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

Input-dependent structural identifiability of nonlinear systems

A dynamic model is structurally identifiable if it is possible to infer its unknown parameters by observing its output. Structural identifiability depends on the system dynamics, output, and input, as well as on the specific values of initial conditions and parameters. Here we present a symbolic method that characterizes the input that a model requires to be structurally identifiable. It determines which derivatives must be non-zero in order to have a sufficiently exciting input. Our approach considers structural identifiability as a generalization of nonlinear observability and incorporates extended Lie derivatives. The methodology assesses structural identifiability for time-varying inputs and, additionally, it can be used to determine the input profile that is required to make the parameters structurally locally identifiable. Furthermore, it is sometimes possible to replace an experiment with time-varying input with multiple experiments with constant inputs. We implement the resulting method as a MATLAB toolbox named STRIKE-GOLDD2. This tool can assist in the design of new experiments for the purpose of parameter estimation

Structural identifiability of large systems biology models

A fundamental principle of systems biology is its perpetual need for new technologies that can solve challenging biological questions. This precept will continue to drive the development of novel analytical tools. The virtuous cycle of biological progress can therefore only exist when experts from different disciplines including biology, chemistry, computer science, engineering, mathematics, and medicine collaborate. General opinion is however that one of the challenges facing the systems biology community is the lag in the development of such technologies. The topic of structural identifiability in particular has been of interest to the systems biology community. This is because researchers in this field often face experimental limitations. These limitations, combined with the fact that systems biology models can contain vast numbers of unknown parameters, necessitate an identifiability analysis. In reality, analysing the structural identifiability of systems biology models, even when they contain only a few states and system parameters, may be challenging. As these models increase in size and complexity, this difficulty is exasperated, and one becomes limited to only a few methods capable of analysing large ordinary differential equation models. In this thesis I study the use of a computationally efficient algorithm, well suited to the analysis of large models, in the model development process. The three related objectives of this thesis are: 1) develop an accurate method to asses the structural identifiability of large possibly nonlinear ordinary differential models, 2) implement thismethod in the preliminary design of experiments, and 3) use the method to address the topic of structural unidentifiability. To improve the method’s accuracy, I systematically study the role of individual factors, such as the number of experimentally measured sensors, on the sharpness of results. Based on the findings, I propose measures that can improve numerical accuracy. To address the second objective, I introduce an iterative identifiability algorithm that can determine minimal sets of outputs that need to be measured to ensure a model’s local structural identifiability. I also illustrate how one could potentially reduce the computational demand of the algorithm, enabling a user to detect minimal output sets of large ordinary differential equation models within minutes. For the last objective, I investigate the role of initial conditions in a model’s structural unidentifiability. I show that the method can detect problematic values for large ordinary differential equation models. I illustrate its role in reinstating the local structural identifiability of a model by identifying problematic initial conditions. I also show that the method can provide theoretical suggestions for the reparameterization of structurally unidentifiable models. The novelty of this work is that the algorithm allows for unknown initial conditions to be parameterised and accordingly, repameterisations requiring the transformation of states, associated with unidentifiable initial conditions, can easily be obtained. The computational efficiency of the method allows for the reparameterisation of large ordinary differential equation models in particular. To conclude, in this thesis I introduce an method that can be used during the model development process in an array of useful applications. These include: 1) determining minimal output sets, 2) reparameterising structurally unidentifiable models and 3) detecting problematic initial conditions. Each of these application can be implemented before any experiments are conducted and can play a potential role in the optimisation of the modelling process

Structural identifiability of dynamic systems biology models

22 páginas, 5 figuras, 2 tablas.-- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.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 areasAFV acknowledges funding from the Galician government (Xunta de Galiza, Consellería de Cultura, Educación e Ordenación Universitaria http://www.edu.xunta.es/portal/taxonomy/term/206) through the I2C postdoctoral program, fellowship ED481B2014/133-0. AB and AFV were partially supported by grant DPI2013-47100-C2-2-P from the Spanish Ministry of Economy and Competitiveness (MINECO). AFV acknowledges additional funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 686282 (CanPathPro). AP was partially supported through EPSRC projects EP/M002454/1 and EP/J012041/1.Peer reviewe

