Causal network inference from gene transcriptional time-series response to glucocorticoids.

Journal Article (Journal Article)

Gene regulatory network inference is essential to uncover complex relationships among gene pathways and inform downstream experiments, ultimately enabling regulatory network re-engineering. Network inference from transcriptional time-series data requires accurate, interpretable, and efficient determination of causal relationships among thousands of genes. Here, we develop Bootstrap Elastic net regression from Time Series (BETS), a statistical framework based on Granger causality for the recovery of a directed gene network from transcriptional time-series data. BETS uses elastic net regression and stability selection from bootstrapped samples to infer causal relationships among genes. BETS is highly parallelized, enabling efficient analysis of large transcriptional data sets. We show competitive accuracy on a community benchmark, the DREAM4 100-gene network inference challenge, where BETS is one of the fastest among methods of similar performance and additionally infers whether causal effects are activating or inhibitory. We apply BETS to transcriptional time-series data of differentially-expressed genes from A549 cells exposed to glucocorticoids over a period of 12 hours. We identify a network of 2768 genes and 31,945 directed edges (FDR ≤ 0.2). We validate inferred causal network edges using two external data sources: Overexpression experiments on the same glucocorticoid system, and genetic variants associated with inferred edges in primary lung tissue in the Genotype-Tissue Expression (GTEx) v6 project. BETS is available as an open source software package at https://github.com/lujonathanh/BETS.

Full Text

Duke Authors

Cited Authors

  • Lu, J; Dumitrascu, B; McDowell, IC; Jo, B; Barrera, A; Hong, LK; Leichter, SM; Reddy, TE; Engelhardt, BE

Published Date

  • January 2021

Published In

Volume / Issue

  • 17 / 1

Start / End Page

  • e1008223 -

PubMed ID

  • 33513136

Pubmed Central ID

  • PMC7875426

Electronic International Standard Serial Number (EISSN)

  • 1553-7358

Digital Object Identifier (DOI)

  • 10.1371/journal.pcbi.1008223

Language

  • eng

Conference Location

  • United States