(89 days)
Not Found
No
The summary describes a device that measures biomarkers and provides a semi-quantitative interpretation based on pre-determined cut-off values derived from a training set using statistical methods (cross-validation and bootstrapping). There is no mention of AI or ML algorithms being used for the interpretation or any other function of the device.
No
The device is an in vitro diagnostic immunoassay system used to aid in the evaluation of patients with suspected mild traumatic brain injury; its purpose is diagnostic, not therapeutic.
Yes
The intended use explicitly states that the device is an "in vitro diagnostic immunoassay" used to "aid in the evaluation of patients" and assist in "determining the need for a CT (computed tomography) scan".
No
The device description clearly states that the system is comprised of the i-STAT Alinity instrument, i-STAT test cartridges, and accessories, which are hardware components. The software runs on the i-STAT Alinity instrument to process signals from the cartridge.
Yes, this device is an IVD (In Vitro Diagnostic).
The "Intended Use / Indications for Use" section explicitly states: "The i-STAT TBI test is a panel of in vitro diagnostic immunoassays..."
The "Device Description" also refers to the i-STAT Alinity instrument as a "in vitro diagnostic device."
N/A
Intended Use / Indications for Use
The i-STAT TBI test is a panel of in vitro diagnostic immunoassays for the quantitative measurements of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) in whole blood and a semi-quantitative interpretation of test results derived from these measurements, using the i-STAT Alinity instrument. The interpretation of test results is used, in conjunction with other clinical information, to aid in the evaluation of patients, 18 years of age or older, presenting with suspected mild traumatic brain injury (Glasgow Coma Scale score 13-15), which may include one of the following four clinical criteria: 1) any period of loss of consciousness, 2) any loss of memory for events immediately before and after the accident, 3) any alteration in mental state at the time of accident, and/or 4) focal neurological deficits, within 24 hours of injury, to assist in determining the need for a CT (computed tomography) scan of the head. A 'Not Elevated' test interpretation is associated with the absence of acute traumatic intracranial lesions visualized on a head CT scan.
The test is to be used with venous whole blood collected with EDTA anticoagulant in point of care or clinical laboratory settings by a healthcare professional.
Product codes (comma separated list FDA assigned to the subject device)
QAT
Device Description
The i-STAT TBI cartridge is a multiplex immunoassay that contains assays for both ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP). The assays test for the presence of these biomarkers in a whole blood sample and vield a semi-quantitative test interpretation based on measurements of both UCH-L1 and GFAP in approximately 15 minutes. The i-STAT TBI cartridge is designed to be run only on the i-STAT Alinity instrument.
The i-STAT Alinity instrument is a handheld, in vitro diagnostic device. The instrument is the main user interface of the i-STAT Alinity System and functions as the electro-mechanical interface to the test cartridge. The instrument executes the test cycle, acquires and processes the electrical sensor signals converting the signals into quantitative results. These functions are controlled by a microprocessor.
The i-STAT Alinity System is comprised of the i-STAT Alinity instrument, the i-STAT test cartridges and accessories (i-STAT Alinity Base Station, Electronic Simulator and Printer).
Assaved quality control materials are also available for use with the i-STAT TBI cartridge and include i-STAT TBI Control Level 1, i-STAT TBI Control Level 2, and the i-STAT TBI Calibration Verification Levels 1-3.
The i-STAT TBI Controls are available to monitor the performance of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) assays on the i-STAT Alinity instrument.
The i-STAT TBI Calibration Verification Materials are available to verify the calibration of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) assays throughout the reportable range on the i-STAT Alinity instrument.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
18 years of age or older
Intended User / Care Setting
point of care or clinical laboratory settings by a healthcare professional.
Description of the training set, sample size, data source, and annotation protocol
The assay cut-offs were determined by analyzing a training set with GFAP and UCH-L1 results from a total of 420 (274 males and 146 females) with suspected mild traumatic brain injury (TBI; Glasgow Coma Scale score of 13-15). Subjects who had blood drawn within 12 hours of injury and a head CT scan determination, were included in the analysis. Using a 10-fold cross validation and bootstrapping method, the cut-off values of 65 pg/mL (GFAP assay) and 360 pg/mL (UCH-L1 assay) were selected for the i-STAT TBI Cartridge using the selection criteria with an adjusted NPV (to 10%) ≥98.5% and sensitivity ≥97%.
Description of the test set, sample size, data source, and annotation protocol
A prospective, multi-center, observational study was conducted to evaluate the clinical performance of the i-STAT TBI cartridge in classifying intended use population subjects with suspected mild TBI for the likely absence of acute intracranial lesions visualized by a head CT scan. Venous whole blood specimens were used for i-STAT TBI cartridge testing.
Venous whole blood specimens were collected in KJEDTA within 24 hours of the head injury from prospectively enrolled subjects, 18 years of age or older, who had experienced a head injury and presented to the health care facility or the emergency department (ED) with suspected mild TBI, with a GCS score of 13-15; and who had a head CT scan ordered as part of their standard of clinical care. Each specimen was tested for GFAP and UCH-L1 using two (2) i-STAT TBI cartridges and two (2) i-STAT Alinity instruments. Testing was performed at 20 external point of care clinical sites across the United States.
CT scans were performed in accordance with the clinical site's standard of care. Images were transmitted to a central data capture system. Images were interpreted by at least two neuroradiologists who were masked to other clinical and laboratory data: procedures for scoring images were established before conducting image review. The clinical outcome was based on the consensus interpretation between two neurologists. Outcomes were positive or negative as defined by the presence or absence of acute traumatic intracranial lesions, respectively. Acute intracranial lesion was defined as any trauma induced or related finding visualized upon head CT scan.
Specimens from 970 subjects were included in the analysis.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Clinical Sensitivity and Specificity: A prospective, multi-center, observational study was conducted to evaluate the clinical performance of the i-STAT TBI cartridge. Specimens from 970 subjects were included in the analysis. Of the 970 evaluable subjects, 283 subjects had positive CT scan results. Of these 283 subjects with positive CT scan results, 273 had an 'Elevated' i-STAT TBI test interpretation (sensitivity = 96.5% (273/283)). Ten (10) subjects with CT scan positive results had an i-STAT TBI test interpretation that was 'Not Elevated'. The rate of false negative (FN) results was 3.5% (10/283). None of these ten (10) subjects with false negative results required surgical intervention related to their head injury as no neurosurgical lesions were identified by CT scan in these subjects.
Of the 687 subjects with negative CT scan results, 277 had an i-STAT TBI test interpretation that was 'Not Elevated' (277/687, specificity = 40.3%). The rate of false positive (FP) results was 59.6% (410/687).
