Observability and Structural Identifiability of Nonlinear Biological Systems

Observability is a modelling property that describes the possibility of inferring the internal state of a system from observations of its output. A related property, structural identifiability, refers to the theoretical possibility of determining the parameter values from the output. In fact, structural identifiability becomes a particular case of observability if the parameters are considered as constant state variables. It is possible to simultaneously analyse the observability and structural identifiability of a model using the conceptual tools of differential geometry. Many complex biological processes can be described by systems of nonlinear ordinary differential equations, and can therefore be analysed with this approach. The purpose of this review article is threefold: (I) to serve as a tutorial on observability and structural identifiability of nonlinear systems, using the differential geometry approach for their analysis; (II) to review recent advances in the field; and (III) to identify open problems and suggest new avenues for research in this area.Comment: Accepted for publication in the special issue "Computational Methods for Identification and Modelling of Complex Biological Systems" of Complexit

Finding and breaking lie symmetries: implications for structural identifiability and observability in biological modelling

A dynamic model is structurally identifiable (respectively, observable) if it is theoretically possible to infer its unknown parameters (respectively, states) by observing its output over time. The two properties, structural identifiability and observability, are completely determined by the model equations. Their analysis is of interest for modellers because it informs about the possibility of gaining insight into a model’s unmeasured variables. Here we cast the problem of analysing structural identifiability and observability as that of finding Lie symmetries. We build on previous results that showed that structural unidentifiability amounts to the existence of Lie symmetries. We consider nonlinear models described by ordinary differential equations and restrict ourselves to rational functions. We revisit a method for finding symmetries by transforming rational expressions into linear systems. We extend the method by enabling it to provide symmetry-breaking transformations, which allows for a semi-automatic model reformulation that renders a non-observable model observable. We provide a MATLAB implementation of the methodology as part of the STRIKE-GOLDD toolbox for observability and identifiability analysis. We illustrate the use of the methodology in the context of biological modelling by applying it to a set of problems taken from the literature.Ministerio de Ciencia, Innovación y Universidades | Ref. DPI2017-82896-C2-2-

Benchmarking tools for a priori identifiability analysis

Motivation: The theoretical possibility of determining the state and parameters of a dynamic model by measuring its outputs is given by its structural identifiability and observability. These properties should be analysed before attempting to calibrate a model, but their a priori analysis can be challenging, requiring symbolic calculations that often have a high computational cost. In recent years a number of software tools have been developed for this task, mostly in the systems biology community. These tools have vastly different features and capabilities, and a critical assessment of their performance is still lacking. Results: Here we present a comprehensive study of the computational resources available for analysing structural identifiability. We consider 13 software tools developed in 7 programming languages and evaluate their performance using a set of 25 case studies created from 21 models. Our results reveal their strengths and weaknesses, provide guidelines for choosing the most appropriate tool for a given problem, and highlight opportunities for future developments. Availability: https://github.com/Xabo-RB/Benchmarking_files.Xunta de Galicia | Ref. ED431F 2021/003Agencia Estatal de Investigación | Ref. PID2020-113992RA-I00MCIN/AEI/10.13039/501100011033 | Ref. RYC-2019-027537-IFinanciado para publicación en acceso aberto: Universidade de Vigo/CISU

A probabilistic algorithm to test local algebraic observability in polynomial time

The following questions are often encountered in system and control theory. Given an algebraic model of a physical process, which variables can be, in theory, deduced from the input-output behavior of an experiment? How many of the remaining variables should we assume to be known in order to determine all the others? These questions are parts of the \emph{local algebraic observability} problem which is concerned with the existence of a non trivial Lie subalgebra of the symmetries of the model letting the inputs and the outputs invariant. We present a \emph{probabilistic seminumerical} algorithm that proposes a solution to this problem in \emph{polynomial time}. A bound for the necessary number of arithmetic operations on the rational field is presented. This bound is polynomial in the \emph{complexity of evaluation} of the model and in the number of variables. Furthermore, we show that the \emph{size} of the integers involved in the computations is polynomial in the number of variables and in the degree of the differential system. Last, we estimate the probability of success of our algorithm and we present some benchmarks from our Maple implementation.Comment: 26 pages. A Maple implementation is availabl

AutoRepar: a method to obtain identifiable and observable reparameterizations of dynamic models with mechanistic insights

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGMechanistic dynamic models of biological systems allow for a quantitative and systematic interpretation of data and the generation of testable hypotheses. However, these models are often over-parameterized, leading to nonidentifiability and nonobservability, that is, the impossibility of inferring their parameters and state variables. The lack of structural identifiability and observability (SIO) compromises a model's ability to make predictions and provide insight. Here we present a methodology, AutoRepar, that corrects SIO deficiencies of nonlinear ODE models automatically, yielding reparameterized models that are structurally identifiable and observable. The reparameterization preserves the mechanistic meaning of selected variables, and has the exact same dynamics and input-output mapping as the original model. We implement AutoRepar as an extension of the STRIKE-GOLDD software toolbox for SIO analysis, applying it to several models from the literature to demonstrate its ability to repair their structural deficiencies. AutoRepar increases the applicability of mechanistic models, enabling them to provide reliable information about their parameters and dynamics.Consejo Superior de Investigaciones Científicas https://doi.org/10.13039/501100003339 | Ref. PIE 202070E062MCIN/AEI/10.13039/501100011033 | Ref. RYC-2019-027537-IMCIN/AEI/10.13039/501100011033 | Ref. PID2020-113992RA-I00MCIN/AEI/ 10.13039/501100011033 | Ref. PID2020-117271RB-C2MCIN/AEI/ 10.13039/501100011033 | Ref. DPI2017-82896-C2-2-RXunta de Galicia | Ref. ED431F 2021/00

