Redundancy-aware unsupervised ranking based on game theory -- application to gene enrichment analysis

TL;DR

This paper introduces a redundancy-aware, unsupervised ranking method for gene set collections using game theory, specifically Shapley values, to improve interpretability and reduce redundancy in gene enrichment analysis.

Contribution

It proposes a novel game-theoretic ranking approach that accounts for redundancy among gene sets, enhancing interpretability without increasing false positives.

Findings

Low redundancy in ranked gene sets

High coverage of genes in top-ranked sets

Effective reduction of gene set collection complexity

Abstract

Gene set collections are a common ground to study the enrichment of genes for specific phenotypic traits. Gene set enrichment analysis aims to identify genes that are over-represented in gene sets collections and might be associated with a specific phenotypic trait. However, as this involves a massive number of hypothesis testing, it is often questionable whether a pre-processing step to reduce gene sets collections' sizes is helpful. Moreover, the often highly overlapping gene sets and the consequent low interpretability of gene sets' collections demand for a reduction of the included gene sets. Inspired by this bioinformatics context, we propose a method to rank sets within a family of sets based on the distribution of the singletons and their size. We obtain sets' importance scores by computing Shapley values without incurring into the usual exponential number of evaluations of the value function. Moreover, we address the challenge of including a redundancy awareness in the rankings obtained where, in our case, sets are redundant if they show prominent intersections. We finally evaluate our approach for gene sets collections; the rankings obtained show low redundancy and high coverage of the genes. The unsupervised nature of the proposed ranking does not allow for an evident increase in the number of significant gene sets for specific phenotypic traits when reducing the size of the collections. However, we believe that the rankings proposed are of use in bioinformatics to increase interpretability of the gene sets collections and a step forward to include redundancy into Shapley values computations.