Abstract High-throughput omics technologies have revolutionised the identification of associations between individual traits and underlying biological characteristics, but still use ‘one effect-size fits all’ approaches. While covariates are often used, their potential as effect modifiers often remains unexplored. To bridge this gap, we introduce ESPClust, a novel unsupervised method designed to identify covariates that modify the effect size of associations between sets of omics variables and outcomes. By extending the concept of moderators to encompass multiple exposures, ESPClust analyses the effect size profile (ESP) to identify regions in covariate space with different ESP, enabling the discovery of subpopulations with distinct associations. Applying ESPClust to insulin resistance and COVID-19 symptom manifestation, we demonstrate its versatility and ability to uncover nuanced effect size modifications that traditional analyses may overlook. By integrating information from multiple exposures, ESPClust identifies effect size modifiers in datasets that are too small for traditional univariate stratified analyses. This method provides a robust framework for understanding complex omics data and holds promise for personalised medicine.

ESPClust: Unsupervised identification of modifiers for the effect size profile in omics association studies