Fig. 1. Schematic of the two possible explanations for variation in levels of antibiotic resistance between bacterial lineages.

The first hypothesis (“everything is everywhere”; left) is that lineages with a long duration of carriage have high resistance frequencies because resistance is more beneficial to these lineages (because longer duration of carriage translates into a greater probability of antibiotic exposure per carriage episode). The second hypothesis (“genetics as limiting factor”; right) is that lineages with high HGT rate have high resistance frequencies because they acquire resistance determinants at a higher rate. Positive associations have been observed between all three variables (resistance, HGT rate, and duration of carriage). If the first hypothesis is correct, the association between resistance and HGT rate could be confounded by the causal path through the duration of carriage; if the second hypothesis is correct, the association between resistance and duration of carriage could be confounded by the causal path through HGT rate. In the case of a confounding effect, these associations will not be robust to adjusting for the confounded variable.