Summary: TOPALi v2 simplifies and automates the use of several methods for the evolutionary analysis of multiple sequence alignments. Jobs are submitted from a Java graphical user interface as TOPALi web services to either run remotely on high-performance computing clusters or locally (with multiple cores supported). Methods available include model selection and phylogenetic tree estimation using the Bayesian inference and maximum likelihood (ML) approaches, in addition to recombination detection methods. The optimal substitution model can be selected for protein or nucleic acid (standard, or protein-coding using a codon position model) data using accurate statistical criteria derived from ML co-estimation of the tree and the substitution model. Phylogenetic software available includes PhyML, RAxML and MrBayes.Availability: Freely downloadable from http://www.topali.org for Windows, Mac OS X, Linux and Solaris.Contact: iain.milne@scri.ac.uk
There have been various attempts to reconstruct gene regulatory networks from microarray expression data in the past. However, owing to the limited amount of independent experimental conditions and noise inherent in the measurements, the results have been rather modest so far. For this reason it seems advisable to include biological prior knowledge, related, for instance, to transcription factor binding locations in promoter regions or partially known signalling pathways from the literature. In the present paper, we consider a Bayesian approach to systematically integrate expression data with multiple sources of prior knowledge. Each source is encoded via a separate energy function, from which a prior distribution over network structures in the form of a Gibbs distribution is constructed. The hyperparameters associated with the different sources of prior knowledge, which measure the influence of the respective prior relative to the data, are sampled from the posterior distribution with MCMC. We have evaluated the proposed scheme on the yeast cell cycle and the Raf signalling pathway. Our findings quantify to what extent the inclusion of independent prior knowledge improves the network reconstruction accuracy, and the values of the hyperparameters inferred with the proposed scheme were found to be close to optimal with respect to minimizing the reconstruction error.
Bayesian-based methodology is presented which automatically penalizes overcomplex models being fitted to unknown data. We show that, with a Gaussian mixture model, the approach is able to select an "optimal" number of components in the model and so partition data sets. The performance of the Bayesian method is compared to other methods of optimal model selection and found to give good results. The methods are tested on synthetic and real data sets.
Applications of Bayesian networks in systems biology are computationally demanding due to the large number of model parameters. Conventional MCMC schemes based on proposal moves in structure space tend to be too slow in mixing and convergence, and have recently been superseded by proposal moves in the space of node orders. A disadvantage of the latter approach is the intrinsic inability to specify the prior probability on network structures explicitly. The relative paucity of different experimental conditions in contemporary systems biology implies a strong influence of the prior probability on the posterior probability and, hence, the outcome of inference. Consequently, the paradigm of performing MCMC proposal moves in order rather than structure space is not entirely satisfactory. In the present article, we propose a new and more extensive edge reversal move in the original structure space, and we show that this significantly improves the convergence of the classical structure MCMC scheme. Keywords Bayesian networks • Structure learning • MCMC sampling 1 Introduction The concept of Bayesian networks is a cornerstone for modern statistical inference on regulatory networks. Following up on the seminal paper by Friedman et al. (2000), it has recently enjoyed considerable popularity in systems biology research. However, the large number of
In this research, we hypothesized that novel biomechanical parameters are discriminative in patients following acute ST-segment elevation myocardial infarction (STEMI). To identify these biomechanical biomarkers and bring computational biomechanics ‘closer to the clinic’, we applied state-of-the-art multiphysics cardiac modelling combined with advanced machine learning and multivariate statistical inference to a clinical database of myocardial infarction. We obtained data from 11 STEMI patients (ClinicalTrials.gov NCT01717573) and 27 healthy volunteers, and developed personalized mathematical models for the left ventricle (LV) using an immersed boundary method. Subject-specific constitutive parameters were achieved by matching to clinical measurements. We have shown, for the first time, that compared with healthy controls, patients with STEMI exhibited increased LV wall active tension when normalized by systolic blood pressure, which suggests an increased demand on the contractile reserve of remote functional myocardium. The statistical analysis reveals that the required patient-specific contractility, normalized active tension and the systolic myofilament kinematics have the strongest explanatory power for identifying the myocardial function changes post-MI. We further observed a strong correlation between two biomarkers and the changes in LV ejection fraction at six months from baseline (the required contractility (r = − 0.79, p < 0.01) and the systolic myofilament kinematics (r = 0.70, p = 0.02)). The clinical and prognostic significance of these biomechanical parameters merits further scrutinization.
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