Immeasurable Time Bias in Self-controlled Designs: Case-crossover, Case-time-control, and Case-case-time-control Analyses

Background Impact of immeasurable time bias (IMTB) is yet to be examined in self-controlled designs. Methods We conducted case-crossover, case-time-control, and case-case-time-control analyses using Korea's healthcare database. Two empirical examples among elderly patients were used: 1) benzodiazepines-hip fracture; 2) benzodiazepines-mortality. For cases, the date of hip fracture diagnosis or death was defined as the index date, and the inherited date of their matched cases for controls or future cases. Exposure was assessed in the 1-30 day (hazard) and 61-90 day (control) windows preceding the index date. A non-missing exposure setting included in- and outpatient prescriptions and the pseudo-outpatient setting included only the outpatients. Conditional logistic regression was done to estimate odds ratio (OR) with 95% confidence intervals (CI), where the relative difference in OR among the two settings was calculated to quantify the IMTB. Results The IMTB had negligible impacts in the hip fracture example in the case-crossover (non-missing exposure setting OR 1.27, 95% CI 1.12-1.44; pseudo-outpatient setting 1.21, 1.06-1.39; magnitude 0.05), case-time-control (1.18, 0.98-1.44; 1.13, 0.92-1.38; 0.04), and case-case-time-control analyses (0.99, 0.80-1.23; 0.94, 0.75-1.18; 0.05). In the mortality example, IMTB had significant impacts in the case-crossover (1.44, 1.36-1.52; 0.72, 0.67-0.78; 1.00), case-time-control (1.38, 1.26-1.51; 0.68, 0.61-0.76; 1.03), and case-case-time-control analyses (1.27, 1.15-1.40; 0.62, 0.55-0.69; 1.05). Conclusions Although IMTB had negligible impacts on the drug's effect on acute events as these are unlikely to be accompanied with hospitalizations, it negatively biased the drug's effect on mortality, an outcome with prodromal phases, in the three self-controlled designs.