Abstract
OBJECTIVES: Sepsis therapies have proven to be elusive because of the difficulty of translating biologically sound and effective interventions in animal models to humans. A part of this problem originates from the fact that septic patients present at various times after the onset of sepsis, whereas the exact time of infection is controlled in animal models. We sought to determine whether data mining longitudinal physiologic data in a nonhuman primate model of Escherichia coli-induced sepsis could help inform the time of onset of infection. DESIGN: A nearest-neighbor approach was used to back cast the time of onset of infection in animal models of sepsis. Animal data were censored to simulate prospective monitoring at any moment along the septic infection. This was compared against an uncensored database to find the most similar animal in order to estimate the infection onset time. Leave-one-out cross-validation was used for validation. Biomarker selection was performed based on the criteria of estimation accuracy and/or ease of measurement. SETTING: Computational experimental on existing experimental data. SUBJECTS: Retrospective data from 33 septic baboons (Papio ursinus) subjected to Escherichia coli infusion. Validation was performed using 14 pigs that were subjected to surgically induced fecal peritonitis and 22 pigs that were subjected to lipopolysaccharide infusion. MEASUREMENTS AND MAIN RESULTS: Longitudinal physiologic and serum markers, time of death. The presence of uniquely changing biomarkers during septic infection enabled the estimation of infection onset time in the datasets. Various combinations of temporal biomarkers, such as WBC, oxygen content, mean arterial pressure, and heart rate, yielded estimation accuracies of up to 97.8%. The use of temporal vital signs and a single measurement of serum biomarkers yielded highly accurate estimates without the need for invasive measurements. Validation in the pig data revealed similar results despite the heterogeneity of multiple experimental cohorts. This suggests that the method may be effective if sufficiently similar subjects are present in the database. CONCLUSIONS: One nearest-neighbor analysis showed promise in accurately identifying the onset of infection given a database of known infection times and of sufficient breadth. We suggest that this approach is ready for evaluation within the clinical setting using human data.