Direction Instability Predicts Cross-Cell-Line Drug Mechanism Transport
Direction Instability Predicts Cross-Cell-Line Drug Mechanism Transport in LINCS L1000
Direction instability (DI) quantifies the directional consistency of a perturbation’s effects across cellular 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. 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
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 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.
Construct Validity for Geometric Perturbation Scores
Construct Validity for Geometric Perturbation Scores: When Does a Number License a Mechanistic Claim?
Tests the validity conditions for direction instability as a mechanistic metric across LINCS L1000 transcriptomics, Perturb-seq genetic perturbation, and JUMP Cell Painting morphology. Establishes when geometric perturbation scores license mechanistic claims and when they do not — a practitioner guide for interpreting DI values in drug discovery pipelines.