(280 days)
The ADVIA Centaur Vitamin D Total (VitD) assay is for in vitro diagnostic use in the quantitative determination of total 25 (OH) vitamin D in human serum and plasma (EDTA, lithium heparin, sodium heparin) using the ADVIA Centaur XP system. The ADVIA Centaur VitD assay is intended as an aid in the determination of vitamin D sufficiency.
The ADVIA Centaur Vitamin D Total (VitD) Calibrators are for in vitro diagnostic use in calibrating ADVIA Centaur systems Vitamin D Total (VitD) assay.
The ADVIA Centaur Vitamin D Total (VitD) OC is for in vitro diagnostic use to monitor the precision and accuracy of the ADVIA Centaur VitD assay on the ADVIA Centaur systems.
The ADVIA Centaur Vitamin D Total (VitD) Master Curve Material is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur VitD assay.
The ADVIA Centaur VitD reagent kit comes in two configurations (100 or 500 test kit) and each kit consists of the following:
- ReadyPack primary reagent:
Lite Reagent: 5.0 mL/reagent pack: anti-VitD (monoclonal mouse) antibody labeled with acridinium ester (~0.8 µg/mL) in buffer with bovine serum albumin, mouse IgG, and sodium azide (
Here's an analysis of the provided text to extract the requested information, focusing on the study related to the modification of the ADVIA Centaur Vitamin D Total (VitD) Assay, as this is the primary focus of the 510(k) submission. The previous clearance (K110586) is referenced for other performance characteristics not directly part of the modification.
1. Table of Acceptance Criteria and Reported Device Performance
The submission primarily focuses on aligning the device's traceability and calibration to the Vitamin D Standardization Program (VDSP). The key acceptance criteria revolve around achieving this alignment and maintaining analytical performance characteristics.
| Acceptance Criteria Category | Specific Criteria (Implicit/Explicit) | Reported Device Performance |
|---|---|---|
| Traceability/Standardization | Alignment with VDSP recognized Reference Measurement Procedure (RMP) (University of Ghent's ID-LC/MS/MS 25 (OH) vitamin D RMP) | Deming regression: y=0.99x + 0.53 ng/mL, r=0.96 (Comparing ADVIA Centaur VitD Assay to University of Ghent's ID-LC/MS/MS) |
| Certification by CDC VDSP | Passed CDC VDSP certification | |
| Method Comparison (vs. RMP) | Good correlation with RMP, especially around medical decision ranges (10-30 ng/mL) | Deming regression: y=0.93x + 2.89, r=0.99 (Comparing candidate device to RMP). "Correlate well around medical decision range of 10 to 30 ng/mL; however results above 50 ng/mL starts to show some scatter. However, the scatter in that part of the assay range is clinically insignificant." |
| Precision/Reproducibility | Acceptable %CV values for within-run and total imprecision | %CV for within-run ranged from 3.0% to 5.3%. %CV for total ranged from 4.2% to 11.9%. (Meeting CLSI Guideline EP5-A2 implicitly) |
| Linearity/Reportable Range | Demonstrates linearity across the claimed measuring range (4.2-150 ng/mL) with good recovery. | y=0.99x + 0.04, r=0.999. % Recovery for samples across the range of 2.92-174.11 ng/mL was between 94% and 108%. Claimed measuring range 4.2-150 ng/mL. |
| Detection Limit (LoB, LoD, LoQ) | Determined according to CLSI guidelines EP17-A2 | LoB: 1.7 ng/mL, LoD: 3.2 ng/mL, LoQ: 4.2 ng/mL |
| Analytical Specificity (Interference) | Identify and characterize potential interferents (e.g., Fluorescein) and specify limitations. | Fluorescein interference detected. At 0.10 mcg/mL, interference caused 8% and 7% bias for two different vitamin D concentrations, leading to a limitation statement: "Do not use samples which contain fluorescein levels > 0.10 ug/mL can produce falsely elevated results in this assay." |
| Stability (Shelf Life, Open Vial) | Maintain analytical performance over specified storage conditions. | Shelf life: 26 weeks (6 months) at 2-8º C. Open vial: 120 days at -20° C, 28 days at 2-8° C, 7 days at 25° C. |
| Expected Values/Reference Range (Pediatric) | Establish a pediatric reference range following CLSI guidelines. | Observed Range (2.5th to 97.5th percentile): 11.4 ng/mL to 46.0 ng/mL for pediatric patients (1-21 years). |
2. Sample Sizes Used for the Test Set and Data Provenance
- Standardization/Traceability Study:
- Sample Size: 170 unique serum samples.
- Data Provenance: Not explicitly stated, but the reference to "University of Ghent's ID-LC/MS/MS 25 (OH) vitamin D Reference Measurement Procedure (RMP)" suggests international collaboration. These are clinical samples used for method correlation.
- Method Comparison Study (Candidate Device vs. Predicate Device):
- Sample Size: 177 native human serum samples.
- Data Provenance: Not explicitly stated. Assumed to be clinical samples.
- Method Comparison Study (Candidate Device vs. RMP - University of Ghent):
- Sample Size: 122 independent serum samples (116 native and 6 spiked samples).
- Data Provenance: Clinical samples.
- Precision/Reproducibility:
- Sample Size: 2 natural patient serum samples and 4 Medical Decision Pools (MDP). Each tested 80 replicates total.
- Data Provenance: Not explicitly stated, but refers to "natural patient serum samples" and "human serum sample pools."
- Linearity/Assay Reportable Range:
- Sample Size: 1 individual patient serum sample (spiked) and 1 low sample (acid treated human serum, charcoal treated, spiked). These were used to generate 9 dilutions.
