Background Success in personalised medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay (PEA) to identify diagnostic and prognostic biomarkers in inflammatory bowel disease (IBD). Methods We conducted a prospective case-control study in an inception cohort of 552 patients (328 IBD, 224 non-IBD), profiling proteins recruited across 6 centres. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross validation was used to examine the performance of diagnostic and prognostic proteins. Results A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls including Matrix Metalloproteinase-12 (Holm adjusted p=4.1×10−23) and Oncostatin-M (OSM, p=3.7×10−16). Nine of these proteins associate with cis - germline variation (59 independent SNPs). Fifteen proteins, all members of TNF independent pathways including interleukin-1 and OSM predicted escalation, over a median follow-up of 518 (IQR 224-756) days. Nested cross-validation of the entire data set allows characterisation of 5-protein-models (96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7, and IL8) which define a high-risk subgroup in IBD (HR 3.90, 95% CI: 2.43-6.26), or allows distinct 2, and 3 protein models for UC and CD respectively. Conclusion We have characterised a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and predicts the evolution of disease over time. The technology could be suitable as a point of care testing in defining risk. Further prospective work is required to characterise the utility of the approach. ### Competing Interest Statement R. Kalla Financial support for research: EC IBD-Character, Lecture fee(s): Ferring, N. Kennedy Financial support for research: Wellcome Trust, Conflict with: Pharmacosmos, Takeda, Janssen, Dr Falk speaker fees. Abbvie, Janssen travel support, A. Adams: None Declared, J. Satsangi Financial support for research: EC grant IBD-BIOM, Wellcome, CSO, MRC, Con-flict with: Consultant for: Takeda, Conflict with: MSD speaker fees. Shire travelling expenses

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