In the clinical study, the prevalence of adjudicated CT scan positive subjects was 29.2% (283/970). Overall, there were 287 subjects with i-STAT TBI test interpretations of 'Not Elevated'. Of these, 277 subjects had negative CT scan results. The negative predictive value (NPV) of the assay was 96.5% (277/287). The results of these studies demonstrate that performance of the GFAP and UCH-L1 assays in the i-STAT TBI cartridge with the i-STAT Alinity System are substantially equivalent to the predicate device.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Clinical Sensitivity: 96.5% (273/283)
Clinical Specificity: 40.3% (277/687)
Negative Predictive Value (NPV): 96.5% (277/287)
Positive Predictive Value (PPV): 40% (273/683)
Likelihood Ratio Negative (LRN): 0.09
Likelihood Ratio Positive (LRP): 1.62
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 866.5830 Brain trauma assessment test.
(a)
Identification. A brain trauma assessment test is a device that consists of reagents used to detect and measure brain injury biomarkers in human specimens. The measurements aid in the evaluation of patients with suspected mild traumatic brain injury in conjunction with other clinical information to assist in determining the need for head imaging per current standard of care.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The 21 CFR 809.10(b) compliant labeling must include detailed descriptions of and results from performance testing conducted to evaluate precision, accuracy, linearity, analytical sensitivity, interference, and cross-reactivity. This information must include the following:
(i) Performance testing of device precision must, at minimum, use one unmodified clinical specimen from the intended use population with concentration of the brain injury biomarker(s) near the medical decision point. Contrived specimens that have been generated from pooling of multiple samples or spiking of purified analyte to cover the measuring range may be used, but the contrived samples must be prepared to mimic clinical specimens as closely as possible. This testing must evaluate repeatability and reproducibility using a protocol from an FDA-recognized standard.
(ii) Device performance data must be demonstrated through a clinical study and must include the following:
(A) Data demonstrating clinical validity including the clinical sensitivity and specificity, and positive and negative predictive value of the test in the intended use population of patients with suspected mild traumatic brain injury (
i.e., Glasgow Coma Score (GCS) of 13-15), or equivalent standard of care for determination of severity of traumatic brain injury (TBI).(B) Study must be performed using the operators and in settings that are representative of the types of operators and settings for which the device is intended to be used.
(C) All eligible subjects must meet the well-defined study inclusion and exclusion criteria that define the intended use population. The prevalence of diseased or injured subjects in the study population must reflect the prevalence of the device's intended use population, or alternatively, statistical measures must be used to account for any bias due to enrichment of subpopulations of the intended use population.
(D) All eligible subjects must have undergone a head computerized tomography (CT) scan or other appropriate clinical diagnostic standard used to determine the presence of an intracranial lesion as part of standard of care and must also be evaluated by the subject device. All clinical diagnostic standards used in the clinical study must follow standard clinical practice in the United States.
(E) Relevant demographic variables and baseline characteristics including medical history and neurological history. In addition, head injury characteristics, neurological assessments, and physical evidence of trauma must be provided for each subject. This information includes but is not limited to the following: Time since head injury, time from head injury to CT scan, time from head injury to blood draw, GCS score or equivalent, experience of loss of consciousness, presence of confusion, episodes of vomiting, post-traumatic amnesia characteristics, presence of post-traumatic seizures, drug or alcohol intoxication, mechanism of injury, acute intracranial lesion type, neurosurgical lesion, and cranial fracture.
(F) Each CT scan or other imaging result must be independently evaluated in a blinded manner by at least two board-certified radiologists to determine whether it is positive or negative as defined by the presence or absence of acute intracranial lesions. This independent review must be conducted without access to test results of the device. Prior to conducting the review, the criteria and procedures to be followed for scoring the images must be established, including the mechanism for determining consensus.
(G) All the clinical samples must be tested with the subject device blinded to the TBI status and the neurological-lesion-status of the subject.
(H) Details on how missing values in data are handled must be provided.
(I) For banked clinical samples, details on storage conditions and storage period must be provided. In addition, a specimen stability study must be conducted for the duration of storage to demonstrate integrity of archived clinical samples. The samples evaluated in the assay test development must not be used to establish the clinical validity of the assays.
(iii) Performance testing of device analytical specificity must include the most commonly reported concomitant medications present in specimens from the intended use population. Additionally, potential cross-reacting endogenous analytes must be evaluated at the highest concentration reported in specimens from the intended use population.
(iv) Expected/reference values generated by testing a statistically appropriate number of samples from apparently healthy normal individuals.
(2) The 21 CFR 809.10(a) and (b) compliant labeling must include the following limitations:
(i) A limiting statement that this device is not intended to be used a stand-alone device but as an adjunct to other clinical information to aid in the evaluation of patients who are being considered for standard of care neuroimaging.
(ii) A limiting statement that reads “A negative result is generally associated with the absence of acute intracranial lesions. An appropriate neuroimaging method is required for diagnosis of acute intracranial lesions.”
(iii) As applicable, a limiting statement that reads “This device is for use by laboratory professionals in a clinical laboratory setting.”
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March 27, 2024
Abbott Point of Care Brian Ma Principal Specialist. Regulatory Affairs 400 College Road East Princeton, New Jersey 08540
Re: K234143
Trade/Device Name: i-STAT TBI Cartridge with the i-STAT Alinity System Regulation Number: 21 CFR 866.5830 Regulation Name: Brain Trauma Assessment Test Regulatory Class: Class II Product Code: QAT Dated: December 28, 2023 Received: December 29, 2023
Dear Brian Ma:
We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
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Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review. the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerelv.
Ying Mao -S
Ying (Katelin) Mao, Ph.D. Branch Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
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Indications for Use
Submission Number (if known)
K234143 Device Name
i-STAT TBI cartridge with the i-STAT Alinity System
Indications for Use (Describe)
The i-STAT TBI test is a panel of in vitro diagnostic immunoassays for the quantitative measurements of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) in whole blood and a semi-quantitative interpretation of test results derived from these measurements, using the i-STAT Alinity instrument. The interpretation of test results is used, in conjunction with other clinical information, to aid in the evaluation of patients, 18 years of age or older, presenting with suspected mild traumatic brain injury (Glasgow Coma Scale score 13-15), which may include one of the following four clinical criteria: 1) any period of loss of consciousness, 2) any loss of memory for events immediately before and after the accident, 3) any alteration in mental state at the time of accident, and/or 4) focal neurological deficits, within 24 hours of injury, to assist in determining the need for a CT (computed tomography) scan of the head. A 'Not Elevated' test interpretation is associated with the absence of acute traumatic intracranial lesions visualized on a head CT scan.
The test is to be used with venous whole blood collected with EDTA anticoagulant in point of care or clinical laboratory settings by a healthcare professional.
Type of Use (Select one or both, as applicable)
Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
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510(k) Summary
The information in this 510(k) summary is being submitted in accordance with the requirements of 21 CFR 807.92.
