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2014 ; 30
(12
): i69-77
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Robust clinical outcome prediction based on Bayesian analysis of transcriptional
profiles and prior causal networks
#MMPMID24932007
Zarringhalam K
; Enayetallah A
; Reddy P
; Ziemek D
Bioinformatics
2014[Jun]; 30
(12
): i69-77
PMID24932007
show ga
MOTIVATION: Understanding and predicting an individual's response in a clinical
trial is the key to better treatments and cost-: effective medicine. Over the
coming years, more and more large-scale omics datasets will become available to
characterize patients with complex and heterogeneous diseases at a molecular
level. Unfortunately, genetic, phenotypical and environmental variation is much
higher in a human trial population than currently modeled or measured in most
animal studies. In our experience, this high variability can lead to failure of
trained predictors in independent studies and undermines the credibility and
utility of promising high-dimensional datasets. METHODS: We propose a method that
utilizes patient-level genome-wide expression data in conjunction with causal
networks based on prior knowledge. Our approach determines a differential
expression profile for each patient and uses a Bayesian approach to infer
corresponding upstream regulators. These regulators and their corresponding
posterior probabilities of activity are used in a regularized regression
framework to predict response. RESULTS: We validated our approach using two
clinically relevant phenotypes, namely acute rejection in kidney transplantation
and response to Infliximab in ulcerative colitis. To demonstrate pitfalls in
translating trained predictors across independent trials, we analyze performance
characteristics of our approach as well as alternative feature sets in the
regression on two independent datasets for each phenotype. We show that the
proposed approach is able to successfully incorporate causal prior knowledge to
give robust performance estimates.