title: Comparative performance of two quantitative safety signalling methods: implications for use in a pharmacovigilance department.
abstract: OBJECTIVE
  There is increasing interest in using disproportionality-based signal detection methods to support postmarketing safety surveillance activities. Two commonly used methods, empirical Bayes multi-item gamma Poisson shrinker (MGPS) and proportional reporting ratio (PRR), perform differently with respect to the number and types of signals detected. The goal of this study was to compare and analyse the performance characteristics of these two methods, to understand why they differ and to consider the practical implications of these differences for a large, industry-based pharmacovigilance department.
  
  
  METHODS
  We compared the numbers and types of signals of disproportionate reporting (SDRs) obtained with MGPS and PRR using two postmarketing safety databases and a simulated database. We recorded signal counts and performed a qualitative comparison of the drug-event combinations signalled by the two methods as well as a sensitivity analysis to better understand how the thresholds commonly used for these methods impact their performance.
  
  
  RESULTS
  PRR detected more SDRs than MGPS. We observed that MGPS is less subject to confounding by demographic factors because it employs stratification and is more stable than PRR when report counts are low. Simulation experiments performed using published empirical thresholds demonstrated that PRR detected false-positive signals at a rate of 1.1%, while MGPS did not detect any statistical false positives. In an attempt to separate the effect of choice of signal threshold from more fundamental methodological differences, we performed a series of experiments in which we modified the conventional threshold values for each method so that each method detected the same number of SDRs for the example drugs studied. This analysis, which provided quantitative examples of the relationship between the published thresholds for the two methods, demonstrates that the signalling criterion published for PRR has a higher signalling frequency than that published for MGPS.
  
  
  CONCLUSIONS
  The performance differences between the PRR and MGPS methods are related to (i) greater confounding by demographic factors with PRR; (ii) a higher tendency of PRR to detect false-positive signals when the number of reports is small; and (iii) the conventional thresholds that have been adapted for each method. PRR tends to be more 'sensitive' and less 'specific' than MGPS. A high-specificity disproportionality method, when used in conjunction with medical triage and investigation of critical medical events, may provide an efficient and robust approach to applying quantitative methods in routine postmarketing pharmacovigilance.
authors.affiliation: Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398, USA. june.s.almenoff@gsk.com
authors.forename: June S
authors.initials: JS
authors.lastname: Almenoff
authors.forename: Karol K
authors.initials: KK
authors.lastname: LaCroix
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Yuen
authors.forename: David
authors.initials: D
authors.lastname: Fram
authors.forename: William
authors.initials: W
authors.lastname: DuMouchel
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000465:Algorithms; D001499:Bayes Theorem; D003625:Data Collection; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D017891:Pharmacoepidemiology; D016012:Poisson Distribution; D011358:Product Surveillance, Postmarketing / Q000379:methods* / Q000706:statistics & numerical data; D015203:Reproducibility of Results; D014481:United States; D014486:United States Food and Drug Administration