Reference construction belongs inside each population holdout
For multiomics gene discovery across diverse populations, rebuilding the cell-state reference within every training fold is essential. If integration parameters, variable genes, or state labels are learned once from the full dataset, the held-out population has already influenced the annotation space.
I would compare population holdout with separate recruitment-site and assay-chemistry holdouts, then report state-level calibration, rejection, and unmapped-cell rates. Gene-state associations should also be checked within cohorts. A failure confined to population holdout may indicate limited reference coverage, while similar failures across site or chemistry holdouts would weaken that interpretation.