(625 days)
The Alinity i STAT High Sensitivity Troponin-I assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of cardiac troponin I (cTnI) in human plasma (lithium heparin) on the Alinity i system.
The Alinity i STAT High Sensitivity Troponin-I assay is to be used as an aid in the diagnosis of myocardial infarction (MI).
The Alinity i STAT High Sensitivity Troponin-I Reagent Kit contains:
- . Microparticles: 1 bottle (6.6 mL per 100 test cartridge / 33.8 mL per 600 test cartridge). Anti-troponin I (mouse, monoclonal) coated microparticles in TRIS buffer with protein (bovine) stabilizer. Minimum concentration: 0.035% solids. Preservative: ProClin 300.
- . Conjugate: 1 bottle (6.1 mL per 100 test cartridge / 33.8 mL per 600 test cartridge). Anti-troponin I (mouse-human chimeric, monoclonal) acridinium-labeled conjugate in MES buffer with protein (bovine) stabilizer and human IgG. Minimum concentration: 0.1 mg/L. Preservative: ProClin 300.
The Alinity i STAT High Sensitivity Troponin-I assay is an automated, two-step immunoassay for the quantitative determination of cTnI in human plasma (lithium heparin) using CMIA technology.
Sample and anti-troponin I antibody-coated paramagnetic microparticles are combined and incubated. The cTnI present in the sample binds to the anti-troponin I coated microparticles. The mixture is washed. Anti-troponin I acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle, Pre-Trigger and Trigger Solutions are added. The resulting chemiluminescent reaction is measured as a relative light unit (RLU). There is a direct relationship between the amount of cTnI in the sample and the RLU detected by the system optics.
Acceptance Criteria and Study for Alinity i STAT High Sensitivity Troponin-I
1. Table of Acceptance Criteria and Reported Device Performance:
The document does not explicitly state formal acceptance criteria in a tabular format for the clinical performance. However, typical performance metrics for diagnostic assays like this include:
| Metric | Acceptance Criteria (Implicit/Assumed) | Reported Device Performance (Alinity i STAT High Sensitivity Troponin-I) | Notes |
|---|---|---|---|
| Precision (Reproducibility) | Generally low %CV across different concentrations. Specific thresholds are not provided in the document. | Reproducibility (Overall %CV): Ranges from 2.7% to 12.7% across different concentrations (3.5 ng/L to 2871.4 ng/L). Highest %CV seen at lower concentrations. | Good precision observed, especially at higher concentrations. The higher %CV at lower concentrations is typical for immunoassays near their detection limits. |
| Within-Laboratory Precision (%CV) | Generally low %CV. Specific thresholds are not provided. | Within-Lab %CV: Low Control: 4.1%; Medium Control: 3.6%; Bio-Rad Level 2: 4.2%. | Consistent and good precision over 20 days. |
| Lower Limits of Measurement (LoD, LoQ) | Levels should be adequately low for early detection of MI. Often compared to established guidelines. | LoB: 0.0 ng/L; LoD: 0.9 ng/L; LoQ: 2.7 ng/L. | These values demonstrate the assay's ability to detect very low levels of troponin I, which is crucial for high-sensitivity assays in MI diagnosis. |
| Linearity (Analytical Measuring Interval) | Wide range that covers clinically relevant concentrations. | 2.7 to 3600.0 ng/L (pg/mL). | A broad linear range ensures accurate measurements across a wide spectrum of troponin concentrations encountered in clinical practice. |
| Analytical Specificity (Interference) | Interference within ±10% for common substances/drugs. Identified interferences should be noted. | Endogenous: Bilirubin, Hemoglobin, Intralipid: no significant interference (within ±10%). Total Protein > 8.8 g/dL showed interference (up to -16.3%). | |
| Drugs: Most tested drugs showed no significant interference (within ±10%). Fibrinogen at 1000 mg/dL showed 24.3% interference at 15 ng/L. | |||
| Other Conditions: HAMA > 150 ng/mL showed up to -11.0% interference. RF > 1200 IU/mL showed up to -18.9% interference. | Most common interferents are within acceptable limits. Identified interferences (high total protein, fibrinogen, HAMA, RF) are noted, prompting caution in interpretation for affected patients. | ||
| Cross-Reactants | ≤ 1% cross-reactivity for related cardiac/muscle proteins. | ≤ 1% for Actin, Cardiac troponin C, Cardiac troponin T, CK-MB, Myoglobin, Myosin, Skeletal troponin I, Tropomyosin. | Excellent specificity for cardiac troponin I, minimizing false positives from other muscle proteins. |
| Diagnostic Accuracy (Sensitivity, Specificity, PPV, NPV) for MI diagnosis (at various time points relative to ED presentation) | These values should align with clinical needs for an "aid in diagnosis of MI" especially regarding high NPV for ruling out MI and acceptable sensitivity/specificity. Generally, high sensitivity and NPV are critical for MI rule-out. The document presents ranges and 95% CIs. Specific numerical acceptance criteria are not explicitly stated, but the performance is presented to demonstrate clinical utility. | Sex-specific cutoffs (Female 14 ng/L, Male 35 ng/L): |
- Sensitivity: 85.29% to 98.46% (Female), 72.20% to 92.06% (Male) depending on time point.