Identifiability of large nonlinear biochemical networks

Dynamic models formulated as a set of ordinary differential equations provide a detailed description of the time-evolution of a system. Such models of (bio)chemical reaction networks have contributed to important advances in biotechnology and biomedical applications, and their impact is foreseen to increase in the near future. Hence, the task of dynamic model building has attracted much attention from scientists working at the intersection of biochemistry, systems theory, mathematics, and computer science, among other disciplines-an area sometimes called systems biology. Before a model can be effectively used, the values of its unknown parameters have to be estimated from experimental data. A necessary condition for parameter estimation is identifiability, the property that, for a certain output, there exists a unique (or finite) set of parameter values that produces it. Identifiability can be analysed from two complementary points of view: structural (which searches for symmetries in the model equations that may prevent parameters from being uniquely determined) or practical (which focuses on the limitations introduced by the quantity and quality of the data available for parameter estimation). Both types of analyses are often difficult for nonlinear models, and their complexity increases rapidly with the problem size. Hence, assessing the identifiability of realistic dynamic models of biochemical networks remains a challenging task. Despite the fact that many methods have been developed for this purpose, it is still an open problem and an active area of research. Here we review the theory and tools available for the study of identifiability, and discuss some closely related concepts such as sensitivity to parameter perturbations, observability, distinguishability, and optimal experimental design, among others.This work was funded by the Galician government (Xunta de Galiza) through the I2C postdoctoral program (fellowship ED481B2014/133-0), and by the Spanish Ministry of Economy and Competitiveness (grant DPI2013-47100-C2-2-P)

Low-Order Nonlinear Animal Model of Glucose Dynamics for a Bihormonal Intraperitoneal Artificial Pancreas

Objective: The design of an Artificial Pancreas to regulate blood glucose levels requires reliable control methods. Model Predictive Control has emerged as a promising approach for glycemia control. However, model-based control methods require computationally simple and identifiable mathematical models that represent glucose dynamics accurately, which is challenging due to the complexity of glucose homeostasis. Methods: In this work, a simple model is deduced to estimate blood glucose concentration in subjects with Type 1 Diabetes Mellitus. Novel features in the model are power-law kinetics for intraperitoneal insulin absorption and a separate glucagon sensitivity state. Profile likelihood and a method based on singular value decomposition of the sensitivity matrix are carried out to assess parameter identifiability and guide a model reduction for improving the identification of parameters. Results: A reduced model with 10 parameters is obtained and calibrated, showing good fit to experimental data from pigs where insulin and glucagon boluses were delivered in the intraperitoneal cavity. Conclusion: A simple model with power-law kinetics can accurately represent glucose dynamics submitted to intraperitoneal insulin and glucagon injections. Importance: The parameters of the reduced model were not found to lack of local practical or structural identifiability

ESTIMATION-BASED SOLUTIONS TO INCOMPLETE INFORMATION PURSUIT-EVASION GAMES

Differential games are a useful tool both for modeling conflict between autonomous systems and for synthesizing robust control solutions. The traditional study of games has assumed decision agents possess complete information about one another’s strategies and numerical weights. This dissertation relaxes this assumption. Instead, uncertainty in the opponent’s strategy is treated as a symptom of the inevitable gap between modeling assumptions and applications. By combining nonlinear estimation approaches with problem domain knowledge, procedures are developed for acting under uncertainty using established methods that are suitable for applications on embedded systems. The dissertation begins by using nonlinear estimation to account for parametric uncertainty in an opponent’s strategy. A solution is proposed for engagements in which both players use this approach simultaneously. This method is demonstrated on a numerical example of an orbital pursuit-evasion game, and the findings motivate additional developments. First, the solutions of the governing Riccati differential equations are approximated, using automatic differentiation to obtain high-degree Taylor series approximations. Second, constrained estimation is introduced to prevent estimator failures in near-singular engagements. Numerical conditions for nonsingularity are approximated using Chebyshev polynomial basis functions, and applied as constraints to a state estimate. Third and finally, multiple model estimation is suggested as a practical solution for time-critical engagements in which the form of the opponent’s strategy is uncertain. Deceptive opponent strategies are identified as a candidate approach to use against an adaptive player, and a procedure for designing such strategies is proposed. The new developments are demonstrated in a missile interception pursuit-evasion game in which the evader selects from a set of candidate strategies with unknown weights

A fast algorithm to assess local structural identifiability

The paper presents a novel method for assessing the local structural identifiability question for a general non-linear state-space model. The method is a combination of (i) the application of a singular value decomposition to a parametric output sensitivity matrix that is created by simply integrating the model once and, (ii) a symbolic computation for a reduced model that is guided by the SVD results and allows a confirmation of the conclusions regarding identifiability obtained in the first step. In case there is a lack of identifiability, the symbolic computation quickly results in determination of the exact structure of the nullspace and a suitable re-parametrisation. The method is discussed in detail and applied to three case studies, of which the last two are considerably large, containing 22 and 43 parameters to be identified, respectively