1. Submitter Information
| Owner | Abbott Point of Care Inc.
400 College Road East
Princeton, NJ 08540 |
|---------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Contact | Primary: Brian Ma, PhD
Principal Specialist Regulatory Affairs
Phone: 613-688-5949
Secondary: Mojgan Soleimani
Associate Director, Regulatory Affairs
Phone: 613-295-0932 |
| Date Prepared | March 25, 2024 |
2. Device Information
Proprietary Name: i-STAT TBI cartridge with the i-STAT Alinity System
Glial fibrillary acidic protein (GFAP) Common Name: Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1)
K234143 510(k) Number
| Product
Code | Device Classification Name | Regulation
Number | Class | Panel |
|-----------------|------------------------------|----------------------|--------------------------|------------|
| QAT | Brain trauma assessment test | 866.5830 | II (special
controls) | Immunology |
Predicate Device 3.
i-STAT TBI Plasma cartridge with the i-STAT Alinity System Proprietary Name 510(k) Number K201778
| Product
Code | Device Classification Name | Regulation
Number | Class | Panel |
|-----------------|------------------------------|----------------------|--------------------------|------------|
| QAT | Brain trauma assessment test | 866.5830 | II (special
controls) | Immunology |
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4. Device Description
The i-STAT TBI cartridge is a multiplex immunoassay that contains assays for both ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP). The assays test for the presence of these biomarkers in a whole blood sample and vield a semi-quantitative test interpretation based on measurements of both UCH-L1 and GFAP in approximately 15 minutes. The i-STAT TBI cartridge is designed to be run only on the i-STAT Alinity instrument.
The i-STAT Alinity instrument is a handheld, in vitro diagnostic device. The instrument is the main user interface of the i-STAT Alinity System and functions as the electro-mechanical interface to the test cartridge. The instrument executes the test cycle, acquires and processes the electrical sensor signals converting the signals into quantitative results. These functions are controlled by a microprocessor.
The i-STAT Alinity System is comprised of the i-STAT Alinity instrument, the i-STAT test cartridges and accessories (i-STAT Alinity Base Station, Electronic Simulator and Printer).
Assaved quality control materials are also available for use with the i-STAT TBI cartridge and include i-STAT TBI Control Level 1, i-STAT TBI Control Level 2, and the i-STAT TBI Calibration Verification Levels 1-3.
The i-STAT TBI Controls are available to monitor the performance of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) assays on the i-STAT Alinity instrument.
The i-STAT TBI Calibration Verification Materials are available to verify the calibration of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) assays throughout the reportable range on the i-STAT Alinity instrument.
5. Intended Use Statement
The i-STAT TBI test is a panel of in vitro diagnostic immunoassays for the quantitative measurements of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) in whole blood and a semi-quantitative interpretation of test results derived from these measurements, using the i-STAT Alinity instrument. The interpretation of test results is used, in conjunction with other clinical information, to aid in the evaluation of patients, 18 years of age or older, presenting with suspected mild traumatic brain injury (Glasgow Coma Scale score 13-15), which may include one of the following four clinical criteria: 1) any period of loss of consciousness, 2) any loss of memory for events immediately before and after the accident. 3) any alteration in mental state at the time of accident. and/or 4) focal neurological deficits, within 24 hours of injury, to assist in determining the need for a CT (computed tomography) scan of the head. A "Not Elevated" TBI test interpretation is associated with the absence of acute traumatic intracranial lesions visualized on a head CT scan.
The test is to be used with venous whole blood collected with EDTA anticoagulant in point of care or clinical laboratory settings by a healthcare professional.
5
| Similarities and Differences: System (Test and Instrument) | ||
|---|---|---|
| Feature or | ||
| Characteristic | Candidate Device: | |
| i-STAT TBI cartridge with the i-STAT | ||
| Alinity System | Predicate Device: | |
| i-STAT TBI Plasma cartridge with the | ||
| i-STAT Alinity System | ||
| (K201778) | ||
| Intended Use | The i-STAT TBI test is a panel of in vitro | |
| diagnostic immunoassays for the | ||
| quantitative measurements of glial | ||
| fibrillary acidic protein (GFAP) and | ||
| ubiquitin carboxyl-terminal hydrolase | ||
| L1 (UCH-L1) in whole blood and a | ||
| semi-quantitative interpretation of | ||
| test results derived from these | ||
| measurements, using the i-STAT Alinity | ||
| instrument. The interpretation of test | ||
| results is used, in conjunction with | ||
| other clinical information, to aid in the | ||
| evaluation of patients, 18 years of age | ||
| or older, presenting with suspected | ||
| mild traumatic brain injury (Glasgow | ||
| Coma Scale score 13-15), which may | ||
| include one of the following four | ||
| clinical criteria: 1) any period of loss of | ||
| consciousness, 2) any loss of memory | ||
| for events immediately before and | ||
| after the accident, 3) any alteration in | ||
| mental state at the time of accident, | ||
| and/or 4) focal neurological deficits, | ||
| within 24 hours of injury, to assist in | ||
| determining the need for a CT | ||
| (computed tomography) scan of the | ||
| head. A 'Not Elevated' test | ||
| interpretation is associated with the | ||
| absence of acute traumatic intracranial | ||
| lesions visualized on a head CT scan. | ||
| The test is to be used with venous | ||
| whole blood collected with EDTA | ||
| anticoagulant in point of care or | ||
| clinical laboratory settings by a | ||
| healthcare professional. | The i-STAT TBI Plasma test is a | |
| panel of in vitro diagnostic | ||
| immunoassays for the quantitative | ||
| measurements of glial fibrillary acidic | ||
| protein (GFAP) and ubiquitin carboxyl- | ||
| terminal hydrolase L1 (UCH-L1) in | ||
| plasma and a semi- quantitative | ||
