The complex language of eukaryotic gene expression remains incompletely understood. Despite the importance suggested by many noncoding variants statistically associated with human disease, nearly all such variants have unknown mechanisms. Here, we address this challenge using an approach based on a recent machine learning advance—deep convolutional neural networks (CNNs). We introduce the open source package Basset to apply CNNs to learn the functional activity of DNA sequences from genomics data. We trained Basset on a compendium of accessible genomic sites mapped in 164 cell types by DNase-seq, and demonstrate greater predictive accuracy than previous methods. Basset predictions for the change in accessibility between variant alleles were far greater for Genome-wide association study (GWAS) SNPs that are likely to be causal relative to nearby SNPs in linkage disequilibrium with them. With Basset, a researcher can perform a single sequencing assay in their cell type of interest and simultaneously learn that cell's chromatin accessibility code and annotate every mutation in the genome with its influence on present accessibility and latent potential for accessibility. Thus, Basset offers a powerful computational approach to annotate and interpret the noncoding genome.

Models for predicting phenotypic outcomes from genotypes have important applications to understanding genomic function and improving human health. Here, we develop a machine-learning system to predict cell-type-specific epigenetic and transcriptional profiles in large mammalian genomes from DNA sequence alone. By use of convolutional neural networks, this system identifies promoters and distal regulatory elements and synthesizes their content to make effective gene expression predictions. We show that model predictions for the influence of genomic variants on gene expression align well to causal variants underlying eQTLs in human populations and can be useful for generating mechanistic hypotheses to enable fine mapping of disease loci.

The complex language of eukaryotic gene expression remains incompletely understood. Thus, most of the many noncoding variants statistically associated with human disease have unknown mechanism. Here, we address this challenge using an approach based on a recent machine learning advance-deep convolutional neural networks (CNNs). We introduce an open source package Basset (https://github.com/ davek44/Basset) to apply deep CNNs to learn the functional activity of DNA sequences from genomics data. We trained Basset on a compendium of accessible genomic sites mapped in 164 cell types by DNaseI-seq. Basset predictions for the change in accessibility between two variant alleles were far greater for GWAS SNPs that are likely to be causal relative to nearby SNPs in linkage disequilibrium with them. With Basset, a researcher can perform a single sequencing assay in their cell type of interest and simultaneously learn that cell's chromatin accessibility code and annotate every mutation in the genome with its influence on present accessibility and latent potential for accessibility. Thus, Basset offers a powerful computational approach to annotate and interpret the noncoding genome.

There is great excitement that medical artificial intelligence (AI) based on machine learning (ML) can be used to improve decision making at the patient level in a variety of healthcare settings. However, the quantification and communication of uncertainty for individual predictions is often neglected even though uncertainty estimates could lead to more principled decision-making and enable machine learning models to automatically or semi-automatically abstain on samples for which there is high uncertainty. In this article, we provide an overview of different approaches to uncertainty quantification and abstention for machine learning and highlight how these techniques could improve the safety and reliability of current ML systems being used in healthcare settings. Effective quantification and communication of uncertainty could help to engender trust with healthcare workers, while providing safeguards against known failure modes of current machine learning approaches. As machine learning becomes further integrated into healthcare environments, the ability to say “I’m not sure” or “I don’t know” when uncertain is a necessary capability to enable safe clinical deployment.

Recent advances in deep reinforcement learning have made significant strides in performance on applications such as Go and Atari games. However, developing practical methods to balance exploration and exploitation in complex domains remains largely unsolved. Thompson Sampling and its extension to reinforcement learning provide an elegant approach to exploration that only requires access to posterior samples of the model. At the same time, advances in approximate Bayesian methods have made posterior approximation for flexible neural network models practical. Thus, it is attractive to consider approximate Bayesian neural networks in a Thompson Sampling framework. To understand the impact of using an approximate posterior on Thompson Sampling, we benchmark well-established and recently developed methods for approximate posterior sampling combined with Thompson Sampling over a series of contextual bandit problems. We found that many approaches that have been successful in the supervised learning setting underperformed in the sequential decision-making scenario. In particular, we highlight the challenge of adapting slowly converging uncertainty estimates to the online setting.