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

被引：61

作者：

Allesoe, Rosa Lundbye ^{[1
,2
,3
]}

Lundgaard, Agnete Troen ^{[1
,2
]}

Medina, Ricardo Hernandez ^{[1
]}

Aguayo-Orozco, Alejandro ^{[1
,2
]}

Johansen, Joachim ^{[1
,2
]}

Nissen, Jakob Nybo ^{[1
]}

Brorsson, Caroline ^{[1
,2
]}

Mazzoni, Gianluca ^{[1
,2
]}

Niu, Lili ^{[1
]}

Biel, Jorge Hernansanz ^{[1
,2
]}

Brasas, Valentas ^{[1
]}

Webel, Henry ^{[1
]}

Benros, Michael Eriksen ^{[3
,4
]}

Pedersen, Anders Gorm ^{[2
]}

Chmura, Piotr Jaroslaw ^{[1
,2
]}

Jacobsen, Ulrik Plesner ^{[1
,2
]}

Mari, Andrea ^{[5
]}

Koivula, Robert ^{[6
]}

Mahajan, Anubha ^{[6
]}

Vinuela, Ana ^{[7
,8
]}

Tajes, Juan Fernandez ^{[6
]}

Sharma, Sapna ^{[9
,10
,11
]}

Haid, Mark ^{[12
]}

Hong, Mun-Gwan ^{[13
]}

Musholt, Petra B. ^{[14
]}

De Masi, Federico ^{[1
,2
]}

Vogt, Josef ^{[15
]}

Pedersen, Helle Krogh ^{[2
,15
]}

Gudmundsdottir, Valborg ^{[1
,2
]}

Jones, Angus ^{[16
]}

Kennedy, Gwen ^{[17
]}

Bell, Jimmy ^{[18
]}

Thomas, E. Louise ^{[18
]}

Frost, Gary ^{[19
]}

Thomsen, Henrik ^{[20
]}

Hansen, Elizaveta ^{[20
]}

Hansen, Tue Haldor ^{[15
]}

Vestergaard, Henrik ^{[15
]}

Muilwijk, Mirthe ^{[21
]}

Blom, Marieke T. ^{[22
]}

Hart, Leen M. T. ^{[21
,23
,24
]}

Pattou, Francois ^{[25
]}

Raverdy, Violeta ^{[25
]}

Brage, Soren ^{[26
]}

Kokkola, Tarja ^{[27
]}

Heggie, Alison ^{[28
]}

McEvoy, Donna ^{[29
]}

Mourby, Miranda ^{[30
]}

Kaye, Jane ^{[30
]}

Hattersley, Andrew ^{[16
]}

机构：

[1] Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth & Med Sci, Copenhagen, Denmark

[2] Tech Univ Denmark, Dept Hlth Technol, Lyngby, Denmark

[3] Copenhagen Univ Hosp, Copenhagen Res Ctr Mental Hlth, Mental Hlth Ctr Copenhagen, Copenhagen, Denmark

[4] Univ Copenhagen, Fac Hlth & Med Sci, Dept Immunol & Microbiol, Copenhagen, Denmark

[5] CNR, Inst Neurosci, Padua, Italy

[6] Univ Oxford, Wellcome Ctr Human Genet, Oxford, England

[7] Univ Geneva, Dept Genet Med & Dev, Med Sch, Geneva, Switzerland

[8] Newcastle Univ, Fac Med Sci, Biosci Inst, Newcastle Upon Tyne, Tyne & Wear, England

[9] Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany

[10] Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany

[11] Tech Univ Munich, Chair Food Chem & Mol & Sensory Sci, Freising Weihenstephan, Germany

[12] Helmholtz Zentrum Muenchen, German Res Ctr Environm Hlth, Metabol & Prote Core, Neuherberg, Germany

[13] KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, Affin Prote, Solna, Sweden

[14] Sanofi Aventis Deutschland, Res & Dev Global Dev Translat Med & Clin Pharmaco, Frankfurt, Germany

[15] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark

[16] Univ Exeter Med Sch, Exeter, Devon, England

[17] Univ Dundee, Sch Med, Immunoassay Biomarker Core Lab, Dundee, Scotland

[18] Univ Westminster, Res Ctr Optimal Hlth, Dept Life Sci, London, England

[19] Imperial Coll London, Fac Med, Sect Nutr Res, London, England

[20] Copenhagen Univ Hosp Herlev Gentofte, Dept Radiol, Herlev, Denmark

[21] Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Dept Epidemiol & Data Sci, Amsterdam UMC, Amsterdam, Netherlands

[22] Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Dept Gen Practice, Amsterdam UMC, Amsterdam, Netherlands

[23] Leiden Univ Med Ctr, Dept Biomed Data Sci, Sect Mol Epidemiol, Leiden, Netherlands

[24] Leiden Univ Med Ctr, Dept Cell & Chem Biol, Leiden, Netherlands

[25] Univ Lille, Lille Pasteur Inst, EGID, CHU Lille,Inserm, Lille, France

[26] Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge, England

[27] Univ Eastern Finland, Dept Med, Kuopio, Finland

[28] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England

[29] Royal Victoria Infirm, Diabet Res Network, Newcastle Upon Tyne, Tyne & Wear, England

