(59 days)
The Total Bilirubin2 assay is used for the quantitation of total bilirubin in human serum or plasma, of adults and neonates, on the ARCHITECT c System.
Measurement of total bilirubin, an organic compound formed during the normal destruction of red blood cells, is used in the diagnosis and treatment of liver, hematological, and metabolic disorders, including hepatitis and disorders of the biliary tract. In newborn infants, the Total Bilirubin2 assay is intended to measure the levels of total bilirubin (conjugated and unconjugated) in serum or plasma to aid in the diagnosis and management of neonatal jaundice and hemolytic disease of the newborn.
The Total Bilirubin2 assay (subject device) is an automated clinical chemistry assay for the quantitation of total bilirubin in human serum or plasma, of adults and neonates, on the ARCHITECT c System. Total (conjugated and unconjugated) bilirubin couples with a diazo reagent in the presence of a surfactant to form azobilirubin. The diazo reaction is accelerated by the addition of surfactant as a solubilizing agent. The increase in absorbance at 548 nm due to azobilirubin is directly proportional to the total bilirubin concentration. The methodology is Diazonium salt.
The provided text describes a 510(k) premarket notification for a medical device called "Total Bilirubin2", an in vitro diagnostic assay. This type of submission focuses on demonstrating substantial equivalence to a legally marketed predicate device, rather than proving clinical effectiveness through the extensive studies typically associated with AI/ML diagnostic tools. Therefore, the questions related to AI/ML specific criteria (like MRMC studies, number of experts for ground truth, sample size for training sets, etc.) are not applicable in this context.
The document primarily details the analytical performance of the Total Bilirubin2 assay.
Here's an analysis based on the information provided, adhering to the request:
Acceptance Criteria and Reported Device Performance
The acceptance criteria for this in vitro diagnostic device are typically defined by ranges of acceptable analytical performance, following established CLSI (Clinical and Laboratory Standards Institute) guidelines. The reported device performance is compared against these internal acceptance criteria.
| Performance Metric | Acceptance Criteria (Implicit from CLSI Guidelines/Industry Standards) | Reported Device Performance (as stated) |
|---|---|---|
| Reportable Interval (Range) | Established analytical measuring interval, extended measuring interval, and reportable interval. | Analytical Measuring Interval (AMI): 0.1 – 25.0 mg/dL |
| Extended Measuring Interval (EMI): 25.0 – 125.0 mg/dL | ||
| Reportable Interval: 0.1 – 125.0 mg/dL | ||
| Within-Laboratory Precision (SD/CV%) | Specific maximum acceptable SD and %CV for different concentrations, as per CLSI EP05-A3 guidelines. | Control Level 1 (1.1 mg/dL): SD: 0.04 (Range 0.02-0.04), %CV: 3.4 (Range 1.8-3.4) |
| Control Level 2 (4.2 mg/dL): SD: 0.09 (Range 0.09-0.10), %CV: 2.1 (Range 2.0-2.2) | ||
| Panel A (0.3 mg/dL): SD: 0.00 (Range 0.00-0.03), %CV: 0.0 (Range 0.0-9.2) | ||
| Panel B (13.3 mg/dL): SD: 0.11 (Range 0.09-0.12), %CV: 0.8 (Range 0.7-0.9) | ||
| Panel C (22.3 mg/dL): SD: 0.16 (Range 0.16-0.18), %CV: 0.7 (Range 0.7-0.8) | ||
| System Reproducibility (SD/CV%) | Specific maximum acceptable SD and %CV for different concentrations, as per CLSI EP05-A3 guidelines. | Control Level 1 (1.1 mg/dL): SD: 0.02, %CV: 2.2 |
| Control Level 2 (4.5 mg/dL): SD: 0.16, %CV: 3.5 | ||
| Panel B (13.4 mg/dL): SD: 0.57, %CV: 4.3 | ||
| Panel C (22.4 mg/dL): SD: 1.12, %CV: 5.0 | ||
| Accuracy (Bias) | Bias within an acceptable range, relative to a reference method (Doumas). | Bias ranged from -0.1% to 3.7%. |
| Lower Limits of Measurement | Defined LoB, LoD, and LoQ based on CLSI EP17-A2 guidelines. | LoB: 0.02 mg/dL |
| LoD: 0.04 mg/dL | ||
| LoQ: 0.07 mg/dL | ||
| Linearity | Linearity across the specified analytical measuring interval. | Linear across the analytical measuring interval of 0.1 to 25.0 mg/dL. |
| Interference (Endogenous) | Interference within ± 10% for specified substances at given concentrations. | Hemoglobin (1000 mg/dL), Total protein (15 g/dL), Triglycerides (1500 mg/dL): No significant interference (within ± 10%). |
| Indican (1 mg/dL): No significant interference. | ||
| Indican (2 mg/dL): 17% interference (beyond ±10%). | ||
| Interference (Exogenous) | Interference within ± 10% for specified substances at given concentrations. | Variety of common drugs tested; no significant interference for most. |
| Indocyanine green (10 mg/L): 9% interference. | ||
