(299 days)
The BioPlex™ 2200 MMRV IgG kit is a multiplex flow immunoassay intended for the qualitative detection of IgG antibodies to Measles, Mumps, Rubella, and Varicella-zoster virus (VZV) in human serum and EDTA or heparinized plasma. The BioPlex 2200 MMRV IgG kit is intended for use with the Bio-Rad BioPlex 2200 System.
This kit is intended as an aid in the determination of serological status to Measles, Mumps, Rubella, and VZV. This kit is not intended for use in screening blood or plasma donors.
The performance of this assay has not been established for use in neonates, pediatrics and immunocompromised patients, or for use at point of care facilities.
The BioPlex 2200 MMRV IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional EIA, but permits simultaneous detection and identification of many antibodies in a single tube. Four (4) different populations of dyed beads are coated with antigens to identify the presence of IgG class antibodies associated with Measles, Mumps, Rubella and Varicella-zoster. The BioPlex 2200 System combines an aliquot of patient sample, sample diluent, and bead set reagent into a reaction vessel. The mixture is incubated at 37°C. After a wash cycle, anti-human IgG antibody, conjugated to phycoerythrin (PE), is added to the dyed beads and this mixture is incubated at 37°C. The excess conjugate is removed in another wash cycle, and the beads are resuspended 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. Raw data is calculated in relative fluorescence intensity (RFI). 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 to the reaction vessel and the absence of significant non-specific binding in serum.
The instrument is calibrated using a set of three (3) distinct calibrator vials, supplied separately by Bio-Rad Laboratories.
The BioPlex 2200 MMRV IgG kit is a multiplex flow immunoassay intended for the qualitative detection of IgG antibodies to Measles, Mumps, Rubella, and Varicella-zoster virus (VZV) in human serum and EDTA or heparinized plasma. It is intended for use with the Bio-Rad BioPlex 2200 System as an aid in determining serological status to these viruses. It is not intended for screening blood/plasma donors, and performance has not been established for neonates, pediatrics, immunocompromised patients, or point-of-care facilities.
Here's an analysis of the acceptance criteria and the studies performed:
1. Table of Acceptance Criteria and Reported Device Performance
The submission does not explicitly state pre-defined acceptance criteria (e.g., minimum sensitivity/specificity percentages). Instead, the performance is demonstrated through comparative testing against legally marketed predicate devices and reproducibility studies. The tables below summarize the reported device performance.
Comparative Testing: BioPlex 2200 MMRV IgG vs. Commercially Available EIAs
| Target Analyte | Study Population | Agreement Type (EIA vs. BioPlex) | Reported Performance (95% CI) |
|---|---|---|---|
| Measles IgG | Pregnant Women (N=396) | Positive % Agreement | 93.3% (90.4 - 95.4%) |
| Negative % Agreement | 100% (67.5 - 100%) | ||
| Test Ordered (N=1183) | Positive % Agreement | 94.7% (93.2 - 95.9%) | |
| Negative % Agreement | 80.2% (70.3 - 87.5%) | ||
| Mumps IgG | Pregnant Women (N=396) | Positive % Agreement | 94.3% (91.5 - 96.3%) |
| Negative % Agreement | 96.2% (81.1 - 99.3%) | ||
| Test Ordered (N=1183) | Positive % Agreement | 90.4% (88.5 - 92.0%) | |
| Negative % Agreement | 91.0% (81.8 - 95.8%) | ||
| Rubella IgG | Pregnant Women (N=396) | Positive % Agreement | 97.9% (95.9 - 98.9%) |
