Abstract
The discovery of molecular relationships from high-dimensional data is a major open problem in bioinformatics. Machine learning and feature attribution models have shown great promise in this context but lack causal interpretation. Here, we show that a popular feature attribution model, under certain assumptions, estimates an average of a causal quantity reflecting the direct influence of one variable on another. We leverage this insight to propose a precise definition of a gene regulatory relationship and implement a new tool, CIMLA (Counterfactual Inference by Machine Learning and Attribution Models), to identify differences in gene regulatory networks between biological conditions, a problem that has received great attention in recent years. Using extensive benchmarking on simulated data, we show that CIMLA is more robust to confounding variables and is more accurate than leading methods. Last, we use CIMLA to analyze a previously published single-cell RNA sequencing dataset from subjects with and without Alzheimer's disease (AD), discovering several potential regulators of AD.