36,660 research outputs found
The Inferred Cardiogenic Gene Regulatory Network in the Mammalian Heart
Cardiac development is a complex, multiscale process encompassing cell fate adoption, differentiation and morphogenesis. To elucidate pathways underlying this process, a recently developed algorithm to reverse engineer gene regulatory networks was applied to time-course microarray data obtained from the developing mouse heart. Approximately 200 genes of interest were input into the algorithm to generate putative network topologies that are capable of explaining the experimental data via model simulation. To cull specious network interactions, thousands of putative networks are merged and filtered to generate scale-free, hierarchical networks that are statistically significant and biologically relevant. The networks are validated with known gene interactions and used to predict regulatory pathways important for the developing mammalian heart. Area under the precision-recall curve and receiver operator characteristic curve are 9% and 58%, respectively. Of the top 10 ranked predicted interactions, 4 have already been validated. The algorithm is further tested using a network enriched with known interactions and another depleted of them. The inferred networks contained more interactions for the enriched network versus the depleted network. In all test cases, maximum performance of the algorithm was achieved when the purely data-driven method of network inference was combined with a data-independent, functional-based association method. Lastly, the network generated from the list of approximately 200 genes of interest was expanded using gene-profile uniqueness metrics to include approximately 900 additional known mouse genes and to form the most likely cardiogenic gene regulatory network. The resultant network supports known regulatory interactions and contains several novel cardiogenic regulatory interactions. The method outlined herein provides an informative approach to network inference and leads to clear testable hypotheses related to gene regulation
Analysis of a data matrix and a graph: Metagenomic data and the phylogenetic tree
In biological experiments researchers often have information in the form of a
graph that supplements observed numerical data. Incorporating the knowledge
contained in these graphs into an analysis of the numerical data is an
important and nontrivial task. We look at the example of metagenomic
data---data from a genomic survey of the abundance of different species of
bacteria in a sample. Here, the graph of interest is a phylogenetic tree
depicting the interspecies relationships among the bacteria species. We
illustrate that analysis of the data in a nonstandard inner-product space
effectively uses this additional graphical information and produces more
meaningful results.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS402 the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
Elucidation of Directionality for Co-Expressed Genes: Predicting Intra-Operon Termination Sites
We present a novel framework for inferring regulatory and sequence-level
information from gene co-expression networks. The key idea of our methodology
is the systematic integration of network inference and network topological
analysis approaches for uncovering biological insights. We determine the gene
co-expression network of Bacillus subtilis using Affymetrix GeneChip time
series data and show how the inferred network topology can be linked to
sequence-level information hard-wired in the organism's genome. We propose a
systematic way for determining the correlation threshold at which two genes are
assessed to be co-expressed by using the clustering coefficient and we expand
the scope of the gene co-expression network by proposing the slope ratio metric
as a means for incorporating directionality on the edges. We show through
specific examples for B. subtilis that by incorporating expression level
information in addition to the temporal expression patterns, we can uncover
sequence-level biological insights. In particular, we are able to identify a
number of cases where (i) the co-expressed genes are part of a single
transcriptional unit or operon and (ii) the inferred directionality arises due
to the presence of intra-operon transcription termination sites.Comment: 7 pages, 8 figures, accepted in Bioinformatic
A kernel-based framework for learning graded relations from data
Driven by a large number of potential applications in areas like
bioinformatics, information retrieval and social network analysis, the problem
setting of inferring relations between pairs of data objects has recently been
investigated quite intensively in the machine learning community. To this end,
current approaches typically consider datasets containing crisp relations, so
that standard classification methods can be adopted. However, relations between
objects like similarities and preferences are often expressed in a graded
manner in real-world applications. A general kernel-based framework for
learning relations from data is introduced here. It extends existing approaches
because both crisp and graded relations are considered, and it unifies existing
approaches because different types of graded relations can be modeled,
including symmetric and reciprocal relations. This framework establishes
important links between recent developments in fuzzy set theory and machine
learning. Its usefulness is demonstrated through various experiments on
synthetic and real-world data.Comment: This work has been submitted to the IEEE for possible publication.
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A multi-species functional embedding integrating sequence and network structure
A key challenge to transferring knowledge between species is that different species have fundamentally different genetic architectures. Initial computational approaches to transfer knowledge across species have relied on measures of heredity such as genetic homology, but these approaches suffer from limitations. First, only a small subset of genes have homologs, limiting the amount of knowledge that can be transferred, and second, genes change or repurpose functions, complicating the transfer of knowledge. Many approaches address this problem by expanding the notion of homology by leveraging high-throughput genomic and proteomic measurements, such as through network alignment. In this work, we take a new approach to transferring knowledge across species by expanding the notion of homology through explicit measures of functional similarity between proteins in different species. Specifically, our kernel-based method, HANDL (Homology Assessment across Networks using Diffusion and Landmarks), integrates sequence and network structure to create a functional embedding in which proteins from different species are embedded in the same vector space. We show that inner products in this space and the vectors themselves capture functional similarity across species, and are useful for a variety of functional tasks. We perform the first whole-genome method for predicting phenologs, generating many that were previously identified, but also predicting new phenologs supported from the biological literature. We also demonstrate the HANDL embedding captures pairwise gene function, in that gene pairs with synthetic lethal interactions are significantly separated in HANDL space, and the direction of separation is conserved across species. Software for the HANDL algorithm is available at http://bit.ly/lrgr-handl.Published versio
Metric learning pairwise kernel for graph inference
Much recent work in bioinformatics has focused on the inference of various
types of biological networks, representing gene regulation, metabolic
processes, protein-protein interactions, etc. A common setting involves
inferring network edges in a supervised fashion from a set of high-confidence
edges, possibly characterized by multiple, heterogeneous data sets (protein
sequence, gene expression, etc.). Here, we distinguish between two modes of
inference in this setting: direct inference based upon similarities between
nodes joined by an edge, and indirect inference based upon similarities between
one pair of nodes and another pair of nodes. We propose a supervised approach
for the direct case by translating it into a distance metric learning problem.
A relaxation of the resulting convex optimization problem leads to the support
vector machine (SVM) algorithm with a particular kernel for pairs, which we
call the metric learning pairwise kernel (MLPK). We demonstrate, using several
real biological networks, that this direct approach often improves upon the
state-of-the-art SVM for indirect inference with the tensor product pairwise
kernel
A framework for list representation, enabling list stabilization through incorporation of gene exchangeabilities
Analysis of multivariate data sets from e.g. microarray studies frequently
results in lists of genes which are associated with some response of interest.
The biological interpretation is often complicated by the statistical
instability of the obtained gene lists with respect to sampling variations,
which may partly be due to the functional redundancy among genes, implying that
multiple genes can play exchangeable roles in the cell. In this paper we use
the concept of exchangeability of random variables to model this functional
redundancy and thereby account for the instability attributable to sampling
variations. We present a flexible framework to incorporate the exchangeability
into the representation of lists. The proposed framework supports
straightforward robust comparison between any two lists. It can also be used to
generate new, more stable gene rankings incorporating more information from the
experimental data. Using a microarray data set from lung cancer patients we
show that the proposed method provides more robust gene rankings than existing
methods with respect to sampling variations, without compromising the
biological significance
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