Dissecting inflammatory complications in critically injured patients by within-patient gene expression changes

A longitudinal clinical genomics study

Inflammation and the Host Response to Injury Large-Scale Collaborative Research Program

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background: Trauma is the number one killer of individuals 1-44 y of age in the United States. The prognosis and treatment of inflammatory complications in critically injured patients continue to be challenging, with a history of failed clinical trials and poorly understood biology. New approaches are therefore needed to improve our ability to diagnose and treat this clinical condition. Methods and Findings: We conducted a large-scale study on 168 blunt-force trauma patients over 28 d, measuring ~400 clinical variables and longitudinally profiling leukocyte gene expression with ~800 microarrays. Marshall MOF (multiple organ failure) clinical score trajectories were first utilized to organize the patients into five categories of increasingly poor outcomes. We then developed an analysis framework modeling early within-patient expression changes to produce a robust characterization of the genomic response to trauma. A quarter of the genome shows early expression changes associated with longer-term post-injury complications, captured by at least five dynamic co-expression modules of functionally related genes. In particular, early down-regulation of MHC-class II genes and up-regulation of p38 MAPK signaling pathway were found to strongly associate with longer-term post-injury complications, providing discrimination among patient outcomes from expression changes during the 40-80 h window post-injury. Conclusions: The genomic characterization provided here substantially expands the scope by which the molecular response to trauma may be characterized and understood. These results may be instrumental in furthering our understanding of the disease process and identifying potential targets for therapeutic intervention. Additionally, the quantitative approach we have introduced is potentially applicable to future genomics studies of rapidly progressing clinical conditions. Trial Registration: ClinicalTrials.gov NCT00257231.

Original languageEnglish (US)
Article numbere1001093
JournalPLoS Medicine
Volume8
Issue number9
DOIs
StatePublished - Sep 1 2011
Externally publishedYes

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Genomics
Gene Expression
Wounds and Injuries
Organ Dysfunction Scores
MHC Class II Genes
Multiple Organ Failure
Gene Expression Profiling
p38 Mitogen-Activated Protein Kinases
Clinical Studies
Leukocytes
Up-Regulation
Down-Regulation
Clinical Trials
Genome
Therapeutics
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dissecting inflammatory complications in critically injured patients by within-patient gene expression changes : A longitudinal clinical genomics study. / Inflammation and the Host Response to Injury Large-Scale Collaborative Research Program.

In: PLoS Medicine, Vol. 8, No. 9, e1001093, 01.09.2011.

Research output: Contribution to journalArticle

Inflammation and the Host Response to Injury Large-Scale Collaborative Research Program. / Dissecting inflammatory complications in critically injured patients by within-patient gene expression changes : A longitudinal clinical genomics study. In: PLoS Medicine. 2011 ; Vol. 8, No. 9.
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abstract = "Background: Trauma is the number one killer of individuals 1-44 y of age in the United States. The prognosis and treatment of inflammatory complications in critically injured patients continue to be challenging, with a history of failed clinical trials and poorly understood biology. New approaches are therefore needed to improve our ability to diagnose and treat this clinical condition. Methods and Findings: We conducted a large-scale study on 168 blunt-force trauma patients over 28 d, measuring ~400 clinical variables and longitudinally profiling leukocyte gene expression with ~800 microarrays. Marshall MOF (multiple organ failure) clinical score trajectories were first utilized to organize the patients into five categories of increasingly poor outcomes. We then developed an analysis framework modeling early within-patient expression changes to produce a robust characterization of the genomic response to trauma. A quarter of the genome shows early expression changes associated with longer-term post-injury complications, captured by at least five dynamic co-expression modules of functionally related genes. In particular, early down-regulation of MHC-class II genes and up-regulation of p38 MAPK signaling pathway were found to strongly associate with longer-term post-injury complications, providing discrimination among patient outcomes from expression changes during the 40-80 h window post-injury. Conclusions: The genomic characterization provided here substantially expands the scope by which the molecular response to trauma may be characterized and understood. These results may be instrumental in furthering our understanding of the disease process and identifying potential targets for therapeutic intervention. Additionally, the quantitative approach we have introduced is potentially applicable to future genomics studies of rapidly progressing clinical conditions. Trial Registration: ClinicalTrials.gov NCT00257231.",
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T1 - Dissecting inflammatory complications in critically injured patients by within-patient gene expression changes

T2 - A longitudinal clinical genomics study

AU - Inflammation and the Host Response to Injury Large-Scale Collaborative Research Program

AU - Desai, Keyur H.

AU - Tan, Chuen Seng

AU - Leek, Jeffrey T.

AU - Maier, Ronald V.

AU - Tompkins, Ronald G.

