Diagnosing mild traumatic brain injury using saliva RNA compared to cognitive and balance testing.

Steven D Hicks ,Zofia Gagnon ,Callan D Mcloughlin ,Andrea C Loeffert ,Gregory Fedorchak ,Jayson Loeffert ,Cayce Onks ,Aakanksha Rangnekar ,Raymond Y Kim ,Hallie Zwibel ,John J Leddy ,Aaron M Yengo‐Kahn ,Jason R Randall ,Kevin Zhen ,Miguel M Madeira ,Mohammad Nadir Haider ,Matthew Heller ,Samantha Devita ,Christopher Neville ,Chuck Monteith ,Robert P Olympia ,Thomas R Campbell ,Rebekah Mannix ,Aaron P Roberts ,Samantha Johnson ,Matthew Badia ,Justin Wenzel ,Michael N Dretsch ,Frank Middleton

doi:10.1002/ctm2.197

Abstract

BackgroundEarly, accurate diagnosis of mild traumatic brain injury (mTBI) can improve clinical outcomes for patients, but mTBI remains difficult to diagnose because of reliance on subjective symptom reports. An objective biomarker could increase diagnostic accuracy and improve clinical outcomes. The aim of this study was to assess the ability of salivary noncoding RNA (ncRNA) to serve as a diagnostic adjunct to current clinical tools. We hypothesized that saliva ncRNA levels would demonstrate comparable accuracy for identifying mTBI as measures of symptom burden, neurocognition, and balance.MethodsThis case‐control study involved 538 individuals. Participants included 251 individuals with mTBI, enrolled ≤14 days postinjury, from 11 clinical sites. Saliva samples (n = 679) were collected at five time points (≤3, 4‐7, 8‐14, 15‐30, and 31‐60 days post‐mTBI). Levels of ncRNAs (microRNAs, small nucleolar RNAs, and piwi‐interacting RNAs) were quantified within each sample using RNA sequencing. The first sample from each mTBI participant was compared to saliva samples from 287 controls. Samples were divided into testing (n = 430; mTBI = 201 and control = 239) and training sets (n = 108; mTBI = 50 and control = 58). The test set was used to identify ncRNA diagnostic candidates and create a diagnostic model. Model accuracy was assessed in the naïve test set.ResultsA model utilizing seven ncRNA ratios, along with participant age and chronic headache status, differentiated mTBI and control participants with a cross‐validated area under the curve (AUC) of .857 in the training set (95% CI, .816‐.903) and .823 in the naïve test set. In a subset of participants (n = 321; mTBI = 176 and control = 145) assessed for symptom burden (Post‐Concussion Symptom Scale), as well as neurocognition and balance (ClearEdge System), these clinical measures yielded cross‐validated AUC of .835 (95% CI, .782‐.880) and .853 (95% CI, .803‐.899), respectively. A model employing symptom burden and four neurocognitive measures identified mTBI participants with similar AUC (.888; CI, .845‐.925) as symptom burden and four ncRNAs (.932; 95% CI, .890‐.965).ConclusionSalivary ncRNA levels represent a noninvasive, biologic measure that can aid objective, accurate diagnosis of mTBI.

Highlights

Mild traumatic brain injury is characterized by brief confusion, loss of consciousness, posttraumatic amnesia, and/or other transient neurological abnormalities, with a Glasgow Coma Scale score of 13-15 after 30 min postinjury or later.[1]
This study identifies a set of ncRNA biomarkers in saliva that differentiate individuals with Mild traumatic brain injury (mTBI) from peers without mTBI in both training (n = 430) and naive test sets (n = 108)
In a subset of participants assessed with computerized neurocognitive testing, objective balance measures, and standardized symptom scales (n = 321), the ncRNA model displays similar accuracy for identifying mTBI status as these more traditional approaches.[16]

Summary

Introduction

Mild traumatic brain injury (mTBI) is characterized by brief confusion, loss of consciousness, posttraumatic amnesia, and/or other transient neurological abnormalities (eg, seizure), with a Glasgow Coma Scale score of 13-15 after 30 min postinjury or later.[1]. MTBI is associated with significant morbidity, including headaches, fatigue, and difficulties with concentration.[2,7]. MTBI is associated with missed school or work, and increased healthcare utilization.[8] mTBI can have a wide range of effects on physical, cognitive, and psychological function, negatively impacting cognitive abilities, academic performance, behavior, social interaction, and employment.[9,10,11] It can be difficult to identify the physical and neurocognitive effects of mTBI, as some effects may be attributed to other causes such as anxiety, depression, attention deficit hyperactivity disorder (ADHD), exercise-related fatigue, or chronic headache disorder.

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