Probabilistic sensitivity analysis of biochemical reaction systems

Sensitivity analysis is an indispensable tool for studying the robustness and fragility properties of biochemical reaction systems as well as for designing optimal approaches for selective perturbation and intervention. Deterministic sensitivity analysis techniques, using derivatives of the system response, have been extensively used in the literature. However, these techniques suffer from several drawbacks, which must be carefully considered before using them in problems of systems biology. We develop here a probabilistic approach to sensitivity analysis of biochemical reaction systems. The proposed technique employs a biophysically derived model for parameter fluctuations and, by using a recently suggested variance-based approach to sensitivity analysis [Saltelli et al., Chem. Rev. (Washington, D.C.) 105, 2811 (2005)], it leads to a powerful sensitivity analysis methodology for biochemical reaction systems. The approach presented in this paper addresses many problems associated with derivative-based sensitivity analysis techniques. Most importantly, it produces thermodynamically consistent sensitivity analysis results, can easily accommodate appreciable parameter variations, and allows for systematic investigation of high-order interaction effects. By employing a computational model of the mitogen-activated protein kinase signaling cascade, we demonstrate that our approach is well suited for sensitivity analysis of biochemical reaction systems and can produce a wealth of information about the sensitivity properties of such systems. The price to be paid, however, is a substantial increase in computational complexity over derivative-based techniques, which must be effectively addressed in order to make the proposed approach to sensitivity analysis more practical

Thermodynamically consistent model calibration in chemical kinetics

<p>Abstract</p> <p>Background</p> <p>The dynamics of biochemical reaction systems are constrained by the fundamental laws of thermodynamics, which impose well-defined relationships among the reaction rate constants characterizing these systems. Constructing biochemical reaction systems from experimental observations often leads to parameter values that do not satisfy the necessary thermodynamic constraints. This can result in models that are not physically realizable and may lead to inaccurate, or even erroneous, descriptions of cellular function.</p> <p>Results</p> <p>We introduce a thermodynamically consistent model calibration (TCMC) method that can be effectively used to provide thermodynamically feasible values for the parameters of an <it>open </it>biochemical reaction system. The proposed method formulates the model calibration problem as a constrained optimization problem that takes thermodynamic constraints (and, if desired, additional non-thermodynamic constraints) into account. By calculating thermodynamically feasible values for the kinetic parameters of a well-known model of the EGF/ERK signaling cascade, we demonstrate the qualitative and quantitative significance of imposing thermodynamic constraints on these parameters and the effectiveness of our method for accomplishing this important task. MATLAB software, using the Systems Biology Toolbox 2.1, can be accessed from <url>http://www.cis.jhu.edu/~goutsias/CSS lab/software.html</url>. An SBML file containing the thermodynamically feasible EGF/ERK signaling cascade model can be found in the BioModels database.</p> <p>Conclusions</p> <p>TCMC is a simple and flexible method for obtaining physically plausible values for the kinetic parameters of open biochemical reaction systems. It can be effectively used to recalculate a thermodynamically consistent set of parameter values for existing thermodynamically infeasible biochemical reaction models of cellular function as well as to estimate thermodynamically feasible values for the parameters of new models. Furthermore, TCMC can provide dimensionality reduction, better estimation performance, and lower computational complexity, and can help to alleviate the problem of data overfitting.</p

Multiresolution signal decomposition schemes

[PNA-R9810] Interest in multiresolution techniques for signal processing and analysis is increasing steadily. An important instance of such a technique is the so-called pyramid decomposition scheme. This report proposes a general axiomatic pyramid decomposition scheme for signal analysis and synthesis. This scheme comprises the following ingredients: (i) the pyramid consists of a (finite or infinite) number of levels such that the information content decreases towards higher levels; (ii) each step towards a higher level is constituted by an (information-reducing) analysis operator, whereas each step towards a lower level is modeled by an (information-preserving) synthesis operator. One basic assumption is necessary: synthesis followed by analysis yields the identity operator, meaning that no information is lost by these two consecutive steps. In this report, several examples are described of linear as well as nonlinear (e.g., morphological) pyramid decomposition schemes. Some of these examples are known from the literature (Laplacian pyramid, morphological granulometries, skeleton decomposition) and some of them are new (morphological Haar pyramid, median pyramid). Furthermore, the report makes a distinction between single-scale and multiscale decomposition schemes (i.e. without or with sample reduction).#[PNA-R9905] In its original form, the wavelet transform is a linear tool. However, it has been increasingly recognized that nonlinear extensions are possible. A major impulse to the development of nonlinea

Multiresolution signal decomposition schemes. Part 2: Morphological wavelets

In its original form, the wavelet transform is a linear tool. However, it has been increasingly recognized that nonlinear extensions are possible. A major impulse to the development of nonlinear wavelet transforms has been given by the introduction of the lifting scheme by Sweldens. The aim of this report, which is a sequel to a previous report devoted exclusively to the pyramid transform, is to present an axiomatic framework encompassing most existing linear and nonlinear wavelet decompositions. Furthermore, it introduces some, thus far unknown, wavelets based on mathematical morphology, such as the morphological Haar wavelet, both in one and two dimensions. A general and flexible approach for the construction of nonlinear (morphological) wavelets is provided by the lifting scheme. This paper discusses one example in considerable detail, the max-lifting scheme, which has the intriguing property that it preserves local maxima in a signal over a range of scales, depending on how local or global these maxima are

A Unified Algebraic Framework for Fuzzy Image Compression and Mathematical Morphology

In this paper we show how certain techniques of image processing, having different scopes, can be joined together under a common "algebraic roof"

A morphological algorithm for improving radio-frequency interference detection

A technique is described that is used to improve the detection of radio-frequency interference in astronomical radio observatories. It is applied on a two-dimensional interference mask after regular detection in the time-frequency domain with existing techniques. The scale-invariant rank (SIR) operator is defined, which is a one-dimensional mathematical morphology technique that can be used to find adjacent intervals in the time or frequency domain that are likely to be affected by RFI. The technique might also be applicable in other areas in which morphological scale-invariant behaviour is desired, such as source detection. A new algorithm is described, that is shown to perform quite well, has linear time complexity and is fast enough to be applied in modern high resolution observatories. It is used in the default pipeline of the LOFAR observatory.Comment: Accepted for publication in A&

On the Stability and the Approximation of Branching Distribution Flows, with Applications to Nonlinear Multiple Target Filtering

We analyse the exponential stability properties of a class of measure-valued equations arising in nonlinear multi-target filtering problems. We also prove the uniform convergence properties w.r.t. the time parameter of a rather general class of stochastic filtering algorithms, including sequential Monte Carlo type models and mean eld particle interpretation models. We illustrate these results in the context of the Bernoulli and the Probability Hypothesis Density filter, yielding what seems to be the first results of this kind in this subject