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The BioPlex® 2200 Rubella and CMV IgM kit is a multiplex flow immunoassay intended for the qualitative detection of IgM antibodies to Rubella and Cytomegalovirus (CMV) in human serum and potassium EDTA or sodium heparin plasma.

The BioPlex 2200 Rubella and CMV IgM kit is intended for use with the Bio-Rad BioPlex 2200 System.

This kit is intended as an aid in the diagnosis of a current or recent Rubella and/or CMV infection, in individuals suspected of having one of the respective disease states including women of child bearing age.

This assay is not FDA cleared or approved for use in testing (screening) blood or plasma donors.

Performance characteristics for the Rubella and CMV IgM assays have not been evaluated in immunosupressed or organ transplant individuals. Performance characteristics of this kit have not been established for use in neonatal screening or for use at point of care facilities.

The BioPlex® 2200 Rubella and CMV IgM Calibrator Set is intended for calibration of the BioPlex 2200 Rubella and CMV IgM Reagent Pack.

The BioPlex 2200 Rubella and CMV IgM Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 Instrument and BioPlex Rubella and CMV IgM Reagent Pack in the clinical laboratory. The performance of the BioPlex 2200 Rubella and CMV IgM Control Set has not been established with any other Rubella or Cytomegalovirus (CMV) IgM antibody assays.

The BioPlex® 2200 Rubella and CMV IgM 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. Rubella and CMV IgM test is to detect antibodies to Rubella and Cytomegalovirus (CMV).

Two (2) different populations of dyed beads are coated with cell lysates bearing Rubella or CMV antigens. The BioPlex 2200 System combines an aliquot of patient sample, sample diluent, 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 conjugate 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. Raw data are reported as 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 or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma.

The instrument is calibrated using a set of three (3) distinct serum based calibrators. A negative and CMV IgM calibrator is used to calibrate CMV assay, and a negrative and rubella IgM calibrator is used to calibrate the rubella IgM assay, The cul-off value and assignment of the calibrators are determined by performing concordance and Receiver Operator Characteristic (ROC) analysis using the Centaur Rubella IgM and VIDAS CMV IgM predicate results as the standard. For Rubella and CMV, results of ≤ 0.8 Al are negative, 0.9 and 1.0 Al are equivocal and results of ≥ 1.1 Al are reported as positive.

The BioPlex 2200 Rubella and CMV IgM Control Set includes a negative control as well as a CMV IgM positive control and a Rubella IgM positive control. The BioPlex Rubella and CMV IgM Positive Controls are manufactured to give positive results, with values above the cut-off for each specific analyte. The BioPlex Rubella and CMV IgM Negative Control are manufactured to give negative results, with values below the cut-off for each specific analyte. The recommended frequency for performing quality control is once every 24-hour testing period. Performing quality control is also necessary after each new assay calibration and certain service procedures.

Here's an analysis of the provided text regarding the BioPlex® 2200 Rubella and CMV IgM kit, focusing on acceptance criteria and the supporting studies:

Summary of Acceptance Criteria and Device Performance (Based on Method Comparison Studies)

The acceptance criteria for the BioPlex® 2200 Rubella and CMV IgM kit are not explicitly stated as numerical targets in the provided document, but rather implied through comparison to predicate devices and general performance metrics like Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA).

1. Table of Acceptance Criteria and Reported Device Performance

Notes on Acceptance Criteria:

• The document implies that "comparable performance" or "performed according to its specifications" is the acceptance criterion for many aspects. For quantitative measurements like reproducibility and matrix comparison, specific numerical targets (e.g., %CV ranges, slope 1.0 +/- 0.2, r >= 0.98) are explicitly mentioned and met.
• The PPA values for the prospective study, especially for Rubella IgM (66.7%) and CMV IgM (53.8%), seem low initially. However, these are based on a very small number of positive samples (3 for Rubella IgM and 13 for CMV IgM), which leads to wide confidence intervals. The larger retrospective study with presumptive positive samples shows much higher PPA values (96.3% for Rubella IgM and 91.3% for CMV IgM), suggesting strong overall positive agreement when sufficient positive samples are present. The low positive counts in the prospective study are likely due to the low prevalence of acute infections in the "test ordered" population.

2. Sample Sizes Used for the Test Set and Data Provenance

• Reproducibility (Internal): 3 panels (serum, EDTA plasma, heparinized plasma). Assayed 2 times in 2 separate daily runs over 20 days (n=80).
• Reproducibility (External): 3 panels (serum, EDTA plasma, heparinized plasma). Tested in quadruplicate over 5 days at 3 sites (n=60 replicates per panel member).
• Interfering Substances: Specific substances tested at varying concentrations. Number of samples not explicitly stated per substance, but implied to be sufficient to observe interference if present.
• Cross-Reactivity: Varied numbers of samples (typically 9-10) for each potential cross-reactant. Samples were known positive for the given cross-reactant and negative by predicate devices.
• IgM Detection (DTT treatment): 10 Rubella IgM-positive samples and 10 CMV IgM-positive samples.
• Seroconversion Testing: 3 commercial Rubella IgM seroconversion panels (RP001, RP011, RP014) and 1 commercial CMV IgM seroconversion panel (RP003). Each panel consists of multiple bleeds over time.
• Expected Values:
  • Rubella IgM: 300 samples (US origin).
  • CMV IgM: 400 samples (300 US, 100 Europe).
• Method Comparison (Prospective Study):
  • Rubella IgM: 300 samples (US origin), including 71 pregnant women.
  • CMV IgM: 400 samples (300 US, 100 Europe).
• Method Comparison (Retrospective Study - Presumptive Positive):
  • Rubella IgM: 107 samples.
  • CMV IgM: 229 samples.
• Matrix Comparison: 20 individual donors for matched serum, potassium EDTA plasma, and sodium heparin plasma samples. Evaluated in replicates of 10.

