(56 days)
In vitro diagnostic use in the quantitative determination of vitamin B12 in serum, heparinized plasma, or EDTA plasma using the ADVIA Centaur System.
The ACS:180 VB12 and ADVIA Centaur assays are competitive assays. Vitamin B12, or cyanocobalamin, is a complex corrinoid compound containing four pyrrole rings that surround a single cobalt atom. Humans obtain vitamin B12 exclusively from animal dietary sources, such as meat, eggs, and milk. Vitamin B12 requires intrinsic factor, a protein secreted by the parietal cells in the gastric mucosa, for absorption. Vitamin B12 and intrinsic factor form a complex that attaches to receptors in the ileal mucosa, where proteins known as trans-cobalamins transport the vitamin B12 from the mucosal cells to the blood and tissues. Most vitamin B12 is stored in the liver as well as in the bone marrow and other tissues. The ACS:180 VB12 and ADVIA Centaur VB12 assays are competitive assays in which vitamin B12 from the patient sample competes with vitamin B12 labeled with acridinium ester in the Lite Reagent, for a limited amount of purified intrinsic factor, which is covalently coupled to paramagnetic particles in the Solid Phase. The assay uses Releasing Agent (sodium hydroxide) and DTT to release the vitamin B12 from the endogenous binding proteins in the sample and cobinamide to prevent rebinding after the Solid Phase is added to the sample.
Here's an analysis of the provided text regarding the acceptance criteria and study for the Bayer Diagnostics ACS:180 VB12 and ADVIA Centaur VB12 assays.
1. Table of Acceptance Criteria and Reported Device Performance
The document provided does not explicitly state "acceptance criteria" through a pass/fail threshold, but rather presents various performance characteristics that would be evaluated for substantial equivalence. I will interpret the reported performance characteristics as meeting the implied acceptance criteria for a device of this type.
| Performance Characteristic | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Reference Range | Established for normal and deficient populations. | ACS:180 / ADVIA Centaur: |
| Normal (253 samples): 211-911 pg/mL (Median: 382 pg/mL, 95% range) | ||
| Deficient (45 samples): 32-246 pg/mL (Median: 160 pg/mL) | ||
| Assay Reportable Range | Demonstrated ability to measure a specific range of values. | ACS:180 / ADVIA Centaur: |
| Up to 2000 pg/mL (1476 pmol/L) | ||
| Minimum Detectable Concentration (Sensitivity) | Demonstrated ability to detect low concentrations. | ACS:180 / ADVIA Centaur: |
| 30 pg/mL (22 pmol/L) | ||
| Serum vs. Plasma Method Comparison (Correlation) | High correlation (r-value) and close agreement between serum and plasma measurements. | ACS:180: |
| Plasma VB12 = 1.04 (serum VB12) + 9 pg/mL, r = 0.96 (213 pairs) | ||
| ADVIA Centaur: | ||
| Plasma VB12 = 1.03 (serum VB12) + 12 pg/mL, r = 0.96 (207 pairs) | ||
| Precision (Within-Run & Total %CV) | Low coefficient of variation (CV%) to demonstrate reproducibility. | ACS:180 (n=231 per sample): |
- 1147 pg/mL: Within-run 2.68% CV, Total 3.44% CV
- 661 pg/mL: Within-run 2.70% CV, Total 3.24% CV
- 204 pg/mL: Within-run 3.73% CV, Total 4.79% CV
- 169 pg/mL: Within-run 5.33% CV, Total 6.28% CV
ADVIA Centaur (n=72 per sample): - 178.76 pg/mL: Within-run 5.0% CV, Run-to-run 9.2% CV, Total 10.4% CV
- 207.22 pg/mL: Within-run 4.0% CV, Run-to-run 4.4% CV, Total 5.9% CV
- 608.83 pg/mL: Within-run 2.7% CV, Run-to-run 2.7% CV, Total 3.8% CV
- 1343.87 pg/mL: Within-run 2.4% CV, Run-to-run 3.0% CV, Total 3.9% CV |
2. Sample Size Used for the Test Set and Data Provenance
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Reference Range Determination:
- Sample Size: 298 serum samples (253 from apparently healthy individuals, 45 from physician-diagnosed vitamin B12 deficient patients).
