Tying research question and analytical strategy when variables are affected by medication use

Ill-defined research questions could be particularly problematic in an epidemiological setting where measurements fluctuate over time due to intercurrent events, such as medication use. When a research question fails to specify how medication use should be handled methodologically, arbitrary decisions may be made during the analysis phase, which likely leads to a mismatch between the intended question and the performed analysis. The mismatch can result in vastly different or meaningless interpretations of estimated effects. Thus, a research question such as "what is the effect of X on Y?" requires further elaboration, and it should consider whether and how medication use has affected the measurements of interest. In our study, we will discuss how well-defined questions can be formulated when medication use is involved in observational studies. We will distinguish between a situation where an exposure is affected by medication use and where the outcome of interest is affected by medication use. For each setting, we will give examples of different research questions that could be asked depending on how medication use is considered in the estimand and discuss methodological considerations under each question.