Trauma in silico: Individual-specific mathematical models and virtual clinical populations.
Trauma-induced critical illness is driven by acute inflammation, and elevated systemic interleukin-6 (IL-6) after trauma is a biomarker of adverse outcomes. We constructed a multicompartment, ordinary differential equation model that represents a virtual trauma patient. Individual-specific variants of this model reproduced both systemic inflammation and outcomes of 33 blunt trauma survivors, from which a cohort of 10,000 virtual trauma patients was generated. Model-predicted length of stay in the intensive care unit, degree of multiple organ dysfunction, and IL-6 area under the curve as a function of injury severity were in concordance with the results from a validation cohort of 147 blunt trauma patients. In a subcohort of 98 trauma patients, those with high-IL-6 single-nucleotide polymorphisms (SNPs) exhibited higher plasma IL-6 levels than those with low IL-6 SNPs, matching model predictions. Although IL-6 could drive mortality in individual virtual patients, simulated outcomes in the overall cohort were independent of the propensity to produce IL-6, a prediction verified in the 98-patient subcohort. In silico randomized clinical trials suggested a small survival benefit of IL-6 inhibition, little benefit of IL-1β inhibition, and worse survival after tumor necrosis factor-α inhibition. This study demonstrates the limitations of extrapolating from reductionist mechanisms to outcomes in individuals and populations and demonstrates the use of mechanistic simulation in complex diseases.
Immunetrics Inc., Pittsburgh, PA 15219, USA.
David
D
Brown
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Rami A
RA
Namas
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Khalid
K
Almahmoud
Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Akram
A
Zaaqoq
Immunetrics Inc., Pittsburgh, PA 15219, USA.
Joydeep
J
Sarkar
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Derek A
DA
Barclay
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Jinling
J
Yin
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Ali
A
Ghuma
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Andrew
A
Abboud
Department of Mathematics, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Gregory
G
Constantine
Department of Surgery, Upstate Medical University, Syracuse, NY 13210, USA.
Gary
G
Nieman
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA.
Ruben
R
Zamora
Immunetrics Inc., Pittsburgh, PA 15219, USA.
Steven C
SC
Chang
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Timothy R
TR
Billiar
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA. vodovotzy@upmc.edu.
Yoram
Y
Vodovotz
D000818:Animals; D015331:Cohort Studies; D003198:Computer Simulation; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D015233:Models, Statistical; D014949:Wounds, Nonpenetrating / Q000503:physiopathology*
D015850:Interleukin-6