MO805CAUSAL PATHWAY-BASED PHYSIOLOGICAL MODELING OF VASCULAR CALCIFICATION IN HEMODIALYSIS PATIENTS

Background and Aims Vascular calcification (VC) is common sequelae in chronic and end-stage kidney diseases (CKD/ESKD), and is associated with multiple risk factors, including disturbed bone metabolism and mineral disorders (CKD-BMD), uremia, leading to increased morbidity and mortality. The mechanism involves multiple physiological processes and is not well understood. The study aims to develop a causal pathway-based physiological model describing patient-specific drivers of vascular calcification. Method We develop a causal pathway-based physiological modeling that utilizes clinical data to identify patients with high risks of progression of VC and cardiometabolic diseases to provide multifactorial intervention strategies targeting the risk factors. We investigate the response of pulse pressure (PP, a proxy for pulse wave velocity) to parathyroid hormones (PTH), calcium (Ca), phosphate (PO4), calcium-phosphate product (CaPO4), neutrophil-lymphocyte ratio (NLR), and albumin (Alb). Pulse pressure may account for both cardiac and vascular conditions (e.g., atrial fibrillation, aortic insufficiency, arterial stiffness or arteriovenous malformation, aortic valve stenosis, cardiac insufficiency or cardiac tamponade). Results We demonstrate the causal pathway of PTH, Ca, PO4, NLR, and Alb on PP, and find that there are likely paths from PTH, Ca, PO4, CaPO4, NLR to PP, where the strength of the relationships vary from patient to patient. Figure 1 shows a representative patient. Figure 1(a) shows the longitudinal data for the aforementioned clinical parameters. Using a subset of the data (1 year was used), we extracted causal relationships between the clinical (Fig. 1(b)). As shown in Fig. 1(c), some of the relationships are physiologically consistent with current knowledge of the PTH, Ca, and PO4 disturbances on CKD-BMD, vascular calcification being one of the axes. Also, NLR is a measure of inflammation, which is also known to promote vascular calcification. Further, potential pathways were also detected, namely the direct or mediated effects of Alb and PTH on PP (as shown in Figs. 1(b)-(c)). Using these pathways, a dynamic model describing these interactions can be used to prescriptive investigate the impact of the dynamics on the progression of calcification. Conclusion From the clinical variables, the method was able to extract both known and potential drivers for changes on PP for the representative patients. Additional study is needed to confirm these relationships both prospectively, clinical investigation of potential pathways, and to further observe the long-term clinical manifestation of vascular calcification.

Physiological Modeling and Simulation—Validation, Credibility, and Application

In this review, we discuss the science of model validation as it applies to physiological modeling. There is widespread disagreement and ambiguity about what constitutes model validity. In areas in which models affect real-world decision-making, including within the clinic, in regulatory science, or in the design and engineering of novel therapeutics, this question is of critical importance. Without an answer, it impairs the usefulness of models and casts a shadow over model credibility in all domains. To address this question, we examine the use of nonmathematical models in physiological research, in medical practice, and in engineering to see how models in other domains are used and accepted. We reflect on historic physiological models and how they have been presented to the scientific community. Finally, we look at various validation frameworks that have been proposed as potential solutions during the past decade.