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The ADVIA Centaur EBV-EBNA IgG (EBVnaG) assay is for in vitro diagnostic use in the qualitative detection of IqG antibodies to Epstein-Barr virus (EBV) nuclear antigen (EBNA) in human pediatric (2-21 years old) and adult serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP system. When used in conjunction with other EBV markers, this assay is intended for use as an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis.

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The provided text describes the performance of the ADVIA Centaur EBV-EBNA IgG assay, an in vitro diagnostic device for the qualitative detection of IgG antibodies to Epstein-Barr virus (EBV) nuclear antigen (EBNA).

Here's an analysis of the acceptance criteria and study data:

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria for the ADVIA Centaur EBV-EBNA IgG assay are primarily demonstrated through its agreement with an FDA-cleared reference EBV EBNA IgG assay. While explicit "acceptance criteria" are not listed with numerical thresholds in a dedicated table, the clinical study results (Positive Percent Agreement - PPA and Negative Percent Agreement - NPA) are implicitly compared against an expectation of substantial equivalence to the predicate device.

For precision and reproducibility, specific targets are mentioned.

• NPA: 92.8% (95% CI: 89.6% - 95.1%)
• PPA: 99.4% (95% CI: 98.8% - 99.7%)

Population 2 (Known EBV EBNA IgG negative individuals)

• NPA: 98.2% (95% CI: 94.9% - 99.4%)

Pediatric Population (Population 1 - symptomatic)

• NPA: 97.3% (95% CI: 94.3% - 98.8%)
• PPA: 98.4% (95% CI: 96.0% - 99.4%)

Pediatric Population (Population 2 - known negative)

• NPA: 100% (95% CI: 94.9% - 100%) |
  | Precision | Not explicitly stated as a single value, but individual sample CVs are presented. | Serum Samples: Total Precision CVs range from 4.4% to 13.3%.
  Plasma, EDTA Samples: Total Precision CVs range from 4.3% to 9.5%.
  Controls: Control 1 (0.32 Index) Total Precision SD 0.014; Control 2 (3.16 Index) Total Precision CV 4.1%. |
  | Reproducibility | - Concentration $\le$ 0.80 Index: N/A (for CV)
• Concentration > 0.80 Index: $\le$ 20.0% CV | Serum Samples:
• Serum A (0.77 Index): SD 0.048, CV N/A (within $\le$ 0.80 Index)
• Serum B-E (1.07 to 8.85 Index): CVs range from 4.0% to 9.8% (all $\le$ 20.0%)
  Plasma, EDTA Samples:
• Plasma A (0.78 Index): SD 0.044, CV N/A (within $\le$ 0.80 Index)
• Plasma B-E (1.06 to 8.75 Index): CVs range from 5.0% to 10.7% (all $\le$ 20.0%)
  Controls: Control 1 (0.36 Index) SD 0.022, CV N/A; Control 2 (3.31 Index) CV 4.0%. |
  | Specimen Equivalency | Regression equation close to y=x, high correlation coefficient (r). | EDTA Plasma vs. Serum: y = 1.00x - 0.01 Index; r = 1.00
  Lithium Heparin Plasma vs. Serum: y = 0.98x - 0.01 Index; r = 0.99
  Conclusion: EDTA Plasma and Lithium Heparin Plasma are equivalent matrixes to Serum. |
  | Interferences | ±10% bias for reactive samples and ±0.10 Index for nonreactive samples. | The listed substances (Hemoglobin, Bilirubin, Lipemia, Biotin, Cholesterol, Protein, etc.) do not interfere at the indicated concentrations. |
  | Cross-reactivity | Not explicitly stated as a numerical criterion, but demonstrated by testing against various viral antibodies and disease states. | Data presented for 330 samples across 29 clinical categories, showing agreement or defined discrepancies with the comparative assay. For HCV, Mycoplasma pneumoniae IgG, HSV-1 IgG, and HSV-2 IgG, possible cross-reactivity cannot be excluded for a few discordant samples and should be interpreted clinically. |
  | Onboard Stability | 28 days for reagents, 28 days for calibration. | Reagents: 28 days. Calibration: 28 days. |
  | Calibrator Stability (Opened Vial) | 60 days when stored at 2-8ºC. | 60 days when stored at 2-8ºC. |
  | Unopened Reagents/Calibrators Stability | Until expiration date when stored at 2-8°C. | Until expiration date when stored at 2-8°C. |

2. Sample Size and Data Provenance

Clinical Study (Test Set):

• Total Study Population (Population 1): 1428 leftover samples.
  • Provenance: Collected over a contiguous time period from individuals for whom an EBV test was ordered. The document does not specify the country of origin but implies a clinical setting ("symptoms and signs for whom an EBV antibody test was ordered"). It is a retrospective collection of leftover samples.
• Known EBV EBNA IgG Negative Population (Population 2): 167 samples.
  • Provenance: Samples with a known EBV EBNA IgG negative result, used to supplement numbers for negative EBV EBNA IgG. Retrospective.
• Pediatric Population: Subsets of Population 1 (479 samples including 84 unclassified serostatus individuals) and Population 2 (72 samples including 6 unclassified serostatus individuals).
• Cross-reactivity Study: 330 samples across various clinical categories.
• Specimen Equivalency Study: 97-98 sets of matched samples (SST, EDTA plasma, lithium heparin plasma).
  • Provenance: Commercial sources.

3. Number of Experts and Qualifications for Ground Truth

The document explicitly states that the ground truth for the clinical study was established by an "FDA cleared EBV EBNA IgG reference assay."
It also states: "Equivocal reference assay results were resolved by 2 other comparative assays."

• Number of 'Experts' (resolving assays): 2 (for equivocal cases from the primary reference assay).
• "Qualifications" of these 'experts': These were "comparative assays" rather than human experts. The document does not specify if these were other FDA-cleared assays or the nature of their qualification, but the implication is that they served as a consensus mechanism to resolve indeterminate results from the primary reference assay.

4. Adjudication Method for the Test Set

The adjudication method for equivocal results from the primary reference assay was by "2 other comparative assays." This is a form of 2+0 or 1+2 (primary reference + 2 comparative). If the two comparative assays agreed, that likely established the reconciled ground truth for the equivocal samples. The document does not describe what happened if the two comparative assays disagreed.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC comparative effectiveness study was done. This device is an in vitro diagnostic assay, which typically does not involve human readers interpreting images or data alongside AI. The device is evaluated for its analytical and clinical performance against a reference method. Therefore, there is no information on how much human readers improve with AI vs. without AI assistance.

6. Standalone (Algorithm only without human-in-the loop performance)

Yes, a standalone performance study was done. The entire clinical study, precision, reproducibility, specimen equivalency, and interference studies evaluate the performance of the ADVIA Centaur EBV-EBNA IgG assay as a standalone device (algorithm/assay only) against a reference method or predetermined analytical specifications. There is no human-in-the-loop component described for its primary intended use and evaluation.

7. Type of Ground Truth Used

The ground truth used for the clinical study was based on an FDA-cleared EBV EBNA IgG reference assay, with equivocal results resolved by 2 other comparative assays. This indicates a reference method or comparative assay-based ground truth.

