A Precision Medicine Approach Based on Discrete Time Windows for Predicting Outcomes of Polytrauma Patients

Background: Trauma (severe injury) with our without traumatic brain injury (TBI) is a leading cause of morbidity and mortality in both military and civilian populations. It is unclear why some trauma victims multiple organ dysfunction syndrome (MODS) and/or die, while others, with apparently similar injury characteristics, do not.

Objectives: We will utilize Precision Medicine approaches in a three-phase study of military and civilian trauma. In Phase 1 (Narrow-Window Diagnostic), we will further develop a novel concept based on time windows following severe injury, in which the earliest period post-injury is used to obtain biomarkers of short-term MODS outcomes, correlated with in-hospital outcomes, and eventually with long-term outcomes. In Phase 2 (Wide-Window Diagnostic), the predictive model from Phase 1, which is based on single time point data, will be compared against a Wide-Window algorithm involving multiple initial readings in the first 24 hours following injury. In Phase 3 (Optimized Patient Stratification), we will determine the optimal number of time points and variables that will best predict both in-hospital and 6-month outcomes of severely injured patients.

Focus Areas: This work will align with Focus Area 3 ('Environmental, physiological, and physical factors that govern an individual's predisposition to various responses to trauma' and 'Physiological, genetic, or physical factors that govern the individual's response to blood loss…'); Focus Area 4 ('Computational algorithms and predictive tools for physiological status monitoring…' and 'Evidence-based clinical decision support tools … for the prehospital environment and throughout the continuum of care to include en route care …'); and lastly Focus Area 1 ('Identification and/or characterization of TBI biomarkers that are specific to TBI alone and/or TBI with concomitant injuries'). Patient population: The proposed studies would benefit severely injured Warfighters and civilians with or without TBI.

Clinical Applications, Benefits, and Risks: The main anticipated clinical application is in the development of highly precise, quantitative means of defining which severely injured Warfighters will go on to have a complicated clinical course such as MODS or hospital-acquired infections and possibly succumb, and which ones will not. This will provide a major benefit to these individuals as well as to the medical personnel providing care. A longer-term application involves the use of these Precision Medicine tools to define which injured patients should be included in clinical trials of highly targeted therapies. Risks include the possibility of misdiagnosing or incorrectly predicting outcomes and thus mistargeting care, or, longer-term, incorrectly including or excluding patients from a clinical trial. However, these risks are mitigated by the fact that current knowledge and tools are sufficiently crude so as to have resulted in zero therapeutic options for MODS.

Projected Timeline: Each phase described above will last 12 months (36 months total).

Benefit to Military and Veteran Personnel/Families: Improvements in battlefield casualty evacuation combined with advances in surgical critical care have combined to dramatically improve the survivability of combat injuries. Paradoxically, however, this reduction in mortality has resulted in a greater burden of morbidity: Warfighters that survive their initial injuries are at risk of developing MODS, which can linger for months to years even after discharge from the hospital. Some of this burden is due to inadequate diagnosis and management of MODS during the hospital stay. The proposed studies are aimed at better targeting care for injured Warfighters, with the goal of reducing morbidity in the hospital setting and reducing the long-term burden of care for families.