of the SOGMM model, the large parameter set makes the model prone to overfitting if all parameters are identified. Moreover, the existence of a high nonlinear function like [Formula: see text] prevents the use of tools from the linear systems theory.
| S-EPMC6134618 | biostudies-literature
Project description:[This corrects the article DOI: 10.1371/journal.pcbi.1005431.].
| S-EPMC5513402 | biostudies-other