8. Sample Size for the Training Set

The document is a 510(k) summary for an in vitro diagnostic assay. It does not provide information regarding a "training set" in the context of machine learning or AI models.
The samples mentioned are for performance evaluation (clinical study, precision, etc.) and are analogous to test or validation sets. For IVD devices, a "training set" might refer to samples used during the development and optimization of the assay's reagents and parameters, but this information is not typically disclosed in a 510(k) summary in this format.

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

As there is no "training set" described in the context of an AI/ML model for this IVD assay according to the provided document, this information is not applicable and not available.

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The ADVIA Centaur EBV-VCA IgM (EBVM) assay is for in vitro diagnostic use in the qualitative detection of lgM antibodies to the viral capsid antigen (VCA) of the Epstein-Barr virus (EBV) in human pediatric (2-21 years old) and adult serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP system. When used in conjunction with other EBV markers, this assay is intended for use as an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis.

The ADVIA Centaur EBV-VCA IgM assay is a fully automated 2-step sandwich immunoassay using acridinium ester chemiluminescent technology. The specimen is incubated with the Ancillary Well Reagent and the Solid Phase, which contains an EBV-VCA IgM specific antigen. Antigen-antibody complexes will form if anti EBV-VCA IgM antibody is present in the specimen. The Lite Reagent contains monoclonal anti-human IgM labeled with acridinium ester and is used to detect EBV-VCA IgM in the specimen.

Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:

Device: ADVIA Centaur EBV-VCA IgM

1. Table of Acceptance Criteria and Reported Device Performance:

The document implicitly defines acceptance criteria through the reported performance metrics. For a diagnostic device intended to aid in the diagnosis of infection, common acceptance criteria would include achieving certain levels of Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to a reference method, especially in relevant clinical populations (e.g., primary acute infection). Precision and reproducibility are also key acceptance criteria for laboratory assays.

2. Sample Size and Data Provenance:

• Clinical Study Test Set:
  • Total Study Population: 1428 leftover samples (Population 1) + 202 samples with known EBV VCA IgM positive result (Population 2). Total = 1630 samples.
    • Population 1: Collected over a contiguous time period from individuals for whom an EBV test was ordered.
    • Population 2: Samples with a known EBV VCA IgM positive result.
  • Pediatric Population: 479 samples (from Population 1) + 155 samples (from Population 2). Total = 634 samples.
  • Data Provenance: The document states "leftover samples were collected over a contiguous time period" and "multisite clinical study," suggesting diverse geographical sources and a real-world setting. It does not explicitly state country of origin but implies a clinical laboratory setting. The samples are retrospective (leftover samples).

3. Number of Experts and Qualifications for Ground Truth:

• This information is not explicitly provided in the document. The comparison is made against an "FDA-cleared EBV VCA IgM reference assay."
• For equivocal reference assay results, the ground truth was "resolved by 2 other comparative assays." This implies an algorithmic or rule-based resolution rather than human expert consensus for these specific cases.

4. Adjudication Method for the Test Set:

• The document states: "Equivocal reference assay results were resolved by 2 other comparative assays." This indicates a form of algorithmic or rule-based adjudication rather than a human expert consensus method (like 2+1 or 3+1). If the two additional comparative assays agreed, that would constitute a form of resolution. If they disagreed, the method for final resolution is not detailed.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

• No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) assay, not an imaging device or a device requiring human interpretation as part of its primary function where reader performance would be a direct outcome. The performance is assessed by comparing the assay's output to a reference method, not by how human readers improve with or without AI assistance.

6. Standalone (Algorithm Only) Performance:

• Yes, a standalone performance study was done. The entire clinical and analytical performance evaluation describes the ADVIA Centaur EBV-VCA IgM assay's performance independently (as an algorithm/assay) against a reference standard or for its inherent analytical characteristics (precision, reproducibility). There is no "human-in-the-loop" component described for the assay's function itself; it is an automated immunoassay.

7. Type of Ground Truth Used:

• The primary ground truth was established by an "FDA-cleared EBV VCA IgM reference assay."
• For cases where the reference assay was equivocal, "2 other comparative assays" were used for resolution.
• For defining "primary acute infection," the presence of "either EBV IgM or heterophile antibodies, and the absence of EBNA IgG" was used – this relies on a combination of other serological markers/tests.

8. Sample Size for the Training Set:

• The document does not provide information on the training set for the ADVIA Centaur EBV-VCA IgM assay. As a chemical immunoassay, its "training" involves the development and optimization of its chemical components, reagents, and detection parameters, using internal development studies that are typically not detailed as "training sets" in the same way as machine learning models. The reported studies are for validation/testing.

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

• As the document does not mention a "training set" in the context of machine learning, this question is not applicable/not addressed by the provided text. The development process for such an immunoassay typically involves extensive R&D, analytical characterization, and optimization using well-characterized samples, but this is distinct from establishing ground truth for a machine learning training dataset.

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The LIAISON® VCA IgG assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer family* for the qualitative determination of specific IgG antibodies to Epstein-Barr virus (EBV) viral capsid antigen (VCA) p18 synthetic peptide in human serum. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr Viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis.

The DiaSorin LIAISON® VCA IgG Serum Control Set is intended for use as assayed quality control samples to monitor the performance of the LIAISON® VCA IgG assay on the LIAISON® Analyzer family*. The performance characteristics of the LIAISON® VCA IgG controls have not been established for any other assay or instrument platforms different from the LIAISON® and LIAISON® XL.

*(LIAISON® and LIAISON® XL).

The LIAISON® EBNA IgG assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer family* for the qualitative determination of specific IgG antibodies to Epstein-Barr virus (EBV) nuclear antigen synthetic peptide (EBNA-1) in human serum. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr Viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis.

The DiaSorin LIAISON® EBNA IgG Serum Control Set is intended for use as assayed quality control samples to monitor the performance of the LIAISON® EBNA IgG assay on the LIAISON® Analyzer family*. The performance characteristics of the LIAISON® EBNA IgG controls have not been established for any other assay or instrument platforms different from the LIAISON® and LIAISON® XL.

*(LIAISON® and LIAISON® XL).

The LIAISON® VCA IgG assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer family for the qualitative determination of specific IgG antibodies to Epstein-Barr virus (EBV) viral capsid antigen (VCA) p18 synthetic peptide in human serum.

The LIAISON® VCA IgG Serum Control Set (negative and positive) consists of liquid ready-touse controls in human serum/defibrinated plasma. The negative control is intended to provide an assay response characteristic of negative patient specimens and the positive control is intended to provide an assay response characteristic of positive patient specimens.

The controls are designed for use with DiaSorin LIAISON® VCA IgG assay on the LIAISON® Analyzer family.

The LIAISON® EBNA IgG assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer family for the qualitative determination of specific IgG antibodies to Epstein-Barr virus (EBV) nuclear antigen synthetic peptide (EBNA-1) in human serum.

The LIAISON® EBNA IgG Serum Control Set (negative) consists of liquid ready-touse controls in human serum. The negative control is intended to provide an assay response characteristic of negative patient specimens and the positive control is intended to provide an assay response characteristic of positive patient specimens.

