Computation of biochemical pathway fluctuations beyond the linear noise approximation using iNA

The linear noise approximation is commonly used to obtain intrinsic noise statistics for biochemical networks. These estimates are accurate for networks with large numbers of molecules. However it is well known that many biochemical networks are characterized by at least one species with a small number of molecules. We here describe version 0.3 of the software intrinsic Noise Analyzer (iNA) which allows for accurate computation of noise statistics over wide ranges of molecule numbers. This is achieved by calculating the next order corrections to the linear noise approximation's estimates of variance and covariance of concentration fluctuations. The efficiency of the methods is significantly improved by automated just-in-time compilation using the LLVM framework leading to a fluctuation analysis which typically outperforms that obtained by means of exact stochastic simulations. iNA is hence particularly well suited for the needs of the computational biology community.Comment: 5 pages, 2 figures, conference proceeding IEEE International Conference on Bioinformatics and Biomedicine (BIBM) 201

How reliable is the linear noise approximation of gene regulatory networks?

Background The linear noise approximation (LNA) is commonly used to predict how noise is regulated and exploited at the cellular level. These predictions are exact for reaction networks composed exclusively of first order reactions or for networks involving bimolecular reactions and large numbers of molecules. It is however well known that gene regulation involves bimolecular interactions with molecule numbers as small as a single copy of a particular gene. It is therefore questionable how reliable are the LNA predictions for these systems. Results We implement in the software package intrinsic Noise Analyzer (iNA), a system size expansion based method which calculates the mean concentrations and the variances of the fluctuations to an order of accuracy higher than the LNA. We then use iNA to explore the parametric dependence of the Fano factors and of the coefficients of variation of the mRNA and protein fluctuations in models of genetic networks involving nonlinear protein degradation, post-transcriptional, post-translational and negative feedback regulation. We find that the LNA can significantly underestimate the amplitude and period of noise-induced oscillations in genetic oscillators. We also identify cases where the LNA predicts that noise levels can be optimized by tuning a bimolecular rate constant whereas our method shows that no such regulation is possible. All our results are confirmed by stochastic simulations. Conclusion The software iNA allows the investigation of parameter regimes where the LNA fares well and where it does not. We have shown that the parametric dependence of the coefficients of variation and Fano factors for common gene regulatory networks is better described by including terms of higher order than LNA in the system size expansion. This analysis is considerably faster than stochastic simulations due to the extensive ensemble averaging needed to obtain statistically meaningful results. Hence iNA is well suited for performing computationally efficient and quantitative studies of intrinsic noise in gene regulatory networks

Synchronization of muscular oscillations between two subjects during isometric interaction

Muscles oscillate with a frequency around 10 Hz. But what happens with myofascial oscillations, if two neuromuscular systems interact? The purpose of this study was to examine this question, initially, on the basis of a case study. Oscillations of the triceps brachii muscles of two subjects were determined through mechanomyography (MMG) during isometric interaction. The MMG-signals were analyzed concerning the interaction of the two subjects with algorithms of nonlinear dynamics. In this case study it could be shown, that the muscles of both neuromuscular systems also oscillate with the known frequency (here 12 Hz) during interaction. Furthermore, both subjects were able to adapt their oscillations against each other. This adjustment induced a significant ( < .05) coherent behavior, which was characterized by a phase shifting of approximately 90°. The authors draw the conclusion, that the complementary neuromuscular partners potentially have the ability of mutual synchronization

Intrinsic Noise Analyzer: A Software Package for the Exploration of Stochastic Biochemical Kinetics Using the System Size Expansion

The accepted stochastic descriptions of biochemical dynamics under well-mixed conditions are given by the Chemical Master Equation and the Stochastic Simulation Algorithm, which are equivalent. The latter is a Monte-Carlo method, which, despite enjoying broad availability in a large number of existing software packages, is computationally expensive due to the huge amounts of ensemble averaging required for obtaining accurate statistical information. The former is a set of coupled differential-difference equations for the probability of the system being in any one of the possible mesoscopic states; these equations are typically computationally intractable because of the inherently large state space. Here we introduce the software package intrinsic Noise Analyzer (iNA), which allows for systematic analysis of stochastic biochemical kinetics by means of van Kampen’s system size expansion of the Chemical Master Equation. iNA is platform independent and supports the popular SBML format natively. The present implementation is the first to adopt a complementary approach that combines state-of-the-art analysis tools using the computer algebra system Ginac with traditional methods of stochastic simulation. iNA integrates two approximation methods based on the system size expansion, the Linear Noise Approximation and effective mesoscopic rate equations, which to-date have not been available to non-expert users, into an easy-to-use graphical user interface. In particular, the present methods allow for quick approximate analysis of time-dependent mean concentrations, variances, covariances and correlations coefficients, which typically outperforms stochastic simulations. These analytical tools are complemented by automated multi-core stochastic simulations with direct statistical evaluation and visualization. We showcase iNA’s performance by using it to explore the stochastic properties of cooperative and non-cooperative enzyme kinetics and a gene network associated with circadian rhythms. The software iNA is freely available as executable binaries for Linux, MacOSX and Microsoft Windows, as well as the full source code under an open source license

How reliable is the linear noise approximation of gene regulatory networks?

