Osteoarthritis endotype discovery via clustering of biochemical marker data

Abstract

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.

Keywords: epidemiology; knee; osteoarthritis.

Conflict of interest statement

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.

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