The controls are designed for use with DiaSorin LIAISON® EBNA IgG assay on the LIAISON® Analyzer family.

This document describes two devices, the LIAISON® VCA IgG and LIAISON® EBNA IgG assays and their respective Serum Control Sets. The provided text primarily focuses on the control sets, detailing the modifications made to them and the studies conducted to demonstrate that these modifications do not compromise the performance or safety of the assays.

A. Acceptance Criteria and Reported Device Performance (LIAISON® VCA IgG Serum Control Set & LIAISON® EBNA IgG Serum Control Set)

The acceptance criteria stated for both control sets are related to their ability to function as intended without introducing new risks after modifications. The performance data section describes the types of studies conducted rather than specific numeric acceptance criteria and resulting reported performance values.

However, based on the description of the studies, we can infer the acceptance criteria and a summary of reported performance:

1. Commutability between samples and controls (matrix effect).
2. Precision equivalence between samples and controls.
3. Accurate control value assignment.
4. Appropriate control range definition. | "Non-clinical verification and validation testing... demonstrate that the modified device meets predetermined acceptance criteria, supporting equivalency of the modified device to the cleared device."
   Specific values are not provided. |
   | Stability (Shelf-life) | The control set should maintain its performance over a 12-month shelf-life when stored at 2-8°C. | Supported a "Shelf-life of 12 months at (2-8°C)". |
   | Stability (Open Use) | The control set should maintain its performance for eight (8) weeks after opening when stored at 2-8°C between uses. | Supported "Eight (8) weeks open use stability when stored at 2-8°C between uses." |
   | Risk Assessment | The modifications should not introduce any new risks to the performance of the device. | "Based on the results from the validation and verification activities, the modifications to the LIAISON® VCA IgG Serum Control Set [and EBNA IgG Serum Control Set] do not introduce any new risks to the performance of the device." |

B. Sample Size Used for the Test Set and Data Provenance

The document does not specify the exact sample sizes for the test sets used in the validation and verification studies (e.g., for commutability, precision, value assignment, or stability). It only states that these studies were conducted.

The data provenance is not explicitly mentioned with respect to country of origin, but the controls are described as being made from "Human serum/defibrinated plasma." The studies are retrospective as they validated modifications to an already cleared device.

C. Number of Experts Used to Establish Ground Truth and Qualifications

This information is not provided. The document describes in-vitro diagnostic devices (immunoassays and control sets), and the ground truth for such devices is typically established through reference methods, certified materials, or clinical samples with confirmed status, rather than expert consensus on interpretation of device output.

D. Adjudication Method

Not applicable for this type of in-vitro diagnostic device validation. Adjudication methods like 2+1 or 3+1 are typically used in clinical studies involving interpretation by human readers.

E. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

Not applicable. This is an in-vitro diagnostic device, not an imaging or interpretation assistance device for human readers. The studies focus on the analytical performance of the control sets themselves.

F. Standalone Performance

The devices in question are control sets for existing immunoassays. Their performance is inherently tied to the assay they are controlling. The document describes "non-clinical verification and validation testing" demonstrating that the modified control sets meet acceptance criteria, implying an assessment of their analytical performance in a standalone context as control materials. However, "standalone" in the context of an algorithm without human-in-the-loop performance is not relevant here. The "performance characteristics of the LIAISON® VCA IgG controls have not been established for any other assay or instrument platforms different from the LIAISON® and LIAISON® XL," indicating their intended specific use.

G. Type of Ground Truth Used

The ground truth for the performance of these control sets would be established against the expected performance of the LIAISON® VCA IgG and LIAISON® EBNA IgG assays. This would involve using:

• Reference materials: Potentially, certified reference materials or established in-house reference materials to assign values and check accuracy.
• Clinical samples: Patient samples with known positive or negative status (likely determined by established reference methods for EBV) would be used to assess commutability and ensure the controls behave similarly to actual patient samples.
• Established assay performance: The predicate device's known performance characteristics (precision, accuracy, etc.) would serve as a benchmark for evaluating the equivalency of the modified control sets.

The document implicitly refers to this by stating the studies "demonstrate that the modified device meets predetermined acceptance criteria, supporting equivalency of the modified device to the cleared device."

H. Sample Size for the Training Set

The document does not mention a "training set" in the context of machine learning, as this is an in-vitro diagnostic device (immunoassay control set). The studies described are validation and verification studies for analytical performance and stability, not a machine learning model.

I. How the Ground Truth for the Training Set was Established

Not applicable, as there is no mention of a machine learning training set.

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The LIAISON® EA IgG assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer family* for the qualitative determination of specific IgG antibodies to Epstein-Barr virus (EBV) early antigen-diffuse [EA(D)] in human serum. This assay uses a 47-kDa recombinant antigen expressed in E. coli DH-1 cells. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr Viral Syndrome in patients with signs and symptoms of EBV infectious mononucleosis.

The DiaSorin LIAISON® EA IgG Serum Control Set is intended for use as assayed quality control samples to monitor the performance of the LIAISON® EA IgG assay on the LIAISON® Analyzer family*. The performance characteristics of the LIAISON® EA IgG controls have not been established for any other assay or instrument platforms different from the LIAISON® and LIAISON® XL.

*(LIAISON® and LIAISON® XL)

The LIAISON® EA IgG is an indirect chemiluminescence immunassay (CLIA) technology on the LIAISON Analyzer family* for the qualitative determination of IgG antibodies to Epstine-Barr virus (EBV) early antigen-diffuse [ea(D)] in human serum.

The LIAISON® EA IgG Serum Control Set (negative and positive) consists of liquid ready-to-use controls in human serum/defibrinated plasma. The negative control is intended to provide an assay response characteristic of negative patient specimens and the positive control is intended to provide an assay response characteristic of positive patient specimens.

The controls are designed for use with DiaSorin LIAISON® EA IgG assay on the LIAISON® Analyzer family.

The provided document is a 510(k) summary for a medical device called LIAISON® EA IgG and LIAISON® EA IgG Serum Control Set. It details the device's characteristics, intended use, and a comparison to a predicate device, focusing on modifications made to the control set. The information necessary to fully address all parts of your request, particularly those related to detailed study methodologies, expert qualifications, and specific numerical acceptance criteria/results for diagnostic accuracy (like sensitivity/specificity or AUROC), is not present in this 510(k) summary. This document primarily focuses on demonstrating substantial equivalence through performance characteristics of the controls and proving that changes do not introduce new risks to the assay's performance, rather than a full diagnostic accuracy study of the assay itself.

However, I can extract and infer the following:

1. A table of acceptance criteria and the reported device performance

The document states that "Non-clinical verification and validation testing conducted with the LIAISON® EA IgG and LIAISON® EA IgG Serum Control Set demonstrate that the modified device meets predetermined acceptance criteria". While the specific numerical acceptance criteria are not explicitly detailed (e.g., a specific percentage for precision or commutability), the types of performance evaluated and confirmed are listed.

