title: Identifying Drug-Drug Interactions by Data Mining: A Pilot Study of Warfarin-Associated Drug Interactions.
abstract: Knowledge about drug-drug interactions commonly arises from preclinical trials, from adverse drug reports, or based on knowledge of mechanisms of action. Our aim was to investigate whether drug-drug interactions were discoverable without prior hypotheses using data mining. We focused on warfarin-drug interactions as the prototype.
  
  
  
  We analyzed altered prothrombin time (measured as international normalized ratio [INR]) after initiation of a novel prescription in previously INR-stable warfarin-treated patients with nonvalvular atrial fibrillation. Data sets were retrieved from clinical work. Random forest (a machine-learning method) was set up to predict altered INR levels after novel prescriptions. The most important drug groups from the analysis were further investigated using logistic regression in a new data set. Two hundred and twenty drug groups were analyzed in 61 190 novel prescriptions. We rediscovered 2 drug groups having known interactions (β-lactamase-resistant penicillins [dicloxacillin] and carboxamide derivatives) and 3 antithrombotic/anticoagulant agents (platelet aggregation inhibitors excluding heparin, direct thrombin inhibitors [dabigatran etexilate], and heparins) causing decreasing INR. Six drug groups with known interactions were rediscovered causing increasing INR (antiarrhythmics class III [amiodarone], other opioids [tramadol], glucocorticoids, triazole derivatives, and combinations of penicillins, including β-lactamase inhibitors) and two had a known interaction in a closely related drug group (oripavine derivatives [buprenorphine] and natural opium alkaloids). Antipropulsives had an unknown signal of increasing INR.
  
  
  
