53,090 research outputs found
TREEOME: A framework for epigenetic and transcriptomic data integration to explore regulatory interactions controlling transcription
Motivation: Predictive modelling of gene expression is a powerful framework
for the in silico exploration of transcriptional regulatory interactions
through the integration of high-throughput -omics data. A major limitation of
previous approaches is their inability to handle conditional and synergistic
interactions that emerge when collectively analysing genes subject to different
regulatory mechanisms. This limitation reduces overall predictive power and
thus the reliability of downstream biological inference.
Results: We introduce an analytical modelling framework (TREEOME: tree of
models of expression) that integrates epigenetic and transcriptomic data by
separating genes into putative regulatory classes. Current predictive modelling
approaches have found both DNA methylation and histone modification epigenetic
data to provide little or no improvement in accuracy of prediction of
transcript abundance despite, for example, distinct anti-correlation between
mRNA levels and promoter-localised DNA methylation. To improve on this, in
TREEOME we evaluate four possible methods of formulating gene-level DNA
methylation metrics, which provide a foundation for identifying gene-level
methylation events and subsequent differential analysis, whereas most previous
techniques operate at the level of individual CpG dinucleotides. We demonstrate
TREEOME by integrating gene-level DNA methylation (bisulfite-seq) and histone
modification (ChIP-seq) data to accurately predict genome-wide mRNA transcript
abundance (RNA-seq) for H1-hESC and GM12878 cell lines.
Availability: TREEOME is implemented using open-source software and made
available as a pre-configured bootable reference environment. All scripts and
data presented in this study are available online at
http://sourceforge.net/projects/budden2015treeome/.Comment: 14 pages, 6 figure
Refining interaction search through signed iterative Random Forests
Advances in supervised learning have enabled accurate prediction in
biological systems governed by complex interactions among biomolecules.
However, state-of-the-art predictive algorithms are typically black-boxes,
learning statistical interactions that are difficult to translate into testable
hypotheses. The iterative Random Forest algorithm took a step towards bridging
this gap by providing a computationally tractable procedure to identify the
stable, high-order feature interactions that drive the predictive accuracy of
Random Forests (RF). Here we refine the interactions identified by iRF to
explicitly map responses as a function of interacting features. Our method,
signed iRF, describes subsets of rules that frequently occur on RF decision
paths. We refer to these rule subsets as signed interactions. Signed
interactions share not only the same set of interacting features but also
exhibit similar thresholding behavior, and thus describe a consistent
functional relationship between interacting features and responses. We describe
stable and predictive importance metrics to rank signed interactions. For each
SPIM, we define null importance metrics that characterize its expected behavior
under known structure. We evaluate our proposed approach in biologically
inspired simulations and two case studies: predicting enhancer activity and
spatial gene expression patterns. In the case of enhancer activity, s-iRF
recovers one of the few experimentally validated high-order interactions and
suggests novel enhancer elements where this interaction may be active. In the
case of spatial gene expression patterns, s-iRF recovers all 11 reported links
in the gap gene network. By refining the process of interaction recovery, our
approach has the potential to guide mechanistic inquiry into systems whose
scale and complexity is beyond human comprehension
Iterative Random Forests to detect predictive and stable high-order interactions
Genomics has revolutionized biology, enabling the interrogation of whole
transcriptomes, genome-wide binding sites for proteins, and many other
molecular processes. However, individual genomic assays measure elements that
interact in vivo as components of larger molecular machines. Understanding how
these high-order interactions drive gene expression presents a substantial
statistical challenge. Building on Random Forests (RF), Random Intersection
Trees (RITs), and through extensive, biologically inspired simulations, we
developed the iterative Random Forest algorithm (iRF). iRF trains a
feature-weighted ensemble of decision trees to detect stable, high-order
interactions with same order of computational cost as RF. We demonstrate the
utility of iRF for high-order interaction discovery in two prediction problems:
enhancer activity in the early Drosophila embryo and alternative splicing of
primary transcripts in human derived cell lines. In Drosophila, among the 20
pairwise transcription factor interactions iRF identifies as stable (returned
in more than half of bootstrap replicates), 80% have been previously reported
as physical interactions. Moreover, novel third-order interactions, e.g.
between Zelda (Zld), Giant (Gt), and Twist (Twi), suggest high-order
relationships that are candidates for follow-up experiments. In human-derived
cells, iRF re-discovered a central role of H3K36me3 in chromatin-mediated
splicing regulation, and identified novel 5th and 6th order interactions,
indicative of multi-valent nucleosomes with specific roles in splicing
regulation. By decoupling the order of interactions from the computational cost
of identification, iRF opens new avenues of inquiry into the molecular
mechanisms underlying genome biology
Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways.
