Reliable Prediction Errors for Deep Neural Networks Using Test-Time Dropout.

While the use of deep learning in drug discovery is gaining increasing attention, the lack of methods to compute reliable errors in prediction for Neural Networks prevents their application to guide decision making in domains where identifying unreliable predictions is essential, e.g., precision medicine. Here, we present a framework to compute reliable errors in prediction for Neural Networks using Test-Time Dropout and Conformal Prediction. Specifically, the algorithm consists of training a Neural Network using dropout, and then to both the validation and test sets, also employing dropout in this step. Therefore, for each instance in the validation and test sets an ensemble of predictions are generated. The residuals and absolute errors in prediction for the validation set are then used to compute prediction errors for the test set instances using Conformal Prediction. We show using 24 bioactivity data sets from ChEMBL 23 that Dropout Conformal Predictors are valid (i.e., the fraction of instances whose true value lies within the predicted interval strongly correlates with the confidence level) and efficient, as the predicted confidence intervals span a narrower set of values than those computed with Conformal Predictors generated using Random Forest (RF) models. Lastly, we show in retrospective virtual screening experiments that dropout and RF-based Conformal Predictors lead to comparable retrieval rates of active compounds. Overall, we propose a computationally efficient framework (as only extra forward passes are required in addition to training a single network) to harness Test-Time Dropout and the Conformal Prediction framework, which is generally applicable to generate reliable prediction errors for Deep Neural Networks in drug discovery and beyond.