Sampling designs for rare time-depen-dent exposures-A Comparison of the nested exposure case-control design and exposure density sampling

In extensive cohort studies, the ascertainment of covariate information on all individuals can be challenging. In hospital epidemiology, an additional issue is often the time-dependency of the exposure of interest. We revisit and compare two sampling designs constructed for rare time-dependent exposures and possibly common outcomes-the nested exposure case-control design and exposure density sampling. Both designs enable effcient hazard ratio estimation by sampling all exposed individuals but only a small fraction of the unexposed ones. Moreover, they account for timedependent exposure to avoid immortal time bias. We evaluate and compare their performance using data of patients hospitalized in the neuro-intensive care unit at the Burdenko Neurosurgery Institute (NSI) in Moscow, Russia. Three different types of hospital-acquired infections with different prevalence are considered. Additionally, inffation factors, a primary performance measure, are discussed. We enhance both designs to allow for a competitive analysis of combined and competing endpoints compared to the full cohort approach while substantially reducing the amount of necessary information. Nonetheless, exposure density sampling outperforms the nested exposure case-control design concerning effciency and accuracy in most considered settings.