Interpretable neural architecture search and transfer learning for understanding CRISPR/Cas9 off-target enzymatic reactions

• URL: http://arxiv.org/abs/2305.11917v2
• Date: Fri, 29 Sep 2023 16:36:45 GMT
• Title: Interpretable neural architecture search and transfer learning for understanding CRISPR/Cas9 off-target enzymatic reactions
• Authors: Zijun Zhang, Adam R. Lamson, Michael Shelley, Olga Troyanskaya
• Abstract summary: Elektrum is a deep learning framework for determining the kinetics of biochemical systems. It employs a novel transfer learning step, where the KINNs are inserted as intermediary layers into deeper convolutional neural networks. We apply Elektrum to predict CRISPR-Cas9 off-target editing probabilities and demonstrate that it achieves state-of-the-art performance.
• Score: 3.5994174958472307
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: Finely-tuned enzymatic pathways control cellular processes, and their dysregulation can lead to disease. Creating predictive and interpretable models for these pathways is challenging because of the complexity of the pathways and of the cellular and genomic contexts. Here we introduce Elektrum, a deep learning framework which addresses these challenges with data-driven and biophysically interpretable models for determining the kinetics of biochemical systems. First, it uses in vitro kinetic assays to rapidly hypothesize an ensemble of high-quality Kinetically Interpretable Neural Networks (KINNs) that predict reaction rates. It then employs a novel transfer learning step, where the KINNs are inserted as intermediary layers into deeper convolutional neural networks, fine-tuning the predictions for reaction-dependent in vivo outcomes. Elektrum makes effective use of the limited, but clean in vitro data and the complex, yet plentiful in vivo data that captures cellular context. We apply Elektrum to predict CRISPR-Cas9 off-target editing probabilities and demonstrate that Elektrum achieves state-of-the-art performance, regularizes neural network architectures, and maintains physical interpretability.

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