3,269 research outputs found
Detection of regulator genes and eQTLs in gene networks
Genetic differences between individuals associated to quantitative phenotypic
traits, including disease states, are usually found in non-coding genomic
regions. These genetic variants are often also associated to differences in
expression levels of nearby genes (they are "expression quantitative trait
loci" or eQTLs for short) and presumably play a gene regulatory role, affecting
the status of molecular networks of interacting genes, proteins and
metabolites. Computational systems biology approaches to reconstruct causal
gene networks from large-scale omics data have therefore become essential to
understand the structure of networks controlled by eQTLs together with other
regulatory genes, and to generate detailed hypotheses about the molecular
mechanisms that lead from genotype to phenotype. Here we review the main
analytical methods and softwares to identify eQTLs and their associated genes,
to reconstruct co-expression networks and modules, to reconstruct causal
Bayesian gene and module networks, and to validate predicted networks in
silico.Comment: minor revision with typos corrected; review article; 24 pages, 2
figure
Defining a robust biological prior from Pathway Analysis to drive Network Inference
Inferring genetic networks from gene expression data is one of the most
challenging work in the post-genomic era, partly due to the vast space of
possible networks and the relatively small amount of data available. In this
field, Gaussian Graphical Model (GGM) provides a convenient framework for the
discovery of biological networks. In this paper, we propose an original
approach for inferring gene regulation networks using a robust biological prior
on their structure in order to limit the set of candidate networks.
Pathways, that represent biological knowledge on the regulatory networks,
will be used as an informative prior knowledge to drive Network Inference. This
approach is based on the selection of a relevant set of genes, called the
"molecular signature", associated with a condition of interest (for instance,
the genes involved in disease development). In this context, differential
expression analysis is a well established strategy. However outcome signatures
are often not consistent and show little overlap between studies. Thus, we will
dedicate the first part of our work to the improvement of the standard process
of biomarker identification to guarantee the robustness and reproducibility of
the molecular signature.
Our approach enables to compare the networks inferred between two conditions
of interest (for instance case and control networks) and help along the
biological interpretation of results. Thus it allows to identify differential
regulations that occur in these conditions. We illustrate the proposed approach
by applying our method to a study of breast cancer's response to treatment
Machine Learning and Integrative Analysis of Biomedical Big Data.
Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues
Variable selection for BART: An application to gene regulation
We consider the task of discovering gene regulatory networks, which are
defined as sets of genes and the corresponding transcription factors which
regulate their expression levels. This can be viewed as a variable selection
problem, potentially with high dimensionality. Variable selection is especially
challenging in high-dimensional settings, where it is difficult to detect
subtle individual effects and interactions between predictors. Bayesian
Additive Regression Trees [BART, Ann. Appl. Stat. 4 (2010) 266-298] provides a
novel nonparametric alternative to parametric regression approaches, such as
the lasso or stepwise regression, especially when the number of relevant
predictors is sparse relative to the total number of available predictors and
the fundamental relationships are nonlinear. We develop a principled
permutation-based inferential approach for determining when the effect of a
selected predictor is likely to be real. Going further, we adapt the BART
procedure to incorporate informed prior information about variable importance.
We present simulations demonstrating that our method compares favorably to
existing parametric and nonparametric procedures in a variety of data settings.
To demonstrate the potential of our approach in a biological context, we apply
it to the task of inferring the gene regulatory network in yeast (Saccharomyces
cerevisiae). We find that our BART-based procedure is best able to recover the
subset of covariates with the largest signal compared to other variable
selection methods. The methods developed in this work are readily available in
the R package bartMachine.Comment: Published in at http://dx.doi.org/10.1214/14-AOAS755 the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
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