title: Personalized medicine: genetic variation and loss of physiologic complexity are associated with mortality in 644 trauma patients.
abstract: OBJECTIVE
  Personalized medicine merges genetics, physiology, and patient outcome. Loss of physiologic complexity (heart rate [HR] variability) is a bedside biomarker for autonomic nervous system (ANS) dysfunction. We hypothesized that variability in ANS receptor proteins (genetics) and loss of complexity (physiology) are independently associated with mortality in critical illness.
  
  
  BACKGROUND
  Decreased HR complexity has been associated with increased mortality and morbidity in trauma and other critically ill populations. Genetic variations in alpha-1A and beta-2 adrenergic receptors (ADRA1A, ADRB2) have been associated with changes in smooth muscle tone in various tissues, and implicated in bronchial hyper-responsiveness, metabolic syndrome, and other disorders.
  
  
  METHODS
  A cohort of 644 trauma intensive care unit (ICU) admissions had complexity data and genetic samples. Two ANS receptor polymorphisms (rs1048101, Alpha ADRA1A and rs1042714, Beta ADRB2) were genotyped. Physiologic complexity at various points in the ICU stay was measured using previously-studied integer HR multiscale entropy (MSE) over 6-hour intervals (~21,600 HR data points/interval/patient). Logistic regression assessed the concurrent relationship of genotypes, complexity, and probability of survival, an acuity score incorporating age, injury mechanism/severity, and admission vitals, to risk of death.
  
  
  RESULTS
  Of total, 96 patients (15%) died. Nonsurvivors had lower complexity at early, middle, and late portions of ICU stay (median MSE at least 25% less in nonsurvivors, P < 0.001) and lower incidence of the GG ADRB2 genotype (7.5% vs. 18.3%, P < 0.001). In multivariable logistic regression, the GG ADRB2 genotype carried ~3-fold decrease in mortality odds (odd ratio [OR] = 0.33, P = 0.01), independent of significant effects in HR MSE (OR = 0.93, P < 0.001), and probability of survival (OR = 0.22, P < 0.001).
  
  
  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); and (3) Simultaneous assessment of ANS physiology and genetics may yield novel research, diagnostic, and therapeutic opportunities in critical illness.
authors.affiliation: Division of Trauma and Surgical Critical Care, Vanderbilt University, Nashville, Tennessee, USA. patrick.norris@vanderbilt.edu
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Norris
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Canter
authors.forename: Judith M
authors.initials: JM
authors.lastname: Jenkins
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.forename: Anna E
authors.initials: AE
authors.lastname: Williams
authors.forename: John A
authors.initials: JA
authors.lastname: Morris
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D015601:Injury Severity Score; D007362:Intensive Care Units; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D012372:ROC Curve; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012189:Retrospective Studies; D013714:Tennessee / Q000453:epidemiology; D014947:Wounds and Injuries / Q000235:genetics* / Q000401:mortality*
chemical_list: C547713:ADRA1A protein, human; C553443:ADRB2 protein, human; D015415:Biomarkers; D018340:Receptors, Adrenergic, alpha-1; D018343:Receptors, Adrenergic, beta-2