2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

The document does not provide details on the specific sample sizes used for the "test set" in terms of number of patient samples. The studies mentioned ("Commutability," "Precision equivalence," "Control value assignment," "Control range definition," and "Real Time Stability") relate to the performance of the controls and the assay system with these controls. Information regarding data provenance (country, retrospective/prospective) for these specific validation studies is also not provided.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This information is not applicable and not provided in the context of this 510(k) summary. The document pertains to a serological assay (LIAISON® EA IgG) and its controls, not an AI or imaging device that uses expert-established ground truth for a test set in the traditional sense of diagnostic accuracy studies. The "ground truth" for a serological assay would typically be established through other laboratory methods, clinical diagnosis, or a composite reference standard, rather than expert interpretation of images or other data that requires such qualifications.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

This information is not applicable and not provided. See point 3.

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

This is not an AI-assisted device and therefore no MRMC study or AI-related effectiveness study was conducted or reported.

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

This is not an AI algorithm. It is a serological immunoassay kit and its controls.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

For the LIAISON® EA IgG assay itself (not the controls), the "ground truth" for its intended use is defined by its ability to detect specific IgG antibodies to EBV early antigen-diffuse [EA(D)]. This is a biochemical "truth" established by the immunological reaction in the assay. The assay is intended to be used "in conjunction with other EBV markers" as an aid in clinical laboratory diagnosis of Epstein-Barr Viral Syndrome in patients with signs and symptoms of EBV infectious mononucleosis. Therefore, the ultimate clinical ground truth for the disease diagnosis would involve a combination of various EBV markers and clinical symptoms/outcomes, but the "ground truth" for the device's performance itself is its accuracy in detecting the target antibody. The document does not provide details on how the original assay (K060204) was validated against clinical ground truth or other reference methods in terms of sensitivity and specificity for disease diagnosis. This 510(k) is specifically for modifications to the controls and showing they do not negatively impact the previously cleared assay.

8. The sample size for the training set

This is not an AI algorithm. The concept of a "training set" in the machine learning sense does not apply here. The "training" for such an assay involves method development and optimization using various reagent lots, antigen sources, and panels of known positive/negative samples, but these are not quantified in terms of a "training set" like in AI.

9. How the ground truth for the training set was established

Not applicable as described for AI (see point 8). For the development of the assay, the "ground truth" for calibrators and controls would be established through careful characterization using reference methods, purified antigens/antibodies, and panels of clinically characterized patient samples (e.g., samples from confirmed EBV infections and healthy individuals), but specific details are not provided in this summary.

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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 BioPlex® 2200 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.

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

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® EBV IgM Reagent Pack in the clinical laboratory. The performance of the BioPlex® EBV IgM Control Set has not been established with any other EBV IgM antibody assays.

The BioPlex 2200 EBV IgM kit is a multiplexed micro particle bead based immunoassay for the qualitative detection of IgM antibodies to EBV VCA GP125/p18 and Heterophile antigen in human serum using the Luminex flow cytometry technology. The BioPlex 2200 EBV IgM Calibrators set consists of two (2) distinct serum based calibrators. The BioPlex 2200 EBV IgM Control set consists of 2 vials of the BioPlex 2200 EBV IgM Positive Control and 2 vials of the BioPlex 2200 EBV IgM Negative Control. The positive controls are provided in a human serum matrix made from defibrinated plasma with added antibodies to EBV VCA GP125/p18 and Heterophile antigen derived from human disease state plasma. The negative controls are provided in a human serum matrix made from defibrinated plasma.

{
  "1. A table of acceptance criteria and the reported device performance": {
    "VCA IgM Performance": {
      "Acceptance Criteria": "(Implied) Performance equivalent to Predicate device ([K062213](https://510k.innolitics.com/search/K062213))",
      "Reported Device Performance": {
        "Positive Percent Agreement (PPA)": "98.7% (78/79)",
        "Negative Percent Agreement (NPA)": "98.7% (528/535)"
      }
    },
    "Heterophile IgM Performance": {
      "Acceptance Criteria": "(Implied) Performance equivalent to Predicate device ([K062213](https://510k.innolitics.com/search/K062213))",
      "Reported Device Performance": {
        "Positive Percent Agreement (PPA)": "100% (28/28)",
        "Negative Percent Agreement (NPA)": "100% (593/593)"
      }
    },
    "Precision/Reproducibility (Total Precision %CV) - VCA IgM": {
      "Acceptance Criteria": "(Implied) Comparable or improved CVs relative to Predicate device",
      "Reported Device Performance (Modified Device)": {
        "High Negative": "5.6% - 9.0%",
        "Near Cutoff": "6.4% - 7.7%",
        "Low Positive": "5.1% - 8.1%",
        "High Positive": "2.7% - 4.5%"
      }
    },
    "Precision/Reproducibility (Total Precision %CV) - Heterophile IgM": {
      "Acceptance Criteria": "(Implied) Comparable or improved CVs relative to Predicate device",
      "Reported Device Performance (Modified Device)": {
        "High Negative": "7.9% - 8.4%",
        "Near Cutoff": "7.0% - 7.1%",
        "Low Positive": "5.4% - 6.0%",
        "High Positive": "5.1% - 5.3%"
      }
    },
    "Analytical Specificity (Interference)": {
      "Acceptance Criteria": "(Implied) Percent change in signal within acceptable limits and equivalent to original device. Specifically, for predicate, ranged from -5.6% to 5.6% for VCA IgM and -7.4% to 4.2% for Heterophile IgM.",
      "Reported Device Performance": {
        "VCA IgM": "Percent change in signal ranged from -10.0% to 0.0%",
        "Heterophile IgM": "Percent change in signal ranged from -11.1% to 7.4%"
      }
    },
    "LSP Remediation (Risk Analysis)": {
      "Acceptance Criteria": "Residual Risk acceptability criteria (RPN score) ≤ 19.",
      "Reported Device Performance": "RPN scores ranged from 6 for false positive results to 12 for false negative results for both EBV VCA IgM and Heterophile IgM assays."
    },
    "LSP Remediation (Contamination Studies)": {
      "Acceptance Criteria": "Adequate protection against bacteria and mold contamination, with only minimal signal loss within specifications even at extreme contamination levels.",
      "Reported Device Performance": "Proposed EBV IgM formulation provides adequate protection against bacteria and mold contamination as compared to reagent packs without remediation."
    }
  },
  "2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)": {
    "Method Comparison (Prospective)": {
      "Sample Size": "N=622 (individuals where EBV IgM test was ordered)",
      "Data Provenance": "Prospective, human serum samples."
    },
    "Retrospective Positive Samples": {
      "Sample Size": "N=81 (for both VCA IgM and Heterophile IgM)",
      "Data Provenance": "Retrospective, from individuals presumptively positive for either VCA IgM or Heterophile IgM."
    },
    "Precision Panel": {
      "Sample Size": "9 serum panel members for each analyte.",
      "Data Provenance": "Panel members prepared by Bio-Rad Laboratories."
    }
  },
  "3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)": "Not applicable. Ground truth for comparison studies was established by the predicate device (BioPlex 2200 EBV IgM Kit, [K062213](https://510k.innolitics.com/search/K062213)) or by presumptive positive status for retrospective samples. No independent expert review for ground truth determination is mentioned.",
  "4. Adjudication method (e.g. 2+1, 3+1, none) for the test set": "Not applicable. The study compares the performance of the modified device directly against a predicate device, which serves as the reference, or uses samples presumptively positive. There is no mention of an adjudication process by human experts.",
  "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": "Not applicable. This is not a study involving human readers or AI assistance. It is a comparison of an in vitro diagnostic (IVD) device (EBV IgM kit) to a predicate IVD device.",
  "6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done": "Yes, this is a standalone performance study. The BioPlex 2200 EBV IgM kit is an automated system (algorithm only) for qualitative detection of antibodies. Its performance is evaluated independently of human interpretation, beyond the standard use of such a diagnostic tool in a clinical laboratory.",
  "7. The type of ground truth used (expert concensus, pathology, outcomes data, etc)": "The ground truth for the comparison studies was primarily established by the performance of the predicate device (BioPlex 2200 EBV IgM Kit, [K062213](https://510k.innolitics.com/search/K062213)). For retrospective positive samples, their 'presumptively positive' status served as a form of ground truth, likely based on prior diagnostic results or clinical indicators, though the specific method of presumptive positivity is not detailed.",
  "8. The sample size for the training set": "Not applicable. This document describes a modification to an existing device and its performance evaluation, not the development or training of a new algorithm where a dedicated training set would typically be described. The study uses patient samples for comparison and precision, not for model training.",
  "9. How the ground truth for the training set was established": "Not applicable, as there is no described training set for the modified device."
}

