NaRnEA: An Information Theoretic Framework for Gene Set Analysis

• Published in: Entropy (Basel, Switzerland) Vol. 25; no. 3; p. 542
• Main Authors: Griffin, Aaron T, Vlahos, Lukas J, Chiuzan, Codruta, Califano, Andrea
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2023; MDPI
• Subjects: Algorithms; Analysis; Biology; Empirical analysis; Enrichment; Fuzzy sets; Gene expression; gene set analysis; Genome-wide association studies; Genotype & phenotype; Heuristic methods; Information theory; Mass spectrometry; Mathematical analysis; Maximum entropy; Metabolism; Methods; Nonparametric statistics; Ontology; principle of maximum entropy; protein activity; Proteins; Ranking and selection (Statistics); regulatory networks; Set theory; Statistical significance; Tumors; United States; principle of maximum entropy; regulatory networks; nonparametric statistics; gene set analysis; protein activity
• ISSN: 1099-4300; 1099-4300
• DOI: 10.3390/e25030542

Gene sets are being increasingly leveraged to make high-level biological inferences from transcriptomic data; however, existing gene set analysis methods rely on overly conservative, heuristic approaches for quantifying the statistical significance of gene set enrichment. We created Nonparametric analytical-Rank-based Enrichment Analysis (NaRnEA) to facilitate accurate and robust gene set analysis with an optimal null model derived using the information theoretic Principle of Maximum Entropy. By measuring the differential activity of ~2500 transcriptional regulatory proteins based on the differential expression of each protein's transcriptional targets between primary tumors and normal tissue samples in three cohorts from The Cancer Genome Atlas (TCGA), we demonstrate that NaRnEA critically improves in two widely used gene set analysis methods: Gene Set Enrichment Analysis (GSEA) and analytical-Rank-based Enrichment Analysis (aREA). We show that the NaRnEA-inferred differential protein activity is significantly correlated with differential protein abundance inferred from independent, phenotype-matched mass spectrometry data in the Clinical Proteomic Tumor Analysis Consortium (CPTAC), confirming the statistical and biological accuracy of our approach. Additionally, our analysis crucially demonstrates that the sample-shuffling empirical null models leveraged by GSEA and aREA for gene set analysis are overly conservative, a shortcoming that is avoided by the newly developed Maximum Entropy analytical null model employed by NaRnEA.