The normative modelling framework for traumatic brain injury

Abstract

This review examines the principles, applications, and methodological foundations of normative modelling, emphasising its potential to assist in mitigating longstanding challenges in traumatic brain injury (TBI) research and management. TBI remains a major global health concern, with an incidence exceeding 50-60 million cases worldwide. Progress in research and clinical practice has been hindered by the complex and heterogeneous nature of TBI, arising from diverse aetiologies, injury mechanisms, and pathophysiological processes that lead to variable clinical presentations. A significant obstacle, particularly present within neuroimaging, is the continued reliance on classification scales and analytical models that do not account for nuanced differences among patients. For example, the Glasgow Coma Scale (GCS) and many prevalent models categorise injury severity levels by assuming homogeneity within groups, which inevitably results in heterogeneity and obscures individual variability. Similarly, traditional case-control research designs separate injury and control groups to conduct group difference testing, diluting valuable individual data by focusing on mean comparisons. We advocate for a paradigm shift towards normative modelling - a flexible framework that assesses individual differences by comparing patients to a reference cohort. This approach moves beyond traditional methods that emphasise group differences, addressing the limitations of conventional classification by avoiding the aggregation of TBI patients into heterogeneous categories based on simplistic measures. By capturing the full spectrum of variability, normative modelling has the potential to improve patient selection in clinical trials and foster more personalised treatment strategies. Adopting this innovative approach aims to enhance outcomes for TBI patients by emphasising individual variability rather than relying on broad group classifications. Normative modelling promises to transform the translation of TBI research into clinical practice, ultimately driving progress towards more effective, tailored interventions.

Keywords: heterogeneity; neuroimaging; normative modelling; peronalised medicine; traumatic brain injury.