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2016 ; 17
(1
): 318
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Interpreting transcriptional changes using causal graphs: new methods and their
practical utility on public networks
#MMPMID27553489
Fakhry CT
; Choudhary P
; Gutteridge A
; Sidders B
; Chen P
; Ziemek D
; Zarringhalam K
BMC Bioinformatics
2016[Aug]; 17
(1
): 318
PMID27553489
show ga
BACKGROUND: Inference of active regulatory cascades under specific molecular and
environmental perturbations is a recurring task in transcriptional data analysis.
Commercial tools based on large, manually curated networks of causal
relationships offering such functionality have been used in thousands of articles
in the biomedical literature. The adoption and extension of such methods in the
academic community has been hampered by the lack of freely available, efficient
algorithms and an accompanying demonstration of their applicability using current
public networks. RESULTS: In this article, we propose a new statistical method
that will infer likely upstream regulators based on observed patterns of up- and
down-regulated transcripts. The method is suitable for use with public
interaction networks with a mix of signed and unsigned causal edges. It subsumes
and extends two previously published approaches and we provide a novel
algorithmic method for efficient statistical inference. Notably, we demonstrate
the feasibility of using the approach to generate biological insights given
current public networks in the context of controlled in-vitro overexpression
experiments, stem-cell differentiation data and animal disease models. We also
provide an efficient implementation of our method in the R package QuaternaryProd
available to download from Bioconductor. CONCLUSIONS: In this work, we have
closed an important gap in utilizing causal networks to analyze differentially
expressed genes. Our proposed Quaternary test statistic incorporates all
available evidence on the potential relevance of an upstream regulator. The new
approach broadens the use of these types of statistics for highly curated signed
networks in which ambiguities arise but also enables the use of networks with
unsigned edges. We design and implement a novel computational method that can
efficiently estimate p-values for upstream regulators in current biological
settings. We demonstrate the ready applicability of the implemented method to
analyze differentially expressed genes using the publicly available networks.