I-SAFE: Wasserstein Coherence Metrics for Structural Auditing of Scientific AI Models

Deep learning models are increasingly used in scientific prediction tasks where strong benchmark performance is often interpreted as evidence of scientifically meaningful behavior. This interpretation is fragile, as models may exploit shortcut features, dataset-specific regularities, or distributional biases that are predictive on held-out data but not aligned with domain-relevant structure. To address this limitation, we introduce the \textsc{I-SAFE} (Interventional Secure, Accurate, Fair and Explainable) framework, a post-hoc distributional auditing framework for scientific AI models centered on the Wasserstein Coherence Metric (WCM). Given a trained black-box predictor and an external structural prior encoding domain knowledge about task-relevant input structure, \textsc{I-SAFE} evaluates raw model outputs under structurally guided perturbations of the input. The proposed audit measures output-distribution coherence through three complementary metrics: a Quantile-Based Metric (QBM) for location-level coherence, the WCM for ordinal coherence, and a translation-invariant WCM variant for shape coherence. We instantiate \textsc{I-SAFE} on drug--target interaction (DTI) prediction using the Davis kinase benchmark, KLIFS (Kinase--Ligand Interaction Fingerprints and Structures) binding-pocket annotations, and three sequence-based DTI models: DeepConvDTI, DeepDTA, and TAPB. Although the models operate in a comparable predictive regime, \textsc{I-SAFE} reveals substantially different distributional response profiles, a distinction invisible to accuracy-based evaluation. The framework is model-agnostic and applicable to any domain where inputs admit a structured decomposition and an external prior is available.

ISAAC: Auditing Causal Reasoning in Deep Models for Drug-Target Interaction

Deep learning models for drug--target interaction (DTI) prediction often achieve strong benchmark performance without necessarily relying on mechanistically meaningful molecular features, a limitation that standard accuracy-based evaluation cannot detect. We introduce ISAAC (Intervention-based Structural Auditing Approach for Causal Reasoning), a post-hoc framework that evaluates prior-relative structural sensitivity by probing frozen models through matched mechanistic and spurious input-level interventions, independently of predictive accuracy. Applied to three sequence-based DTI architectures on the Davis benchmark, ISAAC reveals approximately 25\% relative differences in reasoning scores across models with comparable AUROC (within around 3\%), stable across training and intervention seeds and two distinct perturbation operators. These discrepancies, undetectable under conventional accuracy metrics, motivate the use of post-hoc structural auditing as a complement to standard performance evaluation in scientific machine learning for molecular modeling.