4,029 research outputs found
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
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
Joining Forces of Bayesian and Frequentist Methodology: A Study for Inference in the Presence of Non-Identifiability
Increasingly complex applications involve large datasets in combination with
non-linear and high dimensional mathematical models. In this context,
statistical inference is a challenging issue that calls for pragmatic
approaches that take advantage of both Bayesian and frequentist methods. The
elegance of Bayesian methodology is founded in the propagation of information
content provided by experimental data and prior assumptions to the posterior
probability distribution of model predictions. However, for complex
applications experimental data and prior assumptions potentially constrain the
posterior probability distribution insufficiently. In these situations Bayesian
Markov chain Monte Carlo sampling can be infeasible. From a frequentist point
of view insufficient experimental data and prior assumptions can be interpreted
as non-identifiability. The profile likelihood approach offers to detect and to
resolve non-identifiability by experimental design iteratively. Therefore, it
allows one to better constrain the posterior probability distribution until
Markov chain Monte Carlo sampling can be used securely. Using an application
from cell biology we compare both methods and show that a successive
application of both methods facilitates a realistic assessment of uncertainty
in model predictions.Comment: Article to appear in Phil. Trans. Roy. Soc.
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
emgr - The Empirical Gramian Framework
System Gramian matrices are a well-known encoding for properties of
input-output systems such as controllability, observability or minimality.
These so-called system Gramians were developed in linear system theory for
applications such as model order reduction of control systems. Empirical
Gramian are an extension to the system Gramians for parametric and nonlinear
systems as well as a data-driven method of computation. The empirical Gramian
framework - emgr - implements the empirical Gramians in a uniform and
configurable manner, with applications such as Gramian-based (nonlinear) model
reduction, decentralized control, sensitivity analysis, parameter
identification and combined state and parameter reduction
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
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
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