AU - Storey, John D.

AU - Altstein, L.

AU - Baker, H. V.

AU - Balis, U. G.

AU - Bankey, P. E.

AU - Billiar, T. R.

AU - Brownstein, B. H.

AU - Calvano, S. E.

AU - Camp, D. G.

AU - Perren Cobb, J.

AU - Cuschieri, J.

AU - Davis, R. W.

AU - De, A. K.

AU - Finnerty, Celeste

AU - Gamelli, R. L.

AU - Gibran, N. S.

AU - Harbrecht, B. G.

AU - Hayden, D. L.

AU - Hennessy, L.

AU - Herndon, David

AU - Honari, S. E.

AU - Jeschke, M. G.

AU - Johnson, J. L.

AU - Klein, M. B.

AU - Lowry, S. F.

AU - Mason, P. H.

AU - McDonald-Smith, G. P.

AU - McKinley, B. A.

AU - Miller-Graziano, C. L.

AU - Mindrinos, M. N.

AU - Minei, J. P.

AU - Moldawer, L. L.

AU - Moore, E. E.

AU - Moore, F. A.

AU - Nathens, A. B.

AU - O'Keefe, G. E.

AU - Rahme, L. G.

AU - Remick, D. G.

AU - Schoenfeld, D. A.

AU - Shapiro, M. B.

AU - Smith, R. D.

AU - Sperry, J.

AU - Tibshirani, R.

AU - Toner, M.

AU - Xiao, W.

PY - 2011/9/1

Y1 - 2011/9/1

N2 - Background: Trauma is the number one killer of individuals 1-44 y of age in the United States. The prognosis and treatment of inflammatory complications in critically injured patients continue to be challenging, with a history of failed clinical trials and poorly understood biology. New approaches are therefore needed to improve our ability to diagnose and treat this clinical condition. Methods and Findings: We conducted a large-scale study on 168 blunt-force trauma patients over 28 d, measuring ~400 clinical variables and longitudinally profiling leukocyte gene expression with ~800 microarrays. Marshall MOF (multiple organ failure) clinical score trajectories were first utilized to organize the patients into five categories of increasingly poor outcomes. We then developed an analysis framework modeling early within-patient expression changes to produce a robust characterization of the genomic response to trauma. A quarter of the genome shows early expression changes associated with longer-term post-injury complications, captured by at least five dynamic co-expression modules of functionally related genes. In particular, early down-regulation of MHC-class II genes and up-regulation of p38 MAPK signaling pathway were found to strongly associate with longer-term post-injury complications, providing discrimination among patient outcomes from expression changes during the 40-80 h window post-injury. Conclusions: The genomic characterization provided here substantially expands the scope by which the molecular response to trauma may be characterized and understood. These results may be instrumental in furthering our understanding of the disease process and identifying potential targets for therapeutic intervention. Additionally, the quantitative approach we have introduced is potentially applicable to future genomics studies of rapidly progressing clinical conditions. Trial Registration: ClinicalTrials.gov NCT00257231.

AB - Background: Trauma is the number one killer of individuals 1-44 y of age in the United States. The prognosis and treatment of inflammatory complications in critically injured patients continue to be challenging, with a history of failed clinical trials and poorly understood biology. New approaches are therefore needed to improve our ability to diagnose and treat this clinical condition. Methods and Findings: We conducted a large-scale study on 168 blunt-force trauma patients over 28 d, measuring ~400 clinical variables and longitudinally profiling leukocyte gene expression with ~800 microarrays. Marshall MOF (multiple organ failure) clinical score trajectories were first utilized to organize the patients into five categories of increasingly poor outcomes. We then developed an analysis framework modeling early within-patient expression changes to produce a robust characterization of the genomic response to trauma. A quarter of the genome shows early expression changes associated with longer-term post-injury complications, captured by at least five dynamic co-expression modules of functionally related genes. In particular, early down-regulation of MHC-class II genes and up-regulation of p38 MAPK signaling pathway were found to strongly associate with longer-term post-injury complications, providing discrimination among patient outcomes from expression changes during the 40-80 h window post-injury. Conclusions: The genomic characterization provided here substantially expands the scope by which the molecular response to trauma may be characterized and understood. These results may be instrumental in furthering our understanding of the disease process and identifying potential targets for therapeutic intervention. Additionally, the quantitative approach we have introduced is potentially applicable to future genomics studies of rapidly progressing clinical conditions. Trial Registration: ClinicalTrials.gov NCT00257231.

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U2 - 10.1371/journal.pmed.1001093

DO - 10.1371/journal.pmed.1001093

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JO - PLoS Medicine

JF - PLoS Medicine

SN - 1549-1277

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