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The BioPlex® 2200 EBV IgG kit is a multiplex flow immunoassay intended for the qualitative detection of IgG antibodies to three (3) separate EBV antigens; Epstein-Barr Virus Nuclear Antigen-1 (EBV NA-1), Viral Capsid Antigen (EBV VCA), and Early Antigen diffuse (EBV EA-D) in human serum. The test system can be used in conjunction with the BioPlex 2200 EBV IgM kit as an aid in the laboratory diagnosis of infectious mononucleosis (IM).

The EBV IgG 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.

The BioPlex® 2200 Syphilis IgG kit is a multiplex flow immunoassay intended for the qualitative detection of Treponema pallidum IgG antibodies in human serum. The test system, when used in conjunction with non-treponemal based assays, provides serological evidence of infection with T. pallidum. This test system also confirms reactive test results form non-treponemal based screening assays.

The Syphilis IgG kit is intended for use with the Bio-Rad BioPlex 2200 System.

The BioPlex 2200 Syphilis IgG kit is not intended for use in screening blood or plasma donors

Warning: A positive result is not useful for establishing a diagnosis of Syphilis. In most situations, such a result may reflect prior treated infection; a negative result can exclude a diagnosis of syphilis except for incubating or early primary disease.

The EBV IgG 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. Three (3) different populations of beads are coated with E. coli derived recombinant proteins, EBV NA-1 (28kD and 45kD), EBV VCA p18 (40kD), and EBV EA-D (28kD) associated with infectious mononucleosis. 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, antihuman 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 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 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 or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma. Refer to the BioPlex 2200 System Operation Manual for more information. The instrument is calibrated using a set of seven (7) distinct calibrator vials, supplied separately by Bio-Rad Laboratories. A combination of four (4) vials representing four (4) different antibody concentrations are used for semiquantitative calibration. The result for each of these antibodies is expressed as an antibody index (AI).

The Syphilis IgG 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. Three (3) different populations of beads are coated with recombinant proteins associated with T. pallidum (15kD. 17kD. and 47kD). The BioPlex 2200 System combines an aliquot of patient sample diluent, and bead 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 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 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 or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma. Refer to the BioPlex 2200 System Operation Manual for more information.

The system is calibrated using a set of four (4) distinct calibrator vials, supplied separately by Bio-Rad Laboratories. Four (4) vials representing two (2) or three (3) different antibody concentrations are used for calibration. Results are calculated for each of the three (3) antibodies and are compared against their own respective cut-off and are expressed as an antibody index (AI). A single result is reported after completing a composite analysis of all the antibodies (the highest AI value is reported).

This is a 510(k) premarket notification for device modifications to the BioPlex 2200 EBV IgG and Syphilis IgG kits. The modifications are related to reducing the frequency of Quality Control (QC) testing and adding protein stabilizers and protease inhibitors to the particle diluent. The document asserts that the performance of the modified QC test frequency is substantially equivalent to the current cleared kit, meaning no new clinical studies were conducted to prove device performance against acceptance criteria. Instead, a risk analysis was performed.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The documents do not provide specific quantitative acceptance criteria or reported device performance metrics (e.g., sensitivity, specificity, accuracy) for the modified devices. The core assertion is that the devices remain substantially equivalent to their predicate devices due to internal design control activities and risk assessment, rather than new performance testing.

The acceptance criteria for the changes are related to the risk management report and ensuring the modified QC procedure fulfills the requirements of the specifications of the design control process. The reported "performance" for the modified components is that they are considered substantially equivalent.

2. Sample Size for the Test Set and Data Provenance

No specific test set sample size, country of origin, or whether data was retrospective or prospective is mentioned for a new study to prove device performance. The modifications were assessed through design control activities and risk analysis rather than new clinical trials or performance studies involving patient samples.

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

Not applicable. No new test set requiring expert ground truth establishment was conducted for the device modifications. The substantial equivalence determination was based on internal risk analysis and FMEA.

4. Adjudication Method for the Test Set

Not applicable. No new test set requiring adjudication was conducted.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC study was performed or mentioned. These devices are in vitro diagnostic kits, not AI-assisted reader systems.

6. Standalone (i.e., algorithm only without human-in-the-loop performance) Study

Not applicable. These are diagnostic kits, not algorithms that operate without human interaction in the diagnostic process (though the instrument automates parts of it, the overall use involves human input and interpretation). The changes relate to QC frequency and reagent formulation, not the core analytical algorithm.

7. Type of Ground Truth Used

Not applicable for new device performance testing. The "ground truth" for the acceptance of these modifications was the internal design control process, FMEA, and risk analysis, which concluded that the modifications maintained substantial equivalence to the predicate devices. The predicate devices themselves would have had their performance validated against clinical ground truth (e.g., clinical diagnosis of infection) in their original 510(k) submissions.

8. Sample Size for the Training Set

Not applicable. The document describes modifications to existing in vitro diagnostic kits and does not involve machine learning algorithms with training sets.

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

Not applicable, as there is no training set mentioned.

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The SeraQuest EBV EA-D IgG test is for the qualitative detection of human IgG antibodies to Epstein-Barr virus early antigen diffuse (EA-D) in human serum by enzyme immunoassay. This assay uses a 28 kd E. coli expressed recombinant Epstein-Barr virus early antigen. When performed in conjunction with other EBV serological tests, this assay can be used as an aid in the laboratory diagnosis of EBV infectious mononucleosis in patients with signs and symptoms of EBV infectious mononucleosis. For In Vitro Diagnostic Use Only.

