The InTAD paper states InTAD can be applied to any heterogeneous cohort of samples analyzed by a combination of gene expression and epigenetic profiling techniques and integrates either public or custom information of TAD boundaries. What I am missing is a statement on its application on non-cohort data. We have a murine cell lines profiled with ATAC-seq and RNA-seq with three to four replicates each. TADs from in situ Hi-C are available based on a closely-related primary cell type.

Can you comment on InTAD probably behaves with these replicate numbers? Is it advisable to perform the analysis with this setup given the tool was developed and verified based on cohort data?

Actually the sample size definitely has specific effect. For example, we observed loss of associations based on subsampling of the dataset. It is described in the figure S1A (https://static-content.springer.com/esm/art%3A10.1186%2Fs12859-019-2655-2/MediaObjects/1285920192655MOESM1ESM.pdf ). The minimum limit is at least 3 samples, but increase definitely would be beneficial.

Also, the InTAD strategy was previously applied in other study where the focus was on lymphoblastoid cell lines and approach appeared to be suitable: https://www.sciencedirect.com/science/article/pii/S0092867415009770