Similarity-based transfer learning with deep learning networks for accurate CRISPR-Cas9 off-target prediction

Transfer learning has emerged as a powerful tool for enhancing predictive accuracy in complex tasks, particularly in scenarios where data is limited or imbalanced. This study explores the use of similarity-based pre-evaluation as a methodology to identify optimal source datasets for transfer learning, addressing the dual challenge of efficient source-target dataset pairing and off-target prediction in CRISPR-Cas9, while existing transfer learning applications in the field of gene editing often lack a principled method for source dataset selection. We use cosine, Euclidean, and Manhattan distances to evaluate similarity between the source and target datasets used in our transfer learning experiments. Four deep learning network architectures, i.e. Multilayer Perceptron (MLP), Convolutional Neural Networks (CNNs), Feedforward Neural Networks (FNNs), and Recurrent Neural Networks (RNNs), and two traditional machine learning models, i.e. Logistic Regression (LR) and Random Forest (RF), were tested and compared in our simulations. The results suggest that similarity scores are reliable indicators for pre-selecting source datasets in CRISPR-Cas9 transfer learning experiments, with cosine distance proving to be a more effective dataset comparison metric than either Euclidean or Manhattan distances. An RNN-GRU, a 5-layer FNN, and two MLP variants provided the best overall prediction results in our simulations. By integrating similarity-based source pre-selection with machine learning outcomes, we propose a dual-layered framework that not only streamlines the transfer learning process but also significantly improves off-target prediction accuracy. The code and data used in this study are freely available at: https://github.com/dagrate/transferlearning_offtargets.Author summary: CRISPR-Cas9 is a popular gene-editing technology that allows researchers to modify an organism’s genomic DNA at precise locations. Significant research efforts have been focusing on improving its precision and effectiveness, with particular emphasis on minimizing off-target effects. At the same time, transfer learning techniques are becoming increasingly important for addressing deep learning challenges in computational biology, especially in the field of CRISPR-Cas9, where plausible training data availability can be limited. This study investigates the effectiveness of integrating similarity-based analysis with transfer learning for improving CRISPR-Cas9 off-target prediction. Our key contribution consists in an experimental evaluation of three distance metrics, i.e. cosine, Euclidean, and Manhattan distances, along with several traditional machine learning and deep learning models, in the context of knowledge transfer by transfer learning applied to gene editing data. For each considered target dataset our transfer learning framework determines the most suitable source dataset to be used in the model pre-training. The proposed computational framework offers a reliable and systematic method for selecting suitable source data, streamlining the transfer learning process, and improving prediction accuracy.