Osteoarthritis endotype discovery via clustering of biochemical marker data.

epidemiology; knee; osteoarthritis; Biomarkers; Cluster Analysis; Disease Progression; Humans; Inflammation; Bone Resorption; Cartilage, Articular; Osteoarthritis, Knee/drug therapy; Osteoarthritis, Knee; Rheumatology; Immunology and Allergy; Immunology; Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology

Abstract :

[en] OBJECTIVES: Osteoarthritis (OA) patient stratification is an important challenge to design tailored treatments and drive drug development. Biochemical markers reflecting joint tissue turnover were measured in the IMI-APPROACH cohort at baseline and analysed using a machine learning approach in order to study OA-dominant phenotypes driven by the endotype-related clusters and discover the driving features and their disease-context meaning. METHOD: Data quality assessment was performed to design appropriate data preprocessing techniques. The k-means clustering algorithm was used to find dominant subgroups of patients based on the biochemical markers data. Classification models were trained to predict cluster membership, and Explainable AI techniques were used to interpret these to reveal the driving factors behind each cluster and identify phenotypes. Statistical analysis was performed to compare differences between clusters with respect to other markers in the IMI-APPROACH cohort and the longitudinal disease progression. RESULTS: Three dominant endotypes were found, associated with three phenotypes: C1) low tissue turnover (low repair and articular cartilage/subchondral bone turnover), C2) structural damage (high bone formation/resorption, cartilage degradation) and C3) systemic inflammation (joint tissue degradation, inflammation, cartilage degradation). The method achieved consistent results in the FNIH/OAI cohort. C1 had the highest proportion of non-progressors. C2 was mostly linked to longitudinal structural progression, and C3 was linked to sustained or progressive pain. CONCLUSIONS: This work supports the existence of differential phenotypes in OA. The biomarker approach could potentially drive stratification for OA clinical trials and contribute to precision medicine strategies for OA progression in the future. TRIAL REGISTRATION NUMBER: NCT03883568.

Disciplines :

Rheumatology

Author, co-author :

Angelini, Federico ; School of Computing, Newcastle University, Newcastle upon Tyne, UK

Widera, Paweł ; School of Computing, Newcastle University, Newcastle upon Tyne, UK

Mobasheri, Ali ; Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland ; Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania ; Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands ; Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China ; World Health Organization Collaborating Centre for Public Health Aspects of Musculoskeletal Health and Aging, Liege, Belgium

Blair, Joseph ; ImmunoScience, Nordic Bioscience, Herlev, Denmark

Struglics, André ; Faculty of Medicine, Department of Clinical Sciences Lund, Orthopaedics, Lund University, Lund, Sweden

Uebelhoer, Melanie ; Artialis SA, Liège, Belgium

Henrotin, Yves ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM) ; Artialis SA, Liège, Belgium

Marijnissen, Anne Ca; Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands

Kloppenburg, Margreet ; Rheumatology, Leiden Universitair Medisch Centrum, Leiden, The Netherlands ; Department of Clinical Epidemiology, Leiden Universitair Medisch Centrum, Leiden, The Netherlands

Blanco, Francisco J ; Servicio de Reumatologia, INIBIC-Hospital Universitario A Coruña, A Coruña, Spain

More authors (6 more)

Language :

English

Title :

Osteoarthritis endotype discovery via clustering of biochemical marker data.

Publication date :

2022

Journal title :

Annals of the Rheumatic Diseases

ISSN :

0003-4967

eISSN :

1468-2060

Publisher :

BMJ Publishing Group, England

Volume :

Issue :

Pages :

666-675

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://syndication.highwire.org/content/doi/10.1136/annrheumdis-2021-221763

Funders :

IMI - Innovative Medicines Initiative [BE]

Funding text :

Competing interests ACB-J is a full-time employee and shareholder of Nordic Bioscience, a privately owned company involved in the development and commercialisation of biomarkers for fibroinflammatory disorders. YH is the founder and president of Artialis, and MU is a full-time employéé of Artialis, a spin-off company of the University of Liège. YH has also received fees from Tilman, Genequine, Seikagaku, Expanscience, Nestlé, Immubio, Biose and Labhra. CL was an employee of Merck at project start. IKH consults for Abbvie and Novartis and has received funding from Pfizer. JL is employed by and shareholder in GlaxoSmithKline. FB reports personal fees from AstraZeneca, Boehringer, Bone Therapeutics, CellProthera, Expanscience, Galapagos, Gilead, Grunenthal, GSK, Eli Lilly, Merck Sereno, MSD, Nordic, Nordic Bioscience, Novartis, Pfizer, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, 4P Pharma, 4Moving Biotech and grants from TRB Chemedica, outside the submitted work. FJB reports funding from Gedeon Richter, Bristol-Myers Squibb, Sun Pharma Global FZE, Celgene, Janssen Cilag, Janssen Research & Development, Viela Bio, Astrazeneca, UCB BIOSCIENCES, UCB BIOPHARMA SPRL, AbbVie Deutschland, Merck, Amgen, Novartis Farmacéutica, Boehringer Ingelheim España, CSL Behring, Glaxosmithkline Research & Development, Pfizer, Lilly, Corbus Pharmaceuticals, Biohope Scientific Solutions for Human Health, Centrexion Therapeutics, Sanofi, TEDEC-MEIJI FARMA, Kiniksa Pharmaceuticals, Fundación para la Investigación Biomédica Del Hospital Clínico San Carlos, Grünenthal and Galapagos. MK receives consulting fees from Abbvie, Pfizer, Levicept, GlaxoSmithKline, Merck-Serono, Kiniksa, Flexion, Galapagos, Jansen, CHDR, Novartis, UCB. AM receives fees/funding from Merck, Kolon TissueGene, Pfizer, Galapagos-Servier, Image Analysis Group (IAG), Artialis, Aché Laboratórios Farmacêuticos, AbbVie, Guidepoint Global, Alphasights, Science Branding Communications, GSK, Flexion Therapeutics, Pacira Biosciences, Sterifarma, Bioiberica, SANOFI, Genacol, Kolon Life Science, BRASIT/BRASOS, GEOS, MCI Group, Alcimed, Abbot, Laboratoires Expansciences, SPRIM Communications, Frontiers Media and University Health Network Toronto.Funding The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under Grant Agreement no 115770, resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. See http://www.imi.europa.eu/ and http:// wwwapproachprojecteu/.

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