Methods for aiding in diagnosing and evaluating a traumatic brain injury in a human subject using a combination of GFAP and UCH-L1
Inventors
McQuiston, Beth • Datwyler, Saul • CHANDRAN, RAJ • Marino, Jaime
Assignees
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Publication Number
US-12105100-B2
Publication Date
2024-10-01
Expiration Date
Abstract
Disclosed herein are methods of aiding in the diagnosis and evaluation of a subject that has sustained or may have sustained an injury to the head. For example, the present disclosure provides methods for aiding in the diagnosis and evaluation of a subject to determine whether the subject has sustained a traumatic brain injury (TBI) by detecting or measuring a combination of the levels of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) in samples taken at various time points within 48 hours after the subject has sustained or may have sustained an injury to the head.
Core Innovation
The disclosed subject matter provides a method for performing at least one assay for ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) in a sample obtained from a human subject within about 48 hours after an actual or suspected injury to the head. The method uses levels of GFAP and UCH-L1 compared to reference levels to determine whether the subject has sustained a traumatic brain injury (TBI) or mild TBI and to guide subsequent actions.
A key feature is combining GFAP and UCH-L1 reference level logic rather than relying on a single biomarker. The disclosure includes establishing reference levels for GFAP and UCH-L1 within specified quantitative ranges, associating those reference levels with diagnostic performance such as sensitivity and specificity, and determining TBI when the levels meet specified reference-level criteria, including criteria that characterize the prediction of an unfavorable likelihood.
The disclosure links the assay outcome to decisions such as not performing a head computerized tomography (CT) scan and/or performing magnetic resonance imaging (MRI) procedures. It further provides treatment options after determining TBI status, including rest, abstaining from physical activities, avoiding light, wearing protective eyewear when in light, therapeutic agents for relief of a headache or migraine and anti-nausea medication, and additional therapeutic agents, surgical procedures, and therapies for moderate, severe, or moderate to severe TBI.
Claims Coverage
Independent claims are identified in the provided list as clm-00001, clm-00011, clm-00018, clm-00024, and clm-00031. Across these independent claims, the inventive features center on combined UCH-L1 and GFAP assays, use of reference level logic including specified ranges and assay performance constraints, and treatment and diagnostic determination of mild TBI and broader TBI categories, with optional MRI decisioning and monitoring.
Combined UCH-L1 and GFAP assay in head-injury samples within about 48 hours
Performing at least one assay for UCH-L1 and GFAP in at least one sample that is whole blood, serum, plasma, or cerebrospinal fluid obtained from a human subject within about 48 hours after the subject has sustained an actual or suspected injury to the head.
Treating mild TBI when GFAP and UCH-L1 match specified reference level ranges
Treating the subject for a mild traumatic brain injury (TBI) when the level of GFAP in the sample is equal to a reference level of GFAP of from about 105 pg/mL to about 890 pg/mL and the level of UCH-L1 in the sample is equal to a reference level of UCH-L1 of from about 110 pg/mL to about 2000 pg/mL, wherein treatment comprises rest; abstaining from physical activities; avoiding light; wearing protective eyewear when in light; and/or one or more therapeutic agents selected from headache or migraine relief medication and anti-nausea medication or combinations thereof.
No head CT scan while treating mild TBI using combined GFAP and UCH-L1 reference levels
Performing at least one assay for UCH-L1 and GFAP in a sample within about 48 hours after head injury; not performing a head computerized tomography (CT) scan; and treating the subject for a mild TBI when the level of GFAP is equal to a reference level of GFAP of from about 50 pg/mL to about 975 pg/mL and the level of UCH-L1 is equal to a reference level of UCH-L1 of from about 90 pg/mL to about 2000 pg/mL.
