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# Obtaining genetics insights from deep learning via explainable artificial intelligence

## Abstract

Artificial intelligence (AI) models based on deep learning now represent the state of the art for making functional predictions in genomics research. However, the underlying basis on which predictive models make such predictions is often unknown. For genomics researchers, this missing explanatory information would frequently be of greater value than the predictions themselves, as it can enable new insights into genetic processes. We review progress in the emerging area of explainable AI (xAI), a field with the potential to empower life science researchers to gain mechanistic insights into complex deep learning models. We discuss and categorize approaches for model interpretation, including an intuitive understanding of how each approach works and their underlying assumptions and limitations in the context of typical high-throughput biological datasets.

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## Acknowledgements

N.D. acknowledges the support of the Pacific Institute for the Mathematical Sciences (PIMS) Postdoctoral Fellowship program. W.W.W. acknowledges support from Natural Sciences and Engineering Research Council of Canada (NSERC) and the British Columbia (BC) Children’s Hospital Foundation. S.M. acknowledges support from the Canadian Institute for Advanced Research (CIFAR). M.W.L. acknowledges support from Genome Canada, Genome BC, NSERC and Health Research BC. The authors thank W. Stafford Noble for helpful comments on the manuscript.

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Correspondence to Maxwell W. Libbrecht, Wyeth W. Wasserman or Sara Mostafavi.

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## Glossary

Features

Scalar inputs to a machine learning model.

Local interpretation

The task of understanding a model’s prediction for a single input.

Global interpretation

The task of understanding how a model makes predictions across all inputs.

Sequence-to-activity models

A class of learning tasks that takes a DNA sequence as input and predicts a property of the activity of that sequence, such as transcription factor binding or chromatin accessibility in a cell type of interest.

Convolutional neural networks

(CNNs). A neural network architecture that includes convolutional nodes.

Recurrent neural networks

(RNNs). A type of neural network architecture in which nodes are arranged in a chain along a sequential input such as a DNA sequence.

Layers

Sets of neural network nodes that take input from nodes of the previous layer and output to nodes of the subsequent layer.

Convolutional nodes

(Also known as filters). A type of neural network node that takes input from a short contiguous sequence of nodes, usually 3–20 bp in sequence-to-activity models.

Nodes

(Also known as units and artificial neurons). The basic units of a neural network. They take input from other nodes and output scalar values to other nodes.

Regulatory element

Region in genomic DNA that can contribute to gene regulation.

Attention mechanism

A component of a neural network that can learn to adaptively prioritize (that is, pay attention to) certain parts of an input by weighting.

Attention weights

Weights learned by the attention mechanism.

Drop-out

A form of regularization typically used during training of neural networks in which activations from subsets of hidden units are zeroed out.

Overfitting

The case when a machine learning model is specific to its training set and does not generalize to other inputs.

Labels

The target outputs of a classification model.

One-hot encoding

The process of converting a DNA letter into a length-4 vector such that one position is set to 1 and the others are set to 0, for use as input to a neural network.

An importance score assigned to a given input feature by a post-hoc local interpretation method.

(Also known as saliency map or relevance map). An estimate of how much each input feature contributes to the output, produced by certain local interpretation methods.

Rectified linear unit

(ReLU). A common type of nonlinear activation function applied to the output of hidden units, which zeros-out the negative part of the output.

Self-attention

A type of attention mechanism in which every part of the input is compared with every other part, including itself.

Activation function

A function applied to the output of neurons, typically to model non-linearity.

Regularization

A common machine learning scheme that controls model expressivity by including a term in the objective function that penalizes model complexity.

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Novakovsky, G., Dexter, N., Libbrecht, M.W. et al. Obtaining genetics insights from deep learning via explainable artificial intelligence. Nat Rev Genet (2022). https://doi.org/10.1038/s41576-022-00532-2

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• DOI: https://doi.org/10.1038/s41576-022-00532-2