Machine learning identifies novel blood protein predictors of penetrating and stricturing complications in newly diagnosed paediatric Crohn's disease

• Type of Material: Article
• Authors: Ryan C. Ungaro, Icahn School of Medicine at Mount Sinai; Liangyuan Hu, Icahn School of Medicine at Mount Sinai; Jiayi Ji, Icahn School of Medicine at Mount Sinai; Shikha Nayar, Icahn School of Medicine at Mount Sinai; Subramaniam Kugathasan, Emory University; Lee A. Denson, Cincinnati Children’s Hospital Medical Center; Jeffrey Hyams, Connecticut Children’s Medical Center; Marla C. Dubinsky, Icahn School of Medicine at Mount Sinai; Bruce E. Sands, Icahn School of Medicine at Mount Sinai; Judy H. Cho, Icahn School of Medicine at Mount Sinai
• Language: English
• Date: 2020-11-01
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2020
• Final Published Version (URL): http://dx.doi.org/10.1111/apt.16136
• Title of Journal or Parent Work: ALIMENTARY PHARMACOLOGY & THERAPEUTICS
• Volume: 53
• Issue: 2
• Start Page: 281
• End Page: 290
• Grant/Funding Information: RCU is supported by an NIH K23 Career Development Award (K23KD111995-01A1).; The Crohn’s and Colitis Foundation for providing funding for the RISK study, the RISK Steering Committee, and all participating RISK study sites. We also gratefully acknowledge the Sanford J. Grossman Charitable Trust, NIDDK R01 DK106593, U01 DK062422 (JHC).
• Keywords: MANAGEMENT; SOLUBLE CD40 LIGAND; EXPRESSION; ACTIVATION; Science & Technology; Life Sciences & Biomedicine; ULCERATIVE-COLITIS; THERAPY; INFLAMMATORY-BOWEL-DISEASE; Pharmacology & Pharmacy; NORTH; OUTCOMES; MULTICENTER; Gastroenterology & Hepatology
• Research Categories: Health Sciences, Pharmacy; Health Sciences, Pharmacology

Abstract

Background: There is a need for improved risk stratification in Crohn's disease. Aim: To identify novel blood protein biomarkers associated with future Crohn's disease complications. Methods: We performed a case-cohort study utilising a paediatric inception cohort, the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's disease (RISK) study. All patients had inflammatory disease (B1) at baseline. Outcomes were development of stricturing (B2) or penetrating (B3) complications. We assayed 92 inflammation-related proteins in baseline plasma using a proximity extension assay (Olink Proteomics). An ensemble machine learning technique, random survival forests (RSF), selected variables predicting B2 and B3 complications. Selected analytes were compared to clinical variables and serology only models. We examined selected proteins in a single-cell sequencing cohort to analyse differential cell expression in blood and ileum. Results: We included 265 patients with mean age 11.6 years (standard deviation [SD] 3.2). Seventy-three and 34 patients, respectively, had B2 and B3 complications within mean 1123 (SD 477) days for B2 and 1251 (442) for B3. A model with 5 protein markers predicted B3 complications with an area under the curve (AUC) of 0.79 (95% confidence interval [CI] 0.76-0.82) compared to 0.69 (95% CI 0.66-0.72) for serologies and 0.74 (95% CI 0.71-0.77) for clinical variables. A model with 4 protein markers predicted B2 complications with an AUC of 0.68 (95% CI 0.65-0.71) compared to 0.62 (95% CI 0.59-0.65) for serologies and 0.52 (95% CI 0.50-0.55) for clinical variables. B2 analytes were highly expressed in ileal stromal cells while B3 analytes were prominent in peripheral blood and ileal T cells. Conclusions: We identified novel blood proteomic markers, distinct for B2 and B3, associated with progression of paediatric Crohn's disease.