| Negative % Agreement | 73.7% (51.2 - 88.2%) | ||
| Test Ordered (N=1183) | Positive % Agreement | 94.8% (93.3 - 96.0%) | |
| Negative % Agreement | 86.2% (75.7 - 92.5%) | ||
| VZV IgG | Pregnant Women (N=396) | Positive % Agreement | 95.1% (92.4 - 96.9%) |
| Negative % Agreement | 100% (88.6 - 100%) | ||
| Test Ordered (N=1183) | Positive % Agreement | 94.0% (92.4 - 95.2%) | |
| Negative % Agreement | 98.4% (91.3 - 99.7%) |
Retrospective Negative Samples: BioPlex 2200 MMRV IgG vs. EIA
| Target Analyte | Sample Count (N) | BioPlex Pos (+) | BioPlex Eqv | BioPlex Neg (-) | Negative % Agreement (95% CI) |
|---|---|---|---|---|---|
| Measles IgG | 93 | 0 | 0 | 93 | 100% (96.0 - 100%) |
| Mumps IgG | 96 | 6 | 7 | 83 | 100% (95.6 - 100%) |
| Rubella IgG | 268 | 3 | 8 | 257 | 95.9% (92.8 - 97.7%) |
| VZV IgG | 143 | 0 | 0 | 143 | 100% (97.4 - 100%) |
Reproducibility (Total %CV for Serum, across sites, days, runs)
| Analyte | High Positive Range (Total %CV) | Low Positive Range (Total %CV) | Near Cutoff Range (Total %CV) | High Negative Range (Total %CV) | Positive Control (Total %CV) |
|---|---|---|---|---|---|
| Measles IgG | 10.2 - 13.9 | 13.5 - 16.0 | 10.4 - 14.8 | 9.4 - 11.5 | 12.3 |
| Mumps IgG | 7.2 - 10.2 | 5.7 - 6.9 | 7.4 - 7.6 | 5.3 - 8.4 | 7.5 |
| Rubella IgG | 10.1 - 15.2 | 8.0 - 12.1 | 9.0 - 11.0 | 10.9 - 11.5 | 10.7 |
| VZV IgG | 9.0 - 10.0 | 6.8 - 9.3 | 8.7 - 9.8 | 6.1 - 13.6 | 7.9 |
2. Sample Sizes Used for the Test Set and Data Provenance
- Prospective Comparative Testing:
- Pregnant Women: N = 396 serum samples. Data provenance: Not explicitly stated, but the study was conducted at 3 U.S. clinical trial sites. Retrospective or prospective nature is not specified for collection.
- Measles, Mumps, Rubella, or VZV Test Ordered: N = 1183 serum samples. This population included (N = 790) samples submitted for routine testing and (N = 393) samples for pre-employment evaluation. Data provenance: Not explicitly stated, but the study was conducted at 3 U.S. clinical trial sites.
- Retrospective Comparative Testing (Negative Samples):
- Measles IgG: N = 93 serum samples.
- Mumps IgG: N = 96 serum samples.
- Rubella IgG: N = 268 serum samples.
- VZV IgG: N = 143 serum samples.
- Data provenance: Not explicitly stated, but implies these were pre-existing samples.
- CDC Rubella Evaluation Serum Panel: N = 100 serum samples (82 positive, 18 negative). Data provenance: Provided by the CDC.
- Reproducibility Studies: A "reproducibility panel" was prepared, consisting of positive panel members in serum, EDTA plasma, and sodium heparin plasma, along with a positive and negative control. The exact number of panel members is not explicitly stated beyond "varying levels of antibodies" and a "positive control." Each panel member and controls were tested in quadruplicate on 1 run per day over 5 days at each of 3 sites (4 replicates x 1 run x 5 days x number of panel members = total Sample N for reproducibility analysis, which for each measured point was N=60).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The ground truth for the comparative testing was established using commercially available EIA (Enzyme Immunoassay) predicate devices, which are conventional laboratory tests. No human experts establishing a ground truth in the manner of, for example, radiologists interpreting images, are mentioned for these studies.
For the CDC Rubella Evaluation Serum Panel, the samples were "masked, characterized" by the CDC. This implies expert characterization by the CDC, but the specific number and qualifications of experts are not described.
