Parameter estimation in models of biological oscillators: an automated regularised estimation approach View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Jake Alan Pitt, Julio R. Banga

ABSTRACT

BACKGROUND: Dynamic modelling is a core element in the systems biology approach to understanding complex biosystems. Here, we consider the problem of parameter estimation in models of biological oscillators described by deterministic nonlinear differential equations. These problems can be extremely challenging due to several common pitfalls: (i) a lack of prior knowledge about parameters (i.e. massive search spaces), (ii) convergence to local optima (due to multimodality of the cost function), (iii) overfitting (fitting the noise instead of the signal) and (iv) a lack of identifiability. As a consequence, the use of standard estimation methods (such as gradient-based local ones) will often result in wrong solutions. Overfitting can be particularly problematic, since it produces very good calibrations, giving the impression of an excellent result. However, overfitted models exhibit poor predictive power. Here, we present a novel automated approach to overcome these pitfalls. Its workflow makes use of two sequential optimisation steps incorporating three key algorithms: (1) sampling strategies to systematically tighten the parameter bounds reducing the search space, (2) efficient global optimisation to avoid convergence to local solutions, (3) an advanced regularisation technique to fight overfitting. In addition, this workflow incorporates tests for structural and practical identifiability. RESULTS: We successfully evaluate this novel approach considering four difficult case studies regarding the calibration of well-known biological oscillators (Goodwin, FitzHugh-Nagumo, Repressilator and a metabolic oscillator). In contrast, we show how local gradient-based approaches, even if used in multi-start fashion, are unable to avoid the above-mentioned pitfalls. CONCLUSIONS: Our approach results in more efficient estimations (thanks to the bounding strategy) which are able to escape convergence to local optima (thanks to the global optimisation approach). Further, the use of regularisation allows us to avoid overfitting, resulting in more generalisable calibrated models (i.e. models with greater predictive power). More... »

PAGES

82

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s12859-019-2630-y

    DOI

    http://dx.doi.org/10.1186/s12859-019-2630-y

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1112168760

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30770736


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