4,049 research outputs found
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
Dynamical compensation and structural identifiability: analysis, implications, and reconciliation
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. Here we show that, according to
its original definition, dynamical compensation is equivalent to lack of
structural identifiability. This is relevant if model parameters need to be
estimated, which is often the case in biological modelling. This realization
prompts us to warn that 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
Identification of parameter correlations for parameter estimation in dynamic biological models
Background:
One of the challenging tasks in systems biology is parameter estimation in nonlinear dynamic models. A biological model usually contains a large number of correlated parameters leading to non-identifiability problems. Although many approaches have been developed to address both structural and practical non-identifiability problems, very few studies have been made to systematically investigate parameter correlations.
Results:
In this study we present an approach that is able to identify both pairwise parameter correlations and higher order interrelationships among parameters in nonlinear dynamic models. Correlations are interpreted as surfaces in the subspaces of correlated parameters. Based on the correlation information obtained in this way both structural and practical non-identifiability can be clarified. Moreover, it can be concluded from the correlation analysis that a minimum number of data sets with different inputs for experimental design are needed to relieve the parameter correlations, which corresponds to the maximum number of correlated parameters among the correlation groups.
Conclusions:
The information of pairwise and higher order interrelationships among parameters in biological models gives a deeper insight into the cause of non-identifiability problems. The result of our correlation analysis provides a necessary condition for experimental design in order to acquire suitable measurement data for unique parameter estimation
Insights into the behaviour of systems biology models from dynamic sensitivity and identifiability analysis: a case study of an NF-kB signaling pathway
Mathematical modelling offers a variety of useful techniques to help in understanding the intrinsic behaviour of complex signal transduction networks. From the system engineering point of view, the dynamics of metabolic and signal transduction models can always be described by nonlinear ordinary differential equations (ODEs) following mass balance principles. Based on the state-space formulation, many methods from the area of automatic control can conveniently be applied to the modelling, analysis and design of cell networks. In the present study, dynamic sensitivity analysis is performed on a model of the IB-NF-B signal pathway system. Univariate analysis of the Euclidean-form overall sensitivities shows that only 8 out of the 64 parameters in the model have major influence on the nuclear NF-B oscillations. The sensitivity matrix is then used to address correlation analysis, identifiability assessment and measurement set selection within the framework of least squares estimation and multivariate analysis. It is shown that certain pairs of parameters are exactly or highly correlated to each other in terms of their effects on the measured variables. The experimental design strategy provides guidance on which proteins should best be considered for measurement such that the unknown parameters can be estimated with the best statistical precision. The whole analysis scheme we describe provides efficient parameter estimation techniques for complex cell networks
The Parameter Houlihan: a solution to high-throughput identifiability indeterminacy for brutally ill-posed problems
One way to interject knowledge into clinically impactful forecasting is to
use data assimilation, a nonlinear regression that projects data onto a
mechanistic physiologic model, instead of a set of functions, such as neural
networks. Such regressions have an advantage of being useful with particularly
sparse, non-stationary clinical data. However, physiological models are often
nonlinear and can have many parameters, leading to potential problems with
parameter identifiability, or the ability to find a unique set of parameters
that minimize forecasting error. The identifiability problems can be minimized
or eliminated by reducing the number of parameters estimated, but reducing the
number of estimated parameters also reduces the flexibility of the model and
hence increases forecasting error. We propose a method, the parameter Houlihan,
that combines traditional machine learning techniques with data assimilation,
to select the right set of model parameters to minimize forecasting error while
reducing identifiability problems. The method worked well: the data
assimilation-based glucose forecasts and estimates for our cohort using the
Houlihan-selected parameter sets generally also minimize forecasting errors
compared to other parameter selection methods such as by-hand parameter
selection. Nevertheless, the forecast with the lowest forecast error does not
always accurately represent physiology, but further advancements of the
algorithm provide a path for improving physiologic fidelity as well. Our hope
is that this methodology represents a first step toward combining machine
learning with data assimilation and provides a lower-threshold entry point for
using data assimilation with clinical data by helping select the right
parameters to estimate
Adaptive optimal operation of a parallel robotic liquid handling station
Results are presented from the optimal operation of a fully automated robotic liquid handling station where parallel experiments are performed for calibrating a kinetic fermentation model. To increase the robustness against uncertainties and/or wrong assumptions about the parameter values, an iterative calibration and experiment design approach is adopted. Its implementation yields a stepwise reduction of parameter uncertainties together with an adaptive redesign of reactor feeding strategies whenever new measurement information is available. The case study considers the adaptive optimal design of 4 parallel fed-batch strategies implemented in 8 mini-bioreactors. Details are given on the size and complexity of the problem and the challenges related to calibration of over-parameterized models and scarce and non-informative measurement data. It is shown how methods for parameter identifiability analysis and numerical regularization can be used for monitoring the progress of the experimental campaigns in terms of generated information regarding parameters and selection of the best fitting parameter subset.BMBF, 02PJ1150, Verbundprojekt: Plattformtechnologien für automatisierte Bioprozessentwicklung (AutoBio); Teilprojekt: Automatisierte Bioprozessentwicklung am Beispiel von neuen Nukleosidphosphorylase
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
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