| Method Comparison (Correlation) | High correlation coefficient and acceptable slope/intercept when compared to predicate device. | Serum: Correlation Coefficient: 1.00, Intercept: -0.03, Slope: 1.03 (Range 0.1–22.5 mg/dL) |
| Neonatal serum: Correlation Coefficient: 1.00, Intercept: 0.00, Slope: 1.00 (Range 0.2–22.8 mg/dL) | ||
| Tube Type Suitability | Acceptable performance across specified tube types. | Serum tubes, Serum separator tubes, Dipotassium EDTA tubes, Lithium heparin tubes, Lithium heparin separator tubes, Sodium heparin tubes were acceptable. |
| Dilution Verification (% Recovery & %CV) | % recovery within 100% ± 10%; imprecision ≤ 7 %CV for automated dilution, ≤ 8 %CV for manual dilution. | Automated Dilution: 96.3% to 104.4% recovery, 1.6% to 2.5% CV. |
| Manual Dilution: 95.0% to 106.7% recovery, 2.2% to 4.9% CV. |
Study Details:
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Sample size used for the test set and the data provenance:
- Precision (Within-Laboratory): 80 replicates for each control/panel (on a representative combination out of 3 multi-lot/instrument combinations).
- Reproducibility (System): 84 replicates for each control/panel.
- Lower Limits of Measurement: ≥ 60 replicates for LoB and LoD for each of 3 lots on 2 instruments.
- Interfering Substances: Not explicitly stated, but "Each substance was tested at 2 levels of the analyte."
- Method Comparison:
- Serum: 167 samples
- Neonatal serum: 163 samples
- Tube Type: Samples collected from a minimum of 40 donors.
- Dilution Verification: 5 samples prepared with varying concentrations.
- Data Provenance: Not explicitly stated regarding country of origin or whether retrospective/prospective. However, given the nature of in vitro diagnostic analytical studies, samples are typically acquired prospectively or from biobanks for specific analytical testing purposes.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- For in vitro diagnostic devices like this bilirubin assay, "ground truth" is established by reference methods or highly characterized calibrators/control materials, not by expert human readers. The accuracy study, for example, compares results to material standardized to the Doumas Total Bilirubin reference method, which represents the "ground truth" for bilirubin measurement. Therefore, expert readers/adjudicators as typically seen in imaging AI studies are not applicable here.
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Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Not applicable. This is an in vitro diagnostic assay, and its performance is evaluated against analytical measurements, not human interpretations requiring adjudication.
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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:
- Not applicable. This device is an in vitro diagnostic test, not an AI/ML-driven imaging or diagnostic algorithm designed to assist human readers.
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If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Not applicable. This is an assay performed on an automated system, providing a quantitative result. Its "performance" is inherently "standalone" in generating the numerical value, but it's not an AI algorithm in the sense of image interpretation or complex diagnostic inference.
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The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- For analytical performance studies, the "ground truth" for bilirubin concentration is established by reference methods (e.g., the Doumas method for accuracy) or by using certified reference materials and calibrators with known concentrations. This is the gold standard for quantitative in vitro diagnostic measurements.
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The sample size for the training set:
- Not applicable. This is not an AI/ML device that requires a "training set" in the computational sense. The device's performance is a function of its reagents, instrument, and established methodology, not a learned algorithm.
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How the ground truth for the training set was established:
- Not applicable. See above.
§ 862.1110 Bilirubin (total or direct) test system.
(a)
Identification. A bilirubin (total or direct) test system is a device intended to measure the levels of bilirubin (total or direct) in plasma or serum. Measurements of the levels of bilirubin, an organic compound formed during the normal and abnormal distruction of red blood cells, if used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.(b)
Classification. Class II.