| interpretation of test results derived | ||
| from these measurements, using the | ||
| i-STAT Alinity Instrument. The | ||
| interpretation of test results is used, | ||
| in conjunction with other clinical | ||
| information, to aid in the evaluation | ||
| of patients, 18 years of age or older, | ||
| presenting with suspected mild | ||
| traumatic brain injury (Glasgow Coma | ||
| Scale score 13-15) within 12 hours of | ||
| injury, to assist in determining the | ||
| need for a CT (computed tomography) | ||
| scan of the head. A 'Not Elevated' test | ||
| interpretation is associated with the | ||
| absence of acute traumatic | ||
| intracranial lesions visualized on a | ||
| head CT scan. | ||
| The test is to be used with plasma | ||
| prepared from EDTA anticoagulated | ||
| specimens in clinical laboratory | ||
| settings by a healthcare professional. | ||
| The i-STAT TBI Plasma test is not | ||
| intended to be used in point of care | ||
| settings. | ||
| Similarities and Differences: System (Test and Instrument) | ||
| Feature or | ||
| Characteristic | Candidate Device: | |
| i-STAT TBI cartridge with the i-STAT | ||
| Alinity System | Predicate Device: | |
| i-STAT TBI Plasma cartridge with the | ||
| i-STAT Alinity System | ||
| (K201778) | ||
| Intended Use | ||
| Setting | Clinical Laboratory and Point of Care | Clinical Laboratory |
| Measurands | GFAP and UCH-L1 | Same |
| Assay | ||
| Technology | Enzyme-linked immunosorbent assay | Same |
| Assay Format | Single use multiplex cartridge (both | |
| assays (GFAP and UCH-L1) in one | ||
| cartridge) | Same | |
| Detection | ||
| Technology | Electrochemical | Same |
| Sample Type | Whole Blood | Plasma |
| Sample Volume | 20 μL | Same |
| Automation | Test and wash cycles are fully | |
| automated after sample loading step | Same | |
| Analytical | ||
| Measuring | ||
| Interval | GFAP: 47 - 10,000 pg/mL | |
| UCH-L1: 87 - 3,200 pg/mL | GFAP: 30 - 10,000 pg/mL | |
| UCH-L1: 200 - 3,200 pg/mL | ||
| Time to Result | 15 minutes | Same |
| Reportable | ||
| Result | Quantitative results for GFAP and | |
| UCH-L1 and semi-quantitative | ||
| interpretation | Same | |
| Instrument | ||
| Platform | i-STAT Alinity | Same |
| Calibration | No calibration needed by the end | |
| user, calibration is pre-set during | ||
| manufacture of the cartridge | Same | |
| Controls | GFAP and UCH-L1 combined: | |
| i-STAT TBI Controls (Levels 1 and 2) | ||
| i-STAT TBI Calibration Verification | ||
| Materials (Levels 1, 2, 3) | Same | |
| Traceability | GFAP and UCH-L1 values assigned to | |
| i-STAT controls and calibration | ||
| verification materials are traceable to | ||
| Abbott's working calibrators prepared | ||
| using recombinant GFAP and UCH-L1 | ||
| (expressed and purified from E. coli). | Same | |
| Assay Cut-off | GFAP: 65 pg/ml | |
| UCH-L1: 360 pg/ml | GFAP: 30 pg/ml | |
| UCH-L1: 360 pg/ml |
6. Summary Comparison of Technological Characteristics
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Performance Characteristics 7.
A. Analytical Performance
a. Precision/Reproducibility:
Semi-quantitative 20-day precision: The precision of the GFAP and UCH-L1 assays in the i-STAT TBI cartridge with the i-STAT Alinity System was evaluated using plasma samples spiked with native or recombinant GFAP and UCH-L1 antigens at various levels across the reportable range of the GFAP and UCH-L1 assays, and two (2) controls (i- STAT TBI Control L1 and Control L2). The study was executed over 20 non-consecutive days, two (2) runs per day that were separated by minimum two (2) hours, by at least two (2) operators using three (3) lots of i-STAT TBI cartridges. Due to the inability to store or freeze whole blood samples to maintain sample stability over multiple days, plasma samples were used for this study. The study followed the standard single-site 20x2x2 experimental design based on guidance provided in CLSI EP05-A3; Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline -Third Edition. The components of variability were estimated for GFAP and UCH-L1 and the precision results for the plasma panel are shown in Table 2, and for the i-STAT TBI Controls in Table 3.
| Table 1: Estimate of GFAP Assay Precision | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Repeatability | Between-run | Between-day | Between-lot | Within-Laboratory | ||||||||
| Plasma | N | Mean | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV |
| Sample | (pg/mL) | (pg/mL) | (%) | (pg/mL) | (%) | (pg/mL) | (%) | (pg/mL) | (%) | (pg/mL) | (%) | |
| 1B | 240 | 78.8 | 3.04 | 3.86 | 0.85 | 1.07 | 0.57 | 0.72 | 2.17 | 2.76 | 3.90 | 4.95 |
| 2B | 240 | 98.6 | 6.03 | 6.12 | 1.40 | 1.42 | 0.72 | 0.73 | 2.57 | 2.61 | 6.78 | 6.87 |
| 3A | 240 | 880.6 | 21.29 | 2.42 | 15.78 | 1.79 | 1.66 | 0.19 | 9.76 | 1.11 | 28.79 | 3.27 |
| 4A | 240 | 4415.3 | 144.73 | 3.28 | 67.27 | 1.52 | 17.25 | 0.39 | 135.59 | 3.07 | 212.16 | 4.81 |
| 5A | 240 | 8346.7 | 285.03 | 3.41 | 151.07 | 1.81 | 56.69 | 0.68 | 347.63 | 4.16 | 479.49 | 5.74 |
్ Pooled plasma from normal donors spiked with Qualitative multi-site precision: The qualitative agreement of cartridge results relative to the expected sample result was evaluated for all measurements per test material for each assay above. The mean value of the test material was used as the expected result to classify the sample as below cut-off, near cut-off (overall mean ± 25% of cut-off), or above cut-off for each assay. The mean, total number of replicates, total number of elevated results, and % correct call for each test material is presented in Table 8 for GFAP and Table 9 for UCH-L1.
| Table 8: Qualitative Precision Analysis - GFAP Assay - All Sites | |||||
|---|---|---|---|---|---|
| Test Material | Mean (pg/mL) | N | Qualitative Agreement | % Correct call | |
| Total # of results at or above the assay cut-off | Total # of results below the assay cut-off | ||||
| 2B | 66.4 | 90 | 74 | 16 | 82.22* |
| 4C | 86.0 | 90 | 89 | 1 | 98.89 |
| 5C | 980.9 | 90 | 90 | 0 | 100.00 |
| 6C | 2785.5 | 90 | 90 | 0 | 100.00 |
| 7C | 5357.3 | 90 | 90 | 0 | 100.00 |
| 8C | 7652.6 | 90 | 90 | 0 | 100.00 |
A Below cut-off; 8 Near cut-off (overall mean ± 25%); ^ Above cut-off
*Determination of correct call based on test material mean. Replicates for sample with mean near cut-off can have replicates below cut-off or at/above cut-off.
