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

Global Identifiability of Differential Models

Many real-world processes and phenomena are modeled using systems of ordinary differential equations with parameters. Given such a system, we say that a parameter is globally identifiable if it can be uniquely recovered from input and output data. The main contribution of this paper is to provide theory, an algorithm, and software for deciding global identifiability. First, we rigorously derive an algebraic criterion for global identifiability (this is an analytic property), which yields a deterministic algorithm. Second, we improve the efficiency by randomizing the algorithm while guaranteeing the probability of correctness. With our new algorithm, we can tackle problems that could not be tackled before. A software based on the algorithm (called SIAN) is available at https://github.com/pogudingleb/SIAN

Determining Structurally Identifiable Parameter Combinations Using Subset Profiling

Identifiability is a necessary condition for successful parameter estimation of dynamic system models. A major component of identifiability analysis is determining the identifiable parameter combinations, the functional forms for the dependencies between unidentifiable parameters. Identifiable combinations can help in model reparameterization and also in determining which parameters may be experimentally measured to recover model identifiability. Several numerical approaches to determining identifiability of differential equation models have been developed, however the question of determining identifiable combinations remains incompletely addressed. In this paper, we present a new approach which uses parameter subset selection methods based on the Fisher Information Matrix, together with the profile likelihood, to effectively estimate identifiable combinations. We demonstrate this approach on several example models in pharmacokinetics, cellular biology, and physiology

Structural identifiability analyses of candidate models for in vitro Pitavastatin hepatic uptake

In this paper a review of the application of four different techniques (a version of the similarity transformation approach for autonomous uncontrolled systems, a non-differential input/output observable normal form approach, the characteristic set differential algebra and a recent algebraic input/output relationship approach) to determine the structural identifiability of certain in vitro nonlinear pharmacokinetic models is provided. The Organic Anion Transporting Polypeptide (OATP) substrate, Pitavastatin, is used as a probe on freshly isolated animal and human hepatocytes. Candidate pharmacokinetic non-linear compartmental models have been derived to characterise the uptake process of Pitavastatin. As a prerequisite to parameter estimation, structural identifiability analyses are performed to establish that all unknown parameters can be identified from the experimental observations available

Structural identifiability analysis of linear reaction–advection–diffusion processes in mathematical biology

Effective application of mathematical models to interpret biological data and make accurate predictions often requires that model parameters are identifiable. Approaches to assess the so-called structural identifiability of models are well established for ordinary differential equation models, yet there are no commonly adopted approaches that can be applied to assess the structural identifiability of the partial differential equation (PDE) models that are requisite to capture spatial features inherent to many phenomena. The differential algebra approach to structural identifiability has recently been demonstrated to be applicable to several specific PDE models. In this brief article, we present general methodology for performing structural identifiability analysis on partially observed reaction–advection–diffusion PDE models that are linear in the unobserved quantities. We show that the differential algebra approach can always, in theory, be applied to such models. Moreover, despite the perceived complexity introduced by the addition of advection and diffusion terms, consideration of spatial analogues of non-spatial models cannot exacerbate structural identifiability. We conclude by discussing future possibilities and the computational cost of performing structural identifiability analysis on more general PDE models

Identification and estimation of continuous time dynamic systems with exogenous variables using panel data

This paper deals with the identification and maximum likelihood estimation of the parameters of a stochastic differential equation from discrete time sampling. Score function and maximum likelihood equations are derived explicitly. The stochastic differential equation system is extended to allow for random effects and the analysis of panel data. In addition, we investigate the identifiability of the continuous time parameters, in particular the impact of the inclusion of exogenous variables

Parameter identifiability and input-output equations

Structural parameter identifiability is a property of a differential model with parameters that allows for the parameters to be determined from the model equations in the absence of noise. One of the standard approaches to assessing this problem is via input-output equations and, in particular, characteristic sets of differential ideals. The precise relation between identifiability and input-output identifiability is subtle. The goal of this note is to clarify this relation. The main results are: 1) identifiability implies input-output identifiability; 2) these notions coincide if the model does not have rational first integrals; 3) the field of input-output identifiable functions is generated by the coefficients of a "minimal" characteristic set of the corresponding differential ideal. We expect that some of these facts may be known to the experts in the area, but we are not aware of any articles in which these facts are stated precisely and rigorously proved.Comment: arXiv admin note: substantial text overlap with arXiv:1910.0396