Kinship Decouple and Phenotype Selection (KDPS): a tool for phenotype-aware decoupling of related subjects.

Relatedness within genomic cohorts is a potential source of bias for many genetic analyses. Existing tools to break relatedness are phenotype-naïve; they indiscriminately remove subjects to break relationship, risking the loss of valuable data, especially in studies targeting uncommon and rare phenotypes. To address this limitation, we developed the Kinship Decouple and Phenotype Selection (KDPS) tool, with a novel algorithm designed to enhance the precision of subject selection in genetic and epidemiological research by incorporating phenotype prioritization. KDPS separates related individuals by considering relatedness (kinship or identity by descent) scores and allows prioritizing subjects based on phenotypes of interest. This approach enables the retention of valuable subjects for analysis, even in the face of necessary exclusions due to relatedness. Furthermore, KDPS accommodates a wide range of phenotypes, including quantitative and categorical, and allows for customization to either prioritize specific phenotypes or maximization of sample size. In simulations based on the UK Biobank dataset and real-world datasets, KDPS demonstrated significant improvements in retention of subjects with prioritized phenotypes and computational efficiency compared to previously published software. The ability of this method to process biobank-scale studies within practical timeframes marks the ability of this method to process biobank-scale studies within practical timeframes and marks a considerable advancement over existing techniques. KDPS offers tailored solutions for complex analytical challenges and broad applicability in genetics and epidemiology research. To our knowledge, KDPS is the first tool to perform phenotype-aware decoupling, paving the way for more powerful genetic and epidemiological analyses.