Prospective Validation of a Transcriptomic Metric in Severe Trauma

Abstract

Objective:: To prospectively validate a previously discovered transcriptomic biomarker consisting of 63 blood leukocyte gene expression (S63) values to discriminate between trauma patients who rapidly recover and those with prolonged hospital stays who would benefit from early biological interventions.

Background:: Many severe trauma patients are successfully resuscitated but have complicated clinical trajectories leading to long-term functional, physical, and cognitive deficiencies. Identifying those trauma patients early would improve treatment plans and resource allocation. Unfortunately, current clinical scores and biomarkers used in trauma clinical trials have typically lacked adequate predictive ability.

Methods:: An independent, prospective, observational cohort study was performed involving 127 trauma subjects. The prospective cohort included patients admitted between October 2013 and August 2016 at 2 United States Level-1 trauma centers. An additional secondary analysis was performed using the Activation of Coagulation and Inflammation in Trauma (ACIT2) database of 26 trauma patients.

Results:: The S63 transcriptomic metric (AUC 0.80) outperformed clinical markers and plasma interleukin-6 for prospectively predicting trauma patients who require intensive care unit stays longer than 5 days with ongoing organ dysfunction. The same metric applied to an existing dataset (ACIT2) was similarly effective (AUC 0.85) at predicting multiorgan failure.

Conclusions:: A single transcriptomic metric of blood leukocyte gene expression can be used in blunt trauma cohorts at 24 hours to distinguish patients who rapidly recover from those with complicated clinical trajectories. The transcriptomic metric has been operationalized on an Food and Drug Administration 510(k)-cleared platform otherwise used for cancer diagnostics. This metric is only modestly improved when combined with clinical markers.

FIGURE 1.

Mean transcriptomic and plasma IL-6 concentrations in trauma patients with different clinical outcomes. S63 (A) gene expression scores and plasma IL-6 concentrations (B) in patients stratified into uncomplicated, intermediate, and complicated trajectories. S63 (A) scores for the 3 stratified groups were significantly different at 24 hours; ^†P < 0.05). At <12 h, only the levels of S63 in the uncomplicated group significantly differed from the other 2 groups (*P < 0.05 by ANOVA and Tukey post-hoc comparison). In contrast, IL-6 concentrations at both <12 and 24 h were significantly greater in complicated patients than in the other 2 groups (*P < 0.05).

FIGURE 2.

Predictive modeling of clinical outcome. A, Univariate predictive modeling of complicated/intermediate versus uncomplicated outcome for trauma cohort based on values at 24 h. Curves corresponding to ISS, APACHE, IL-6, and S63 models were created with univariate AUC provided in parentheses. B, Multivariate predictive modeling of complicated/intermediate versus uncomplicated outcome for trauma cohort based on values at 24 h. Curves corresponding to multivariate models of S63+IL-6, S63+APACHE+ISS, and S63+APACHE+ISS+IL-6 were created with AUC provided in parentheses. C, S63 Threshold optimization. Here the predictive probability was plotted against the scores for the 2 outcome groups and optimized thresholds identified. D, Predictive modeling of multiple organ dysfunction syndrome versus no multiple organ dysfunction syndrome for community cohort. The community dataset utilized illumina rather than nanostring transcriptomic analysis and reported data on 58 of 63 genes. A curve corresponding to S58 prediction of MODS was created with corresponding AUC in parentheses.

FIGURE 3.

Transcriptomic metrics derived from S63 focused on inflammation, adaptive immunity, and endothelial activation. Individual metrics derived from subsets of genes involved in inflammation, endothelial activation, and adaptive immunity (S Table 2, http://links.lww.com/SLA/B564) were calculated in the 3 discrete outcomes. All values from trauma patients at <12 and 24 h were significantly greater than seen in healthy controls (^†††). For endothelial activation and inflammation, 24 h metrics were significantly lower than <12 h (P < 0.05 by paired- t test). (*P < 0.05; ^** P < 0.01 vs complicated outcome).