Instrumental variables in real‐world clinical studies of dementia and neurodegenerative disease: Systematic review of the subject‐matter argumentation, falsification test, and study design strategies to justify a valid instrument

Objectives We systematically reviewed how investigators argued for and justified the validity of their instrumental variables (IV) in clinical studies of dementia and neurodegenerative disease. Methods We included studies using IV analysis with observational data to investigate causal effects in clinical research studies of dementia and neurodegenerative disease. We reported the subject‐matter argumentation, falsification test, and study design strategies used to satisfy the three assumptions of a valid IV: relevance, exclusion restriction, and exchangeability. Results Justification for the relevance assumption was performed in all 12 included studies, exclusion restriction in seven studies, and exchangeability in nine studies. Two subject‐matter argumentation strategies emerged from seven studies on the relevance of their IV. All studies except one provided quantitative evidence for the strength of the association between the IV and exposure variable. Four argumentation strategies emerged for exclusion restriction from six studies. Four falsification tests were performed across three studies. Three argumentation strategies emerged for exchangeability across four studies. Nine falsification tests were performed across nine studies. Two notable study design strategies were reported. Conclusion Our results reinforce IV analysis as a feasible option for clinical researchers in dementia and neurodegenerative disease by clarifying known strategies used to validate an IV.