Assessment of Quadrivalent Human Papillomavirus Vaccine Safety Using the Self-Controlled Tree-Temporal Scan Statistic Signal-Detection Method in the Sentinel System

Abstract

The self-controlled tree-temporal scan statistic—a new signal-detection method—can evaluate whether any of a wide variety of health outcomes are temporally associated with receipt of a specific vaccine, while adjusting for multiple testing. Neither health outcomes nor post-vaccination potential periods of increased risk need be pre-specified. Using US medical claims data in the Sentinel System, the method was used to evaluate adverse events after quadrivalent human papillomavirus vaccine (4vHPV). Incident outcomes occurring in emergency department or inpatient settings within 56 days after first doses of 4vHPV received by 9-through-26-year-olds in 2006–2014 were identified using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes and analyzed by pairing the new method with a standard hierarchical classification of diagnoses. On scanning diagnoses of 1.9 million 4vHPV recipients, two statistically significant categories of adverse event were found: cellulitis on Days 2–3 after vaccination and "other complications of surgical and medical procedures" on Days 1–3. Cellulitis is a known adverse event. Clinically-informed investigation of electronic claims records of the patients with "other complications" did not suggest any previously unknown vaccine safety problem. Considering that thousands of potential short-term adverse events and hundreds of potential risk intervals were evaluated, these findings add significantly to the growing safety record of 4vHPV.