title: Generalized enrichment analysis improves the detection of adverse drug events from the biomedical literature.
abstract: BACKGROUND
  Identification of associations between marketed drugs and adverse events from the biomedical literature assists drug safety monitoring efforts. Assessing the significance of such literature-derived associations and determining the granularity at which they should be captured remains a challenge. Here, we assess how defining a selection of adverse event terms from MeSH, based on information content, can improve the detection of adverse events for drugs and drug classes.
  
  
  RESULTS
  We analyze a set of 105,354 candidate drug adverse event pairs extracted from article indexes in MEDLINE. First, we harmonize extracted adverse event terms by aggregating them into higher-level MeSH terms based on the terms' information content. Then, we determine statistical enrichment of adverse events associated with drug and drug classes using a conditional hypergeometric test that adjusts for dependencies among associated terms. We compare our results with methods based on disproportionality analysis (proportional reporting ratio, PRR) and quantify the improvement in signal detection with our generalized enrichment analysis (GEA) approach using a gold standard of drug-adverse event associations spanning 174 drugs and four events. For single drugs, the best GEA method (Precision: .92/Recall: .71/F1-measure: .80) outperforms the best PRR based method (.69/.69/.69) on all four adverse event outcomes in our gold standard. For drug classes, our GEA performs similarly (.85/.69/.74) when increasing the level of abstraction for adverse event terms. Finally, on examining the 1609 individual drugs in our MEDLINE set, which map to chemical substances in ATC, we find signals for 1379 drugs (10,122 unique adverse event associations) on applying GEA with p < 0.005.
  
  
  CONCLUSIONS
  We present an approach based on generalized enrichment analysis that can be used to detect associations between drugs, drug classes and adverse events at a given level of granularity, at the same time correcting for known dependencies among events. Our study demonstrates the use of GEA, and the importance of choosing appropriate abstraction levels to complement current drug safety methods. We provide an R package for exploration of alternative abstraction levels of adverse event terms based on information content.
authors.affiliation: Stanford Center for Biomedical Informatics Research, 1265 Welch Road, MSOB, Stanford, CA, 94305, USA. rainer.winnenburg@stanford.edu.
authors.forename: Rainer
authors.initials: R
authors.lastname: Winnenburg
authors.affiliation: Stanford Center for Biomedical Informatics Research, 1265 Welch Road, MSOB, Stanford, CA, 94305, USA.
authors.forename: Nigam H
authors.initials: NH
authors.lastname: Shah
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D016247:Information Storage and Retrieval; D016239:MEDLINE; D046650:Medical Subject Headings; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: Enrichment analysis; Information retrieval; MeSH indexing; Postmarketing pharmacovigilance