Accounting for confounding by time, early intervention adoption, and time-varying effect modification in the design and analysis of stepped-wedge designs: application to a proposed study design to reduce opioid-related mortality.

Mixed effects models can adjust for different combinations of external factors through correct specification of fixed and random time effects. Since model choice has considerable impact on validity of results and study power, careful consideration must be given to how these external factors impact study endpoints and what estimands are most appropriate in the presence of such factors.