title: A supervised adverse drug reaction signalling framework imitating Bradford Hill's causality considerations.
abstract: Big longitudinal observational medical data potentially hold a wealth of information and have been recognised as potential sources for gaining new drug safety knowledge. Unfortunately there are many complexities and underlying issues when analysing longitudinal observational data. Due to these complexities, existing methods for large-scale detection of negative side effects using observational data all tend to have issues distinguishing between association and causality. New methods that can better discriminate causal and non-causal relationships need to be developed to fully utilise the data. In this paper we propose using a set of causality considerations developed by the epidemiologist Bradford Hill as a basis for engineering features that enable the application of supervised learning for the problem of detecting negative side effects. The Bradford Hill considerations look at various perspectives of a drug and outcome relationship to determine whether it shows causal traits. We taught a classifier to find patterns within these perspectives and it learned to discriminate between association and causality. The novelty of this research is the combination of supervised learning and Bradford Hill's causality considerations to automate the Bradford Hill's causality assessment. We evaluated the framework on a drug safety gold standard known as the observational medical outcomes partnership's non-specified association reference set. The methodology obtained excellent discrimination ability with area under the curves ranging between 0.792 and 0.940 (existing method optimal: 0.73) and a mean average precision of 0.640 (existing method optimal: 0.141). The proposed features can be calculated efficiently and be readily updated, making the framework suitable for big observational data.
authors.affiliation: School of Computer Science, University of Nottingham, NG8 1BB, UK. Electronic address: jenna.reps@nottingham.ac.uk.
authors.forename: Jenna Marie
authors.initials: JM
authors.lastname: Reps
authors.affiliation: School of Computer Science, University of Nottingham, NG8 1BB, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Garibaldi
authors.affiliation: School of Computer Science, University of Nottingham, NG8 1BB, UK.
authors.forename: Uwe
authors.initials: U
authors.lastname: Aickelin
authors.affiliation: Division of Epidemiology and Public Health, University of Nottingham, UK.
authors.forename: Jack E
authors.initials: JE
authors.lastname: Gibson
authors.affiliation: Division of Epidemiology and Public Health, University of Nottingham, UK.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hubbard
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000465:Algorithms; D000928:Antidepressive Agents / Q000009:adverse effects; D019540:Area Under Curve; D003625:Data Collection; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D004813:Epidemiology; D005189:False Positive Reactions; D008490:Medical Informatics / Q000295:instrumentation* / Q000379:methods; D017063:Outcome Assessment, Health Care; D004364:Pharmaceutical Preparations; D012372:ROC Curve; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D012984:Software; D006113:United Kingdom
chemical_list: D000928:Antidepressive Agents; D004364:Pharmaceutical Preparations
keywords: Big data; Causal effects; Longitudinal observational data; Pharmacovigilance; Signal detection