4. Adjudication Method for the Test Set
- Prospective Comparative Testing:
- For Mumps and Measles, equivocal results on the commercially available EIAs were "further tested on two additional commercially available EIAs for consensus." This implies a 2 out of 3 consensus method for adjudicating equivocal results from the primary predicate EIA, using the two additional EIAs. The exact consensus rule (e.g., majority or all agree) is not explicitly stated but "consensus" suggests agreement among at least two.
- For Rubella, equivocal results on the commercially available EIA were "re-tested on the commercially available EIA, following the manufacturer's recommendations." This is a re-testing procedure, not a multi-reader adjudication.
- For VZV, no specific adjudication method for equivocal results is mentioned in the tables provided.
- Retrospective Comparative Testing:
- For Measles and Mumps negative samples, they were "selected using a consensus of two out of three commercially available EIAs." This is a pre-selection method for the test samples based on consensus, rather than adjudication of results from the BioPlex device.
- For Rubella and VZV negative samples, they were "selected using the respective commercially available EIAs used for the comparative analysis." No consensus method is mentioned here for selection.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Its Effect Size
No MRMC comparative effectiveness study was described. The study focuses on comparing the BioPlex device's performance to existing immunoassays, rather than assessing human reader performance with and without AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, the studies described are standalone performance evaluations of the BioPlex 2200 MMRV IgG kit against predicate devices. The device is an automated immunoassay system, and its performance metrics (agreement, reproducibility) reflect its standalone operational capabilities. There is no human-in-the-loop component mentioned in its operational or evaluation methodology that would constitute an "AI assistance" scenario.
7. The Type of Ground Truth Used
The primary ground truth for evaluating the BioPlex 2200 MMRV IgG kit's performance was established using results from legally marketed, commercially available EIA (Enzyme Immunoassay) predicate devices.
- For Measles and Mumps, this involved consensus results from two out of three commercially available EIAs for equivocal samples.
- For Rubella, re-testing with the predicate EIA was used for equivocal results.
- For the CDC Rubella panel, the ground truth was "masked, characterized" CDC reference sera.
8. The Sample Size for the Training Set
No training set is explicitly mentioned, as this is a traditional immunoassay device, not a machine learning or AI-driven algorithm in the context of typical training/validation/test sets for pattern recognition. The device is calibrated using a "set of three (3) distinct calibrator vials, supplied separately by Bio-Rad Laboratories" and controls are used for quality assurance.
9. How the Ground Truth for the Training Set Was Established
Since no traditional "training set" in the context of AI/ML was used, this question is not applicable. The device's operational parameters are based on established immunoassay principles, calibration, and quality control using defined calibrator and control materials.
§ 866.3510 Rubella virus serological reagents.
(a)
Identification. Rubella virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to rubella virus in serum. The identification aids in the diagnosis of rubella (German measles) or confirmation of a person's immune status from past infections or immunizations and provides epidemiological information on German measles. Newborns infected in the uterus with rubella virus may be born with multiple congenital defects (rubella syndrome).(b)
Classification. Class II. The special controls for this device are:(1) National Committee for Clinical Laboratory Standards':
(i) 1/LA6 “Detection and Quantitation of Rubella IgG Antibody: Evaluation and Performance Criteria for Multiple Component Test Products, Speciment Handling, and Use of the Test Products in the Clinical Laboratory, October 1997,”
(ii) 1/LA18 “Specifications for Immunological Testing for Infectious Diseases, December 1994,”
(iii) D13 “Agglutination Characteristics, Methodology, Limitations, and Clinical Validation, October 1993,”
(iv) EP5 “Evaluation of Precision Performance of Clinical Chemistry Devices, February 1999,” and
(v) EP10 “Preliminary Evaluation of the Linearity of Quantitive Clinical Laboratory Methods, May 1998,”
(2) Centers for Disease Control's:
(i) Low Titer Rubella Standard,
(ii) Reference Panel of Well Characterized Rubella Sera, and
(3) World Health Organization's International Rubella Standard.