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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 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 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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The BioPlex 2200 EBV IgM kit is a multiplex flow immunoassay intended for the qualitative detection of two (2) separate analytes; Epstein-Barr Virus Viral Capsid Antigen (EBV VCA) IgM antibodies and Heterophile antibodies in human serum. The test system can be used in conjunction with the BioPlex 2200 EBV IgG kit as an aid in the laboratory diagnosis of infectious mononucleosis (IM).

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

Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients, cord blood, neonatal specimens, or infants. Assay performance characteristics have not been established for the diagnosis of nasopharyngeal carcinoma, Burkitt's lymphoma, and other EBV-associated lymphomas.

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

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

The BioPlex 2200 EBV IgM kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional ElA, but permits simultaneous detection and identification of many antibodies in a single tube. Two (2) different populations of dyed beads are coated with proteins associated with infectious mononucleosis. One (1) is coated with an E. coli derived recombinant fusion protein, EBV VCA p18 (40kD), and the other is coated with horse erythrocyte stromal extract (heterophile antigen). The BioPlex 2200 System combines an aliquot of patient sample, sample diluent containing goat anti-human IgG, and bead reagent into a reaction vessel. The mixture is incubated at 37°C. After a wash cycle, anti-human IgM antibody, conjugated to phycoerythrin (PE), is added to the dyed beads and this mixture is incubated at 37°C. The excess coniugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the fluorescence of the attached PE.

Three additional dyed beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB), and a Reagent Blank Bead (RBB), are present in each reaction mixture to verify detector response, the addition of serum or plasma to the reaction vessel, and the absence of significant non-specific binding in serum or plasma respectively. The instrument is calibrated using a set of two (2) distinct calibrator vials, supplied separately by Bio-Rad Laboratories. A combination of two (2) vials representing two (2) different antibody concentrations is used for calibration. The result for each of these antibodies is expressed as an antibody index (AI).

Here's a summary of the acceptance criteria and study details for the BioPlex 2200 EBV IgM Kit, Calibrators, and Controls, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly present a table of acceptance criteria in numerical targets for performance metrics like sensitivity, specificity, or %CV. Instead, it presents the results of the studies conducted and implies that these results were deemed acceptable for FDA clearance. The performance is assessed through reproducibility, precision, and comparative testing against predicate devices and known serological patterns.

However, we can infer performance metrics from the results provided:

2. Sample Size and Data Provenance

• Test Set (Comparative Testing):

  • Main Comparative Study: 621 banked serum samples from patients for whom an EBV test was ordered. Two samples were excluded due to RBB errors, resulting in N=619 for initial analyses and N=618 for serological pattern comparisons.
    • Provenance: 3 U.S. clinical testing sites (retrospective, banked serum samples).
  • Known EBV VCA IgM Positive Samples: 100 purchased EBV VCA IgM positive samples.
    • Provenance: A U.S. clinical testing site (retrospective, purchased samples).

• Reproducibility and Precision Studies: These studies used "panel members" prepared by Bio-Rad Laboratories. The number of panel members was 6 (2 high positive, 2 near cutoff, 2 negative). Each panel member was tested multiple times across days and sites. These are typically internal validation samples, not patient data in the same way as the comparative testing.

3. Number of Experts and Qualifications

The document does not specify the number or qualifications of experts used to establish the ground truth for the test set. The ground truth in comparative testing was established by "corresponding commercially available microplate EIA/agglutination tests" and subsequent serological pattern characterization. It is implied that these predicate devices and the serological algorithm (Table 16) serve as the 'expert' reference. For the purpose of result interpretation, the algorithm defines different EBV serological statuses based on various antibody responses.

4. Adjudication Method

The document does not describe an adjudication method for the test set by human experts in the traditional sense (e.g., 2+1, 3+1). Instead, the results of the BioPlex 2200 system were compared to the results of predicate commercial assays. For percent agreement calculations in comparative testing, BioPlex 2200 "equivocal results were assigned to the opposite clinical interpretation than that of the corresponding reference assay result." This acts as a conservative rule for calculating agreement.

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

No MRMC comparative effectiveness study was described. The device is an automated in vitro diagnostic (IVD) device for detecting antibodies, not an imaging device requiring human reader interpretation. Therefore, a study to measure human reader improvement with AI assistance is not applicable. The comparison is between the new automated assay and existing commercial laboratory assays (EIA and agglutination tests).

6. Standalone Performance

Yes, a standalone performance study was done. The reproducibility and precision studies evaluate the device's inherent performance characteristics as a standalone assay. The comparative testing also assesses the BioPlex 2200 EBV IgM kit alone against predicate devices, indicating its standalone diagnostic utility. The results (Antibody Index (AI) values, %CV, positive/negative agreement with reference methods) are presented for the BioPlex 2200 system directly.

