Evaluation of a Rapid Immunoassay for Molecular Subphenotype Classification in Pediatric Acute Cardiorespiratory Failure

Molecular subphenotypes, identified through biomarker profiling independent of clinical diagnosis, have the potential to guide targeted therapeutics in critical care. We have previously published that intensive insulin management has subphenotype-specific beneficial effects among children with hyperglycemia accompanying cardiorespiratory failure. However, due to the operational aspects of biomarker assays, prospective real-time application of subphenotype-based strategies remains daunting. This study compared biomarker values measured via a rapid immunoassay requiring minimal handling to a conventional laboratory-based multiplex assay, assessed its ability to classify subphenotypes with a parsimonious classifier, and compared clinical outcomes between rapid immunoassay-based subphenotypes. This retrospective multicenter study included re-assaying plasma samples from 269 children with acute cardiorespiratory failure and hyperglycemia. Latent class analysis (LCA) was previously used to derive hyper-inflammatory and hypo-inflammatory classes. A parsimonious classifier was fit to LCA-derived subphenotypes and produced a model consisting of IL-6, IL-8, and sTNFR-1. We found that, despite the rapid immunoassay systematically overestimating biomarker values relative to the conventional assay, biomarkers were strongly correlated between platforms (Pearson r =  0.87–0.93). Using the parsimonious classifier, subphenotype classifications matched between platforms in 95% of patients (n = 256/269). When compared to previously derived LCA-derived subphenotypes, rapid immunoassay-based subphenotypes demonstrated an AUC of 0.90 (95% CI 0.85–0.95). The rapid immunoassay-based hyper-inflammatory class was associated with higher mortality (26% vs. 11%; P = 0.01) and heterogeneity of treatment effect to intensive insulin management (interaction P = 0.01). Our findings suggest that subphenotyping using a rapid immunoassay is feasible and accurate, laying the foundation for future precision medicine strategies in pediatric critical care.