I would like to compared two biological cell line samples treated differently but originated from a common reference sample. The naive way of comparing the two is to just do DE analysis between them irrespective of the common reference. But given that the references are not perfectly identical (e.g. not identically sequenced and not identically conditioned), the DE analysis should be conditioned on "almost identical" references.

Is there any approach using a generalized version of DESeq2 for DE analysis that is conditioned on a third sample?

Thank you for any comment.

This has been asked before on the support site, but it's not easy to find the answer perhaps.

There is no point to conditioning on a third sample, if it is shared:

(C/A) / (B/A) = C/B