7. Type of Ground Truth Used

The ground truth used for the comparative studies was:

• Reference Assays: Results from "corresponding commercially available microplate EIA/agglutination tests." These are established diagnostic assays for EBV.
• Serological Pattern Characterization: A generally accepted algorithm for classifying patients into EBV serological status (Table 16) based on results from various EBV antibody tests (including EBV NA-1 IgG, EBV VCA IgG, EBV EA-D IgG, EBV VCA IgM, and Heterophile Antibody).

8. Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of an AI/ML algorithm, as this device appears to be a laboratory immunoassay rather than an AI-driven one. Therefore, there is no concept of a training set for an algorithm in this submission. The panel members for reproducibility and precision studies can be thought of as internal validation sets, but not "training sets" for an AI model.

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

As there is no mention of an AI/ML model or a specific training set with ground truth in the document, this question is not applicable. The characterization of panel members for reproducibility and precision studies would have been established internally by Bio-Rad Laboratories based on known antibody levels or clinical samples.

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The LIAISON® EA IgG assay and LIAISON® EA IgG Controls use chemiluniescent immunoassay (CLIA) technology on the LIAISON Analyzer for the qualitative determination of IgG antibodies to Epstein-Barr virus early antigen-diffuse [EA(D)] in human serum. 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 (IM).

The method for qualititative determination of specific IgG to Epstein-Barr virus early antigen-diffuse (EA(D) recombinant polypeptide] is an indirect chemiluminescence immunoassay (CLIA). All assay steps (with the exception of magnetic particle resuspension) and incubations are performed by the LIAISON® Analyzer. The principal components of the test are magnetic particles (solid phase) coated with EA(D) recombinant polypeptide and a conjugate of mouse monoclonal antibody to human IgG linked to an isoluminol derivative (isoluminol-antibody conjugate). During the first incubation, EA(D) antibodies present in calibrators, samples or controls bind to the solid phase. During the second incubation, the antibody conjugate reacts with EA(D) antibodies that are already bound to the solid phase. After each incubation, unbound material is removed with a wash cycle. Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminol-antibody conjugate, is measured by a photomultiplier as relative light units (RLU) and is indicative of the presence of EA(D) IgG antibodies present in calibrators, samples or controls.

Here's a breakdown of the acceptance criteria and study information for the DiaSorin LIAISON® EA IgG assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state pre-defined "acceptance criteria" as a separate set of pass/fail thresholds. Instead, it presents the performance results of the device and concludes that these results demonstrate "equivalent performance to the corresponding FDA-cleared assay" and "agreement with the comparison method higher then 92% among prospectively collected samples and 100% agreement among retrospective selected samples."

Therefore, the performance of the predicate device (DiaSorin ETI-EA-G ELISA Kit) effectively serves as the benchmark for acceptance.

Inferred Acceptance Criteria (based on predicate device performance and stated conclusions):

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

• Prospective Samples:
  • Sample Size: 823 samples
  • Data Provenance: Subjects sent to the laboratory for EBV testing in the US (specifically from two external US laboratories and DiaSorin). The samples were collected prospectively.
• Retrospective Samples:
  • Sample Size: 70 samples
  • Data Provenance: VCA IgM-positive samples, implying a pre-selected cohort. No specific country of origin is mentioned beyond the US clinical trial sites, but it's likely from the same geographical region. These were retrospective samples from a repository.
• Reproducibility Panel: 9 frozen repository serum samples.
• Interference Samples: Not specified, but involved controlled studies with substances at given concentrations.
• Cross-Reactivity Panel: 183 specimens from various organism/condition categories.

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

The study uses a comparison assay (DiaSorin ETI-EA-G ELISA Kit) as the "ground truth" or reference method for the clinical trials. This is a common practice for 510(k) submissions of in-vitro diagnostic devices where an existing FDA-cleared predicate device serves as the a reference.

Therefore, there were no human experts establishing ground truth in the way a radiologist might read images. Instead, the ground truth was established by the results of the already-cleared predicate device.

4. Adjudication Method for the Test Set

Since the ground truth was established by a comparison assay (DiaSorin ETI-EA-G ELISA Kit), there was no explicit mention of a human expert adjudication method (like 2+1 or 3+1) for the clinical trial results presented. The results of the LIAISON® EA IgG assay were compared directly against the results of the predicate device.

