Data-Driven Modeling for Precision Medicine in Pediatric Acute Liver Failure

TLDR

Pediatric Acute Liver Failure lacks early outcome biomarkers, complicating clinical and transplant decisions. The study aimed to map dynamic interactions of inflammatory mediators to differentiate PALF outcome subgroups. Serum from 101 PALF patients was assayed for 27 inflammatory mediators over the first week, and data‑driven algorithms—including a dynamic robustness index—were used to model inter‑mediator networks and compare outcomes at 21 days. Dynamic Bayesian networks revealed HMGB1 as a central node, with survivors and transplant patients sharing similar, less interconnected networks, whereas non‑survivors exhibited increasingly connected networks, linking higher connectivity to poorer outcomes and suggesting improved stratification.

Abstract

Absence of early outcome biomarkers for Pediatric Acute Liver Failure (PALF) hinders medical and liver transplant decisions. We sought to define dynamic interactions among circulating inflammatory mediators to gain insights into PALF outcome sub-groups. Serum samples from 101 participants in the PALF study, collected over the first 7 days following enrollment, were assayed for 27 inflammatory mediators. Outcomes (Spontaneous survivors [S, n=61], Non-survivors [NS, n=12], and liver transplant patients [LTx, n=28]) were assessed at 21 days post-enrollment. Dynamic interrelations among mediators were defined using data-driven algorithms. Dynamic Bayesian Network inference identified a common network motif with HMGB1 as a central node in all patient sub-groups. The networks in S and LTx were similar, and differed from NS. Dynamic Network Analysis suggested similar dynamic connectivity in S and LTx, but a more highly-interconnected network in NS that increased with time. A Dynamic Robustness Index calculated to quantify how inflammatory network connectivity changes as a function of correlation stringency differentiated all three patient sub-groups. Our results suggest that increasing inflammatory network connectivity is associated with non-survival in PALF, and may ultimately lead to better patient outcome stratification.