Refinement of a rapid saliva miRNA diagnostic test for concussion

Summary/Abstract - Quadrant Biosciences is developing a new diagnostic to aid in the clinical detection of mild traumatic brain injury (mTBI) in school-aged children and young adults (13–22 years). Based on salivary microRNA (miRNA) biomarkers, Quadrant’s diagnostic will provide an accurate, objective, and non-invasive method for mTBI diagnosis. Such a method is critically needed, as the number of pediatric mTBIs is on the rise, and the developing brains of young patients are more vulnerable to the after-effects of mechanical forces, leading to a wide range of negative effects on physical, cognitive, and psychological function. The diagnosis and assessment of mTBI in adolescents are challenging and rely on subjective measures, leading many mTBIs to go undiagnosed or underreported. This results in suboptimal post-injury treatment and patient management. A biologic assay to accurately diagnose adolescent mTBI would therefore provide an invaluable guide for clinical care, potentially guiding decisions for imaging, return to play, return to school, and therapeutic interventions. While a number of potential biomarkers for objectively detecting mTBI have been proposed, including the blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin c-terminal hydrolase (UCH-L1), recent research questions the ability of blood-based biomarkers to differentiate patients with mTBI from those with acute orthopedic trauma, particularly in pediatric populations. Moreover, these assays require venipuncture expertise that is not always available, particularly in the case of sports-related concussions, which account for nearly 1/3 of mTBIs in this patient population. To address these shortcomings, Quadrant Biosciences is creating a novel, objective diagnostic tool based on a panel of saliva miRNA biomarkers that are differentially expressed in patients with mTBI. Pilot studies in over 200 individuals with mTBI have identified a panel of saliva miRNAs capable of diagnosing mTBI and predicting symptom duration. In the proposed Fast Track project, Quadrant will advance development of this test by establishing a rapid, accurate method for quantifying these miRNAs and refining/validating a diagnostic algorithm to differentiate adolescents and young adults with mTBI from peers with symptomology that mimics mTBI (e.g. chronic headaches, anxiety/depression, ADHD, exercise-related fatigue, and orthopedic injury). In Phase I, Quadrant will refine a diagnostic algorithm for mTBI using a rapid quantification technique for saliva miRNAs. Machine learning will be used to develop a diagnostic algorithm that employs miRNA levels from the rapid multiplex assay alongside participant medical and demographic characteristics to predict mTBI status. In Phase II, Quadrant will validate the diagnostic algorithm for differentiating mTBI from medical conditions with overlapping symptomology in a prospective, case-control study of 2500 adolescents and young adults (age 13–22 years) to refine the saliva-based diagnostic aid for mTBI. Ultimately, Quadrant’s proposed salivary miRNA-based test will yield a minimally invasive, objective, biologic test that can aid diagnosis of mTBI, including among patients with confounding psychologic conditions.Narrative - Children and adolescents account for approximately 2/3 of the 3 million concussions that occur in the U.S. each year, placing them at risk for negative impacts on physical, cognitive, and psychological function, including poor academic performance, behavior, social interactions, and reduced subsequent employment. Unfortunately, mild traumatic brain injury (mTBI) is underdiagnosed due to the poor sensitivity of conventional methods (neurological assessment, self-reporting, imaging, etc.) and lack of an objective, non-invasive diagnostic tool. Quadrant Biosciences’ rapid, accurate, objective aid for the diagnosis of mTBIs in adolescents and young adults will enable timely and accurate decision-making in mTBI assessment, resulting in reduced re- injury/morbidity, individualized patient management, and improved long-term patient outcomes.