For the cross-reactivity study, some equivocal results were noted, and the document states, "...Since it was not possible to acquire follow-up samples collected one to two weeks later as recommended." This suggests that for discordant or equivocal results, a follow-up sample might typically be used for adjudication or clarification, but this was not feasible in all cases during the cross-reactivity testing.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This study focuses on the performance of an automated immunoassay device compared to another automated immunoassay device (predicate), not on 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 study is a standalone performance evaluation of the DiaSorin LIAISON® EA IgG immunoassay. It measures the device's ability to qualitatively detect specific IgG antibodies to EBV EA(D) in human serum without human intervention in the result interpretation, beyond standard laboratory quality control and reporting procedures. The "algorithm" here refers to the immunoassay's reagents and the LIAISON® Analyzer's automated processing and signal interpretation to yield a positive, equivocal, or negative result.

7. The Type of Ground Truth Used

The primary ground truth used for the comparative clinical trials was the results obtained from an FDA-cleared predicate device, the DiaSorin ETI-EA-G ELISA Kit. This is a form of "reference standard" based on another established diagnostic method.

8. The Sample Size for the Training Set

The document does not provide information on a specific training set for the DiaSorin LIAISON® EA IgG assay. Immunoassays, particularly those developed before the widespread adoption of machine learning in diagnostics, typically do not involve a distinct "training set" in the same way a machine learning algorithm would. The development process would involve reagent optimization, calibration curve establishment, and analytical validation (e.g., specificity, sensitivity, reproducibility) using panels of known samples, but these are not usually referred to as "training sets" in the context of this type of device.

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

As noted above, there is no explicit mention of a "training set" in the provided text. Therefore, the method for establishing ground truth for a training set is not applicable or not described in this 510(k) submission.

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• 1. For In Vitro Diagnostic Use
• 2. For the qualitative and semi-quantitative detection of human IgG antibodies to Epstein-Barr (EB) viral capsid antigen (VCA) in human serum by enzyme immunoassay.
• 3. For use as an aid in differentiating active or recent infection, from past infection.

The SeraQuest EB VCA 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 Epstein-Barr virus capsid antigen, in human serum. The Calibrators in the SeraQuest EB VCA IgG test set have been assigned Index values based on an in-house standard. Test results are reported as Index values.

Acceptance Criteria and Device Performance Study for SeraQuest EB VCA IgG

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state pre-defined acceptance criteria for the SeraQuest EB VCA IgG device. Instead, it presents results and compares them to a predicate device. Based on the "Overall agreement" calculated, we infer that an agreement level with the predicate device was the primary metric of performance.

*Excluding equivocal results.

2. Sample Size and Data Provenance

• Sample Size for Test Set: 113 serum samples.
• Data Provenance: Not explicitly stated, but the study compares the SeraQuest device to a predicate device (Zeus EBV VCA IgG) using "serum samples." The document is from a US regulatory submission, suggesting the data may be from the US, but this is not confirmed. The data appears to be retrospective as it compares the new device's performance against existing results from another test.

3. Number and Qualifications of Experts for Ground Truth

• Number of Experts: Not applicable. The ground truth for this study was established using a predicate device's results, not expert interpretation of samples.
• Qualifications of Experts: Not applicable.

4. Adjudication Method for Test Set

• Adjudication Method: Not applicable. The comparison was directly against the results of the predicate device (Zeus EBV VCA IgG), not against a consensus of human readers.

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

• MRMC Study: No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. The study compares the performance of the new device to a predicate device, not to human readers with and without AI assistance.

6. Standalone Performance Study

• Standalone Performance Study: Yes, a standalone performance study was conducted. The SeraQuest EB VCA IgG device's performance (specifically its agreement with the predicate device) was evaluated independently. The table detailing the "Results of SeraQuest VCA IgG Assays (Modified Device) and Zeus VCA IgG Assays on 113 Serum Samples" directly shows the device's output against the predicate device's output.

7. Type of Ground Truth Used

• Type of Ground Truth: The ground truth was established by the results of a predicate device (Zeus EBV VCA IgG Test System). The predicate device's results were used as the reference against which the SeraQuest device's performance was measured.

8. Sample Size for Training Set

• Sample Size for Training Set: Not applicable. This device is a diagnostic assay (solid-phase enzyme immunoassay, EIA), not an AI/machine learning algorithm that requires a training set in the conventional sense. The "training" or development of such a device involves chemical and biological optimization, not data-driven model training.

9. How Ground Truth for Training Set was Established

• How Ground Truth for Training Set was Established: Not applicable, as it's not an AI/machine learning device with a training set. The development of the assay would have involved standard laboratory methods and internal validation to optimize its components and ensure it accurately detects IgG antibodies to Epstein-Barr virus capsid antigen.

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The Epstein-Barr Virus Viral Capsid-p18 Antigen (EBV VCA-p18) IgG ELISA is for the qualitative detection of IgG antibodies to EBV VCA in serum as an aid in the clinical laboratory diagnosis of EBV infection in patients with clinical symptoms consistent with infectious mononucleosis (IM). The PANBIO EBV VCA-p18 IgG ELISA should be used in conjunction with other EBV serologies.

