Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.

Journal: Nature biotechnology
Published Date: Jan 2, 2023

Abstract

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

Authors

  • Rosa Lundbye Allesøe
    Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.
  • Agnete Troen Lundgaard
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Ricardo Hernández Medina
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Alejandro Aguayo-Orozco
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Joachim Johansen
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Jakob Nybo Nissen
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Caroline Brorsson
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Gianluca Mazzoni
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Lili Niu
    NNF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Jorge Hernansanz Biel
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Cristina Leal Rodríguez
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Valentas Brasas
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Henry Webel
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Michael Eriksen Benros
    Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.
  • Anders Gorm Pedersen
    Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.
  • Piotr Jaroslaw Chmura
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Ulrik Plesner Jacobsen
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Andrea Mari
  • Robert Koivula
    Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Anubha Mahajan
    Wellcome Centre for Human Genetics, Oxford, United Kingdom.
  • Ana Viñuela
    Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
  • Juan Fernandez Tajes
    Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Sapna Sharma
    German Center for Diabetes Research, Neuherberg, Germany.
  • Mark Haid
    Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, Neuherberg, Germany.
  • Mun-Gwan Hong
    Affinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden.
  • Petra B Musholt
    Diabetes Division, Research and Development, Sanofi, Frankfurt, Germany.
  • Federico De Masi
    Department of Bio and Health Informatics, DTU Bioinformatics, Technical University of Denmark, Lyngby, 2800, Denmark.
  • Josef Vogt
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Helle Krogh Pedersen
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Valborg Gudmundsdottir
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Angus Jones
    University of Exeter Medical School, Exeter, UK.
  • Gwen Kennedy
    Immunoassay Biomarker Core Laboratory, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom.
  • Jimmy Bell
    Research Centre for Optimal Health, Department of Life Sciences, University of Westminster, London, UK.
  • E Louise Thomas
    Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom.
  • Gary Frost
    Section for Nutrition Research, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.
  • Henrik Thomsen
    Department of Radiology, Copenhagen University Hospital Herlev-Gentofte, Herlev, Denmark.
  • Elizaveta Hansen
    Department of Radiology, Copenhagen University Hospital Herlev-Gentofte, Herlev, Denmark.
  • Tue Haldor Hansen
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Henrik Vestergaard
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Mirthe Muilwijk
    Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • Marieke T Blom
    Department of General Practice, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • Leen M 't Hart
    Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam UMC, Amsterdam, the Netherlands.
  • Francois Pattou
    University of Lille, Inserm, UMR 1190, Translational Research in Diabetes, Department of Endocrine Surgery, CHU Lille, Lille, France.
  • Violeta Raverdy
    University of Lille, Inserm, UMR 1190, Translational Research in Diabetes, Department of Endocrine Surgery, CHU Lille, Lille, France.
  • Soren Brage
    MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
  • Tarja Kokkola
    Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
  • Alison Heggie
    Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • Donna McEvoy
    Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • Miranda Mourby
    Centre for Health, Law and Emerging Technologies (HeLEX), Faculty of Law, University of Oxford, Oxford, UK.
  • Jane Kaye
    Centre for Health, Law and Emerging Technologies (HeLEX), Faculty of Law, University of Oxford, Oxford, UK.
  • Andrew Hattersley
    University of Exeter Medical School, Exeter, UK.
  • Timothy McDonald
    University of Exeter Medical School, Exeter, UK.
  • Martin Ridderstråle
    Department of Endocrinology, Clinical Obesity Research, Skåne University Hospital 214 28, Malmö, Sweden.
  • Mark Walker
    Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
  • Ian Forgie
    Division of Population Health & Genomics, School of Medicine, University of Dundee, Dundee, UK.
  • Giuseppe N Giordano
    Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
  • Imre Pavo
    Eli Lilly Regional Operations, Vienna, Austria.
  • Hartmut Ruetten
    Sanofi-Aventis Deutschland, Frankfurt am Main, Germany.
  • Oluf Pedersen
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Torben Hansen
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Emmanouil Dermitzakis
    Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
  • Paul W Franks
    Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
  • Jochen M Schwenk
    Affinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden.
  • Jerzy Adamski
    Research Unit Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan 85350, Germany; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore.
  • Mark I McCarthy
    Wellcome Centre for Human Genetics, Oxford, United Kingdom.
  • Ewan Pearson
    Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, United Kingdom.
  • Karina Banasik
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Simon Rasmussen
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Søren Brunak
    NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

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