title: Refining adverse drug reaction signals by incorporating interaction variables identified using emergent pattern mining.
abstract: OBJECTIVE
  To develop a framework for identifying and incorporating candidate confounding interaction terms into a regularised cox regression analysis to refine adverse drug reaction signals obtained via longitudinal observational data.
  
  
  METHODS
  We considered six drug families that are commonly associated with myocardial infarction in observational healthcare data, but where the causal relationship ground truth is known (adverse drug reaction or not). We applied emergent pattern mining to find itemsets of drugs and medical events that are associated with the development of myocardial infarction. These are the candidate confounding interaction terms. We then implemented a cohort study design using regularised cox regression that incorporated and accounted for the candidate confounding interaction terms.
  
  
  RESULTS
  The methodology was able to account for signals generated due to confounding and a cox regression with elastic net regularisation correctly ranking the drug families known to be true adverse drug reactions above those that are not. This was not the case without the inclusion of the candidate confounding interaction terms, where confounding leads to a non-adverse drug reaction being ranked highest.
  
  
  CONCLUSIONS
  The methodology is efficient, can identify high-order confounding interactions and does not require expert input to specify outcome specific confounders, so it can be applied for any outcome of interest to quickly refine its signals. The proposed method shows excellent potential to overcome some forms of confounding and therefore reduce the false positive rate for signal analysis using longitudinal data.
authors.affiliation: School of Computer Science, Jubilee Campus, University of Nottingham, NG8 1BB, United Kingdom. Electronic address: jenna.m.reps@gmail.com.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Reps
authors.affiliation: School of Computer Science, Jubilee Campus, University of Nottingham, NG8 1BB, United Kingdom.
authors.forename: Uwe
authors.initials: U
authors.lastname: Aickelin
authors.affiliation: School of Medicine, University of Nottingham, Nottingham NG5 1PB, United Kingdom.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hubbard
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D057225:Data Mining / Q000379:methods*; D016208:Databases, Factual; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy*; D010363:Pattern Recognition, Automated / Q000379:methods*
keywords: Confounding; Data mining; Emergent pattern mining; Medical informatics; Observational data; Signal refinement