The SeraQuest EBV EA-D IgG Test is a solid-phase enzyme immunoassay (EIA), which is performed in microwells, at room temperature, in three thirty minute incubations. It has been developed to detect IgG antibodies which are directed against EBV Early Antigen D (EA-D), in human serum.

The document describes the SeraQuest EBV EA-D IgG Test, a solid-phase enzyme immunoassay (EIA) designed for the qualitative detection of human IgG antibodies to Epstein-Barr virus early antigen diffuse (EA-D) in human serum. This assay aids in the laboratory diagnosis of EBV infectious mononucleosis when used with other EBV serological tests.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria with specific numerical thresholds (e.g., "Positive Agreement must be >X%"). Instead, it presents various performance metrics derived from its clinical evaluation, which are then compared to a legally marketed predicate device. The implicit acceptance criterion appears to be "substantial equivalence" to the predicate device in terms of performance characteristics for diagnostic aid in EBV infectious mononucleosis.

The performance is reported in terms of percent agreement and associated confidence intervals, categorized by EBV serological status.

Note: For comparison, the predicate device (Comparator EBV EA-D IgG Test) achieved:

• Acute Infection Positive Agreement: 41.9% (13/31) with CI 24.5-60.9% (prospectively tested)
• Acute Infection Positive Agreement: 64.0% (32/50) with CI 49.2-77.1% (retrospectively tested)
• EBV Seronegative Negative Agreement: 78.3% (47/60) with CI 65.8-87.9% (prospectively tested)
• No Infection Negative Agreement: 73.3% (11/15) with CI 44.9-92.2% (retrospectively tested)
• Past Infection Negative Agreement: 62.7% (195/311) with CI 57.3-68.1% (prospectively tested)

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

• Total Test Set Sample Size: 542 serum samples.
  • Prospectively Collected and Prospectively Tested: 477 samples.
  • Prospectively Collected but Retrospectively Tested: 65 samples (50 acute specimens, 15 EBV seronegative).
• Data Provenance:
  • Country of Origin: 3 U.S. clinical testing sites.
  • Nature of Data: Mixed; primarily prospective (477 samples) with a supplementary retrospective component (65 samples that were prospectively collected but retrospectively tested). The study notes that the 65 specimens were retrospectively tested to "supplement the prospective study data."

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

The document states that specimens were classified into EBV serological states (Acute, EBV seronegative, Past Infection, Indeterminate) "as determined by other EBV serological reagents" and "reference EBV serology assays for EBV VCA IgG, EBV VCA IgM, and EBV EBNA-1 IgG." It does not mention the use of human "experts" or their qualifications to establish the ground truth for the test set. The ground truth was established by the results of established reference serological assays.

4. Adjudication Method for the Test Set

The document does not describe an "adjudication method" in the traditional sense involving human review of discrepancies. Instead, it details how equivocal results from both the SeraQuest test and the comparator test were handled for percent agreement calculations:

• "SeraQuest EBV EA-D IgG test equivocal results were assigned to the opposite test result interpretation than that of the corresponding comparative test results."
• "Likewise, the comparative test equivocal results were assigned to the opposite test result interpretation than that of the corresponding SeraQuest EBV EA-D IgG Test results."
  This is a statistical adjustment for calculation rather than clinical adjudication by experts.

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

This section is not applicable to this device. The SeraQuest EBV EA-D IgG Test is an in vitro diagnostic (IVD) immunoassay, not an AI-assisted diagnostic imaging or interpretation device that would involve human "readers" or "AI assistance." The "comparator" in this study refers to another commercially available EBV EA-D IgG ELISA test, not human readers or an AI system.

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

This section is applicable as the SeraQuest EBV EA-D IgG Test is an immunoassay that operates independently to produce a result. Its performance was evaluated in a standalone manner by comparing its output (positive, negative, equivocal) to the serological classification derived from reference EBV serology assays. The results presented in Tables 6 and 7 directly reflect the standalone performance of the SeraQuest test relative to the established EBV serological classification.

7. The Type of Ground Truth Used

The ground truth for classifying specimens into EBV serological states (Acute, EBV seronegative, Past Infection, Indeterminate) was established using a combination of results from reference EBV serology assays: EBV VCA IgG, EBV VCA IgM, and EBV EBNA-1 IgG. This can be categorized as serological reference assay data. The document explicitly states: "The EBV EA-D IgG result generated by the commercially available comparator EBV EA-D IgG ELISA test was not considered for purposes of characterizing the EBV serological state of the specimen."

8. The Sample Size for the Training Set

The document does not mention a "training set." This device is an immunoassay kit, not a machine learning or AI algorithm that requires a training set in the typical sense. The studies described are for clinical performance validation, not for training a model.

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

Since there is no mention of a "training set" in the context of this immunoassay, this question is not applicable. The "ground truth" for the performance evaluation (test set) was established using reference EBV serology assays, as described in point 7.

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Focus Diagnostics' Plexus™ EBV IgM Multi-Analyte Diagnostics test kit is intended for qualitatively detecting the presence or absence of human IgM class antibodies to viral capsid antigen (VCA), and heterophile antibodies in human sera. The test is indicated as an aid in the diagnosis of EBV infection and EBV-associated infectious mononucleosis.

The performance of this assay has not been established for use in the diagnosis of nasopharyngeal carcinoma and Burkitt's lymphoma, for testing of immunocompromised patients, for use by a point of care facility or for use with automated equipment. This assay has not been evaluated for donor screening.

Multiplexed Immunoassay for the Qualitative Detection of Human IgM Antibodies to Epstein-Barr Virus

The Focus Diagnostics Plexus™ EBV IgM uses an Antigen Bead suspension that contains two distinct EBV antigen bead types (VCA and Heterophile) and one process control bead type that fluoresce at different wavelengths and/or intensities.

The Focus Diagnostics Plexus™ EBV IgM is a three step procedure.

1. Patient sera are diluted, and the diluted sera are incubated with Antigen Beads. If EBV antibodies are present, then the antibodies bind to the corresponding antigen beads.
2. Phycoerythrin-conjugated goat Anti-human IgM (Conjugate) is added, binds to the bound EBV antibody (if present), and forms a Conjugate-EBV antibody-antigen bead sandwich.
3. Fluorescence from each distinct EBV antigen bead type is measured and compared against a Cutoff Calibrator.

Plexus EBV IgM Multi-Analyte Diagnostics Acceptance Criteria and Study Details

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state "acceptance criteria" in a table format with pre-defined thresholds. Instead, it presents performance data (positive and negative percent agreements) against predicate devices and then justifies substantial equivalence. Based on the comparative studies, the implicit acceptance criteria are that the device's performance should be comparable to or better than the FDA-cleared predicate devices.

2. Sample Size and Data Provenance

• Test Set Sample Size:
  • Prospective Samples: 723 samples (723 for VCA IgM, 723 for Heterophile IgM)
  • Retrospective Samples: 150 samples (150 for VCA IgM, 150 for Heterophile IgM)
• Data Provenance: The studies were conducted at three United States testing sites: a hospital laboratory located in the Northeast, a pediatric hospital laboratory located in the Mid-West, and Focus Diagnostics. Samples included both prospective (n=723) and retrospective (n=150) specimens. The samples were sequentially submitted to the laboratory, archived, and masked.

