Supervised learning on synthetic data for reverse engineering gene regulatory networks from experimental time-series

Abstract

The reconstruction of gene regulatory networks from time resolved gene expression measurements is a key challenge in systems biology with applications in health and disease. While the most popular network inference methods are based on unsupervised learning approaches, supervised learning methods have proven their potential for superior reconstruction performance. However, obtaining the appropriate volume of informative training data constitutes a key limitation for the success of such methods.\n\nHere, we introduce a supervised learning approach to detect gene-gene regulation based on exclusively synthetic training data, termed surrogate learning, and show its performance for synthetic and experimental time-series. We systematically investigate different simulation configurations of biologically representative time-series of transcripts and augmentation of the data with a measurement model. We compare the resulting synthetic datasets to experimental data, and evaluate classifiers trained on them for detection of gene-gene regulation from experimental time-series. For classifiers, we consider hybrid convolutional recurrent neural networks, random forests and logistic regression, and evaluate the reconstruction performance of different simulation settings, data pre-processing and classifiers.\n\nWhen training and test time-courses are generated from the same distribution, we find that the largest tested neural network architecture achieves the best performance of 0.448 {+/-} 0.047 (mean {+/-} std) in maximally achievable F1 score over all datasets outperforming random forests by 32.4 % {+/-} 14 % (mean {+/-} std). Reconstruction performance is sensitive to discrepancies between synthetic training and test data, highlighting the importance of matching training and test data domains. For an experimental gene expression dataset from E.coli, we find that training data generated with measurement model, multi-gene perturbations, but without data standardization is best suited for training classifiers for network reconstruction from the experimental test data. We further demonstrate superiority to multiple unsupervised, state-of-the-art methods for networks comprising 20 genes of the experimental data from E.coli (average AUPR best supervised = 0.22 vs best unsupervised = 0.07).\n\nWe expect the proposed surrogate learning approach to be broadly applicable. It alleviates the requirement for large, difficult to attain volumes of experimental training data and instead relies on easily accessible synthetic data. Successful application for new experimental conditions and other data types is only limited by the automatable and scalable process of designing simulations which generate suitable synthetic data.