Trauma in silico: Individual-specific mathematical models and virtual clinical populations

David Brown, Rami A. Namas, Khalid Almahmoud, Akram Zaaqoq, Joydeep Sarkar, Derek A. Barclay, Jinling Yin, Ali Ghuma, Andrew Abboud, Gregory Constantine, Gary Nieman, Ruben Zamora, Steven C. Chang, Timothy R. Billiar, Yoram Vodovotz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

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. Modelpredicted length of stay in the intensive care unit, degree ofmultiple organ dysfunction, and IL-6 area under the curve as a function of injury severitywere in concordancewith the results froma 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-1b inhibition, and worse survival after tumor necrosis factor-a 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.

Original languageEnglish
Article number285ra61
JournalScience Translational Medicine
Volume7
Issue number285
DOIs
StatePublished - 29 Apr 2015
Externally publishedYes

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