GROMTools: scalable individual-level GReX imputation for mega-biobank-scale cohorts

MotivationThe computational burden of individual-level genetically regulated gene expression (GReX) imputation has risen sharply with the growth of human mega-biobanks and the rapid expansion of transcriptomic imputation models across tissues and single-cell hierarchies. Existing tools were not designed for this setting and require complex, memory-intensive workflows that are poorly matched to shared and cloud-based compute environments, where runtime, memory, and I/O directly determine cost and throughput. GROMTools is an open-source C++ engine with an R interface that exploits sparse prediction weights, streams PLINK2 genotypes, and writes compact binary outputs for scalable individual-level GReX imputation. ResultsIn UK Biobank (UKBB), benchmarks on chromosome 1 across 50,000-450,000 individuals, 388,017 variants, and 11,724 gene-tissue pairs from 32 single-cell models, GROMTools produced near-identical predictions to PrediXcan and PLINK2, with minimum Pearson correlation >0.999 and maximum RMSE <0.001 across all of the imputed genes, while reducing CPU time by about 100-fold and peak memory by about 33-fold. These gains make routine biobank-scale individual-level GReX imputation practical and cost-efficient on standard CPU infrastructure. AvailabilityGROMTools is freely available at https://github.com/voloudakislab/gromtools under the GPL v3 license. Documentation available at https://voloudakislab.github.io/gromtools/. All of our coding scripts used for quality control of data and benchmarking pipelines and all of our log files are archived at DOI: https://doi.org/10.5281/zenodo.19547333.