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. SUMMARY BACKGROUND DATA: 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.
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Most studies and reviews of precision medicine in critical illness focus on host genetics, immune responses, and exposures.
“Most studies and reviews of precision medicine in critical illness, however, focus on host genetics, immune responses, and exposures.153–155”
From The microbiome and critical illness (2016) · cites this paper as [154]
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- Authors
- Norris, P. R., Canter, J. A., Jenkins, J. M., Moore, J. H., Williams, A. E., & Morris, J. A.
- Affiliations
- Vanderbilt University (US)
- Dartmouth College (US)
- Corresponding author
- Norris, Patrick R.
- Jenkins, Judith M.
- Williams, Anna E.
- Morris, John A.
- Venue
- Annals of Surgery
- Published
- 2009-10
- Volume
- 250
- Issue
- 4
- Pages
- 524-530
- ISSN
- 0003-4932 (ISSN-L)
- OpenAlex
- W2074425052
- Cited by
- 40
- References
- 30
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 5 · 2012: 3
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Surgery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hd047447-05)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD047447)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- personalized medicine, heart rate variability, multiscale entropy, autonomic dysfunction, ADRA1A, ADRB2, trauma intensive care, mortality prediction, survival probability, genetic biomarkers, critical illness, personalized risk stratification, personalized treatment planning, personalized prevention, personalized screening, personalized diagnosis, individualized prognosis, personalized treatment
- MeSH terms
- Adult, Female, Genotype, Heart Rate, Humans, Intensive Care Units, Male, Middle Aged, Polymorphism, Genetic, Retrospective Studies, ROC Curve, Tennessee, Genetic Variation, Wounds and Injuries, Biomarkers, Injury Severity Score, Logistic Models, Receptors, Adrenergic, alpha-1, Receptors, Adrenergic, beta-2, Precision Medicine
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