Pharmacology
Direction instability (DI) quantifies the directional consistency of a perturbation’s effects across biological contexts (DI = 1 − mean pairwise cosine similarity). DI is immune to the first-order magnitude confound that dominates Grassmannian geodesic distance, profile variability, and optimal transport cost.
Direction Instability Predicts Cross-Cell-Line Drug Mechanism Transport
Direction Instability Predicts Cross-Cell-Line Drug Mechanism Transport in LINCS L1000
Zenodo 10.5281/zenodo.21213699
Applied to 8,949 LINCS L1000 drugs, DI predicts cross-cell-line mechanism transport with pre-registered, construction-neutral AUROC = 0.945, and is independently validated through Jaccard overlap of perturbed gene sets (AUROC = 0.957), breadth of target gene expression across tissues (ρ = −0.17, p < 0.001), and PRISM cell-viability correlation (ρ = 0.261, p < 0.001).
A Pre-Registered Direction Instability Atlas
A Pre-Registered Direction Instability Atlas Across Three Perturbation Modalities
Zenodo 10.5281/zenodo.21223667
Extends direction instability across three measurement technologies — L1000 transcriptomics, Tahoe-100M single-cell expression, and JUMP Cell Painting morphology — covering ~55,000 drugs and genetic perturbations. Eleven pre-registered hypothesis tests (frozen at commit SHAs 0d07a01, a17c125, 4c34699) reveal that DI is structured by pharmacological mechanism of action (η² = 0.20), concordant across modalities (partial ρ = 0.19), and suppressed by functional constraint (essentiality sign-flip, partial ρ = −0.332). Eight of eleven tests fail their pre-registered criteria, delimiting what the metric captures.