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510(k) Data Aggregation
(129 days)
BIOPLEX 2200 EBV IGM PANEL ON BIOPLEX 2200 MULTI-ANALYTE DETECTION SYSTEM
The BioPlex 2200 EBV IgM kit is a multiplex flow immunoassay intended for the qualitative detection of two (2) separate analytes; Epstein-Barr Virus Viral Capsid Antigen (EBV VCA) IgM antibodies and Heterophile antibodies in human serum. The test system can be used in conjunction with the BioPlex 2200 EBV IgG kit as an aid in the laboratory diagnosis of infectious mononucleosis (IM).
The EBV IgM kit is intended for use with the Bio-Rad BioPlex 2200 System.
Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients, cord blood, neonatal specimens, or infants. Assay performance characteristics have not been established for the diagnosis of nasopharyngeal carcinoma, Burkitt's lymphoma, and other EBV-associated lymphomas.
BioPlex 2200 EBV IgM Calibrator Set: The BioPlex 2200 EBV IgM Calibrator Set is intended for the calibration of the BioPlex 2200 EBV IgM Reagent Pack.
BioPlex 2200 EBV IgM Control Set: The BioPlex 2200 EBV IgM Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 Instrument and BioPlex 2200 EBV IgM Reagent Pack in the clinical laboratory. The performance of the BioPlex 2200 EBV IgM Control Set has not been established with any other EBV assays.
The BioPlex 2200 EBV IgM kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional ElA, but permits simultaneous detection and identification of many antibodies in a single tube. Two (2) different populations of dyed beads are coated with proteins associated with infectious mononucleosis. One (1) is coated with an E. coli derived recombinant fusion protein, EBV VCA p18 (40kD), and the other is coated with horse erythrocyte stromal extract (heterophile antigen). The BioPlex 2200 System combines an aliquot of patient sample, sample diluent containing goat anti-human IgG, and bead reagent into a reaction vessel. The mixture is incubated at 37°C. After a wash cycle, anti-human IgM antibody, conjugated to phycoerythrin (PE), is added to the dyed beads and this mixture is incubated at 37°C. The excess coniugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the fluorescence of the attached PE.
Three additional dyed beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB), and a Reagent Blank Bead (RBB), are present in each reaction mixture to verify detector response, the addition of serum or plasma to the reaction vessel, and the absence of significant non-specific binding in serum or plasma respectively. The instrument is calibrated using a set of two (2) distinct calibrator vials, supplied separately by Bio-Rad Laboratories. A combination of two (2) vials representing two (2) different antibody concentrations is used for calibration. The result for each of these antibodies is expressed as an antibody index (AI).
Here's a summary of the acceptance criteria and study details for the BioPlex 2200 EBV IgM Kit, Calibrators, and Controls, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly present a table of acceptance criteria in numerical targets for performance metrics like sensitivity, specificity, or %CV. Instead, it presents the results of the studies conducted and implies that these results were deemed acceptable for FDA clearance. The performance is assessed through reproducibility, precision, and comparative testing against predicate devices and known serological patterns.
