Kernelized Stein Discrepancies for Biological Sequences

Generative models of biological sequences are a powerful tool for learning from complex sequence data, predicting the effects of mutations, and designing novel biomolecules with desired properties. The problem of measuring differences between high-dimensional distributions is central to the successful construction and use of generative probabilistic models. In this paper we propose the KSD-B, a novel divergence measure for distributions over biological sequences that is based on the kernelized Stein discrepancy (KSD). As for all KSDs, the KSD-B between a model and dataset can be evaluated even when the normalizing constant of the model is unknown; unlike any previous KSD, the KSD-B can be applied to arbitrary distributions over variable-length discrete sequences, and can take into account biological notions of mutational distance. Our theoretical results rigorously establish that the KSD-B is not only a valid divergence measure, but also that it detects non-convergence in distribution. We outline the wide variety of possible applications of the KSD-B, including (a) goodness-of-fit tests, which enable generative sequence models to be evaluated on an absolute instead of relative scale; (b) measurement of posterior sample quality, which enables accurate semi-supervised sequence design and ancestral sequence reconstruction; and (c) selection of a set of representative points, which enables the design of libraries of sequences that are representative of a given generative model for efficient experimental testing.