Background: The linear noise approximation (LNA) is commonly used to predict how noise is regulated and exploited at the cellular level. These predictions are exact for reaction networks composed exclusively of first order reactions or for networks involving bimolecular reactions and large numbers of molecules. It is however well known that gene regulation involves bimolecular interactions with molecule numbers as small as a single copy of a particular gene. It is therefore questionable how reliable are the LNA predictions for these systems. Results: We implement in the software package intrinsic Noise Analyzer (iNA), a system size expansion based method which calculates the mean concentrations and the variances of the fluctuations to an order of accuracy higher than the LNA. We then use iNA to explore the parametric dependence of the Fano factors and of the coefficients of variation of the mRNA and protein fluctuations in models of genetic networks involving nonlinear protein degradation, post-transcriptional, post-translational and negative feedback regulation. We find that the LNA can significantly underestimate the amplitude and period of noise-induced oscillations in genetic oscillators. We also identify cases where the LNA predicts that noise levels can be optimized by tuning a bimolecular rate constant whereas our method shows that no such regulation is possible. All our results are confirmed by stochastic simulations. Conclusion: The software iNA allows the investigation of parameter regimes where the LNA fares well and where it does not. We have shown that the parametric dependence of the coefficients of variation and Fano factors for common gene regulatory networks is better described by including terms of higher order than LNA in the system size expansion. This analysis is considerably faster than stochastic simulations due to the extensive ensemble averaging needed to obtain statistically meaningful results. Hence iNA is well suited for performing computationally efficient and quantitative studies of intrinsic noise in gene regulatory networks

Smoothing Spline ANOVA Decomposition of Arbitrary Splines: An Application to Eye Movements in Reading

<div><p>The Smoothing Spline ANOVA (SS-ANOVA) requires a specialized construction of basis and penalty terms in order to incorporate prior knowledge about the data to be fitted. Typically, one resorts to the most general approach using tensor product splines. This implies severe constraints on the correlation structure, i.e. the assumption of isotropy of smoothness can not be incorporated in general. This may increase the variance of the spline fit, especially if only a relatively small set of observations are given. In this article, we propose an alternative method that allows to incorporate prior knowledge without the need to construct specialized bases and penalties, allowing the researcher to choose the spline basis and penalty according to the prior knowledge of the observations rather than choosing them according to the analysis to be done. The two approaches are compared with an artificial example and with analyses of fixation durations during reading.</p></div

Comparison of SS-ANOVA decompositions using the tensor product and post-hoc approach.

<p>a) The true functions. b) Comparison of the mean </p><p></p><p><mi>E</mi><mo stretchy="false">[</mo></p><p><mi>f</mi><mo>̂</mo></p><mo stretchy="false">]</mo><p></p><p></p> and standard deviation <p></p><p>sd<mo stretchy="false">(</mo></p><p><mi>f</mi><mo>̂</mo></p><mo stretchy="false">)</mo><p></p><p></p> of the main (columns 1 & 2) and interaction effects (column 3) estimators over 100 independent sample sets, each of size <i>N</i> = 30. The first row shows the results using the tensor product approach while the second row shows the same estimators for the post-hoc decomposition of a thin-plate spline. The last column shows the sum of the main and interaction effect means. Although the means are almost identical, the estimators of post-hoc decomposition have a much smaller variance and therefore a much higher reliability. c) Results of the same analysis as above (b) but using a bigger sample size, here <i>N</i> = 300. As more statistical evidence is provided by the data, the <i>a priori</i> knowledge used for the post-hoc decomposition (isotropic smoothness) has a smaller influence on the outcome. Therefore the results are almost identical.<p></p

Michaelis-Menten kinetics in a large compartment of volume .

<p>Plots showing the results of <i>Linear Noise Approximation</i> (a) and <i>Stochastic simulation</i> using an ensemble of independent 1,000 realizations (b). The two are in excellent agreement. Both figures have been obtained from iNA’s analysis of the SBML file F1.</p