  We were able to identify known warfarin-drug interactions without a prior hypothesis using clinical registries. Additionally, we discovered a few potentially novel interactions. This opens up for the use of data mining to discover unknown drug-drug interactions in cardiovascular medicine.
authors.affiliation: From the Danish Heart Foundation, Copenhagen, Denmark (P.W.H., T.S.G.S., E.L.F., G.H.G.); DTU Compute, Technical University of Denmark, Lyngby (L.C.); The Heart Centre, Rigshospitalet (E.L.F., L.K.), and Department of Clinical Medicine (G.H.G.), University of Copenhagen, Denmark; Institute of Health, Science and Technology, Aalborg University, Denmark (C.T.-P.); The National Institute of Public Health, University of Southern Denmark, Copenhagen (G.H.G.); University of Copenhagen, Denmark; and Department of Medicine, Section of Cardiology, Glostrup Hospital, University of Copenhagen, Denmark (C.A.). Waede.sci@gmail.com.
authors.forename: Peter Wæde
authors.initials: PW
authors.lastname: Hansen
authors.affiliation: From the Danish Heart Foundation, Copenhagen, Denmark (P.W.H., T.S.G.S., E.L.F., G.H.G.); DTU Compute, Technical University of Denmark, Lyngby (L.C.); The Heart Centre, Rigshospitalet (E.L.F., L.K.), and Department of Clinical Medicine (G.H.G.), University of Copenhagen, Denmark; Institute of Health, Science and Technology, Aalborg University, Denmark (C.T.-P.); The National Institute of Public Health, University of Southern Denmark, Copenhagen (G.H.G.); University of Copenhagen, Denmark; and Department of Medicine, Section of Cardiology, Glostrup Hospital, University of Copenhagen, Denmark (C.A.).
authors.forename: Line
authors.initials: L
authors.lastname: Clemmensen
authors.affiliation: From the Danish Heart Foundation, Copenhagen, Denmark (P.W.H., T.S.G.S., E.L.F., G.H.G.); DTU Compute, Technical University of Denmark, Lyngby (L.C.); The Heart Centre, Rigshospitalet (E.L.F., L.K.), and Department of Clinical Medicine (G.H.G.), University of Copenhagen, Denmark; Institute of Health, Science and Technology, Aalborg University, Denmark (C.T.-P.); The National Institute of Public Health, University of Southern Denmark, Copenhagen (G.H.G.); University of Copenhagen, Denmark; and Department of Medicine, Section of Cardiology, Glostrup Hospital, University of Copenhagen, Denmark (C.A.).
authors.forename: Thomas S G
authors.initials: TS
authors.lastname: Sehested
authors.affiliation: From the Danish Heart Foundation, Copenhagen, Denmark (P.W.H., T.S.G.S., E.L.F., G.H.G.); DTU Compute, Technical University of Denmark, Lyngby (L.C.); The Heart Centre, Rigshospitalet (E.L.F., L.K.), and Department of Clinical Medicine (G.H.G.), University of Copenhagen, Denmark; Institute of Health, Science and Technology, Aalborg University, Denmark (C.T.-P.); The National Institute of Public Health, University of Southern Denmark, Copenhagen (G.H.G.); University of Copenhagen, Denmark; and Department of Medicine, Section of Cardiology, Glostrup Hospital, University of Copenhagen, Denmark (C.A.).
authors.forename: Emil Loldrup
authors.initials: EL
authors.lastname: Fosbøl
authors.affiliation: From the Danish Heart Foundation, Copenhagen, Denmark (P.W.H., T.S.G.S., E.L.F., G.H.G.); DTU Compute, Technical University of Denmark, Lyngby (L.C.); The Heart Centre, Rigshospitalet (E.L.F., L.K.), and Department of Clinical Medicine (G.H.G.), University of Copenhagen, Denmark; Institute of Health, Science and Technology, Aalborg University, Denmark (C.T.-P.); The National Institute of Public Health, University of Southern Denmark, Copenhagen (G.H.G.); University of Copenhagen, Denmark; and Department of Medicine, Section of Cardiology, Glostrup Hospital, University of Copenhagen, Denmark (C.A.).
authors.forename: Christian
authors.initials: C
authors.lastname: Torp-Pedersen
authors.affiliation: From the Danish Heart Foundation, Copenhagen, Denmark (P.W.H., T.S.G.S., E.L.F., G.H.G.); DTU Compute, Technical University of Denmark, Lyngby (L.C.); The Heart Centre, Rigshospitalet (E.L.F., L.K.), and Department of Clinical Medicine (G.H.G.), University of Copenhagen, Denmark; Institute of Health, Science and Technology, Aalborg University, Denmark (C.T.-P.); The National Institute of Public Health, University of Southern Denmark, Copenhagen (G.H.G.); University of Copenhagen, Denmark; and Department of Medicine, Section of Cardiology, Glostrup Hospital, University of Copenhagen, Denmark (C.A.).
authors.forename: Lars
authors.initials: L
authors.lastname: Køber
authors.affiliation: From the Danish Heart Foundation, Copenhagen, Denmark (P.W.H., T.S.G.S., E.L.F., G.H.G.); DTU Compute, Technical University of Denmark, Lyngby (L.C.); The Heart Centre, Rigshospitalet (E.L.F., L.K.), and Department of Clinical Medicine (G.H.G.), University of Copenhagen, Denmark; Institute of Health, Science and Technology, Aalborg University, Denmark (C.T.-P.); The National Institute of Public Health, University of Southern Denmark, Copenhagen (G.H.G.); University of Copenhagen, Denmark; and Department of Medicine, Section of Cardiology, Glostrup Hospital, University of Copenhagen, Denmark (C.A.).
authors.forename: Gunnar H
authors.initials: GH
authors.lastname: Gislason
authors.affiliation: From the Danish Heart Foundation, Copenhagen, Denmark (P.W.H., T.S.G.S., E.L.F., G.H.G.); DTU Compute, Technical University of Denmark, Lyngby (L.C.); The Heart Centre, Rigshospitalet (E.L.F., L.K.), and Department of Clinical Medicine (G.H.G.), University of Copenhagen, Denmark; Institute of Health, Science and Technology, Aalborg University, Denmark (C.T.-P.); The National Institute of Public Health, University of Southern Denmark, Copenhagen (G.H.G.); University of Copenhagen, Denmark; and Department of Medicine, Section of Cardiology, Glostrup Hospital, University of Copenhagen, Denmark (C.A.).
authors.forename: Charlotte
authors.initials: C
authors.lastname: Andersson
mesh_terms: D000067575:Administrative Claims, Healthcare; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000009:adverse effects*; D001281:Atrial Fibrillation / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D001777:Blood Coagulation / Q000187:drug effects*; D057225:Data Mining / Q000379:methods*; D004347:Drug Interactions; D011307:Drug Prescriptions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D016015:Logistic Models; D000069550:Machine Learning; D008297:Male; D010865:Pilot Projects; D019338:Polypharmacy; D011237:Predictive Value of Tests; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D014859:Warfarin
keywords: big data; data mining; drug interactions; machine learning; registry; warfarin