The EBV VCA-p18 IgG ELISA is an Enzyme Linked Immunosorbent Assay for the qualitative detection of IgG antibodies in human serum to EBV VCA antigen.

Here's a summary of the acceptance criteria and the study details for the PANBIO EBV VCA-p18 IgG ELISA, based on the provided text:

1. Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria in terms of numerical thresholds for sensitivity, specificity, or agreement. Instead, it presents the performance characteristics as a comparison to an equivalent device (DiaSorin EBV VCA IgG ELISA) and established EBV serological status. The study aims to demonstrate that the device performs comparably and effectively identifies different EBV infection states.

However, based on the results and the context of a 510(k) submission, we can infer that the observed performance values for sensitivity, specificity, and agreement, particularly in relation to the predicate device and the known EBV status, were considered acceptable by the manufacturer for regulatory clearance.

Table of Reported Device Performance for PANBIO EBV VCA-p18 IgG ELISA (Study Site 1):

Table of Reported Device Performance for PANBIO EBV VCA-p18 IgG ELISA (Study Site 3):

2. Sample Sizes and Data Provenance

Study Site 1 (Primary Performance Study):

• Sample Size (Test Set): 342 sera
  • Seronegative: 45
  • Acute IM: 41
  • Past Exposure to EBV: 256
• Data Provenance: Prospective sera collected from a private pathology laboratory in Queensland, Australia.

Study Site 3 (Confirmatory Performance Study):

• Sample Size (Test Set): 148 sera
  • Seronegative: 25
  • Acute IM: 23
  • Past Exposure to EBV: 100
• Data Provenance: Frozen retrospective sera submitted to a state health laboratory in Maryland, USA.

3. Number of Experts and their Qualifications (for Ground Truth)

The document does not explicitly mention the use of "experts" for establishing the ground truth in the traditional sense of clinicians or radiologists reviewing cases. Instead, the ground truth for the EBV status of the test sets was established by the results of other standard EBV serological assays.

The "EBV Status" was defined based on a combination of different assay results:

• Seronegative: VCA IgG (-), VCA IgM (-), EBNA IgG (-)
• Acute IM: VCA IgM (+), EBNA IgG (-)
• Past Infection: VCA IgG (+), VCA IgM (-), EBNA IgG (+)

This implies that the "experts" were the laboratory personnel and clinicians who interpreted these existing serological results to categorize the samples. No specific number or qualifications for individual experts interpreting these criteria are provided.

4. Adjudication Method

The document does not describe an adjudication method in the context of multiple expert readers. The ground truth was established by comparing the device's results to the serological EBV status determined by a panel of other EBV serologies. For the study at Site 3, it is noted that re-testing of equivocal samples was not conducted because the samples were unavailable. This suggests that there was no specific adjudication process for discordant results against the "EBV Status" ground truth, beyond the initial classification based on the serological panel.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This study focuses on the standalone performance of an in vitro diagnostic device (ELISA) against serological ground truth and a predicate device, not on human reader performance with or without AI assistance.

6. Standalone (Algorithm Only) Performance

Yes, a standalone performance study (i.e., algorithm only without human-in-the-loop performance) was done. The PANBIO EBV VCA-p18 IgG ELISA is an automated/semi-automated test that provides a quantitative result (absorbance) which is then interpreted qualitatively (Positive/Negative/Equivocal) based on a cut-off ratio. The reported sensitivity, specificity, and agreement values are for the device itself.

7. Type of Ground Truth Used

The ground truth used was expert consensus derived from other EBV serological assays. The "EBV Status" for each sample was determined by a panel of a priori defined serological markers for VCA IgG, VCA IgM, and EBNA IgG, which are established indicators of different stages of EBV infection.

The study explicitly states: "Note: "Serological" sensitivity and specificity refers to the comparison of the PANBIO assay results to that of other assays normally used to diagnose EBV associated IM. There was not an attempt to correlate the assay's results with disease presence or absence. No judgement can be made on the comparison's accuracy to predict disease." This clarifies that the ground truth is based on laboratory-defined serological status, not direct clinical outcomes or pathology reports.

8. Sample Size for the Training Set

The document does not provide information about a distinct "training set." The studies described are performance evaluations of the finalized device (test sets). For an ELISA, development typically involves optimization using a set of samples, but these are not explicitly called out as a "training set" with specific numbers.

9. How Ground Truth for the Training Set Was Established

As no specific training set is detailed, information on how its ground truth was established is not provided. Typically, in the development of such assays, candidate samples would be characterized using established reference methods for the target analyte (EBV VCA IgG antibodies).

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