Comparison of normalization methods for Hi-C data.

Hi-C has been predominately used to study the genome-wide interactions of genomes. In Hi-C experiments, it is believed that biases originating from different systematic deviations lead to extraneous variability among raw samples, and affect the reliability of downstream interpretations. As an important pipeline in Hi-C analysis, normalization seeks to remove the unwanted systematic biases; thus, a comparison between Hi-C normalization methods benefits their choice and the downstream analysis. In this article, a comprehensive comparison is proposed to investigate six Hi-C normalization methods in terms of multiple considerations. In light of comparison results, it has been shown that a cross-sample approach significantly outperforms individual sample methods in most considerations. The differences between these methods are analyzed, some practical recommendations are given, and the results are summarized in a table to facilitate the choice of the six normalization methods. The source code for the implementation of these methods is available at https://github.com/lhqxinghun/bioinformatics/tree/master/Hi-C/NormCompare.