However, we can infer performance metrics from the results provided:
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance (Summary from text) |
|---|---|---|
| Reproducibility (EBV VCA IgM) | Low %CV for within-run, between-day, between-run, between-site. | High Positive 1 (AI 1.9): Total %CV 8.4% |
| High Positive 2 (AI 2.0): Total %CV 7.1% | ||
| Low Positive 1 (AI 1.2): Total %CV 8.3% | ||
| Low Positive 2 (AI 1.4): Total %CV 7.9% | ||
| Positive Control (AI 2.0): Total %CV 17.2% | ||
| Reproducibility (Heterophile) | Low %CV for within-run, between-day, between-run, between-site. | High Positive 1 (AI 2.8): Total %CV 7.8% |
| High Positive 2 (AI 2.7): Total %CV 5.5% | ||
| Low Positive 1 (AI 1.9): Total %CV 5.5% | ||
| Low Positive 2 (AI 1.8): Total %CV 7.4% | ||
| Positive Control (AI 2.5): Total %CV 5.9% | ||
| Precision (EBV VCA IgM) | Low %CV for within-run, between-day, between-run. | High Positive 1 (AI 2.5): Total %CV 11.2% |
| High Positive 2 (AI 2.7): Total %CV 9.1% | ||
| Low Positive 1 (AI 1.6): Total %CV 7.8% | ||
| Low Positive 2 (AI 1.9): Total %CV 7.1% | ||
| High Negative (AI 0.7): Total %CV 7.0% | ||
| Low Negative (AI 0.1): Total %CV 0.0% | ||
| Precision (Heterophile) | Low %CV for within-run, between-day, between-run. | High Positive 1 (AI 2.8): Total %CV 9.5% |
| High Positive 2 (AI 2.8): Total %CV 12.2% | ||
| Low Positive 1 (AI 2.1): Total %CV 10.5% | ||
| Low Positive 2 (AI 1.9): Total %CV 9.6% | ||
| High Negative (AI 0.7): Total %CV 8.4% | ||
| Low Negative (AI 0.0): Total %CV 0.0% | ||
| Comparative Testing (EBV VCA IgM vs. EIA) Percent Agreement by Serological Pattern Characterization (Table 18) | High positive and negative agreement. | Primary Acute: Positive 96.8% (95% CI 83.8-99.4%) |
| Late Acute: Positive 64.6% (95% CI 50.4-76.6%), Negative 91.9% (95% CI 82.5-96.5%) | ||
| Recovering: Negative 75.0% (95% CI 30.1-95.4%) | ||
| Previous Infection: Negative 96.1% (95% CI 93.2-97.7%) | ||
| Susceptible: Negative 96.9% (95% CI 92.2-98.8%) | ||
| Inconclusive: Positive 100% (95% CI 51.0-100%), Negative 83.8% (95% CI 68.9-92.3%) | ||
| Overall: Positive 78.3% (95% CI 68.3-85.8%), Negative 94.8% (95% CI 92.5-96.4%) | ||
| Comparative Testing (Heterophile vs. Agglutination Test) Percent Agreement by Serological Pattern Characterization (Table 20) | High positive and negative agreement. | Primary Acute: Positive 84.2% (95% CI 62.4-94.5%), Negative 83.3% (95% CI 55.2-95.3%) |
| Late Acute: Positive 75.0% (95% CI 30.1-95.4%), Negative 98.1% (95% CI 93.4-99.5%) | ||
| Recovering: Negative 100% (95% CI 51.0-100%) | ||
| Previous Infection: Negative 99.0% (95% CI 97.1-99.7%) | ||
| Susceptible: Negative 100% (95% CI 97.1-100%) | ||
| Inconclusive: Positive 14.8% (95% CI 5.9-32.5%), Negative 100% (95% CI 78.5-100%) | ||
| Overall: Positive 46.0% (95% CI 33.0-59.6%), Negative 98.8% (95% CI 97.5-99.4%) | ||
| Overall Serological Agreement (Table 25) | High overall serological agreement. | Primary Acute: 96.8% (95% CI 83.8-99.4%) |
| Late Acute: 81.8% (95% CI 73.6-87.9%) | ||
| Recovering: 75.0% (95% CI 30.0-95.4%) | ||
| Previous Infection: 86.2% (95% CI 81.9-89.7%) | ||
| Susceptible: 96.1% (95% CI 91.1-98.3%) | ||
| Inconclusive: 17.1% (95% CI 8.5-31.3%) | ||
| Overall: 83.3% (95% CI 80.2-86.1%) | ||
| Acute vs. Non-acute Serological Agreement (Table 26) | High agreement for acute and non-acute classifications. | Acute: 88.7% (95% CI 82.4-92.9%) |
| Non-Acute: 90.4% (95% CI 87.2-92.8%) | ||
| Inconclusive: 17.1% (95% CI 8.5-31.3%) | ||
| Overall: 85.1% (95% CI 82.1-87.7%) | ||
| Cross-Reactivity | Minimal or no cross-reactivity with tested interfering factors. | Generally low cross-reactivity. A few discrepancies were noted for Toxoplasmosis and CMV IgM samples (up to 5 and 3 discrepants respectively for EBV VCA IgM, and 1 for Heterophile with CMV IgM). Most positive BioPlex 2200 results in these categories were confirmed by commercial assays. |
2. Sample Size and Data Provenance
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Test Set (Comparative Testing):
- Main Comparative Study: 621 banked serum samples from patients for whom an EBV test was ordered. Two samples were excluded due to RBB errors, resulting in
N=619for initial analyses andN=618for serological pattern comparisons.- Provenance: 3 U.S. clinical testing sites (retrospective, banked serum samples).
