TY  - JOUR
PY  - 2015//
TI  - Trauma in silico: individual-specific mathematical models and virtual clinical populations
JO  - Science translational medicine
A1  - Brown, David
A1  - Namas, Rami A.
A1  - Almahmoud, Khalid
A1  - Zaaqoq, Akram M.
A1  - Sarkar, Joydeep
A1  - Barclay, Derek A.
A1  - Yin, Jinling
A1  - Ghuma, Ali
A1  - Abboud, Andrew
A1  - Constantine, Gregory
A1  - Nieman, Gary
A1  - Zamora, Ruben
A1  - Chang, Steven C.
A1  - Billiar, Timothy R.
A1  - Vodovotz, Yoram
SP  - 285ra61
EP  - 285ra61
VL  - 7
IS  - 285
N2  - 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.<p />  <p>Language: en</p>
LA  - en
SN  - 1946-6234
UR  - http://dx.doi.org/10.1126/scitranslmed.aaa3636
ID  - ref1
ER  -