SSIM can robustly identify changes in 3D genome conformation maps

We previously presented Comparison of Hi-C Experiments using Structural Similarity (CHESS), an approach that applies the concept of the structural similarity index (SSIM) to Hi-C matrices 1 , and demonstrated that it could be used to identify both regions with similar 3D chromatin conformation across species, and regions with different chromatin conformation in different conditions. In contrast to the claim of Lee et al. 2 that the SSIM output of CHESS is ‘independent’ of the input data, here we confirm that SSIM depends on both local and global properties of the input Hi-C matrices. We provide two approaches for using CHESS to highlight regions of differential genome organisation for further investigation, and expanded guidelines for choosing appropriate parameters and controls for these analyses.