title: Emergent biomarker derived from next-generation sequencing to identify pain patients requiring uncommonly high opioid doses.
abstract: Next-generation sequencing (NGS) provides unrestricted access to the genome, but it produces 'big data' exceeding in amount and complexity the classical analytical approaches. We introduce a bioinformatics-based classifying biomarker that uses emergent properties in genetics to separate pain patients requiring extremely high opioid doses from controls. Following precisely calculated selection of the 34 most informative markers in the OPRM1, OPRK1, OPRD1 and SIGMAR1 genes, pattern of genotypes belonging to either patient group could be derived using a k-nearest neighbor (kNN) classifier that provided a diagnostic accuracy of 80.6±4%. This outperformed alternative classifiers such as reportedly functional opioid receptor gene variants or complex biomarkers obtained via multiple regression or decision tree analysis. The accumulation of several genetic variants with only minor functional influences may result in a qualitative consequence affecting complex phenotypes, pointing at emergent properties in genetics.
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kringel
authors.affiliation: DataBionics Research Group, University of Marburg, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ultsch
authors.affiliation: Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Schmerzzentrum Berlin, Berlin, Germany.
authors.forename: J-P
authors.initials: JP
authors.lastname: Jansen
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Vienna, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Ilias
authors.affiliation: Zentrum für Anästhesiologie, Intensivmedizin, Schmerztherapie &Palliativmedizin, Benedictus Krankenhaus Tutzing, Tutzing, Germany.|Klinik für Anästhesiologie, Technische Universität München, München, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Freynhagen
authors.affiliation: Department of Anesthesiology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Griessinger
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Freie Universität Berlin-Charité, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kopf
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Freie Universität Berlin-Charité, Berlin, Germany.
authors.forename: C
authors.identifier: 0000-0001-5240-6836
authors.initials: C
authors.lastname: Stein
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Doehring
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Frankfurt am Main, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Resch
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Frankfurt am Main, Germany.|Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Frankfurt am Main, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Lötsch
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000032:analysis*; D059350:Chronic Pain / Q000188:drug therapy* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D011957:Receptors, Opioid / Q000235:genetics*; D017465:Receptors, Opioid, delta / Q000235:genetics; D017473:Receptors, Opioid, kappa / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics; D017480:Receptors, sigma / Q000235:genetics; D000097605:Sigma-1 Receptor
chemical_list: D000701:Analgesics, Opioid; D054316:Biomarkers, Pharmacological; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C529706:OPRD1 protein, human; C515653:OPRK1 protein, human; C485764:OPRM1 protein, human