SHAP zero Explains All-order Feature Interactions in Black-box Genomic Models with Near-zero Query Cost

With the rapid growth of black-box models in machine learning, Shapley values have emerged as a popular method for model explanations due to their theoretical guarantees. Shapley values locally explain a model to an input query using additive features. Yet, in genomics, extracting biological knowledge from black-box models hinges on explaining nonlinear feature interactions globally to hundreds to thousands of input query sequences. Herein, we develop SHAP zero, an algorithm that estimates all-order Shapley feature interactions with a near-zero cost per queried sequence after paying a one-time fee for model sketching. SHAP zero achieves this by establishing a surprisingly underexplored connection between the Shapley interactions and the Fourier transform of the model. Explaining two genomic models, one trained to predict guide RNA binding and the other to predict DNA repair outcomes, we demonstrate that SHAP zero achieves orders of magnitude reduction in amortized computational cost compared to state-of-the-art algorithms. SHAP zero reveals all microhomologous motifs that are predictive of DNA repair outcome, a finding previously inaccessible due to the combinatorial space of possible high-order feature interactions.