[30] Univ Oxford, Fac Law, Ctr Hlth Law & Emerging Technol HeLEX, Oxford, England

[31] Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden

[32] Newcastle Univ, Fac Med Sci, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[33] Univ Dundee, Sch Med, Div Populat Hlth & Genom, Dundee, Scotland

[34] Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Genet & Mol Epidemiol Unit,CRC,SUS, Malmo, Sweden

[35] Eli Lilly Reg Operat, Vienna, Austria

[36] Harvard TH Chan Sch Publ Hlth, Boston, MA USA

[37] Univ Oxford, Radcliffe Dept Med, OCDEM, Oxford, England

[38] German Res Ctr Environm Hlth, Inst Expt Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany

[39] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore

[40] Univ Ljubljana, Fac Med, Inst Biochem, Ljubljana, Slovenia

[41] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[42] Genentech Inc, San Francisco, CA 94080 USA

来源：

NATURE BIOTECHNOLOGY | 2023年 / 41卷 / 03期

关键词：

METFORMIN TREATMENT; MULTI-OMICS; METAANALYSIS; CHOLESTEROL;

D O I：

10.1038/s41587-022-01520-x

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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.

引用

页码：399 / +

页数：17

共 77 条

[11] Metformin-induced changes of the gut microbiota in healthy young men: results of a non-blinded, one-armed intervention study [J].

Bryrup, Thomas ;

Thomsen, Caecilie W. ;

Kern, Timo ;

Allin, Kristine H. ;

Brandslund, Ivan ;

Jorgensen, Nikias R. ;

Vestergaard, Henrik ;

Hansen, Torben ;

Hansen, Tue H. ;

Pedersen, Oluf ;

Nielsen, Trine .

DIABETOLOGIA, 2019, 62 (06) :1024-1035

[12] Multi-omics single-cell data integration and regulatory inference with graph-linked embedding [J].

Cao, Zhi-Jie ;

Gao, Ge .

NATURE BIOTECHNOLOGY, 2022, 40 (10) :1458-+

[13] Deep Learning-Based Multi-Omics Integration Robustly Predicts Survival in Liver Cancer [J].

Chaudharyl, Kumardeep ;

Poirionl, Olivier B. ;

Lu, Liangqun ;

Garmire, Lana X. .

CLINICAL CANCER RESEARCH, 2018, 24 (06) :1248-1259

[14] MetaboAnalystR: an R package for flexible and reproducible analysis of metabolomics data [J].

Chong, Jasmine ;

Xia, Jianguo .

BIOINFORMATICS, 2018, 34 (24) :4313-4314

[15] Unsupervised classification of multi-omics data during cardiac remodeling using deep learning [J].

Chung, Neo Christopher ;

Mirza, Bilal ;

Choi, Howard ;

Wang, Jie ;

Wang, Ding ;

Ping, Peipei ;

Wang, Wei .

METHODS, 2019, 166 :66-73

[16]

Croft D, 2014, NUCLEIC ACIDS RES, V42, pD472, DOI [10.1093/nar/gkz1031, 10.1093/nar/gkt1102]

[17] Interpretable dimensionality reduction of single cell transcriptome data with deep generative models [J].

Ding, Jiarui ;

Condon, Anne ;

Shah, Sohrab P. .

NATURE COMMUNICATIONS, 2018, 9

[18] Amlodipine in hypertension: a first-line agent with efficacy for improving blood pressure and patient outcomes [J].

Fares, Hassan ;

DiNicolantonio, James J. ;

O'Keefe, James H. ;

Lavie, Carl J. .

OPEN HEART, 2016, 3 (02)

[19] Impact of Statin Therapy on Plasma MMP-3, MMP-9, and TIMP-1 Concentrations: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials [J].

Ferretti, Gianna ;

Bacchetti, Tiziana ;

Banach, Maciej ;

Simental-Mendia, Luis E. ;

Sahebkar, Amirhossein .

ANGIOLOGY, 2017, 68 (10) :850-862

[20] Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota [J].

Forslund, Kristoffer ;

Hildebrand, Falk ;

Nielsen, Trine ;

Falony, Gwen ;

Le Chatelier, Emmanuelle ;

Sunagawa, Shinichi ;

Prifti, Edi ;

Vieira-Silva, Sara ;

Gudmundsdottir, Valborg ;

Pedersen, Helle Krogh ;

Arumugam, Manimozhiyan ;

Kristiansen, Karsten ;

Voigt, Anita Yvonne ;

Vestergaard, Henrik ;

Hercog, Rajna ;

Costea, Paul Igor ;

Kultima, Jens Roat ;

Li, Junhua ;

Jorgensen, Torben ;

Levenez, Florence ;

Dore, Joel ;

Nielsen, H. Bjorn ;

Brunak, Soren ;

Raes, Jeroen ;

Hansen, Torben ;

Wang, Jun ;

Ehrlich, S. Dusko ;

Bork, Peer ;

Pedersen, Oluf .

NATURE, 2015, 528 (7581) :262-+

← 1 2 3 4 5 6 7 8 →