Explainable AI for Data-Driven Design of High-Dimensional Predictive Studies
Authors: Junyu Yan, Damian Machlanski, Kurt Butler, Panagiotis Dimitrakopoulos, Ewen M Harrison, Bruce Guthrie, Sotirios A Tsaftaris
Organizations: School of Engineering, University of Edinburgh, Edinburgh, UK · Causality in Healthcare AI Hub (CHAI), UK · Advanced Care Research Centre, Usher School of Population Health Sciences, University of Edinburgh, Edinburgh, UK · Centre for Medical Informatics, Usher School of Population Health Sciences, University of Edinburgh, Edinburgh, UK
Abstract
Predictive modelling is important for health data analysis and data-driven clinical decision-making. However, predictive studies are challenging to design optimally by hand when tens or even hundreds of features require selection, transformation, or interaction modelling. While complex machine learning models offer high performance, their "black-box" nature limits the clinical trust, transparency, and interpretability required for decision-making. We developed and evaluated an Exploratory AI Recommender that provides data-driven recommendations to improve predictive performance of existing interpretable statistical models. The developed framework uses flexible AI modelling to capture complex data patterns and explainable AI techniques to translate the patterns into three recommendation types: feature exclusion, non-linear terms, and feature interactions. We evaluated the framework by comparing predictive performance of a baseline (i.e., no interactions or non-linear terms) Cox Proportional Hazards (CPH) model against an augmented CPH incorporating recommendations suggested by our method. The primary analysis predicts the time to the first occurrence of a fall or related injury in 245,614 patients. Our method recommended excluding 23 features, including non-linear terms for two features, and including 221 suggested feature interactions. The C-index improved from 0.805 (95% CI 0.798-0.812) to 0.815 (95% CI 0.809-0.822), and so did calibration (intercept: -0.006 to 0.003; slope: 1.063 to 0.950). All recommendations were supported by existing literature. The method also proved effective on two additional public datasets, demonstrating wider applicability. The proposed Exploratory AI Recommender demonstrates the potential of explainable AI and data-driven study design to improve the process of developing, and the performance of high-dimensional transparent predictive models.
Inherently interpretable classifiers for tabular data typically rely on sparse features, rules, or patterns that users can inspect directly. The marginal feature-screening step common to these methods can discard variables whose predictive value emerges only through joint configurations with other variables. We present Interaction Aware Interpretable Machine Learning (IAIML), a framework that addresses this limitation through three coordinated mechanisms: adaptive per-feature discretization, finite-grid pairwise interaction scoring, and a partitioned explanation budget. Detected interactions are routed through one of two strategies: relaxing the screening filter so that interaction-supported variables enter the pattern search, or constructing explicit pair terms for a sparse downstream classifier. On a 40-dataset panel comprising 24 real-world tabular benchmarks and 16 synthetic interaction stress tests, evaluated under nested cross-validation, IAIML achieves mean AUC within 1.4 points of tuned gradient-boosted ensembles while requiring roughly 14--28 times fewer fitted explanation components. On datasets with strong pairwise interaction structure and low marginal signal, IAIML outperforms all baselines. Among compact interpretable methods, IAIML is comparable to RuleFit in AUC and component count and is less expensive to tune. EBM obtains a small but significant AUC advantage across the full panel, with a substantially larger lookup-table footprint. Performance degrades on datasets requiring higher-order interactions beyond the pairwise scope. Component-isolated ablations confirm that adaptive discretization and interaction-aware admission each contribute incrementally. These results support IAIML as a compact, interaction-aware framework appropriate for settings where bounded explanation size and controlled treatment of feature interactions are design requirements.
We introduce Retrieval-Augmented Interpretable Learning (RAIL), a probabilistic meta-learning framework for zero-shot generation of task-specific interpretable models that synthesizes coefficient-space structure from natural-language task descriptions and a memory of previously learned task-specific predictors. RAIL retrieves related source tasks, transfers structure through coefficient space, and generates a new predictor in the original diagnostic-feature space, enabling zero-shot and few-shot clinical procedure prediction with feature-level explanations. Its probabilistic formulation provides uncertainty over retrieval, model coefficients, and predictions, supporting reliability-aware deployment: uncertain predictions or unstable explanations can be flagged for additional clinical review rather than treated as automatic decisions. This makes RAIL particularly suited for healthcare settings, where prediction tasks are highly long-tailed, new clinical targets arise frequently, and models must remain inspectable, uncertainty-aware, and compatible with human oversight. Across long-tailed clinical procedure prediction tasks, RAIL maintains reliable performance across data-availability regimes: it achieves 73.4% accuracy in the held-out zero-shot settings, where no supervised task-specific model can be trained, and remains near 73.2% accuracy in the extreme few-shot regime with only 2-4 examples, where supervised task-specific models perform close to chance. RAIL further benefits from clinically informed task representations and yields retrieval, uncertainty, and coefficient-level diagnostics that make model behavior more transparent. These results suggest a path toward scalable clinical prediction systems that can adapt to new tasks while preserving interpretability and reliability.
Predicting cancer drug response from transcriptomic profiles is a cornerstone of precision oncology, yet the scientific value of machine learning models hinges not solely on predictive accuracy, but also on their capacity to generate reliable biological insights. Current explainability approaches in this setting are computationally costly, lack robustness, and reduce complex drug response to univariate gene importance scores, overlooking the coordinated gene activity that drives sensitivity and resistance. In this work, we present ILLUME+, a scalable post-hoc explainability framework that moves beyond single-gene assessments to capture multiple, complementary forms of explanation. Integrated into our end-to-end pipeline, ILLUME+ produces more stable gene importance scores than existing baselines, recovers established drug-gene associations and mechanisms of action, and enables AI-assisted hypothesis generation to uncover novel interaction-driven molecular signals in cancer biology.