11
| Table 9: Qualitative Precision Analysis - UCH-L1 Assay – All Sites | |||||
|---|---|---|---|---|---|
| Test Material | Mean (pg/mL) | N | Qualitative Agreement | ||
| Total # of results at or above the cut-off | Total # of results below the assay cut-off | % Correct call | |||
| 1A | 206.5 | 90 | 0 | 90 | 100.00 |
| 3B | 384.1 | 93 | 83 | 10 | 89.25* |
| 4C | 681.8 | 90 | 90 | 0 | 100.00 |
| 5C | 1225.9 | 90 | 90 | 0 | 100.00 |
| 6C | 2051.2 | 90 | 90 | 0 | 100.00 |
| 8C | 2851.8 | 90 | 90 | 0 | 100.00 |
A Below cut-off; 8 Near cut-off (overall mean ± 25%); 6 Above cut-off
- Determination of correct call based on test material mean. Replicates for sample with mean near cut-off can have replicates below cut-off or at/above cut-off
Semi-quantitative whole blood precision: The precision performance of the GFAP and UCH-L1 assays in the i-STAT TBI cartridge on the i-STAT Alinity System was evaluated in point of care settings at three (3) clinical sites following a modified design based on CLSI EP05-A3: Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline – Third Edition. At each site, test samples across the reportable ranges of each assay were prepared by spiking prospectively collected venous whole blood specimens with recombinant GFAP and/or UCH-L1 or human plasma sample from traumatic brain injury (TBI) patients with native GFAP and UCH-L1. Eight (8) GFAP and eight (8) UCH-L1 samples were prepared at Site 1; eight (8) GFAP and 13 UCH-L1 samples were prepared at Site 2; seven (7) GFAP and eight (8) UCH-L1 samples were prepared at Site 3 At each site, each whole blood sample was tested in three (3) runs, by two (2) different operators, each operator using four (4) i-STAT TBI cartridges on four (4) i-STAT Alinity instruments (1 replicate/instrument/run) for a total of 24 replicates/specimen. For samples with target ranges near the GFAP and UCH-L1 assay cut-offs, a minimum of 2 samples were prepared and tested using the i-STAT TBI cartridges at each clinical site. The estimates of GFAP and UCH-L1 precision are shown in Table 10 and Table 11.
12
| Table 10: Whole Blood Precision at Point-of-Care Sites - GFAP Assay | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Site | Whole | |||||||||||
| Blood | ||||||||||||
| Sample | N | Mean | Repeatability | Between-Instrument | Between-Operator | Within-Site | ||||||
| SD | ||||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | ||||||||||||
| 01 | 1+ | 24 | 63.3 | 9.84 | 15.53 | 0.00 | 0.00 | 2.98 | 4.70 | 10.28 | 16.23 | |
| 2+ | 23‡ | 64.3 | 11.72 | 18.23 | 6.76 | 10.51 | 4.25 | 6.61 | 14.18 | 22.06 | ||
| 3* | 24 | 103.5 | 10.85 | 10.48 | 0.00 | 0.00 | 2.22 | 2.14 | 11.07 | 10.70 | ||
| 4* | 23‡ | 128.5 | 14.51 | 11.29 | 0.00 | 0.00 | 0.00 | 0.00 | 14.51 | 11.29 | ||
| 5* | 24 | 986.3 | 88.48 | 8.97 | 0.00 | 0.00 | 0.00 | 0.00 | 88.48 | 8.97 | ||
| 6* | 24 | 3431.6 | 338.46 | 9.86 | 0.00 | 0.00 | 104.36 | 3.04 | 354.19 | 10.32 | ||
| 7* | 24 | 6371.3 | 637.41 | 10.00 | 0.00 | 0.00 | 162.96 | 2.56 | 657.91 | 10.33 | ||
| 8* | 24 | 7836.9 | 730.91 | 9.33 | 0.00 | 0.00 | 102.96 | 1.31 | 738.13 | 9.42 | ||
| 02 | 1+ | 24 | 57.7 | 7.24 | 12.56 | 4.60 | 7.97 | 5.28 | 9.16 | 10.07 | 17.47 | |
| 2+ | 24 | 60.9 | 11.08 | 18.18 | 0.00 | 0.00 | 2.15 | 3.53 | 11.28 | 18.52 | ||
| 3* | 24 | 83.7 | 6.98 | 8.34 | 0.00 | 0.00 | 0.00 | 0.00 | 6.98 | 8.34 | ||
| 4* | 24 | 148.1 | 12.08 | 8.16 | 0.00 | 0.00 | 0.00 | 0.00 | 12.08 | 8.16 | ||
| 5* | 24 | 900.6 | 28.89 | 3.21 | 10.84 | 1.20 | 0.00 | 0.00 | 30.85 | 3.43 | ||
| 6* | 24 | 3731.1 | 161.63 | 4.33 | 0.00 | 0.00 | 121.29 | 3.25 | 202.08 | 5.42 | ||
| 7* | 24 | 5762.3 | 289.18 | 5.02 | 0.00 | 0.00 | 0.00 | 0.00 | 289.18 | 5.02 | ||
| 8* | 24 | 8310.3 | 499.50 | 6.01 | 0.00 | 0.00 | 0.00 | 0.00 | 499.50 | 6.01 | ||
| 03 | 1+ | 23‡ | 58.9 | 4.47 | 7.59 | 2.60 | 4.41 | 0.00 | 0.00 | 5.17 | 8.78 | |
| 2+ | 22§ | 67.2 | 16.54 | 24.62 | 0.00 | 0.00 | 0.00 | 0.00 | 16.54 | 24.62 | ||
| 3* | 24 | 145.4 | 10.54 | 7.25 | 0.00 | 0.00 | 3.28 | 2.26 | 11.03 | 7.59 | ||
| 4* | 24 | 962.1 | 56.81 | 5.90 | 24.53 | 2.55 | 0.00 | 0.00 | 61.88 | 6.43 | ||
| 5* | 24 | 2954.5 | 167.36 | 5.66 | 0.00 | 0.00 | 3.12 | 0.11 | 167.39 | 5.67 | ||
| 6* | 24 | 6226.4 | 246.48 | 3.96 | 18.23 | 0.29 | 20.69 | 0.33 | 248.02 | 3.98 | ||
| 7* | 23¶ | 8366.9 | 502.57 | 6.01 | 0.00 | 0.00 | 168.21 | 2.01 | 529.97 | 6.33 |
*prospectively collected KչEDTA venous whole blood spiked with 12.1 g/dL. The highest concentration in the reference interval reported by CLSI EP37 is 5.2 g/dL. |
| Amphetamine | 2.44 | 0.033 | GFAP
UCH-L1 | Yes
No | Decreased results at >1.83 µmol/L. The highest drug concentration under therapeutic treatment reported by CLSI EP37 is 0.815 µmol/L. |
| Ascorbic acid | 298 | 5.90 | GFAP
UCH-L1 | No
No | |
| Benzoylecgonine a | 8.64 | 2.5 µg/mL | GFAP
UCH-L1 | No
No | |
| Bilirubin | 684 | 40 | GFAP
UCH-L1 | No
No | |
| Bilirubin (conjugated) | 475 | 40 | GFAP
UCH-L1 | No
No | |
| Caffeine | 556 | 10.8 | GFAP
UCH-L1 | No
No | |
| Chloramphenicol | 241 | 7.79 | GFAP
UCH-L1 | No
No | |
| Clopidogrel a | 21.4 | 0.90 | GFAP
UCH-L1 | No
No | |
| Cocaine a | 3.46 µg/mL | 0.346 | GFAP
UCH-L1 | No
Yes | Decreased results at >2.595 µg/mL. The mean maximum |
| Substance | Test Concentration | | Assay | Interference
