14 months ago by
TMM normalization is based on the idea that normalizing by library size makes sense. In other words, for RNA-Seq, the library size is correlated with the total amount of mRNA that you started with, so if you have two samples and one has 20M reads and the other only has 10M reads, we assume that the second library only had half as much mRNA to begin with, so we want to account for that technical difference.
Things get a bit more murky when you start talking about things like OTU or contig counts. Without knowing anything about your experiment it's difficult to make any recommendation (which I would be hesitant to do regardless), but the main thing to consider is if the total number of counts is independent of your study design.
As a trivial example, say you were doing some microbiome study with gut bacteria and were comparing antibiotic treated vs control subjects. You expect far fewer total OTU counts in the antibiotic treated samples as a consequence of the treatment, so you wouldn't want to normalize by total counts, because that would erase much of your signal.