3. Number of Experts and Qualifications for Ground Truth

The document does not explicitly state the number of individual experts or their qualifications who directly established the "ground truth" for the test set. Instead, it refers to "consensus predicate" and "predicate rapid test."

For VCA IgM, the ground truth was established by a "consensus predicate" involving a combination of:
* A FDA-cleared commercially available ELISA
* A FDA-cleared commercially available immunofluorescent (IFA) test
* A FDA-cleared commercially available flow cytometry-based immunoassay.

For Heterophile IgM, the ground truth was established against a "FDA cleared heterophile rapid test."

The qualifications of the individuals who performed these predicate tests are not specified but would typically be trained laboratory personnel.

4. Adjudication Method for the Test Set

• VCA IgM: A "consensus based algorithm (2/3)" was used to determine the predicate result for comparison with the Plexus VCA IgM result. This means that at least two out of the three predicate devices had to agree on the result (positive or negative) for a consensus to be reached.
• Heterophile IgM: The document states that the Plexus EBV Heterophile IgM analyte was tested against a "FDA cleared heterophile rapid test," implying a direct comparison rather than a consensus among multiple predicates for this analyte.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was mentioned. The study compares the device's performance directly against predicate devices, not human readers with or without AI assistance.

6. Standalone (Algorithm Only) Performance

Yes, a standalone performance study was done. The entire study focuses on the performance of the Plexus EBV IgM Multi-Analyte Diagnostics device (algorithm only, as it is an in vitro diagnostic assay) against predicate devices without human interpretation as part of its core function, other than potentially reading the results of the predicate devices.

7. Type of Ground Truth Used

The ground truth used was based on comparison with predicate devices, which are themselves FDA-cleared diagnostic assays.

• For VCA IgM, it was a "consensus predicate" combining results from an ELISA, IFA, and flow cytometry-based immunoassay.
• For Heterophile IgM, it was a "FDA cleared heterophile rapid test."
  Additionally, a "Typical Antibody Response Classification" table (Plexus EBV Serological Status) outlines an algorithm for classifying EBV infection status using various serological markers, including VCA IgM and Heterophile Antibody. This table serves as a reference for interpreting the combined results in the context of disease diagnosis.

8. Sample Size for the Training Set

The document does not specify a separate "training set" or its sample size. The performance studies described involve prospective and retrospective samples used for comparison with predicate devices. This suggests a validation study rather than a development and training paradigm typical of machine learning algorithms that require distinct training sets. Since this is an immunoassay, the "training" would be tied to the assay's development and optimization, not a separate dataset for an algorithm.

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

As no explicit training set is mentioned in the context of algorithm development, the method for establishing ground truth for a training set is not applicable or detailed in the provided document. The performance evaluation relies on comparing the device's results against established FDA-cleared predicate methods.

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Focus Diagnostics' Plexus™ EBV IgG Multi-Analyte Diagnostics test kit is intended for qualitatively detecting the presence or absence of human IgG class antibodies to viral capsid antigen (VCA), early antigen- diffuse (EA-D), and nuclear antigen (EBNA-1) of Epstein-Barr virus in human sera. The test is indicated as an aid in the diagnosis of EBV infection and EBV-associated infectious mononucleosis.

The performance of this assay has not been established for use in the diagnosis of nasopharyngeal carcinoma and Burkit's lymphoma, for testing of immunocompromised patients, for use by a point of care facility or for use with automated equipment. This assay has not been evaluated for donor screening.

Multiplexed Immunoassay for the Qualitative Detection of Human IgG Antibodies to Epstein-Barr Virus

The Focus Diagnostics Plexus™ EBV IgG uses an Antigen Bead suspension that contains three distinct EBV antigen bead types (EA-D, VCA, & EBNA-1) and one process control bead type that fluoresce at different wavelengths and/or intensities.

The Focus Diagnostics Plexus™ EBV IgG is a three step procedure,

• Patient sera are diluted, and the diluted sera are incubated with Antigen Beads. If EBV antibodies are present, then the antibodies bind to the corresponding antigen beads.
• Phycoerythrin-conjugated goat Anti-human IgG (Conjugate) is added, binds to the bound EBV antibody (if present), and forms a Conjugate-EBV antibody-antigen bead sandwich.
• Fluorescence from each distinct EBV antigen bead type is measured and compared against a Cutoff Calibrator.

Here's an analysis of the provided text regarding the acceptance criteria and study for the Plexus EBV IgG Multi-Analyte Diagnostics device:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria in terms of specific percentages for agreement. Instead, it presents the "Positive Percent Agreement" for different serological statuses when compared against predicate devices. While not an explicit acceptance criterion, the percentage agreement values indicate the device's performance relative to the established ground truth.

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

• Total Sample Size (Test Set): 873 samples
  • Prospective Samples: 723 samples (sequentially submitted for routine EBV testing, masked).
  • Retrospective Samples: 150 samples (pre-selected based on EBV VCA concentrations from a FDA-cleared device, likely to be cases with presumed acute infection).
• Data Provenance: United States
  • Samples were collected at three sites:
    • A hospital laboratory located in the Northeast (USA)
    • A pediatric hospital laboratory located in the Mid-West (USA)
    • Focus Diagnostics (manufacturer's site)

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

The document does not mention the use of "experts" in the traditional sense (e.g., radiologists, pathologists) to establish ground truth for the test set.

Instead, the ground truth was established by comparison to commercially available, FDA-cleared predicate devices and an algorithm based on serological profiles.

• For VCA IgG, the ground truth was a "consensus predicate" derived from a combination of:
  • FDA-cleared commercially available ELISA
  • FDA-cleared commercially available immunofluorescent (IFA) test
  • FDA-cleared commercially available flow cytometry-based immunoassay
• For EBNA-1 IgG and EA-D IgG, the ground truth was a single commercially available ELISA test.
• Additionally, the "Serological status was determined by the use of commercially available ELISA assays for the EBV analytes EBNA-1 IgG, VCA IgG and VCA IgM and a commercially available heterophile rapid test for the Heterophile antibody." This indicates a comprehensive panel of existing diagnostic tests was used to define the overall EBV serological status that the Plexus device was compared against.

4. Adjudication Method for the Test Set

• For Plexus EBV VCA IgG vs. Consensus Predicate: A consensus-based algorithm (2/3 majority rule) was used to determine the predicate result for comparison with the Plexus VCA IgG result. This means that out of the three predicate devices, at least two had to agree on the classification (positive/negative) for a sample to have a definitive "consensus predicate" result. If a 2/3 majority could not be obtained, the sample was reported as "No consensus."
• For Plexus EBV EBNA-1 IgG and Plexus EBNA-1 EA-D IgG: The document implies a direct comparison to a single commercially available ELISA, so a specific adjudication method like 2/3 majority would not apply in that instance.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This study is an in-vitro diagnostic device (IVD) performance study, comparing the device's output to established predicate tests, not measuring human reader performance with or without AI assistance.