(Yes/No) | Comment |
| Diazepam | 105 | 2.99 | GFAP
UCH-L1 | No
No | plasma concentration
(Cmax) per literature is 0.115 µg/mLc. |
| Diclofenac | 81 | 2.58 | GFAP
UCH-L1 | No
No | |
| Dopamine | 4.06 | 0.077 | GFAP
UCH-L1 | No
No | |
| EDDPa | 0.33 | 125 ng/mL | GFAP
UCH-L1 | No
No | |
| Erythromycin | 188 | 13.80 | GFAP
UCH-L1 | No
No | |
| Ethanol | 130 mmol/L | 599 | GFAP
UCH-L1 | No
No | |
| Hemoglobin | 10 g/L | 1000 | GFAP
UCH-L1 | No
No | |
| Human anti-mouse
antibodies (HAMA) a | >80x b | N/A | GFAP
UCH-L1 | No
No | |
| Ibuprofen a | 2425 | 50.0 | GFAP
UCH-L1 | No
No | |
| Intralipid (Intralipid 20%) | N/A | 7075 | GFAP
UCH-L1 | No
No | |
| Methadone | 10.3 | 0.319 | GFAP
UCH-L1 | Yes
No | Decreased results at >7.725 µmol/L. The highest drug
concentration under
therapeutic treatment
reported by CLSI EP37 is 3.43 µmol/L. |
| d-Methamphetamine a | 1.865 | 278.3 ng/mL | GFAP
UCH-L1 | Yes
No | Decreased results at >208.8 ng/mL. The mean maximum
plasma concentration
(Cmax) per literature is 92.8 ng/mL.d |
| Methaqualone a | 32.36 | 8.1 µg/mL | GFAP
UCH-L1 | No
No | |
| Metoprolol a | 18.7 | 1.28 | GFAP
UCH-L1 | No
Yes | Decreased results at >14.025 µmol/L. The highest drug
concentration under
therapeutic treatment |
| Table 16: Interfering Substances Testing | | | | | |
| | Test Concentration | | | Interference | |
| Substance | μmol/L | mg/dL | Assay | (Yes/No) | Comment |
| Morphine | 27.3 | 0.78 | GFAP | No | reported by CLSI EP37 is
1.875 μmol/L. |
| | | | UCH-L1 | No | |
| Nicardipine
hydrochloride | 0.97 | 0.05 | GFAP | No | |
| | | | UCH-L1 | No | |
| Nicotine | 5.97 | 0.0097 | GFAP | No | |
| | | | UCH-L1 | No | |
| Oxazepam | 15.1 | 0.432 | GFAP | No | |
| | | | UCH-L1 | No | |
| Phencyclidine a | 0.0357 | 8.7 ng/mL | GFAP | No | |
| | | | UCH-L1 | No | |
| Phenytoin | 238 | 6.0 | GFAP | No | |
| | | | UCH-L1 | No | |
| Propoxyphene a | 9.46 | 0.32 | GFAP | No | |
| | | | UCH-L1 | Yes | Decreased results at >7.095
µmol/L. The highest drug
concentration under
therapeutic treatment
reported by CLSI EP37 is 3.15
μmol/L. |
| Rheumatoid Factor (RF) a | 1000 IU/mL | N/A | GFAP | No | |
| | | | UCH-L1 | Yes | Decreased results at >875
IU/mL |
| Secobarbital | 66.8 | 1.59 | GFAP | No | |
| | | | UCH-L1 | No | |
| Triglycerides a | 33.88 mmol/L | 3000 | GFAP | No | |
| | | | UCH-L1 | No | |
| Warfarin | 243 | 7.5 | GFAP | No | |
| | | | UCH-L1 | No | |
18
19
†2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
ª The test concentration used for this substance is not from CLSI guideline EP37 1* edition
b The 'x' factor listed indicates the number of times more activity than a known negative sample for its ability to crosslink antibodies in a mouse system assay.
° Scheidweiler, K. B., Spargo, E. A., Kelly, T. L., Cone, E. J., Barnes, A. J., and Huestis, M. A. (2010) Pharmacokinetics of cocaine and metabolites in human oral fluid and correlations after controlled administration. Ther Drug Monit. 32, 628-637
d Karch, S. (2008) Dissociative Anesthetics. In: Karch's Pathology of Drug Abuse, 4th ed. Boca Raton, FL: CRC Press
ii. Cross-reactivity
The i-STAT TBI cartridge on the i-STAT Alinity System were evaluated in the presence of potentially cross-reactive endogenous substances in whole blood specimens based on CLSI guidance EP07-ED3: Interference Testing in Clinical Chemistry, 3rd edition. The effect of each
20
substance was evaluated by comparing the performance of a test sample spiked with a potentially cross-reactive substance and a control sample spiked with an equal volume of blank plasma diluent as per CLSI EP07 ED3. Table 17 below lists the proteins with significant homology to GFAP and UCH-L1 that were tested at highest known physiological levels. None (0) of the nine (9) substances tested were found to cross-react with the GFAP or UCH-L1 assays in the i-STAT TBI cartridge tested on the i-STAT Alinity System.
| Table 17 : Cross-Reactivity | |||
|---|---|---|---|
| Assay | Substance | Substance Test | |
| Concentration | |||
| (pg/mL) | Outcome (Cross-Reactivity/ | ||
| No Cross-Reactivity) | |||
| GFAP | Keratin type II | 10,000 | No Cross-Reactivity |
| Internexin | 77,000 | No Cross-Reactivity | |
| Neurofilament Medium | 8,600 | No Cross-Reactivity | |
| Neurofilament Heavy | 77,000 | No Cross-Reactivity | |
| Neurofilament Light | 68 | No Cross-Reactivity | |
| Peripherin Protein | 5,000 | No Cross-Reactivity | |
| Desmin | 127,000 | No Cross-Reactivity | |
| Vimentin | 354,000 | No Cross-Reactivity | |
| UCH- | |||
| L1 | Ubiquitin Carboxyl- | ||
| Terminal Hydrolase L3 | |||
| (UCH-L3) | 354,000 | No Cross-Reactivity |
iii. Cross-talk
The GFAP and UCH-L1 assays in the i-STAT TBI cartridge were evaluated for potential crosstalk to determine if high levels of the antigen (GFAP or UCH-L1) of one assay have potential to the impact the result of the other assay. Whole Blood samples spiked to low and high GFAP and UCH-L1 levels were evaluated in the presence of a single high level of the other antigen being evaluated for potential cross-talk. As presented in Table 18 no cross-talk effect was observed as the results demonstrated that the GFAP result is not affected when UCH-L1 is present in a sample, and that the UCH-L1 result is not affected when GFAP is present in a sample.