The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy
Bayesian Gene Set Analysis
Gene expression microarray technologies provide the simultaneous measurements
of a large number of genes. Typical analyses of such data focus on the
individual genes, but recent work has demonstrated that evaluating changes in
expression across predefined sets of genes often increases statistical power
and produces more robust results. We introduce a new methodology for
identifying gene sets that are differentially expressed under varying
experimental conditions. Our approach uses a hierarchical Bayesian framework
where a hyperparameter measures the significance of each gene set. Using
simulated data, we compare our proposed method to alternative approaches, such
as Gene Set Enrichment Analysis (GSEA) and Gene Set Analysis (GSA). Our
approach provides the best overall performance. We also discuss the application
of our method to experimental data based on p53 mutation status
On testing the significance of sets of genes
This paper discusses the problem of identifying differentially expressed
groups of genes from a microarray experiment. The groups of genes are
externally defined, for example, sets of gene pathways derived from biological
databases. Our starting point is the interesting Gene Set Enrichment Analysis
(GSEA) procedure of Subramanian et al. [Proc. Natl. Acad. Sci. USA 102 (2005)
15545--15550]. We study the problem in some generality and propose two
potential improvements to GSEA: the maxmean statistic for summarizing
gene-sets, and restandardization for more accurate inferences. We discuss a
variety of examples and extensions, including the use of gene-set scores for
class predictions. We also describe a new R language package GSA that
implements our ideas.Comment: Published at http://dx.doi.org/10.1214/07-AOAS101 in the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
A Multi-Gene Genetic Programming Application for Predicting Students Failure at School
Several efforts to predict student failure rate (SFR) at school accurately
still remains a core problem area faced by many in the educational sector. The
procedure for forecasting SFR are rigid and most often times require data
scaling or conversion into binary form such as is the case of the logistic
model which may lead to lose of information and effect size attenuation. Also,
the high number of factors, incomplete and unbalanced dataset, and black boxing
issues as in Artificial Neural Networks and Fuzzy logic systems exposes the
need for more efficient tools. Currently the application of Genetic Programming
(GP) holds great promises and has produced tremendous positive results in
different sectors. In this regard, this study developed GPSFARPS, a software
application to provide a robust solution to the prediction of SFR using an
evolutionary algorithm known as multi-gene genetic programming. The approach is
validated by feeding a testing data set to the evolved GP models. Result
obtained from GPSFARPS simulations show its unique ability to evolve a suitable
failure rate expression with a fast convergence at 30 generations from a
maximum specified generation of 500. The multi-gene system was also able to
minimize the evolved model expression and accurately predict student failure
rate using a subset of the original expressionComment: 14 pages, 9 figures, Journal paper. arXiv admin note: text overlap
with arXiv:1403.0623 by other author
Network-based stratification of tumor mutations.
Many forms of cancer have multiple subtypes with different causes and clinical outcomes. Somatic tumor genome sequences provide a rich new source of data for uncovering these subtypes but have proven difficult to compare, as two tumors rarely share the same mutations. Here we introduce network-based stratification (NBS), a method to integrate somatic tumor genomes with gene networks. This approach allows for stratification of cancer into informative subtypes by clustering together patients with mutations in similar network regions. We demonstrate NBS in ovarian, uterine and lung cancer cohorts from The Cancer Genome Atlas. For each tissue, NBS identifies subtypes that are predictive of clinical outcomes such as patient survival, response to therapy or tumor histology. We identify network regions characteristic of each subtype and show how mutation-derived subtypes can be used to train an mRNA expression signature, which provides similar information in the absence of DNA sequence
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