325 (HRs) with corresponding 95% CIs, where biomarker levels were 2log-transformed before entry to facilitate results interpretation (per doubling). The proportionality of hazards assumption was checked for all biomarkers to confirm the absence of violation. Multivariable Cox regression models were intended to be performed to adjust for potential confounding factors, but omitted due to a low number of occurring events. Cox regression analyses were repeated using restricted cubic splines (RCS) with three knots to evaluate non-linearity of associations between biomarkers and progression of stricturing or penetrating disease, or the risk of surgical interventions. RCS is a flexible method to model and visualize relationships between continuous predictor variables and prospective outcomes as entered in Cox proportional hazards regression analysis. Furthermore, RCS can be used to test the hypothesis for absence of linear relationships, or summarizing relationships that seem to be too non-linear to be adequately summarized in a linear relationship. Non-linearity in RCS was evaluated using likelihood ratio tests, where nested models were compared using linear or linear and cubic spline terms. Collagen biomarkers and Crohn’s disease behavior
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