- Data Provenance: Not explicitly stated, but clinical samples are generally considered prospective or retrospective from a patient population within a medical setting (e.g., a hospital or clinic). No country of origin is mentioned.
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Serum vs. Plasma Method Comparison:
- ACS:180: 213 pairs of serum and plasma specimens.
- ADVIA Centaur: 207 pairs of serum and plasma specimens.
- Data Provenance: Not explicitly stated. Assumed to be clinical samples.
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Precision Studies:
- ACS:180: 4 samples, assayed 3 times in 7 assays on each of 11 systems over 5 days (n=231 for each sample level).
- ADVIA Centaur: 4 samples, assayed 6 times in each of 12 runs on 6 systems over 3 days (n=72 for each sample level).
- Data Provenance: Not explicitly stated, but these are typically controlled laboratory experiments using known samples rather than patient data.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
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Reference Range Determination:
- The "ground truth" for the deficient samples was established by physician-diagnosed vitamin B12 deficient patients. The number of physicians or their specific qualifications are not mentioned.
-
For the method comparison and precision studies, the "ground truth" is implied to be the actual concentration of vitamin B12 in the samples, measured by the assays themselves or potentially other reference methods, and assessed for consistency. This type of ground truth does not typically involve human expert consensus in the same way image interpretation or diagnostic decisions would.
4. Adjudication Method for the Test Set
- For the performance studies described (reference range, method comparison, precision), no human adjudication method (like 2+1 or 3+1 for clinical diagnosis) is mentioned or appears applicable. These are quantitative measurements where the "ground truth" is the measured analyte concentration or a reference range defined by a cohort.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done
- No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This type of study is typically conducted for diagnostic devices (e.g., imaging devices) where multiple human readers interpret cases with and without AI assistance. The described device is an immunoassay for quantitative determination of a biomarker; its performance is assessed through analytical validation (precision, accuracy, range, correlation) rather than reader studies.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
- Yes, the entire performance validation for these immunoassay systems can be considered a "standalone" assessment of the device's analytical performance. The device directly measures vitamin B12 concentration, and the studies reported (precision, range, method comparison) evaluate the device's output without direct human interpretation influencing the measurement itself. The human element comes in interpreting the result in a clinical context, but the device's output is independent.
7. The Type of Ground Truth Used
- Reference Range Determination:
- For the normal group: Based on a population of "apparently healthy individuals," implying a statistically derived range from a healthy cohort.
- For the deficient group: Based on "physician-diagnosed vitamin B12 deficient patients," indicating a clinical diagnosis as the ground truth.
- Method Comparison and Precision: The ground truth is the quantitative concentration of vitamin B12 in the samples, determined by the assays themselves and compared for consistency and agreement. This is an analytical ground truth.
8. The Sample Size for the Training Set
- The document does not explicitly mention a "training set" in the context of machine learning or AI models. Given that these are immunoassay devices, their development typically involves biochemical optimization and calibration, rather than a machine learning training phase with a distinct training dataset. Therefore, the concept of a training set as understood in AI/ML is not directly applicable here. The development data used for optimizing reagents and protocols would be analogous but not explicitly reported as a "training set" in this context.
9. How the Ground Truth for the Training Set Was Established
- As mentioned in point 8, the concept of a "training set" in the AI/ML sense doesn't directly apply to these immunoassay devices. The ground truth for their development would involve using reference materials, spiked samples, and clinical samples with known (or previously established) vitamin B12 concentrations to calibrate the assay and optimize its performance characteristics. This is part of the standard assay development and validation process for IVD devices.
§ 862.1810 Vitamin B
12 test system.(a)
Identification. A vitamin B12 test system is a device intended to measure vitamin B12 in serum, plasma, and urine. Measurements obtained by this device are used in the diagnosis and treatment of anemias of gastrointestinal malabsorption.(b)
Classification. Class II.