Deep Mendelian Randomization: Investigating the Causal Knowledge of Genomic Deep Learning Models

Abstract Multi-task deep learning (DL) models can accurately predict diverse genomic marks from sequence, but whether these models learn the causal relationships between genomic marks is unknown. Here, we describe Deep Mendelian Randomization (DeepMR), a method for estimating causal relationships between genomic marks learned by genomic DL models. By combining Mendelian Randomization with in silico mutagenesis, DeepMR obtains local (locus specific) and global estimates of (an assumed) linear causal relationship between marks. In a simulation designed to test recovery of pairwise causal relations between transcription factors (TFs), DeepMR gives accurate and unbiased estimates of the ‘true’ global causal effect, but its coverage decays in the presence of sequence-dependent confounding. We then apply DeepMR to examine the global relationships learned by a state-of-the-art DL model, BPNet [Avsec et al., 2020], between TFs involved in reprogramming. DeepMR’s causal effect estimates validate previously hypothesized relationships between TFs and suggest new relationships for future investigation.