These two issues that we raise here, temporal order and sample size, are not new to observational hypothesis-testing research. They apply to all observational studies, beyond the special case of GxE studies. Other meta-analyses of this GxE hypothesis have made these same methodological mistakes before, and these mistakes have been repeatedly pointed out in published articles in the past five years. As such, the protocol as published seems fundamentally and inexplicably flawed. As we said in our 2012 letter to the meta-analysis collaborators, we regret this missed opportunity to do something better.
