Perturbation Detection Through Modeling of Gene Expression on a Latent Biological Pathway Network: A Bayesian Hierarchical Approach

• 成果类型: Article
• 署名作者: Pham, Lisa M.; Carvalho, Luis; Schaus, Scott; Kolaczyk, Eric D.
• 署名单位: Boston University; Boston University
• 刊物名称: JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION
• ISSN/ISSBN: 0162-1459
• DOI: 10.1080/01621459.2015.1110523
• 发表日期: 2016
• 页码: 73-92
• 关键词: cell-cycle; p53; apoptosis; target; dna; doxorubicin; inhibitors; identification; accumulation; geldanamycin

摘要

Cellular response to a perturbation is the result of a dynamic system of biological variables linked in a complex network. A major challenge in drug and disease studies is identifying the key factors of a biological network that are essential in determining the cell's fate. Here, our goal is the identification of perturbed pathways from high-throughput gene expression data. We develop a three-level hierarchical model, where (i) the first level captures the relationship between gene expression and biological pathways using confirmatory factor analysis, (ii) the second level models the behavior within an underlying network of pathways induced by an unknown perturbation using a conditional autoregressive model, and (iii) the third level is a spike-and-slab prior on the perturbations. We then identify perturbations through posterior-based variable selection. We illustrate our approach using gene transcription drug perturbation profiles from the DREAM7 drug sensitivity predication challenge dataset. Our proposed method identified regulatory pathways that are known to play a causative role and that were not readily resolved using gene set enrichment analysis or exploratory factor models. Simulation results are presented assessing the performance of this model relative to a network-free variant and its robustness to inaccuracies in biological databases. Supplementary materials for this article are available online.