- Specificity: 69.13% to 85.64% (Female), 74.22% to 88.98% (Male).
- PPV: 27.02% to 42.74% (Female), 33.78% to 50.00% (Male).
- NPV: 98.80% to 99.85% (Female), 97.05% to 99.19% (Male).
Overall cutoff (27 ng/L):
- Sensitivity: 78.43% to 94.44% (Female), 76.45% to 94.44% (Male)
- Specificity: 66.44% to 92.57% (Female), 66.44% to 88.34% (Male).
- PPV: 35.09% to 47.66% (Female), 29.06% to 44.07% (Male).
- NPV: 98.37% to 99.46% (Female), 97.40% to 99.35% (Male). | The high NPV across all time points and cutoffs is a strong indicator of the assay's ability to rule out MI. Sensitivities are also generally high. The lower PPV reflects the prevalence of non-MI conditions that can elevate troponin and emphasizes the need for combining results with clinical data. The study notes that lower specificity at ≥6 hours is due to study design and patient flow in the ED. |
| AUC | Not explicitly stated as an acceptance criterion, but higher values indicate better diagnostic performance. Generally, AUC > 0.9 is considered excellent. | AUC: 0.9257 to 0.9777 (Female), 0.8994 to 0.9489 (Male) across different time points. | Consistently high AUC values, indicating excellent overall diagnostic accuracy for both sexes and at different time points. |
Study Proving Acceptance Criteria:
The study described is a multi-center prospective clinical study designed to assess the diagnostic accuracy of the Alinity i STAT High Sensitivity Troponin-I assay in patients presenting with chest discomfort or equivalent ischemic symptoms.
2. Sample size used for the test set and the data provenance:
- Sample Size (Clinical Study):
- Total Subjects: 6174
- MI Subjects: 432 (124 female, 308 male)
- Non-MI Subjects: 5742 (2128 female, 3614 male)
- Total Specimens (serial sampling):
- 891 from MI subjects
- 8975 from non-MI subjects
- Data Provenance:
- Country of Origin: United States (implied by the FDA 510(k) submission context for a US population reference range study). The study was conducted at 23 Emergency Departments (EDs) in the US, reflecting regional, urban, and rural patient populations.
- Retrospective or Prospective: Prospective. Specimens were collected prospectively from subjects presenting to the ED.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- Number of Experts: A "panel of board-certified cardiologists" was used. The exact number is not explicitly stated, but "panel" implies more than one.
- Qualifications of Experts: Board-certified cardiologists.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Adjudication Method: The subject diagnoses (MI or non-MI) were adjudicated by a panel of board-certified cardiologists based on the third universal definition of MI. The adjudicators were blinded to the Alinity i STAT High Sensitivity Troponin-I assay results. This indicates an expert consensus method, likely involving all panel members reaching a decision, but the specific voting scheme (e.g., 2+1, 3+1) is not detailed.
5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- No, a MRMC comparative effectiveness study was not done. This document describes the performance of a lab assay (IVD - In Vitro Diagnostic), not an AI-assisted diagnostic tool that would typically involve human readers.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, a standalone performance study was done. The entire clinical study described assesses the performance of the Alinity i STAT High Sensitivity Troponin-I assay (the "algorithm" or device in this context) as a standalone diagnostic tool for aid in MI diagnosis. The results (sensitivity, specificity, PPV, NPV, AUC) are presented for the direct output of the assay. The wording "aid in the diagnosis" implies it's used in conjunction with other clinical information, but its individual performance is what's being evaluated.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc):
- Expert Consensus and Clinical Definition: The ground truth for MI diagnosis was established by a panel of board-certified cardiologists based on the third universal definition of MI. This definition incorporates clinical observations, ECG, and other diagnostic information, which can include pathology and outcomes data indirectly but is primarily an expert consensus application of a standardized clinical definition.
8. The sample size for the training set:
- Not Applicable / Not Explicitly Stated for the Clinical Study. This document describes an IVD device, not an AI/machine learning model in the traditional sense that requires an explicit "training set" of patient data for model development. The "training" for such an assay involves the optimization of reagents, antibodies, and detection protocols during product development. The non-clinical studies (precision, linearity, interference) represent the internal testing and validation that inform the assay's operational parameters. The clinical study described functions as a validation/test set for the final device performance.
9. How the ground truth for the training set was established:
- Not Applicable. As noted above, for this IVD device, there isn't a "training set" of patient data with ground truth in the way there is for AI/ML algorithms. The ground truth for the assay's development and calibration would typically be established using manufactured controls, calibrators, and characterized reference materials with known concentrations of cTnI, following industry standards and guidelines (e.g., CLSI documents referenced in the non-clinical section).
§ 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system.
(a)
Identification. A creatine phosphokinase/creatine kinase or isoenzymes test system is a device intended to measure the activity of the enzyme creatine phosphokinase or its isoenzymes (a group of enzymes with similar biological activity) in plasma and serum. Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.(b)
Classification. Class II.