Silence on the relevant literature and errors in implementation

node j have changed, but other indirectly affected nodes also change because the initial perturbation has propagated through the network. MRA has solved the problem of finding local, direct links between components through the global responses for networks of any size and complexity 2. The development and application of methods that are conceptually similar to MRA (e.g., regulatory strength analysis 8 and maximum likelihood-based MRA 9,10) has reinforced the validity of using MRA-type methods to reconstruct network connections 11–16. The Barzel & Barabási study 1 uses the same concept and strikingly similar terminologies to reconstruct networks by deriving the local connection coefficients from the global response coefficients. Key equations (3) and (4) in their silencing method 1 express the local coefficients in terms of the global coefficients and are a subset of the published MRA equations 2,9,10,17–19 with a formal replacement of the diagonal elements of the local response matrix by zeros instead of minus ones (Supplementary Note 1). Another formal difference is that the variant of the global response matrix used by Barzel & Barabási 1 considers the global change in each node that results To the Editor: In the August 2013 issue of this journal, Barzel & Barabási reported a method for reconstructing network topologies 1. Here we show that the Barzel & Barabási method is a variant of a previously published method, modular response analysis (MRA) 2. We also demonstrate that the implementation of their algorithm using statistical similarity measures as a proxy for global network responses to perturbations is erroneous and its performance is overestimated. The reconstruction of network connections from data remains a fundamental problem in biology. It is not immediately obvious how to capture direct links between individual network nodes from experimental data because a perturbation to a component propagates through a network, causing widespread (global) changes, thereby masking direct (local) connections between nodes. This question has been previously studied in >100 publications, collectively representing MRA (reviewed in refs. 3–7). MRA quantifies direct interactions between network nodes (i and j) using the local response coefficients (also known as connection coefficients), which describe direct effects of a small change in node j on node i, while keeping the remaining nodes unchanged to prevent the spread of the perturbation. The local responses cannot be directly assessed, whereas the global responses can be measured; when following a perturbation to node j, the entire network relaxes to a …