Identifying early pulmonary arterial hypertension biomarkers in systemic sclerosis: machine learning on proteomics from the DETECT cohort.

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort.Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK).Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity/86.5% specificity).This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc.
Competing Interests: Conflict of interest: Y. Bauer is a former employee of Actelion Pharmaceuticals Ltd and Idorsia Pharmaceuticals Ltd, and is now an employee of Galapagos GmbH. Conflict of interest: S. de Bernard reports grants from Idorsia, during the conduct of the study. Conflict of interest: P. Hickey has nothing to disclose. Conflict of interest: K. Ballard is an employee of Myriad RBM. Conflict of interest: J. Cruz is an employee of Myriad RBM. Conflict of interest: P. Cornelisse is a former employee of Actelion Pharmaceuticals Ltd. Conflict of interest: H. Chadha-Boreham is a former employee of Actelion Pharmaceuticals Ltd. Conflict of interest: O. Distler reports personal fees for consultancy from Amgen, AbbVie, Acceleron Pharma, AnaMar, Actelion, Alexion, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Corbuspharma, CSL Behring, ChemomAb, Horizon Pharmaceuticals, Ergonex, Galapagos NV, Glenmark Pharmaceuticals, GSK, Inventiva, Italfarmaco, iQone, iQvia, Kymera, Lilly, Medac, Sanofi, Target Bio Science and UCB, grants and personal fees for consultancy and lectures from Bayer and Boehringer Ingelheim, personal fees for interviewing from Catenion, grants from Competitive Drug Development International Ltd, personal fees for consultancy and lectures from Medscape, MSD, Pfizer and Roche, grants and personal fees for consultancy from Mitsubishi Tanabe Pharma, personal fees for lectures from Novartis, outside the submitted work; and has a patent mir-29 for the treatment of systemic sclerosis issued (US8247389, EP2331143). Conflict of interest: D. Rosenberg is an employee of and hold shares in Johnson and Johnson. Conflict of interest: M. Doelberg is an employee of Actelion Pharmaceuticals Ltd. Conflict of interest: S. Roux is a former employee of Actelion Pharmaceuticals Ltd. Conflict of interest: O. Nayler is a former employee and former stock owner of Actelion Pharmaceuticals Ltd, and current employee and stock owner of Idorsia Pharmaceuticals Ltd. Conflict of interest: A. Lawrie reports grants from the British Heart Foundation and Medical Research Council, grants, personal fees and other (conference attendance and travel) from Actelion Pharmaceuticals, grants and personal fees from GlaxoSmithKline, outside the submitted work.
(Copyright ©ERS 2021.)