Data Provenance:

• US and Europe: Explicitly mentioned for some Expected Values and Method Comparison studies for CMV IgM. Rubella IgM samples are predominantly US.
• Retrospective/Prospective:
  • Prospective: Method Comparison study for general population and pregnant women.
  • Retrospective: Method Comparison study for presumptive positive samples. Seroconversion panels, interfering substances, and cross-reactivity studies are inherently retrospective in their selection (i.e., using pre-characterized samples). Reproducibility studies used panels.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document does not specify the direct involvement of human experts (e.g., radiologists, pathologists) in establishing the ground truth for this device. Instead, the ground truth for most comparative studies is established by:

• Predicate Devices: The ADVIA Centaur® Rubella IgM (K010668) and bioMeriéux VIDAS® CMV IgM (K933549) are used as the reference standard ("predicate results as the standard") for determining cut-off values and for method comparison studies.
• FDA Cleared Devices: For the cross-reactivity study, samples were pre-tested by "FDA cleared devices." For adjudication, "two out of three FDA cleared devices" were used.
• Commercial Seroconversion Panels: Bio-Rad Laboratories Liquichek™ Rubella IgM and CMV IgM seroconversion panels were used, which are typically well-characterized.

Therefore, the ground truth is based on established, FDA-cleared commercial assays and recognized diagnostic panels, rather than direct expert consensus on individual cases.

4. Adjudication Method for the Test Set

• Adjudication by Multiple FDA Cleared Devices: For samples that showed equivocal results by the predicate device in the Method Comparison (Prospective Study), an adjudication method was used: "One sample that was equivocal by the predicate device was adjudicated by two out of three FDA cleared devices." and "Two samples that were equivocal by the predicated by two out of three HDA cleared devices." This is a form of 2-out-of-3 or 3-out-of-3 adjudication against external reference methods.
• No explicit 2+1, 3+1, or similar human expert adjudication is mentioned in the context of interpretation of images or clinical cases. The adjudication is against other laboratory tests.

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 comparative effectiveness study was mentioned or performed. This device is an in vitro diagnostic (IVD) immunoassay kit, not an AI-assisted diagnostic imaging device or tool that involves human "readers" in the traditional sense of interpreting complex data like medical images. Its performance is evaluated against other laboratory assays.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done

The BioPlex® 2200 system operates as a standalone automated immunoassay. The performance studies described (reproducibility, interfering substances, cross-reactivity, seroconversion, method comparison) inherently evaluate its "algorithm only" or automated performance without human intervention in the interpretation process of individual test results. The device provides quantitative results (RFI) which are then interpreted qualitative (negative, equivocal, positive) based on predefined cut-offs.

7. The Type of Ground Truth Used

The ground truth primarily used is "predicate devices" or "FDA cleared devices."

• For method comparison studies, the results from the ADVIA Centaur® Rubella IgM and bioMeriéux VIDAS® CMV IgM predicate devices served as the gold standard.
• For cross-reactivity, samples confirmed positive for specific conditions by other FDA cleared devices were used.
• For seroconversion, commercial seroconversion panels were used, which have well-characterized profiles.
• The calibration itself uses concordance and Receiver Operator Characteristic (ROC) analysis with predicate device results.

8. The Sample Size for the Training Set

The document does not explicitly describe a separate "training set" in the context of machine learning or AI algorithm development. This is an immunoassay kit, where the "training" involves the development and calibration of the assay.

• The calibration process is described using "a set of three (3) distinct serum based calibrators." The cut-off values are determined by "performing concordance and Receiver Operator Characteristic (ROC) analysis using the Centaur Rubella IgM and VIDAS CMV IgM predicate results as the standard." While not a "training set" in the AI sense, this calibrator set and the analysis with predicate results serve a similar function in establishing the assay's operational parameters.

9. How the Ground Truth for the Training Set Was Established

As noted above, there isn't a "training set" in the typical AI sense. For the establishment of assay calibration and cut-offs:

• Predicate Device Results: The ground truth for defining the cut-off values and calibrators was established by comparing the BioPlex 2200's performance against the established results of the predicate devices (ADVIA Centaur® Rubella IgM and bioMeriéux VIDAS® CMV IgM) using concordance and ROC analysis. This means the clinical and analytical performance of those predicate devices, which are already FDA cleared, serve as the reference for tuning the BioPlex 2200's output.

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