A temporal precedence based clustering method for gene expression microarray data

Background: Time-course microarray experiments can produce useful data which can help in understanding the underlying dynamics of the system. Clustering is an important stage in microarray data analysis where the data is grouped together according to certain characteristics. The majority of clustering techniques are based on distance or visual similarity measures which may not be suitable for clustering of temporal microarray data where the sequential nature of time is important. We present a Granger causality based technique to cluster temporal microarray gene expression data, which measures the interdependence between two time-series by statistically testing if one time-series can be used for forecasting the other time-series or not. Results: A gene-association matrix is constructed by testing temporal relationships between pairs of genes using the Granger causality test. The association matrix is further analyzed using a graph-theoretic technique to detect highly connected components representing interesting biological modules. We test our approach on synthesized datasets and real biological datasets obtained for Arabidopsis thaliana. We show the effectiveness of our approach by analyzing the results using the existing biological literature. We also report interesting structural properties of the association network commonly desired in any biological system. Conclusions: Our experiments on synthesized and real microarray datasets show that our approach produces encouraging results. The method is simple in implementation and is statistically traceable at each step. The method can produce sets of functionally related genes which can be further used for reverse-engineering of gene circuits

Gains in Power from Structured Two-Sample Tests of Means on Graphs

We consider multivariate two-sample tests of means, where the location shift between the two populations is expected to be related to a known graph structure. An important application of such tests is the detection of differentially expressed genes between two patient populations, as shifts in expression levels are expected to be coherent with the structure of graphs reflecting gene properties such as biological process, molecular function, regulation, or metabolism. For a fixed graph of interest, we demonstrate that accounting for graph structure can yield more powerful tests under the assumption of smooth distribution shift on the graph. We also investigate the identification of non-homogeneous subgraphs of a given large graph, which poses both computational and multiple testing problems. The relevance and benefits of the proposed approach are illustrated on synthetic data and on breast cancer gene expression data analyzed in context of KEGG pathways

Transformation of metabolism with age and lifestyle in Antarctic seals: a case study of systems biology approach to cross-species microarray experiment

*_Background:_* The metabolic transformation that changes Weddell seal pups born on land into aquatic animals is not only interesting for the study of general biology, but it also provides a model for the acquired and congenital muscle disorders which are associated with oxygen metabolism in skeletal muscle. However, the analysis of gene expression in seals is hampered by the lack of specific microarrays and the very limited annotation of known Weddell seal (_Leptonychotes weddellii_) genes.

*_Results:_* Muscle samples from newborn, juvenile, and adult Weddell seals were collected during an Antarctic expedition. Extracted RNA was hybridized on Affymetrix Human Expression chips. Preliminary studies showed a detectable signal from at least 7000 probe sets present in all samples and replicates. Relative expression levels for these genes was used for further analysis of the biological pathways implicated in the metabolism transformation which occurs in the transition from newborn, to juvenile, to adult seals. Cytoskeletal remodeling, WNT signaling, FAK signaling, hypoxia-induced HIF1 activation, and insulin regulation were identified as being among the most important biological pathways involved in transformation. 

*_Conclusion:_* In spite of certain losses in specificity and sensitivity, the cross-species application of gene expression microarrays is capable of solving challenging puzzles in biology. A Systems Biology approach based on gene interaction patterns can compensate adequately for the lack of species-specific genomics information.
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A Computational Algebra Approach to the Reverse Engineering of Gene Regulatory Networks

This paper proposes a new method to reverse engineer gene regulatory networks from experimental data. The modeling framework used is time-discrete deterministic dynamical systems, with a finite set of states for each of the variables. The simplest examples of such models are Boolean networks, in which variables have only two possible states. The use of a larger number of possible states allows a finer discretization of experimental data and more than one possible mode of action for the variables, depending on threshold values. Furthermore, with a suitable choice of state set, one can employ powerful tools from computational algebra, that underlie the reverse-engineering algorithm, avoiding costly enumeration strategies. To perform well, the algorithm requires wildtype together with perturbation time courses. This makes it suitable for small to meso-scale networks rather than networks on a genome-wide scale. The complexity of the algorithm is quadratic in the number of variables and cubic in the number of time points. The algorithm is validated on a recently published Boolean network model of segment polarity development in Drosophila melanogaster.Comment: 28 pages, 5 EPS figures, uses elsart.cl

Uncovering interactions in the frequency domain

Oscillatory activity plays a critical role in regulating biological processes at levels ranging from subcellular, cellular, and network to the whole organism, and often involves a large number of interacting elements. We shed light on this issue by introducing a novel approach called partial Granger causality to reliably reveal interaction patterns in multivariate data with exogenous inputs and latent variables in the frequency domain. The method is extensively tested with toy models, and successfully applied to experimental datasets, including (1) gene microarray data of HeLa cell cycle; (2) in vivo multielectrode array (MEA) local field potentials (LFPs) recorded from the inferotemporal cortex of a sheep; and (3) in vivo LFPs recorded from distributed sites in the right hemisphere of a macaque monkey

Differential expression analysis with global network adjustment

<p>Background: Large-scale chromosomal deletions or other non-specific perturbations of the transcriptome can alter the expression of hundreds or thousands of genes, and it is of biological interest to understand which genes are most profoundly affected. We present a method for predicting a gene’s expression as a function of other genes thereby accounting for the effect of transcriptional regulation that confounds the identification of genes differentially expressed relative to a regulatory network. The challenge in constructing such models is that the number of possible regulator transcripts within a global network is on the order of thousands, and the number of biological samples is typically on the order of 10. Nevertheless, there are large gene expression databases that can be used to construct networks that could be helpful in modeling transcriptional regulation in smaller experiments.</p> <p>Results: We demonstrate a type of penalized regression model that can be estimated from large gene expression databases, and then applied to smaller experiments. The ridge parameter is selected by minimizing the cross-validation error of the predictions in the independent out-sample. This tends to increase the model stability and leads to a much greater degree of parameter shrinkage, but the resulting biased estimation is mitigated by a second round of regression. Nevertheless, the proposed computationally efficient “over-shrinkage” method outperforms previously used LASSO-based techniques. In two independent datasets, we find that the median proportion of explained variability in expression is approximately 25%, and this results in a substantial increase in the signal-to-noise ratio allowing more powerful inferences on differential gene expression leading to biologically intuitive findings. We also show that a large proportion of gene dependencies are conditional on the biological state, which would be impossible with standard differential expression methods.</p> <p>Conclusions: By adjusting for the effects of the global network on individual genes, both the sensitivity and reliability of differential expression measures are greatly improved.</p&gt