Statistical Approach to Metabonomic Analysis of Rat Urine Following Surgical Trauma

SUMMARY: Acute trauma is often associated with the progressive deterioration of multiple organ systems in humans and is the leading cause of death in trauma care units. Previous studies have suggested that multiple organ failure is likely related to uncontrolled systemic inflammation. However the causal mechanisms remain unknown. Current methods of assessing trauma patient status and predicting outcome are based on a variety of anatomical and/or physiological scoring models. While being useful, these are labor intensive and do not allow for real-time analysis of patient status. In this study, we have developed a metabonomic based approach using a rodent model of acute trauma in order to determine whether statistically significant differences exist between the quantitative and qualitative profile of urinary metabolites of control rats and rats that have experienced surgical trauma. This approach incorporates statistical, analytical and computational tools in order to identify metabolites that are unique to trauma and maybe used to predict the trauma outcome. Statistical analysis showed significant differences between the trauma and the control urinary metabonomes. Partial least square (PLS) and Principle component analysis (PCA) combined with Logistic Regression (LR) were used to categorize subjects into either control or trauma with greater than 80% accuracy. We have also shown that using Bayesian methods that we could classify subjects being traumatic or control with a given credible interval. These results suggest that metabonomics may prove useful for quantifying and identifying biomarkers of trauma status as well as trauma outcome in humans. 1. Introduction Acute trauma with associated hemorrhage, shock and sepsis, often produces a generalized inflammatory response resulting in organ dysfunction and multiple organ failure. Multiple organ failure is associated with high mortality rates and is among the leading causes of death in Americans between the ages of 1 and 44 (Anderson and Smith, 2003). It is also the leading cause of death in trauma intensive care units (Kuhls, Malone, McCarter and Napolitano, 2002). This is despite tremendous technological advances in the use of mechanical ventilation, invasive hemodynamic monitoring, vasoactive therapy, dialysis, and parenteral nutrition. The final pathway leading to organ failure and death, as a consequence of this inflammatory response is defective oxygen and substrate utilization by critical cell populations of the host, presumably mediated by the activation of numerous effector molecules (Regel, Grotz, Weltner, Sturm and Tscherne, 1996). The mechanisms underlying the progression from acute trauma to multiple organ failure remain poorly understood. An emerging …