Abstract
Impact of immeasurable time bias (IMTB) is yet to be examined in self-controlled designs. 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 ratios (ORs) with 95% confidence intervals (CIs), where the relative difference in OR among the two settings was calculated to quantify the IMTB. 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 OR 1.21; 95% CI, 1.06-1.39; magnitude 0.05), case-time-control (OR 1.18; 95% CI, 0.98-1.44; OR 1.13; 95% CI, 0.92-1.38; 0.04, respectively), and case-case-time-control analyses (OR 0.99; 95% CI, 0.80-1.23; OR 0.94; 95% CI, 0.75-1.18; 0.05, respectively). In the mortality example, IMTB had significant impacts in the case-crossover (non-missing exposure setting OR 1.44; 95% CI, 1.36-1.52; pseudo-outpatient setting OR 0.72; 95% CI, 0.67-0.78; magnitude 1.00), case-time-control (OR 1.38; 95% CI, 1.26-1.51; OR 0.68; 95% CI, 0.61-0.76; 1.03, respectively), and case-case-time-control analyses (OR 1.27; 95% CI, 1.15-1.40; OR 0.62; 95% CI, 0.55-0.69; 1.05, respectively). 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.
Highlights
Impact of immeasurable time bias (IMTB) is yet to be examined in selfcontrolled designs
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
Regardless to the design used, immeasurable time bias become evident when the exposure history of persons who become cases is differentially obscured in the time preceding hospitalization, during which dispensing or prescription of medications are not recorded in various administrative healthcare databases
Summary
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. The NHIS-NSC contains information on sociodemographic variables (e.g., age, sex), healthcare utilization (e.g., procedures, hospitalization duration), diagnoses (International Classification of Disease 10th Revision [ICD-10] codes), and prescriptions (e.g., national drug codes, day’s supply, dosage) from all settings, encompassing both inpatient, outpatient, and nursing home stays; this is possible as South Korea uses a feefor-service system for reimbursement. The NHIS-NSC database provides death-related information (cause of death [ICD-10], date of death), which were linked from South Korea’s national vital statistics. ed pt ce Empirical studies. Among elderly patients aged ≥65 years, our first example aimed to assess whether transient use of benzodiazepine was a trigger for hip fracture, and our second example aimed to examine the same exposure as a trigger for all-cause death. The range for the expected magnitude of effect for benzodiazepines and hip fracture was from 1.34
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