Personalized Medicine: Genetic Variation and Early Loss of Physiologic Complexity are Associated with Mortality in 633 Trauma Patients
*Patrick R Norris, *Jeffrey A Canter, *Judith M Jenkins, *Anna E Williams, John A Morris, Jr.
Vanderbilt University Medical Center, Nashville, TN
OBJECTIVE(S): Personalized medicine merges genetics, physiology, and patient outcome. Loss of physiologic complexity (heart rate variability) is a bedside biomarker for autonomic nervous system (ANS) dysfunction. We hypothesized: Variability in ANS receptor proteins (genetics) and loss of complexity (physiology) are independently associated with mortality in critical illness.
METHODS: 633 trauma ICU admissions had complexity data and genetic samples. Two ANS receptor polymorphisms (rs1048101, Alpha ADRA1A; rs1042714, Beta ADRB2) were genotyped. Early physiologic complexity was measured using previously-studied heart rate multiscale entropy (MSE) over the first six hours (~18,000 HR data points/patient). Logistic regression assessed the concurrent relationship of genotypes, complexity, and Probability of Survival [P(S); incorporates age, injury mechanism/severity, admission vitals] to mortality.
RESULTS: 93 patients (15%) died. Non-survivors had lower complexity (MSE 12.5 vs. 15.7, p<.001) and incidence of the GG ADRB2 genotype (7.5% vs. 18.3%, p<.001). Logistic regression: The GG ADRB2 genotype carried ~3-fold decrease in mortality odds (OR=0.37), similar to a 19-unit increase in HR MSE (0.9519=0.37) or a 60% increase in P(S) (0.190.60=0.37).
CONCLUSIONS: This first study to simultaneously examine ANS genetics, the biomarker complexity, and mortality concludes:
1. ANS genetics and physiologic complexity are independently related to mortality.
2. Genetics and complexity add information over traditional acuity scoring (Probability of Survival).
3. Simultaneous assessment of ANS physiology and genetics may yield novel research, diagnostic, and therapeutic opportunities in critical illness.
|OR (95% CI)||P-value||AUC (95% CI)|
|Early HR complexity (MSE)||0.95 (0.02-0.98)||.002||0.72 (0.68-0.78)|
|rs1042714, Beta (GG vs. CC)||0.27 (0.12-0.64)||.003|
|rs1042714, Beta (GC vs. CC)||0.66 (0.40-1.08)||.097|
|rs1048101, Alpha (TT vs. CC)||1.61 (0.82-3.14)||.163|
|rs1048101, Alpha (TC vs. CC)||1.23 (0.68-2.21)||.500|
|Probability of Survival, P(S)||0.19 (0.10-0.37)||<.001|