Outcome Prediction in Mathematical Models of Immune Response to Infection

PLoS One. 2015 Aug 19;10(8):e0135861. doi: 10.1371/journal.pone.0135861. eCollection 2015.

Abstract

Clinicians need to predict patient outcomes with high accuracy as early as possible after disease inception. In this manuscript, we show that patient-to-patient variability sets a fundamental limit on outcome prediction accuracy for a general class of mathematical models for the immune response to infection. However, accuracy can be increased at the expense of delayed prognosis. We investigate several systems of ordinary differential equations (ODEs) that model the host immune response to a pathogen load. Advantages of systems of ODEs for investigating the immune response to infection include the ability to collect data on large numbers of 'virtual patients', each with a given set of model parameters, and obtain many time points during the course of the infection. We implement patient-to-patient variability v in the ODE models by randomly selecting the model parameters from distributions with coefficients of variation v that are centered on physiological values. We use logistic regression with one-versus-all classification to predict the discrete steady-state outcomes of the system. We find that the prediction algorithm achieves near 100% accuracy for v = 0, and the accuracy decreases with increasing v for all ODE models studied. The fact that multiple steady-state outcomes can be obtained for a given initial condition, i.e. the basins of attraction overlap in the space of initial conditions, limits the prediction accuracy for v > 0. Increasing the elapsed time of the variables used to train and test the classifier, increases the prediction accuracy, while adding explicit external noise to the ODE models decreases the prediction accuracy. Our results quantify the competition between early prognosis and high prediction accuracy that is frequently encountered by clinicians.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Bacterial Infections / immunology*
  • Humans
  • Models, Biological
  • Models, Theoretical*
  • Nonlinear Dynamics
  • Outcome Assessment, Health Care / methods*
  • Prognosis
  • Systems Biology / methods*
  • Virus Diseases / immunology*

Grants and funding

This work was partially supported by DARPA (Space and Naval Warfare System Center Pacific, http://www.darpa.mil) under award number N66001-11-1-4184 (M.S., M.K., G.H., and C.O.) and partially supported by the National Science Foundation Grant (www.nsf.gov) No. NSF PHY11-25915 (M.S., C.O., and G.H.). Additional support for this work was provided by Yale University (www.yale.edu) (M.M.) and the Infectious Disease Supercluster, Colorado State University, 2012 seed grant (http://infectiousdisease.colostate.edu/pages/clusters.aspx) (K.W. and M.K.). This work also benefited from the facilities and staff of the Yale University Faculty of Arts and Sciences High Performance Computing Center and NSF Grant No. CNS-0821132 that partially funded acquisition of the computational facilities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.