SBIR-STTR Award

Saliva biomarkers for noninvasive diagnostics of acute mTBI in children Pediatric mild TBI (mTBI) is a global health concern. However, there is no standard approach to diagnose pediatric mTBI. There is unmet need for standard, objective diagnostics of mTBI, a key element for making decisions about returning to learning and play, and preventing second impact syndrome. The ultimate goal of this SBIR project is to develop a rapid commercial test for noninvasive diagnostics of mTBI in children. The proposed Phase I research will provide proof-of-concept for the core technology: saliva biomarkers with high diagnostic accuracy and specificity for acute pediatric mTBI. Preliminary Studies (N=135 human subjects, 180 saliva samples) identified N=10 candidate saliva mTBI biomarkers in adults and showed potential to translate the technology for children. The candidate biomarkers were not confounded by time after injury, mTBI mechanism, CT scan finding, LOC duration, sex and age in healthy controls. SA1 will collect N=420 serial saliva samples from N=180 children age 8-17. mTBI patients (N=60, GCS=13-15) will be enrolled in Houston (40 ED patients, age 8-17) and San Diego (20 HS contact sport athletes, age 15- 17). Saliva and clinical outcome measures will be collected from mTBI and OI at T1-T3: ? 24h, 7d and 30d after injury, and at enrollment from healthy controls. Primary clinical endpoint: acute mTBI. Secondary clinical endpoint: persistent postconcussion symptoms (PPCS) at 30d, and prolonged Return To Play (RTP) ?30d after mTBI. Controls (N=120): mild traumatic orthopedic injury without head injury (OI, ED patients and contact sport athletes), uninjured contact sport athletes (same game as mTBI), healthy pre-season contact sport athletes and healthy nonathletes. SA2 will measure the existing N=10 mTBI markers in whole saliva samples from SA1 using two orthogonal, previously validated laboratory saliva immunoassays. ROC analysis will determine diagnostic accuracy of the saliva markers for acute mTBI. Logistic regression at 95% CI will determine prognostic accuracy of the markers for PPCS and RTP at T1-T3. Expected outcomes: Representative and large sample size (180 children across school age, sex, mTBI mechanism and geography) will provide statistically significant, generalizable clinical data. Orthogonal laboratory assays will provide cross-validated, quantitative biomarker data. Demonstration of technical feasibility in SA2 will provide GO criteria for a full biomarker validation and device development in Phase II. If successful, the project has potential for high impact on TBI management in children by providing novel fluid biomarkers for mTBI diagnostics, and offering new insights into pathophysiology of pediatric mTBI. Objective mTBI diagnostics is a key element for making decisions about return-to-play and learning, preventing second impact syndrome and advancing TBI treatment. The proposed rapid saliva mTBI test for children has a strong commercial potential based on no competition and existing team of proven industry partners.

Project Terms:
Accident and Emergency department; Accounting; Acute; Adult; Age; Assessment tool; base; Biological Assay; Biological Markers; biomarker validation; Brain Concussion; candidate marker; Centers for Disease Control and Prevention (U.S.); Child; Childhood; Clinical; Clinical Data; cohort; Craniocerebral Trauma; Data; Decision Making; Device or Instrument Development; Diagnosis; Diagnostic; diagnostic accuracy; Diagnostic Specificity; Doctor of Medicine; Elements; Emergency Department patient; Emergency Situation; Enrollment; Exercise; Functional disorder; Geography; global health; Goals; Head; Hospitals; human subject; Immunoassay; Individual; industry partner; Injury; insight; Laboratories; Learning; Liquid substance; Logistic Regressions; Measures; Methods; mild traumatic brain injury; Modeling; novel; Orthopedics; Outcome; Outcome Measure; Patients; Pediatric Hospitals; Phase; Play; point of care; predictive marker; prevent; primary outcome; prognostic; Recovery; Research; Research Design; rho; ROC Curve; Saliva; Sample Size; Sampling; Scanning; School-Age Population; Seasons; secondary outcome; sex; Small Business Innovation Research Grant; Specificity; Sports; Sports Medicine; Stains; Statistical Data Interpretation; Symptoms; Syndrome; TBI Patients; TBI treatment; Technology; Testing; Texas; Time; Translating; Traumatic injury; Unconscious State; Visit; Western Blotting; X-Ray Computed Tomography;

Rapid saliva test for diagnosis of mTBI and prognosis of Persistent Post-concussion Symptoms(PPCS) in children and adultsMild traumatic brain injury (mTBI) is a leading cause of mortality and morbidity. Children are at a higher riskdue to high vulnerability of the immature brain to trauma. mTBI is a significant public health concern becauseapproximately 30% patients develop Persistent Post-concussion Symptoms (PPCS) preventing return to work,school and sports. Current diagnostic methods for mTBI and PPCS are inaccurate due to lack of standarddiagnostic criteria. There is unmet need for objective biomarker test. The ultimate goal of this SBIR project is todevelop a commercial saliva test for diagnosis of mTBI and prognosis of PPCS. Phase I showed feasibility ofthe key innovation: saliva biomarkers for diagnosis of mTBI and prognosis of PPCS in children and adults. Theproposed Phase II study aims to clinically validate the final biomarker for the commercial test and develop aprototype device showing feasibility of the commercial product. SA1 will collect N=465 serial saliva samplesfrom N=225 adolescent athletes age 11-21 during a multisite prospective cohort study of mTBI, orthopedicinjury controls (OI) and healthy controls (HC). mTBI will be diagnosed at ≤72h and PPCS at 30d postinjury.Saliva samples will be collected at ≤72h, 7d and 14d postinjury from mTBI and at enrollment form OI and HC.The proposed sample size will provide >80% statistical power to obtain statistically significant biomarker data.SA2 will measure 5 candidate biomarkers in N=1063 saliva samples (N=465 samples from SA1 plus N=598existing samples from ED patients and adult athletes). Statistical modeling of a Training set of subjects(N=475) will down select the final marker and endpoint for the commercial test based on best diagnostic andprognostic performance. The selected marker and endpoint will be validated using a Validation set (N=240)based on ≥90% accuracy, sensitivity and specificity of mTBI diagnosis and PPCS prognosis in children andadults. OI will show mTBI specificity. HC will define normal range of marker concentrations and biologicalvariability. SA3 will develop a prototype lateral flow immunoassay (LFA) for a selected biomarker. ExpectedOutcomes: Results will rigorously clinically validate the saliva biomarker of mTBI and PPCS for thecommercial product. Large and representative sample size (N=715 subjects across mTBI mechanisms ofinjury, outcome, age, sex and geography) will provide statistically significant, generalizable clinical data.N=1063 serial saliva samples and analytically validated assays will provide accurate and reliable biomarkerdata. The prototype device will show technical feasibility of the commercial test. Overall, this project has highpotential for a wide-ranging impact on TBI care by providing an objective, clinically feasible biologicalbiomarker of mTBI and PPCS, and translating this innovation into a practical tool for clinical use in point-of-care. The proposed product has a strong commercial potential based on a proven and low risk LFA device,achievable FDA path, key opinion leaders committed to clinical adoption, competitive patent portfolio andlimited competition.

Public Health Relevance Statement:
PROJECT NARRATIVE Rapid saliva test for diagnosis of mTBI and prognosis of Persistent Post-concussion Symptoms (PPCS) in children and adults Mild traumatic brain injury (mTBI also called concussion) is a leading cause of death and disability, particularly in children. The ultimate goal of this SBIR project is to develop a rapid saliva test that will help children and adults to recover after suffering a mTBI.

Project Terms:
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