Combining mechanistic modeling with machine learning as a strategy to predict inflammatory bowel disease clinical...

Disease activity scores are efficacy endpoints in clinical trials of inflammatory bowel disease (IBD) therapies. Crohn's disease activity index (CDAI), Mayo endoscopic score (MES) and Mayo score are frequently used in clinical trials. They rely on either the physician's observation of the inflammatory state of the patient's gastrointestinal tissue alone or combined with the patient's subjective evaluation of general wellbeing. Given the importance of these scores in evaluating the efficacy of drug treatment and disease severity, there has been interest in developing a computational approach to reliably predict these scores. A promising approach is using mechanistic models such as quantitative systems pharmacology (QSP) which simulate the mechanisms of the disease and its modulation by the drug pharmacology. However, extending QSP model simulations to clinical score predictions has been challenging due to the limited availability of gut biopsy measurements and the subjective nature of some of the evaluation criteria for these scores that cannot be described using mechanistic relationships. In this perspective, we examine details of IBD disease activity scores and current progress in building predictive models for these scores (such as biomarkers for disease activity). Then, we propose a method to leverage simulated markers of inflammation from a QSP model to predict IBD clinical scores using a machine learning algorithm. We will demonstrate how this combined approach can be used to (1) explore mechanistic insights underlying clinical observations; and (2) simulate novel therapeutic strategies that could potentially improve clinical outcomes.