Delineating Parameter Unidentifiabilities in Complex Models

Scientists use mathematical modelling to understand and predict the properties of complex physical systems. In highly parameterised models there often exist relationships between parameters over which model predictions are identical, or nearly so. These are known as structural or practical unidentifiabilities, respectively. They are hard to diagnose and make reliable parameter estimation from data impossible. They furthermore imply the existence of an underlying model simplification. We describe a scalable method for detecting unidentifiabilities, and the functional relations defining them, for generic models. This allows for model simplification, and appreciation of which parameters (or functions thereof) cannot be estimated from data. Our algorithm can identify features such as redundant mechanisms and fast timescale subsystems, as well as the regimes in which such approximations are valid. We base our algorithm on a novel quantification of regional parametric sensitivity: multiscale sloppiness. Traditionally, the link between parametric sensitivity and the conditioning of the parameter estimation problem is made locally, through the Fisher Information Matrix. This is valid in the regime of infinitesimal measurement uncertainty. We demonstrate the duality between multiscale sloppiness and the geometry of confidence regions surrounding parameter estimates made where measurement uncertainty is non-negligible. Further theoretical relationships are provided linking multiscale sloppiness to the Likelihood-ratio test. From this, we show that a local sensitivity analysis (as typically done) is insufficient for determining the reliability of parameter estimation, even with simple (non)linear systems. Our algorithm provides a tractable alternative. We finally apply our methods to a large-scale, benchmark Systems Biology model of NF-$\kappa$B, uncovering previously unknown unidentifiabilities

On the existence of identifiable reparametrizations for linear compartment models

The parameters of a linear compartment model are usually estimated from experimental input-output data. A problem arises when infinitely many parameter values can yield the same result; such a model is called unidentifiable. In this case, one can search for an identifiable reparametrization of the model: a map which reduces the number of parameters, such that the reduced model is identifiable. We study a specific class of models which are known to be unidentifiable. Using algebraic geometry and graph theory, we translate a criterion given by Meshkat and Sullivant for the existence of an identifiable scaling reparametrization to a new criterion based on the rank of a weighted adjacency matrix of a certain bipartite graph. This allows us to derive several new constructions to obtain graphs with an identifiable scaling reparametrization. Using these constructions, a large subclass of such graphs is obtained. Finally, we present a procedure of subdividing or deleting edges to ensure that a model has an identifiable scaling reparametrization

STRIKE-GOLDD 4.0: user-friendly, efficient analysis of structural identifiability and observability

Structural identifiability and observability are desirable properties of systems biology models. Many software toolboxes have been developed for their analysis in the last decades. STRIKE-GOLDD is a generally applicable tool that can analyse non-linear, non-rational ODE models with unknown inputs. However, this generality comes at the expense of a lower computational efficiency than other tools. Here we present STRIKE-GOLDD 4.0, which includes a new algorithm, ProbObsTest, specifically designed for the analysis of rational models. ProbObsTest is significantly faster than the FISPO algorithm - which was already available in older versions of the toolbox - when applied to computationally expensive models. An important feature of both algorithms is their ability to analyse models with unknown inputs. Thus, their coexistence in the same toolbox provides a combination of general applicability and computational efficiency. STRIKE-GOLDD 4.0 is implemented as a free and open-source Matlab toolbox with a user-friendly graphical interface. It is available under a GPLv3 license and it can be downloaded from GitHub at https://github.com/afvillaverde/strike-goldd.Comment: 14 pages, 1 figur

Data-driven modelling of biological multi-scale processes

Biological processes involve a variety of spatial and temporal scales. A holistic understanding of many biological processes therefore requires multi-scale models which capture the relevant properties on all these scales. In this manuscript we review mathematical modelling approaches used to describe the individual spatial scales and how they are integrated into holistic models. We discuss the relation between spatial and temporal scales and the implication of that on multi-scale modelling. Based upon this overview over state-of-the-art modelling approaches, we formulate key challenges in mathematical and computational modelling of biological multi-scale and multi-physics processes. In particular, we considered the availability of analysis tools for multi-scale models and model-based multi-scale data integration. We provide a compact review of methods for model-based data integration and model-based hypothesis testing. Furthermore, novel approaches and recent trends are discussed, including computation time reduction using reduced order and surrogate models, which contribute to the solution of inference problems. We conclude the manuscript by providing a few ideas for the development of tailored multi-scale inference methods.Comment: This manuscript will appear in the Journal of Coupled Systems and Multiscale Dynamics (American Scientific Publishers