J Bioinform Comput Biol. 2026 Jun;24(3):2671003. doi: 10.1142/S0219720026710034. Epub 2026 Jun 12.
ABSTRACT
Some post-GWAS analysis software can run to completion without reporting an error while producing results that are not biologically valid. We call this failure false locality: a result appears to be local to a gene or protein because it was produced from a regional window, but the window or its metadata points to the wrong genomic address. We identify three mechanisms. First, a genome-build address mismatch occurs when GRCh38 protein-QTL coordinates are used with GRCh37 outcome files; in our 91-sentinel audit, 66 coordinates moved by more than 100[Formula: see text]kb and 54 moved by more than 200[Formula: see text]kb after remapping. Second, non-specific regional noise occurs when significant P values persist after the analysis window is deliberately moved to a zero-overlap variant set. Third, location-label blindness occurs when software returns the same output after the declared coordinate label is changed while the SNP table is unchanged; in an official SMR/HEIDI CXCL10 test, the top SNP, SMR P value, and HEIDI P value remained identical across correct, wrong, and shifted labels. We propose a simple Change Test: a result should not be treated as local evidence unless the numerical output changes, weakens, or disappears when the analysis window or coordinate label is intentionally moved to a biologically wrong location. This standard turns software execution from a passive success signal into an explicit spatial-specificity check.
PMID:42324819 | DOI:10.1142/S0219720026710034