Determining TBI based on GFAP and UCH-L1 reference levels and selecting treatment for mild versus moderate/severe
Performing at least one assay for UCH-L1 and GFAP in whole blood, serum, plasma, or cerebrospinal fluid obtained within about 48 hours after actual or suspected head injury; determining that the subject has sustained a traumatic brain injury (TBI) when the level of GFAP is equal to a reference level of GFAP of from about 15 pg/mL to about 40 pg/mL and the level of UCH-L1 is equal to a reference level of UCH-L1 of from about 70 pg/mL to about 150 pg/mL; and treating the subject determined to have sustained a TBI, where mild TBI treatment comprises rest, avoiding physical activities, avoiding light, protective eyewear, and/or selected headache or migraine and anti-nausea therapeutic agents, and where moderate, severe, or moderate to severe TBI treatment comprises one or more therapeutic agents selected from diuretics, anti-convulsant medication, and medication to sedate and put an individual in a drug-induced coma, and/or one or more surgical procedures selected from removal of a hematoma, repairing a skull fracture, and decompressive craniectomy, and/or one or more therapies selected from rehabilitation for TBI, cognitive behavioral therapy, anger management, and counseling psychology or any combinations thereof.
MRI decisioning based on GFAP and UCH-L1 reference level conditions and treating based on MRI procedure
Performing at least one assay for UCH-L1 and GFAP in whole blood, serum, plasma, or cerebrospinal fluid obtained within about 48 hours after actual or suspected head injury; performing a magnetic resonance imaging (MRI) procedure when the level of GFAP and UCH-L1 fall within defined reference level conditions or not performing an MRI procedure when GFAP and UCH-L1 are below defined reference level conditions; and treating the subject determined to have sustained a TBI based on the MRI procedure.
Determining an unfavorable likelihood of TBI from GFAP and UCH-L1 reference levels and selecting TBI treatment
Performing at least one assay for UCH-L1 and GFAP in at least one sample that is whole blood, serum, plasma, a tissue sample, or a bodily fluid obtained from a human subject within about 48 hours after actual or suspected injury to the head; determining that the subject has sustained a traumatic brain injury (TBI) when the level of GFAP is equal to a reference level of GFAP of from about 80 pg/mL to about 2000 pg/mL and the level of UCH-L1 is equal to a reference level of UCH-L1 of from about 130 pg/mL to about 2000 pg/mL predicting a more likely than not an unfavorable for the subject; and treating the subject determined to have sustained a TBI with treatment tailored to mild versus moderate, severe, or moderate to severe TBI.
Across the independent claims, the core shared inventive concept is using assays for UCH-L1 and GFAP obtained within about 48 hours after a head injury, comparing measured levels to specified reference levels to determine TBI status and select corresponding treatment. Additional independent-claim limitations include avoiding head CT scan, deciding whether to perform MRI based on biomarker reference conditions, and expanding sample types beyond blood, plasma, and CSF to tissue and bodily fluid.
Stated Advantages
Extensive performance data is provided showing improved assay performance when using the combination of GFAP and UCH-L1 versus single-biomarker GFAP-only cut-offs, with reported sensitivity, specificity, NPV, and PPV across reference-level combinations and post-injury time windows up to 48 hours.
Benchmarked comparison is described against single-biomarker GFAP-only reference cut-offs.
The disclosure describes correlations with CT scan result, GCS score, MRI positivity, and Extended Glasgow Outcome Scale (GOSE) outcome categories.
The method variants describe diagnostic workflow choices including not performing a head computerized tomography (CT) scan and performing MRI procedure based on biomarker reference-level conditions.
Documented Applications
Diagnostic logic and clinical decision support for traumatic brain injury (TBI), including mild TBI and also moderate, severe, or moderate to severe TBI treatment selection based on combined GFAP and UCH-L1 reference levels.
Guiding whether a head CT scan is performed, including not performing a head CT scan in one independent claim variant, and guiding whether an MRI procedure is performed based on biomarker reference-level conditions.
Outcome-related assessment using correlations to CT findings, GCS score, MRI positivity, and Extended Glasgow Outcome Scale (GOSE) outcome categories, including use of healthy controls and orthopaedic-injury controls in the performance data described.
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