Between haplotypes: needs zero new infrastructure. --modkit_phased already emits sample_hp1.bed.gz/sample_hp2.bed.gz per sample, that's exactly the input pair DMR_CALLING needs, so it's just modkit dmr pair -a hp1 -b hp2 with the module I already built. One comparison per sample, no combinatorics, no samplesheet changes. Happy to put together a PR. Between tumor/normal: same deal if you want it, normal_bam is already in the samplesheet, so pairing is automatic, one comparison per sample, no new columns. One caveat: only valid when normal is tissue-matched. My own "normal" is PBMC, and tumor-vs-PBMC would mostly reflect cell-type identity, not tumor biology, so I'd gate this behind an opt-in flag rather than firing whenever normal_bam is populated. Between arbitrary tumor samples (my tumor6-vs-tumor1 case): agreed, that one's combinatorial and doesn't belong in lrsomatic. Dropping that ask, it already works as an ad-hoc downstream step in our pipeline (NCP's DMR_ONLY, fed directly from lrsomatic's sample.bed.gz), no changes needed on your end. So: haplotype in lrsomatic (low-cost, yes), tumor/normal as opt-in with the tissue caveat (your call), cross-sample stays downstream. Sound right?