title: Detecting time periods of differential gene expression using Gaussian processes: an application to endothelial cells exposed to radiotherapy dose fraction.
abstract: BACKGROUND
  Identifying the set of genes differentially expressed along time is an important task in two-sample time course experiments. Furthermore, estimating at which time periods the differential expression is present can provide additional insight into temporal gene functions. The current differential detection methods are designed to detect difference along observation time intervals or on single measurement points, warranting dense measurements along time to characterize the full temporal differential expression patterns.
  
  
  RESULTS
  We propose a novel Bayesian likelihood ratio test to estimate the differential expression time periods. Applying the ratio test to systems of genes provides the temporal response timings and durations of gene expression to a biological condition. We introduce a novel non-stationary Gaussian process as the underlying expression model, with major improvements on model fitness on perturbation and stress experiments. The method is robust to uneven or sparse measurements along time. We assess the performance of the method on realistically simulated dataset and compare against state-of-the-art methods. We additionally apply the method to the analysis of primary human endothelial cells under an ionizing radiation stress to study the transcriptional perturbations over 283 measured genes in an attempt to better understand the role of endothelium in both normal and cancer tissues during radiotherapy. As a result, using the cascade of differential expression periods, domain literature and gene enrichment analysis, we gain insights into the dynamic response of endothelial cells to irradiation.
  
  
  METHODS
  R package 'nsgp' is available at www.ibisc.fr/en/logiciels_arobas.
authors.affiliation: IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France.
authors.forename: Markus
authors.initials: M
authors.lastname: Heinonen
authors.affiliation: IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Guipaud
authors.affiliation: IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Milliat
authors.affiliation: IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Buard
authors.affiliation: IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Micheau
authors.affiliation: IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Tarlet
authors.affiliation: IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
authors.affiliation: IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France.
authors.forename: Farida
authors.initials: F
authors.lastname: Zehraoui
authors.affiliation: IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France IBISC, Universite d'Évry Val d'Essonne, 23 Boulevard de France, 91025 Évry, France, AMIB, INRIA-Saclay, LRI UMR CNRS 8623, Université Paris Sud, Orsay, France, and Institut de Radioprotection et de Sûreté Nucléaire, LRTE, 92262 Fontenay-aux-roses, France.
authors.forename: Florence
authors.initials: F
authors.lastname: d'Alché-Buc
mesh_terms: D001499:Bayes Theorem; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000532:radiotherapy; D016011:Normal Distribution; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011878:Radiotherapy; D013997:Time Factors