| Table 18 : Cross-talk | ||||
|---|---|---|---|---|
| Assay | Level | Substance | Substance Test | |
| Concentration | ||||
| (pg/mL) | Cross-talk | |||
| GFAP | Low-positive | UCH-L1 | 100,000 | No |
| GFAP | Moderate-positive | UCH-L1 | 100,000 | No |
| UCH-L1 | Low-positive | GFAP | 100,000 | No |
| UCH-L1 | Moderate-positive | GFAP | 100,000 | No |
21
f. Hematocrit Sensitivity
The effect of hematocrit on the GFAP and UCH-L1 assays in the i-STAT TBI cartridge was assessed across a hematocrit range of 15-60% packed cell volume (PCV). The study was conducted using two (2) lots of i-STAT TBI cartridges and i-STAT Alinity instruments. Whole blood samples from six (6) donors were altered to target three (3) GFAP and UCH-L1 levels (low, moderate and high) across the reportable range for each respective assay. Each sample was evaluated at three (3) hematocrit (HCT) levels, with the nominal hematocrit level as control condition and low and high hematocrit levels as test conditions. The hematocrit sensitivity at each GFAP and UCH-L1 level was assessed by comparing the results at the low and high hematocrit levels (test conditions) to the nominal hematocrit level (control condition). Imprecision (CV) and bias exceeding 10% were observed for low level GFAP samples with hematocrit levels above 56% PCV.
g. Assay Cut-Off
The assay cut-offs were determined by analyzing a training set with GFAP and UCH-L1 results from a total of 420 (274 males and 146 females) with suspected mild traumatic brain injury (TBI; Glasgow Coma Scale score of 13-15). Subjects who had blood drawn within 12 hours of injury and a head CT scan determination, were included in the analysis. Using a 10-fold cross validation and bootstrapping method, the cut-off values of 65 pg/mL (GFAP assay) and 360 pg/mL (UCH-L1 assay) were selected for the i-STAT TBI Cartridge using the selection criteria with an adjusted NPV (to 10%) ≥98.5% and sensitivity ≥97%.
B. Clinical Sensitivity and Specificity
A prospective, multi-center, observational study was conducted to evaluate the clinical performance of the i-STAT TBI cartridge in classifying intended use population subjects with suspected mild TBI for the likely absence of acute intracranial lesions visualized by a head CT scan. Venous whole blood specimens were used for i-STAT TBI cartridge testing.
Venous whole blood specimens were collected in KJEDTA within 24 hours of the head injury from prospectively enrolled subjects, 18 years of age or older, who had experienced a head injury and presented to the health care facility or the emergency department (ED) with suspected mild TBI, with a GCS score of 13-15; and who had a head CT scan ordered as part of their standard of clinical care. Each specimen was tested for GFAP and UCH-L1 using two (2) i-STAT TBI cartridges and two (2) i-STAT Alinity instruments. Testing was performed at 20 external point of care clinical sites across the United States.
CT scans were performed in accordance with the clinical site's standard of care. Images were transmitted to a central data capture system. Images were interpreted by at least two neuroradiologists who were masked to other clinical and laboratory data: procedures for scoring images were established before conducting image review. The clinical outcome was based on the consensus interpretation between two neurologists. Outcomes were positive or negative as defined by the presence or absence of acute traumatic intracranial lesions, respectively. Acute intracranial lesion was defined as any trauma induced or related finding visualized upon head CT scan.
Specimens from 970 subjects were included in the analysis.
22
The demographic characteristics of the subjects represented in the clinical performance analysis are summarized in Table 19 below.
| Table 19 : Demographic Characteristics | |||
|---|---|---|---|
| Characteristic | Head CT Scan Result | ||
| Positive | Negative | Total | |
| N | 283 | 687 | 970 |
| Age (Years) | |||
| Mean | 51.1 | 45.0 | 46.8 |
| Median | 52.0 | 42.0 | 46.0 |
| Standard Deviation | 19.68 | 18.92 | 19.33 |
| Minimum | 18 | 18 | 18 |
| Maximum | 96 | 97 | 97 |
| Gender, N (%) | |||
| Male | 187 (66.1%) | 434 (63.2%) | 621 (64.0%) |
| Female | 94 (33.2%) | 252 (36.7%) | 346 (35.7%) |
| Unspecified/ Not Reported | 2 (0.7%) | 1 (0.1%) | 3 (0.3%) |
| Race, N (%) | |||
| White | 224 (79.2%) | 441 (64.2%) | 665 (68.6%) |
| Black or African American | 20 (7.1%) | 152 (22.1%) | 172 (17.7%) |
| Asian | 11 (3.9%) | 38 (5.5%) | 49 (5.1%) |
| Native Hawaiian/Pacific Islander | 4 (1.4%) | 6 (0.9%) | 10 (1.0%) |
| American Indian or Alaska Native | 4 (1.4%) | 8 (1.2%) | 12 (1.2%) |
| Asian, White | 2 (0.7%) | 3 (0.4%) | 5 (0.5%) |
| Asian, Black or African American | 0 (0.0%) | 1 (0.1%) | 1 (0.1%) |
| Black or African American, American Indian or | |||
| Alaska Native | 0 (0.0%) | 2 (0.3%) | 2 (0.2%) |
| White, Black or African American | 0 (0.0%) | 5 (0.7%) | 5 (0.5%) |
| Not Reported | 10 (3.5%) | 19 (2.8%) | 29 (3.0%) |
| Unknown | 8 (2.8%) | 12 (1.7%) | 20 (2.1%) |
| Ethnicity, N (%) | |||
| Hispanic or Latino | 67 (23.7%) | 120 (17.5%) | 187 (19.3%) |
| Not Hispanic or Latino | 209 (73.9%) | 552 (80.3%) | 761 (78.5%) |
| Unknown | 6 (2.1%) | 6 (0.9%) | 12 (1.2%) |
| Not Reported | 1 (0.4%) | 9 (1.3%) | 10 (1.0%) |
23
The head injury characteristics of the 970 subjects in the performance analysis were tabulated. Information regarding time from head injury to exam, head injury to CT scan, and head injury to blood draw, as well as GCS, neurological assessment and physical evidence of trauma, categorized by head CT scan results, are shown in Table 20 below.
