204 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
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
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-B, uncovering
previously unknown unidentifiabilities
Inference of complex biological networks: distinguishability issues and optimization-based solutions
<p>Abstract</p> <p>Background</p> <p>The inference of biological networks from high-throughput data has received huge attention during the last decade and can be considered an important problem class in systems biology. However, it has been recognized that reliable network inference remains an unsolved problem. Most authors have identified lack of data and deficiencies in the inference algorithms as the main reasons for this situation.</p> <p>Results</p> <p>We claim that another major difficulty for solving these inference problems is the frequent lack of uniqueness of many of these networks, especially when prior assumptions have not been taken properly into account. Our contributions aid the distinguishability analysis of chemical reaction network (CRN) models with mass action dynamics. The novel methods are based on linear programming (LP), therefore they allow the efficient analysis of CRNs containing several hundred complexes and reactions. Using these new tools and also previously published ones to obtain the network structure of biological systems from the literature, we find that, often, a unique topology cannot be determined, even if the structure of the corresponding mathematical model is assumed to be known and all dynamical variables are measurable. In other words, certain mechanisms may remain undetected (or they are falsely detected) while the inferred model is fully consistent with the measured data. It is also shown that sparsity enforcing approaches for determining 'true' reaction structures are generally not enough without additional prior information.</p> <p>Conclusions</p> <p>The inference of biological networks can be an extremely challenging problem even in the utopian case of perfect experimental information. Unfortunately, the practical situation is often more complex than that, since the measurements are typically incomplete, noisy and sometimes dynamically not rich enough, introducing further obstacles to the structure/parameter estimation process. In this paper, we show how the structural uniqueness and identifiability of the models can be guaranteed by carefully adding extra constraints, and that these important properties can be checked through appropriate computation methods.</p
Non-linear estimation is easy
Non-linear state estimation and some related topics, like parametric
estimation, fault diagnosis, and perturbation attenuation, are tackled here via
a new methodology in numerical differentiation. The corresponding basic system
theoretic definitions and properties are presented within the framework of
differential algebra, which permits to handle system variables and their
derivatives of any order. Several academic examples and their computer
simulations, with on-line estimations, are illustrating our viewpoint
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