Improving Differentiation of Crohn's Disease and Ulcerative Colitis Proteomes through Protein-Wide Association Study Feature Selection in Machine Learning.

Background And Aims: Diagnostic differentiation between Crohn's disease (CD) and ulcerative colitis (UC) is crucial for timely and suitable therapeutic measures. The current gold standard for differentiating between CD and UC involves endoscopy and histology, which are invasive and costly. We aimed to identify blood plasma proteomic signatures using a Protein-Wide Association Study (PWAS) approach to differentiate CD from UC and evaluate the efficacy of these signatures as features in machine learning (ML) classifiers.

Methods: Among participants (n=1,106; n=636; n=470) of the Study of a Prospective Adult Research Cohort with IBD (SPARC), plasma protein (n=2,920) levels were estimated using Olink proteomics. A PWAS with Bonferroni correction for multiple testing was used to identify proteins associated with disease states after controlling for age, sex, and disease severity. ML classifiers examined the diagnostic utility of these models. Feature importance was determined via SHapley Additive exPlanations (SHAP) analysis.

Results: Thirteen proteins which were significantly differentially abundant in CD vs UC (all |β|s > 0.22, all adjusted p values < 8.42E-06). Random forest models of proteins differentiated between CD and UC with models trained only on PWAS identified proteins (Average ROC-AUC 0.73) outperforming models trained of the full proteome (Average ROC-AUC 0.62). SHAP analysis revealed that Granzyme B, insulin-like peptide 5 (INSL5), and interleukin-12 subunit beta (IL-12B) were the most important features.

Conclusions: Our findings demonstrate that PWAS-based feature selection approaches are a powerful method to identify features in complex, noisy datasets. Importantly, we have identified novel peptide based biomarkers such as INSL5, that can be potentially used to complement existing strategies to differentiate between CD and UC.