title: Reducing the noise in signal detection of adverse drug reactions by standardizing the background: a pilot study on analyses of proportional reporting ratios-by-therapeutic area.
abstract: OBJECTIVE
  Disproportionality screening analysis is acknowledged as a tool for performing signal detection in databases of adverse drug reactions (ADRs), e.g., in the European Union (EU) Drug Authority setting. The purpose of this study was to explore the possibility of decreasing false-positive signals of disproportionate reporting (SDR) by calculating the proportional reporting ratio (PRR)-by-therapeutic area (TA), while still maintaining the ability to detect relevant SDRs.
  
  
  METHODS
  In the EudraVigilance (EV) Database, output from PRR calculated with a restricted TA comparator background was compared in detail to output from conventional authority-setting PRR calculations for four drugs: bicalutamide, abiraterone, metformin, and vildagliptin, within the TAs of prostate gland disease and type 2 diabetes mellitus.
  
  
  RESULTS
  ADR reports per investigated drug ranged from 2,400 to 50,000. The PRR-TA's ability to detect true-positive SDRs (as acknowledged in approved labeling) was increased compared to the conventional PRR, and performed 8-31 % better than a recently proposed stricter EU-SDR definition. The PRR-TA removed false SDRs confounded by disease or disease spill-over by up to 63 %, while retaining/increasing the number of unclassified SDRs relevant for manual validation, and thereby improving the ratio between confounded SDRs (i.e., noise) and unclassified SDRs for all investigated drugs (possible signals).
  
  
  CONCLUSIONS
  The performance of the PRR was improved by background restriction with the PRR-TA method; the number of false-positive SDRs decreased, and the ability to detect true-positive SDRs increased, improving the signal-to-noise ratio. Further development and validation of the method is needed within other TAs and databases, and for disproportionality analysis methods.
authors.affiliation: Department of Surgical Sciences, Uppsala University, 75185, Uppsala, Sweden, birgitta.grundmark@mpa.se.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Grundmark
authors.forename: Lars
authors.initials: L
authors.lastname: Holmberg
authors.forename: Hans
authors.initials: H
authors.lastname: Garmo
authors.forename: Björn
authors.initials: B
authors.lastname: Zethelius
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000592:standards* / Q000706:statistics & numerical data*; D000726:Androgen Antagonists / Q000009:adverse effects; D016208:Databases, Factual / Q000706:statistics & numerical data*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000453:epidemiology*; D005062:European Union; D005189:False Positive Reactions; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects; D015233:Models, Statistical; D060735:Pharmacovigilance; D010865:Pilot Projects
chemical_list: D000726:Androgen Antagonists; D007004:Hypoglycemic Agents