PHARAOH-multi

PHARAOH-multi performs pathway-based multivariate statistical analysis of collapsed rare variants from next-generation sequencing to detect associations between multiple phenotypes and biological pathways and address missing heritability.

Key Features:

• Pathway-Based Analysis: Utilizes pathway information to test associations between biological pathways and multiple phenotypes using rare variants from next-generation sequencing.
• Hierarchical Structure: Incorporates hierarchical structures of collapsed rare variants to model pathway relationships and biological hierarchies.
• Multivariate Approach: Implements multivariate statistical analysis across correlated phenotypes, demonstrated to have advantages in simulation studies.
• Unified Model: Integrates multiple pathways within a single statistical model to jointly assess pathway-level effects.

Scientific Applications:

• Type 2 diabetes-related traits: Applied to six type 2 diabetes-related traits using large-scale whole exome sequencing data to identify pathways not detected by univariate analyses.
• Metabolic disorder risk factors: Investigates pathway associations with metabolic disorder risk factors driven by rare variants.
• Multivariate genetic studies: Suited for multivariate genetic analyses that require pathway-level integration of rare variant signals across correlated phenotypes.

Methodology:

Performs hierarchical collapsing of rare variants and multivariate statistical analysis integrating multiple phenotypes with pathway annotations; employs a unified model that jointly models multiple pathways; validated by simulation studies and applied to large-scale whole exome sequencing data of six type 2 diabetes-related traits.