| Table 20 : Head Injury Characteristics | |||
|---|---|---|---|
| Head CT Scan Result | |||
| Assessment | Positive | Negative | Total |
| N | 283 | 687 | 970 |
| Time from head injury to Initial Assessment (hours)* | |||
| Mean | 2.0 | 1.3 | 1.5 |
| Median | 1.0 | 0.8 | 0.9 |
| Standard Deviation | 2.01 | 1.45 | 1.67 |
| Range | (1.0, 10.2) | (0.8, 10.0) | (0.8, 10.2) |
| Time from head injury to CT scan (hours)* | |||
| Mean | 2.6 | 2.5 | 2.6 |
| Median | 1.7 | 2.0 | 1.9 |
| Standard Deviation | 2.37 | 1.80 | 1.98 |
| Range | (0.2, 11.4) | (0.3, 10.7) | (0.2, 11.4) |
| Time from head injury to blood draw (hours)* | |||
| Mean | 14.5 | 8.8 | 10.4 |
| Median | 13.5 | 5.8 | 8.1 |
| Standard Deviation | 6.65 | 6.43 | 6.99 |
| Range | (2.0, 24.0) | (1.5, 24.0) | (1.5, 24.0) |
| Glasgow Coma Score - N (%) | |||
| 13 | 28 (9.9%) | 11 (1.6%) | 39 (4.0%) |
| 14 | 79 (27.9%) | 90 (13.1%) | 169 (17.4%) |
| 15 | 176 (62.2%) | 586 (85.3%) | 762 (78.6%) |
| Neurological assessment - N (%) of subjects experiencing: | |||
| Loss of Consciousness (LOC) | 225 (79.5%) | 450 (65.5%) | 675 (69.6%) |
| Confusion/Alteration of Consciousness (AOC) | 195 (68.9%) | 504 (73.4%) | 699 (72.1%) |
| Vomiting | 24 (8.5%) | 21 (3.1%) | 45 (4.6%) |
| Post Traumatic Amnesia (PTA) | 196 (69.3%) | 409 (59.5%) | 605 (62.4%) |
| Post Traumatic Seizures | 3 (1.1%) | 0 (0.0%) | 3 (0.3%) |
| Subjects with Drug Intoxication at the Time of | |||
| Presentation to Facility | 48 (17.0%) | 66 (9.6%) | 114 (11.8%) |
| Subjects with Alcohol Intoxication at the Time of | |||
| Presentation to Facility | 49 (17.3%) | 61 (8.9%) | 110 (11.3%) |
| Mechanism of Injury† - N (%) of subjects affected: | |||
| Table 20 : Head Injury Characteristics | |||
| Assessment | Head CT Scan Result | Total | |
| Positive | Negative | ||
| Acceleration/Deceleration | 68 (24.0%) | 221 (32.2%) | 289 (29.8%) |
| Direct Impact (blow to head) | 44 (15.5%) | 85 (12.4%) | 129 (13.3%) |
| Direct Impact (head against object) | 157 (55.5%) | 437 (63.6%) | 594 (61.2%) |
| Crush | 0 (0.0%) | 3 (0.4%) | 3 (0.3%) |
| Blast | 0 (0.0%) | 1 (0.1%) | 1 (0.1%) |
| Ground level fall | 82 (29.0%) | 170 (24.7%) | 252 (26.0%) |
| Fall from Height > 1 meter (3 feet) | 39 (13.8%) | 79 (11.5%) | 118 (12.2%) |
| Other | 15 (2.2%) | 7 (2.5%) | 22 (2.3%) |
| Physical Evidence‡– N (%) of subjects with: | |||
| Visible Trauma Above Clavicle | 214 (75.6%) | 422 (61.4%) | 636 (65.6%) |
| Signs of Basal Skull Fracture | 37 (13.1%) | 7 (1.0%) | 44 (4.5%) |
24
*Based on time subject arrived at the study hospital for neurological assessment.
†A subject could have experienced head injury due to multiple mechanisms of injury. No subjects experienced head injury due to gunshot or fragment (including shell/shrapnel).
‡Prior to head CT scan.
Of the 970 evaluable subjects, 283 subjects had positive CT scan results. Of these 283 subjects with positive CT scan results, 273 had an 'Elevated' i-STAT TBI test interpretation (sensitivity = 96.5% (273/283)). Ten (10) subjects with CT scan positive results had an i-STAT TBI test interpretation that was 'Not Elevated'. The rate of false negative (FN) results was 3.5% (10/283). None of these ten (10) subjects with false negative results required surgical intervention related to their head injury as no neurosurgical lesions were identified by CT scan in these subjects.
Of the 687 subjects with negative CT scan results, 277 had an i-STAT TBI test interpretation that was 'Not Elevated' (277/687, specificity = 40.3 %). The rate of false positive (FP) results was 59.6% (410/687).
In the clinical study, the prevalence of adjudicated CT scan positive subjects was 29.2% (283/970). Overall, there were 287 subjects with i-STAT TBI test interpretations of Not Elevated'. Of these, 277 subjects had negative CT scan results. The negative predictive value (NPV) of the assay was 96.5% (277/287). Table 21 below provides the clinical performance estimates of i-STAT TBI cartridge with i-STAT Alinity instrument.
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| Table 21 : Clinical Performance | |||
|---|---|---|---|
| i-STAT TBI Test | |||
| Interpretation | All Evaluable Results (0-24h) | Total | |
| Adjudicated Head CT Scan | |||
| Positive | Adjudicated Head CT Scan | ||
| Negative | |||
| Elevated | 273 | 410 | 683 |
| Not Elevated | 10 | 277 | 287 |
| Total | 283 | 687 | 970 |
| Clinical Performance Parameters | N=970 | 95% CI | |
| Clinical Sensitivity | 96.5% (273/283) | (93.6%, 98.1%)+ | |
| Clinical Specificity | 40.3% (277/687) | (36.7%, 44.0%)+ | |
| Negative Predictive Value (NPV) * | 96.5% (277/287) | (93.7%, 98.1%)‡ | |
| Positive Predictive Value (PPV) | 40% (273/683) | (38.4%, 41.5%)‡ | |
| Likelihood Ratio Negative (LRN) | 0.09 | (0.05, 0.16)§ | |
| Likelihood Ratio Positive (LRP) | 1.62 | (1.52, 1.73)§ |
- Adjusted NPV at 6% prevalence is 99.4% (95% Cl: 99.0%, 99.7%).
†95% confidence intervals are calculated using the Wilson score method for a binomial portion (see CLSI EP12-Ed3) : 195% confidence intervals for predictive values are calculated based on the confidence intervals of the
corresponding likelihood ratios
§95% confidence intervals are calculated using asymptotic method for a ratio of two binomial proportion
8. Conclusion
The results of these studies demonstrate that performance of the GFAP and UCH-L1 assays in the i-STAT TBI cartridge with the i-STAT Alinity System are substantially equivalent to the predicate device.