Complex signals bioinformatics: evaluation of heart rate characteristics monitoring as a novel risk marker for neonatal sepsis

Heart rate characteristics monitoring for early detection of late-onset neonatal sepsis was first described in 2003. This technique, which uses mathematical methods to report the fold-increase in the risk of imminent neonatal sepsis, adds independent information to laboratory tests and clinical findings, and, in a large randomized trial, reduced NICU mortality of very low birth weight infants. Through re-analysis and new secondary analyses of published studies, we have systematically evaluated the utility of this new risk marker for screening the growing population of premature infants. We followed the guidelines proposed by Hlatky et al. (Circulation, 119:2408-2416, 2009), reviewed past works, and re-analyzed data from 1,489 patients receiving conventional monitoring alone, 348 of whom had 488 episodes of proven sepsis, in the large randomized trial. Heart rate characteristics monitoring passed all phases of risk marker development from proof of concept to improvement of clinical outcomes. The predictiveness curve affirmed good calibration, and addition of the heart rate characteristics index to predictive models using standard risk factors favorably impacted the receiver operating characteristic curve area (increase of 0.030), continuous net reclassification index (0.389) and the integrated discrimination index (0.008), and compares well to other modern risk factors. Heart rate characteristics monitoring is a validated risk marker for sepsis in the NICU.