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

Abstract

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.

How measurements affected by medication use are reported and handled in observational research: A literature review

“…The validity of the method used for each variable was evaluated in relationship to the research aim and whether the affected variable is an exposure, an outcome, or a confounder. The assessment on whether the methods used are in general valid or invalid was based on recommendations from previous methodological studies 2–6,10,11,17–26 . For example, restricting the study population to non‐medication users was considered valid when the exposure or a confounder is affected by medication use regardless of whether the research aim is in the values as observed or if untreated.…”

“…The assessment on whether the methods used are in general valid or invalid was based on recommendations from previous methodological studies. [2][3][4][5][6]10,11,[17][18][19][20][21][22][23][24][25][26] For example, restricting the study population to non-medication users was considered valid when the exposure or a confounder is affected by medication use regardless of whether the research aim is in the values as observed or if untreated. This is because the restriction on a proxy variable of the Exceed 100% when added up, because more than one analysis was performed in some studies.…”

“…10 If the method used for handling medication effect does not match the research question, substantial bias can be introduced and the interpretation of results will be unclear. 11 Thus, it is essential to carefully think about the research question when some individuals in a study population use medication that affects the variables in the dataset. In some situations, the research interest could be in the observed measurements, regardless of whether some individuals' measurements are lowered due to antihypertensive medication use; for instance, when the effect of current blood pressure on the course of the disease for patients infected with Covid-19 is considered.…”

“…Studies have shown that different methods may lead to substantially different effect estimates, 2–5,8–10 and the optimal method depends on (a) the research aim and (b) whether the medication effect is on the exposure, outcome or a confounder 10 . If the method used for handling medication effect does not match the research question, substantial bias can be introduced and the interpretation of results will be unclear 11 …”

Tell me what you want, what you really really want: Estimands in observational pharmacoepidemiologic comparative effectiveness and safety studies

“…Another limitation is that we did not explicate how an estimand can inform the choice of study design and analytical approach. We refer to existing papers on this topic, 29,33,41,[45][46][47] particularly to explanations about aligning estimands to estimators in randomized trials. 38,48 An increasingly popular methodological approach is the target trial emulation framework.…”