Evaluation and Ensembling of Methods for Reverse Engineering of Brain Connectivity from Imaging Data

Brain science is an evolving research area inviting great enthusiasm with its potential for providing insights and thereby, preventing, and treating multiple neuronal disorders affecting millions of patients. Discovery of relationships, such as brain connectivity, is a major goal in basic, translational, and clinical science. Algorithms for causal discovery are used in diverse fields for tackling problems similar to the task of reconstruction of neuronal brain connectivity. Our aim is to understand the strengths and limitations of these methods, measure performance and its determinants, and provide insights to enhance their performance and applicability. We performed extensive empirical testing and benchmarking of reconstruction performance of several state-of-the-art algorithms along with several ensemble techniques used to combine them. Our experiments used a clear and broadly relevant gold standard based on calcium fluorescence time series recordings of thousands of neurons sampled from a previously validated realistic, neuronal model. Correlation, entropy-based measures, Cross-Correlation for short time lags, and Generalized Transfer Entropy had the best performances with area under ROC curve (AUC) in the range of 0.7-0.8 even for smaller sample sizes of n = 100 to 1,000 and converged quickly (at less than n = 1,000). Ensembles of best-performing methods using random forests and neural networks generated AUC of ~0.9 with n = 10,000. Several important insights regarding parameter choice and sample size were gained for guiding the experimental design of studies. Our data are also supportive of the feasibility of reliably reconstructing complex neuronal connectivity using existing techniques.