In Reply: The comments by Drs Deinum and van der Wilt and by Dr Shrier focus on the important question: Once a moderator is found in exploration, what comes next? Both letters propose interesting and potentially viable strategies.
Drs Deinum and van der Wilt propose N-of-1 trials followed up by pooling of the results. Every clinician making treatment decisions for a patient is, in effect, doing an N-of-1 trial, first formulating a hypothesis of what is wrong and what might make it right, testing it, and if the evidence does not support the original hypothesis, reformulating the hypothesis and starting over again. Unfortunately, we cannot generalize results from any such trial or pool multiple N-of-1 trials unless there is consistency in the design.
Kraemer HC, Frank E, Kupfer DJ. A Word From Our Moderator—Reply. JAMA. 2007;297(2):156–157. doi:10.1001/jama.297.2.157-a
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