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

Yes, this was a standalone performance study. The Plexus EBV IgG Multi-Analyte Diagnostics device is an immunoassay kit that generates qualitative results based on fluorescence measurements and automated calculations using Plexus software (as stated in the "Interpretation of test results" section). Its performance was evaluated on its own, comparing its output to that of predicate immunoassay devices. It does not involve human interpretation as a primary output.

7. The Type of Ground Truth Used

The ground truth used was a composite gold standard based on multiple commercially available, FDA-cleared predicate serological assays and a serological algorithm. Specifically:

• For VCA IgG: Consensus from three predicate immunoassays (ELISA, IFA, flow cytometry-based).
• For EBNA-1 IgG and EA-D IgG: Results from a single predicate ELISA.
• The overall "serological status" (e.g., Primary Acute, Late Acute, Previous Infection, No Infection) was classified using an algorithm based on a panel of results from commercially available ELISA assays (EBNA-1 IgG, VCA IgG, VCA IgM) and a heterophile rapid test. This represents an interpretation based on established diagnostic algorithms using multiple reference methods.

8. The Sample Size for the Training Set

The document does not provide information on a training set sample size. This study appears to be solely focused on validating the performance of the device against predicate methods on a test set. Immunoassays typically do not have a "training set" in the same way machine learning algorithms do, as their "learning" or calibration is part of the assay development and reagent formulation process. If any internal calibration or optimization was performed, it is not detailed in this summary.

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

Since no training set details are provided, the method for establishing its ground truth is also not available in the document.

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The BioPlex™ 2200 EBV IgG kit is a multiplex flow immunoassay intended for the qualitative detection of IgG antibodies to three (3) separate EBV antigens; Epstein-Barr Virus Nuclear Antigen-1 (EBV NA-1), Viral Capsid Antigen (EBV VCA), and Early Antigen diffuse (EBV EA-D) in human serum. The test system can be used in conjunction with the BioPlex 2200 EBV IgM kit as an aid in the laboratory diagnosis of infectious mononucleosis (IM).

The EBV IgG 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.

The EBV 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. Three (3) different populations of beads are coated with E. coli derived recombinant proteins, EBV NA-1 (28kD and 45kD), EBV VCA p18 (40kD), and EBV EA-D (28kD) associated with infectious mononucleosis. 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, antihody, 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 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 or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma. Refer to the BioPlex 2200 System Operation Manual for more information. The instrument is calibrated using a set of seven (7) distinct calibrator vials, supplied separately by Bio-Rad Laboratories. A combination of four (4) vials representing four (4) different antibody concentrations are used for semi-quantitative 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 IgG Kit, Calibrators, and Controls, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for the different performance metrics (reproducibility, precision, comparative testing). Instead, it presents the results of these studies as the "Performance Summary." Therefore, the reported performance itself serves as the basis for demonstrating the device's capabilities.

• EBV NA-1 IgG: Overall Positive Agreement: 95.6% (95% CI: 93.2 - 97.1%). Overall Negative Agreement: 97.4% (95% CI: 94.0 - 98.9%). (Table 27)
• EBV VCA IgG: Overall Positive Agreement: 96.2% (95% CI: 93.9 - 97.6%). Overall Negative Agreement: 99.4% (95% CI: 96.8 - 99.9%). (Table 29)
• EBV EA-D IgG: Overall Positive Agreement: 88.1% (95% CI: 81.1 - 92.8%). Overall Negative Agreement: 84.1% (95% CI: 80.6 - 87.0%). (Table 31) |
  | Serological Status Agreement (BioPlex EBV IgG & IgM vs. Predicate Assays) | Comparison of EBV Serological Status: Overall Serological Agreement: 83.3% (95% CI: 80.2 - 86.1%).
  Comparison of Acute and Non-acute EBV Serological Status: Overall Serological Agreement: 85.1% (95% CI: 82.1 - 87.7%). (Tables 32-33) |
  | Cross-Reactivity (Minimal interference from other conditions) | The majority of samples that elicited a positive result with the BioPlex were also confirmed positive by the corresponding commercially available microplate EIA, indicating reactivity to EBV IgG antibodies rather than cross-reactivity with an interfering factor. (Table 34) |

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

• Sample Size for Comparative Testing: A total of 621 banked serum samples from patients for whom an EBV test was ordered were tested. (This number reduced slightly due to analysis errors, with 618 or fewer samples used in some specific analyses).
• Data Provenance: The samples were "banked serum samples" and tested at 3 U.S. clinical testing sites. The study is retrospective, utilizing existing banked samples.

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

The document does not explicitly state that experts (e.g., radiologists) were used to establish ground truth for the test set. Instead, the ground truth for comparative performance and serological status was established by "corresponding commercially available microplate EIAs" and "commercially available microplate EIA and agglutination tests." The serological characterization in Table 25 (e.g., Primary Acute, Late Acute) appears to be a predefined algorithm based on results from these predicate assays.

4. Adjudication Method for the Test Set

No adjudication method by human experts is described for the test set. The interpretation of results (positive, equivocal, negative) for the BioPlex 2200 EBV IgG kit was compared directly against the results of predicate EIA assays. For percent agreement calculations, "equivocal results were assigned to the opposite clinical interpretation than that of the corresponding reference assay result" and vice versa for predicate equivocal results (Page 13).

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC comparative effectiveness study was done. This study focuses on the in-vitro diagnostic device's performance compared to predicate devices, not on human reader performance with or without AI assistance.

6. Standalone (Algorithm Only) Performance

Yes, the study primarily evaluates the standalone performance of the BioPlex 2200 EBV IgG Kit (an in-vitro diagnostic device, essentially an algorithm and assay combined) against predicate EIA assays. There is no human-in-the-loop component described for the interpretation of the BioPlex results in these performance studies; the instrument provides an antibody index (AI) which is then categorized as positive, equivocal, or negative based on predefined cutoffs (≤0.8 Al negative, 0.9 and 1.0 Al equivocal, and ≥1.1 Al positive for analytes, Page 6).

7. Type of Ground Truth Used

The ground truth used for the comparative effectiveness study was the results from "corresponding commercially available microplate EIAs" for individual analytes and "commercially available microplate EIA and agglutination tests" for comprehensive EBV serological status. This is a type of reference standard or predicate device comparison.

8. Sample Size for the Training Set

The document does not mention a distinct "training set" for an algorithm or AI model in the conventional sense. This is a 510(k) submission for an in-vitro diagnostic kit, not an AI/ML device where a separate training set would typically be described. The "expected values" section (Tables 13-18) describes the prevalence of EBV IgG antibodies in different patient populations. While these samples contribute to understanding the device's characteristics in various populations, they are presented as "expected values" rather than a formal training set for an algorithm.

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

As there is no explicitly defined "training set" for an AI/ML algorithm, the concept of establishing ground truth for it does not apply directly in this document. The device's calibration involves a "set of seven (7) distinct calibrator vials" (Page 1), which are used to assign antibody index (AI) values. The specific concentrations or reference values for these calibrators are not detailed, but they would be established by the manufacturer according to internal standards and quality control processes.

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