24,458 research outputs found
Causal graphical models in systems genetics: A unified framework for joint inference of causal network and genetic architecture for correlated phenotypes
Causal inference approaches in systems genetics exploit quantitative trait
loci (QTL) genotypes to infer causal relationships among phenotypes. The
genetic architecture of each phenotype may be complex, and poorly estimated
genetic architectures may compromise the inference of causal relationships
among phenotypes. Existing methods assume QTLs are known or inferred without
regard to the phenotype network structure. In this paper we develop a
QTL-driven phenotype network method (QTLnet) to jointly infer a causal
phenotype network and associated genetic architecture for sets of correlated
phenotypes. Randomization of alleles during meiosis and the unidirectional
influence of genotype on phenotype allow the inference of QTLs causal to
phenotypes. Causal relationships among phenotypes can be inferred using these
QTL nodes, enabling us to distinguish among phenotype networks that would
otherwise be distribution equivalent. We jointly model phenotypes and QTLs
using homogeneous conditional Gaussian regression models, and we derive a
graphical criterion for distribution equivalence. We validate the QTLnet
approach in a simulation study. Finally, we illustrate with simulated data and
a real example how QTLnet can be used to infer both direct and indirect effects
of QTLs and phenotypes that co-map to a genomic region.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS288 the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
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
Bayesian Sparse Factor Analysis of Genetic Covariance Matrices
Quantitative genetic studies that model complex, multivariate phenotypes are
important for both evolutionary prediction and artificial selection. For
example, changes in gene expression can provide insight into developmental and
physiological mechanisms that link genotype and phenotype. However, classical
analytical techniques are poorly suited to quantitative genetic studies of gene
expression where the number of traits assayed per individual can reach many
thousand. Here, we derive a Bayesian genetic sparse factor model for estimating
the genetic covariance matrix (G-matrix) of high-dimensional traits, such as
gene expression, in a mixed effects model. The key idea of our model is that we
need only consider G-matrices that are biologically plausible. An organism's
entire phenotype is the result of processes that are modular and have limited
complexity. This implies that the G-matrix will be highly structured. In
particular, we assume that a limited number of intermediate traits (or factors,
e.g., variations in development or physiology) control the variation in the
high-dimensional phenotype, and that each of these intermediate traits is
sparse -- affecting only a few observed traits. The advantages of this approach
are two-fold. First, sparse factors are interpretable and provide biological
insight into mechanisms underlying the genetic architecture. Second, enforcing
sparsity helps prevent sampling errors from swamping out the true signal in
high-dimensional data. We demonstrate the advantages of our model on simulated
data and in an analysis of a published Drosophila melanogaster gene expression
data set.Comment: 35 pages, 7 figure
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
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