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The CMV Brite™ Turbo Kit is intended for the qualitative detection of Cytomegalovirus (CMV) lower matrix protein pp65 by indirect immunofluorescence using microscopy in isolated peripheral blood leukocytes obtained from ethylenediaminetetraacetic acid (EDTA) or heparin anticoagulated human peripheral blood. The detection of CMV pp65 in human perpheral blood cells aids in the diagnosis of acute or reactivated CMV infection. This product is not FDA cleared (approved) for use in testing (i.e., screening) of blood or plasma donors.

The CMV antigenemia assay has been developed using a cocktail of two monoclonal antibodies (C10/C11) directed against CMV lower matrix protein pp65(6). The assay uses the C10/C11 cocktail in an indirect immunofluorescence staining of cytospin preparations of peripheral blood leukocytes. The CMV Brite™ Turbo antigenemia assay is completed within two hours of blood collection which saves time and means a rapid answer for the clinician. The CMV Brite™ Turbo method consists of:

• Direct lysis of peripheral blood erythrocytes a.
• Preparation of cytospin slides b.
• Fixation and permeabilization C.
• Indirect immunofluorescence staining using monoclonal antibodies directed d. against CMV pp65 protein
• Reading and evaluation of results e.
  The first step in the CMV Brite™ Turbo method involves direct lysis of the peripheral blood erythrocytes(22). Following lysis the leukocytes are cytocentrifuged onto a slide, fixed and permeabilized to allow subsequent detection of CMV pp65 antigen. The presence of the CMV pp65 antigen is detected by the C10/C11 antibody cocktail and visualized by means of a specific secondary FITC-labeled antibody. CMV antigenpositive leukocytes exhibit homogeneous yellow-green polylobate nuclear staining when observed using a fluorescence microscope. The number of CMV antigen-positive cells are counted per duplicate stain.
  The whole procedure can be performed in approximately 2 hours. The total analysis time has been shortened by performing direct erythrocyte lysis on whole blood and avoiding dextran sedimentation. Further time has been saved by shortening individual steps in the protocol so that the whole CMV antigenemia procedure has been reduced in time by more than 50%.

Here's a breakdown of the acceptance criteria and study information for the CMV Brite™ Turbo Kit, based on the provided text:

Acceptance Criteria and Reported Device Performance

The provided document specifically compares the CMV Brite™ Turbo Kit to its predicate device, the CMV Brite™ Test Kit, in terms of performance characteristics. The "acceptance criteria" are implied by the performance of the predicate device, which the new device aims to be "as safe, effective, and performs as well as."

Note: The document states, "The performance characteristics of the CMV Brite™ Turbo Kit are the same as those established for the CMV Brite™ Test Kit." However, the comparative table (Table 1) then lists slightly different numerical values for sensitivity, specificity, and predictive values. This might indicate that "the same" refers to generally comparable performance rather than identical numerical results, or that the table itself is the primary source of the "established" performance for the new device based on its own testing. For the purpose of this response, I'm listing the specific numbers presented in the table for the CMV Brite™ Turbo.

Study Details

1. Sample size used for the test set and the data provenance:

   • Test Set Sample Size: The document does not explicitly state the sample size used for the test set.
   • Data Provenance: The document does not specify the country of origin of the data or whether it was retrospective or prospective.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • The document does not specify the number of experts or their qualifications for establishing ground truth for the test set. The nature of the device (immunofluorescence staining read by microscopy) implies a human reader, but details about independent review or consensus are missing.

3. Adjudication method for the test set:

   • The document does not describe any specific adjudication method (e.g., 2+1, 3+1, none) for the test set.

4. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

   • No, an MRMC comparative effectiveness study was not done. This device is a test kit for laboratory use, involving manual interpretation via fluorescence microscopy, not an AI-assisted diagnostic tool. Therefore, the concept of human readers improving with AI assistance is not applicable here.

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

   • No, a standalone algorithm-only performance study was not done. This device is a manual laboratory test kit that requires human interpretation (microscopy of stained cells) to detect CMV pp65 antigen. It is not an algorithm or AI-driven system.

