Using natural strata when examining unmeasured biases in an observational study of neurological side effects of antibiotics

Fluoroquinolones are widely prescribed antibiotics that carry a US Food and Drug Administration warning about possible side-effects on the central and peripheral nervous system. We compare 436,891 patients with sinusitis treated with fluoroquinolones to two control groups treated with azithromycin or amoxicillin. In addition to looking for nervous system complications, we look for evidence of bias using outcomes for which an effect was not anticipated. The comparison uses ‘natural strata’ that form control groups proportional in size to the treated group and balance many covariates beyond those that define the strata. The main technical contribution is a new method for near-optimal construction of natural strata with multiple groups. The online supplement material contains proofs, details, and information about the R package natstrat and replication.