- Data Provenance: Human serum.
- Detection Limit (LoB, LoD, LoQ):
- Sample Size: 5 treated human serum samples for LoB, 6 low serum samples for LoD, 6 low human samples for LoQ.
- Data Provenance: Human serum.
- Analytical Specificity (Fluorescein Interference):
- Sample Size: 1 serum sample (spiked) for initial screening, 2 serum pools (spiked) for dose response.
- Data Provenance: Human serum.
- Expected Values/Reference Range (Adults):
- Sample Size: 291 apparently healthy adults.
- Data Provenance: North and South of the U.S., collected during different seasons (summer and winter).
- Expected Values/Reference Range (Pediatric):
- Sample Size: 237 pediatric patients.
- Data Provenance: North and South of the U.S., collected during different seasons (summer and winter).
All studies appear to be prospective in nature, as they involve testing samples specifically for these evaluations.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
For the calibration and method comparison studies directly related to the modification, the "ground truth" (or reference standard) was established by the University of Ghent's ID-LC/MS/MS 25 (OH) vitamin D Reference Measurement Procedure (RMP). This is a highly specialized analytical method, not typically performed by "experts" in the sense of medical professionals diagnosing patients, but rather by highly qualified analytical chemists/scientists with expertise in mass spectrometry and vitamin D analysis. The document states it's "traceable to the National Institute of Standards and Technology Standard Reference Material 2972," indicating a gold standard laboratory method. The CDC VDSP also provided certification, implying their expert oversight of the standardization process.
For establishing adult and pediatric reference ranges, the ground truth was based on samples from "apparently healthy" individuals whose PTH, TSH, and calcium values were normal (adults) and who met stringent inclusion/exclusion criteria (pediatrics). The definition of "healthy" and the clinical assessment for inclusion would have implicitly involved medical professionals, but their specific number or qualifications are not detailed beyond the rigorous selection criteria.
4. Adjudication Method for the Test Set
This type of immunoassay (quantitative chemiluminescent) does not typically involve expert adjudication in the way, for example, imaging AI algorithms do. The "ground truth" for the standardization and method comparison studies is the measured value from the RMP (University of Ghent's ID-LC/MS/MS). For precision, linearity, and detection limit studies, the results are statistical derivations from repeated measurements. For interference, it's based on a calculated bias. Therefore, no multi-expert adjudication method (like 2+1 or 3+1) is relevant or described.
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 MRMC study was done. This device is a laboratory assay (in vitro diagnostic device) that directly measures an analyte concentration. It is not an AI-powered imaging or diagnostic tool that assists human readers.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the studies reported are for the standalone performance of the assay system (ADVIA Centaur XP system with the VitD assay). The device directly measures 25(OH) vitamin D concentration from patient samples. There is no human-in-the-loop component for the measurement itself; human operators perform the testing and interpret the numerical results.
7. The type of ground truth used
The primary ground truth used for the device modification and its substantial equivalence claim is Reference Measurement Procedure (RMP) values from the University of Ghent's ID-LC/MS/MS 25 (OH) vitamin D method, which is traceable to NIST SRM 2972. This is a highly accurate and precise analytical method considered the gold standard for vitamin D measurement.
For establishing reference ranges, the ground truth was indirectly informed by the physiological status of "apparently healthy" individuals as assessed by clinical criteria and other biomarker levels (PTH, TSH, calcium).
8. The sample size for the training set
The document does not explicitly describe a separate "training set" in the context of machine learning. For traditional in vitro diagnostic assays like this, the manufacturer develops and refines the assay based on internal research and development. The "standards" and "calibrators" used in the assay are crucial for its performance. The document states:
- "a set of 10 standards have been manufactured whose values have been assigned by method correlation to the RMP [University of Ghent's ID-LC/MS/MS]". This refers to how the internal calibration system was developed or aligned to the RMP.
- "Calibrators, 2-level controls...and MCMs are traceable to internal standards, which are traceable to the Ghent University ID-LC-MS/MS."
- "Production lots of calibrators, controls and master curve materials (MCM) are value assigned against the internal standards using two reagent lots, 2 runs on two different instruments for a total of 24 replicates."
While not a "training set" in the AI sense, these internal standards and calibrators essentially "train" or set the operating parameters of the assay. The 170 unique serum samples (described in the traceability section) used for the initial method correlation to the RMP served as critical data for aligning the assay to the VDSP.
9. How the ground truth for the training set was established
The "ground truth" for establishing the internal standards and calibrators (which "train" the assay) was established by correlation to University of Ghent's ID-LC/MS/MS 25 (OH) vitamin D Reference Measurement Procedure (RMP). The RMP itself is a highly validated and accurate method for measuring 25(OH) vitamin D, representing the scientific "ground truth" for this measurand. The process involved:
- Measuring 170 unique serum samples using the RMP to get assigned values.
- Using these RMP-assigned values to correlate and assign values to manufactured internal standards.
- Then, using these RMP-traceable internal standards to value-assign the actual calibrators, controls, and MCMs provided with the kit.
§ 862.1825 Vitamin D test system.
(a)
Identification. A vitamin D test system is a device intended for use in clinical laboratories for the quantitative determination of 25-hydroxyvitamin D (25-OH-D) and other hydroxylated metabolites of vitamin D in serum or plasma to be used in the assessment of vitamin D sufficiency.(b)
Classification. Class II (special controls). Vitamin D test systems must comply with the following special controls:(1) Labeling in conformance with 21 CFR 809.10 and
(2) Compliance with existing standards of the National Committee on Clinical Laboratory Standards.