DIGEST

DIGEST validates candidate disease mechanisms, gene sets, clusterings, and subnetworks in silico to support mechanistically grounded drug repurposing by assessing functional and genetic coherence.

Key Features:

• Validation Framework: Automates validation of candidate disease mechanisms and gene sets by integrating identifier mapping, enrichment analysis, comparison of shared elements, and background estimation.
• Statistical Significance Assessment: Computes empirical P-values to quantify the plausibility of predicted mechanisms and assess functional and genetic coherence.
• Disease and Gene ID Mapping: Converts diverse disease and gene identifiers into standardized formats for consistent downstream analysis.
• Enrichment Analysis: Identifies statistically significant over-representations of genes or diseases within input datasets.
• Comparison of Shared Genes and Variants: Analyzes common genes and genetic variants between gene sets or disease clusters to infer potential mechanistic links.
• Background Distribution Estimation: Estimates baseline distributions to contextualize observed patterns and support significance testing.
• Automatic Database Updates: Updates external reference databases used in analyses to maintain current input data for validations.

Scientific Applications:

• Drug repurposing validation: Provides in silico evidence to support mechanistic links between diseases and existing drugs.
• Prioritization of candidate mechanisms: Ranks predicted mechanisms for follow-up experimental validation based on statistical coherence and overlap metrics.

Methodology:

DIGEST performs disease and gene ID mapping, enrichment analysis to detect over-represented terms, comparison of shared genes and variants between sets or clusters, estimation of background distributions, and computation of empirical P-values to assess functional and genetic coherence.