- Known EBV VCA IgM Positive Samples: 100 purchased EBV VCA IgM positive samples.
- Provenance: A U.S. clinical testing site (retrospective, purchased samples).
- Main Comparative Study: 621 banked serum samples from patients for whom an EBV test was ordered. Two samples were excluded due to RBB errors, resulting in
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Reproducibility and Precision Studies: These studies used "panel members" prepared by Bio-Rad Laboratories. The number of panel members was 6 (2 high positive, 2 near cutoff, 2 negative). Each panel member was tested multiple times across days and sites. These are typically internal validation samples, not patient data in the same way as the comparative testing.
3. Number of Experts and Qualifications
The document does not specify the number or qualifications of experts used to establish the ground truth for the test set. The ground truth in comparative testing was established by "corresponding commercially available microplate EIA/agglutination tests" and subsequent serological pattern characterization. It is implied that these predicate devices and the serological algorithm (Table 16) serve as the 'expert' reference. For the purpose of result interpretation, the algorithm defines different EBV serological statuses based on various antibody responses.
4. Adjudication Method
The document does not describe an adjudication method for the test set by human experts in the traditional sense (e.g., 2+1, 3+1). Instead, the results of the BioPlex 2200 system were compared to the results of predicate commercial assays. For percent agreement calculations in comparative testing, BioPlex 2200 "equivocal results were assigned to the opposite clinical interpretation than that of the corresponding reference assay result." This acts as a conservative rule for calculating agreement.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC comparative effectiveness study was described. The device is an automated in vitro diagnostic (IVD) device for detecting antibodies, not an imaging device requiring human reader interpretation. Therefore, a study to measure human reader improvement with AI assistance is not applicable. The comparison is between the new automated assay and existing commercial laboratory assays (EIA and agglutination tests).
6. Standalone Performance
Yes, a standalone performance study was done. The reproducibility and precision studies evaluate the device's inherent performance characteristics as a standalone assay. The comparative testing also assesses the BioPlex 2200 EBV IgM kit alone against predicate devices, indicating its standalone diagnostic utility. The results (Antibody Index (AI) values, %CV, positive/negative agreement with reference methods) are presented for the BioPlex 2200 system directly.
7. Type of Ground Truth Used
The ground truth used for the comparative studies was:
- Reference Assays: Results from "corresponding commercially available microplate EIA/agglutination tests." These are established diagnostic assays for EBV.
- Serological Pattern Characterization: A generally accepted algorithm for classifying patients into EBV serological status (Table 16) based on results from various EBV antibody tests (including EBV NA-1 IgG, EBV VCA IgG, EBV EA-D IgG, EBV VCA IgM, and Heterophile Antibody).
8. Sample Size for the Training Set
The document does not explicitly mention a "training set" in the context of an AI/ML algorithm, as this device appears to be a laboratory immunoassay rather than an AI-driven one. Therefore, there is no concept of a training set for an algorithm in this submission. The panel members for reproducibility and precision studies can be thought of as internal validation sets, but not "training sets" for an AI model.
9. How the Ground Truth for the Training Set was Established
As there is no mention of an AI/ML model or a specific training set with ground truth in the document, this question is not applicable. The characterization of panel members for reproducibility and precision studies would have been established internally by Bio-Rad Laboratories based on known antibody levels or clinical samples.
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