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

   • The type of ground truth is not explicitly stated. Given the nature of CMV antigenemia testing, the ground truth would typically be established by clinical diagnosis of CMV infection, often supported by other laboratory methods (e.g., PCR, viral culture, or clinical outcomes), or by expert interpretation of the gold standard for CMV antigenemia. The document describes the new device being compared to a "legally marketed device" (CMV Brite™ Test Kit), implying the predicate device serves as a reference, but the ultimate ground truth for both is not detailed.

7. The sample size for the training set:

   • The document does not mention a "training set" as this is not an machine learning/AI device. The studies described are for validating the performance of a wet laboratory assay.

8. How the ground truth for the training set was established:

   • Not applicable, as there is no "training set" for this type of device.

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The Biotest EA IgG ELISA is an enzyme immunoassay using recombinant antigens for the qualitative detection of IgG antibodies to the Epstein-Barr Virus Early Antigens (EA) p54 and p138 in human serum or plasma. Results obtained with this test, in conjunction with other clinical and patient data obtained in assays for other Epstein-Barr virus-specific antibodies such as anti-Early Antigen IgM and anti-EBNA-1 IgG, assist in serological diagnosis of EBV infection in pediatric and adult populations.

Using recombinant DNA technology, Biotest has developed three highly purified EBV antigens for use in their ELISA test system.

• EBNA-1 p72: Major antigen of the EBNA complex. The recombinant protein does not contain the glycine-alanine copolymer, a structural feature of EBNA-1, which shows cross-reactivities with certain autoantibodies and CMV (IgM response).
• EA-D p64: Early antigen. Dominant immunogen of the EA-D complex.
• EA p138: Early antigen and major DNA binding protein. This highly reactive antigen is not detectable in EA immunofluorescence assays based on chemically induced Raji cells (deletion within the Raji genome).

The EBV immune status will be determined by the detection of specific antibodies directed against EBV proteins according to the principle of the indirect ELISA. The antigens are purified to apparent homogeneity and immobilized on the solid phase (microtest plate, 96 wells). If the patient's serum contains specific antibodies they will bind during the first incubation. Non-specific antibodies are removed by washing steps. During a second incubation the captured IgG or IgM antibodies are labeled. This is performed by addition of murine monoclonal anti-human IgG or IgM antibody-enzyme-conjugates. The final reaction converts a colorless substrate to a colored product. The concentration of color after a definite time is related to the concentration of antibody in the serum sample.

The Biotest EA IgG ELISA is an enzyme immunoassay designed for the qualitative detection of IgG antibodies to Epstein-Barr Virus Early Antigens (EA) p54 and p138 in human serum or plasma. It is intended for use in conjunction with other clinical and patient data from assays for other EBV-specific antibodies (e.g., anti-Early Antigen IgM and anti-EBNA-1 IgG) to aid in the serological diagnosis of EBV infection.

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

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state pre-defined acceptance criteria in terms of specific numeric thresholds for sensitivity, specificity, or agreement. Instead, it presents the results of comparative studies and implicitly uses the performance of existing methods as a benchmark for substantial equivalence. For the purpose of this analysis, we will infer the "acceptance criteria" as the performance demonstrated to achieve substantial equivalence.

Note: "vs. IFA" refers to direct comparison with commercially available or published EA IgG IFA tests. "vs. Int." refers to comparison with clinical interpretation based on antibody patterns and clinical diagnosis.

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

• Sample Size for Test Set: 408 patient samples.
• Data Provenance: The samples were obtained from both pediatric and adult patients (ages 1 to 74) at two geographically distinct locations. The samples represented various stages of EBV infection: acute (139), late acute (34), recent past (12), past (120), reactivation (22), past/probable reactivation (11), and negative (70). The study was a clinical study, suggesting it was prospective in nature, collecting and testing samples for a specific evaluation. The country of origin is not explicitly stated, but the submission is to the US FDA, implying that the study was likely conducted in the US or under US regulatory standards.

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

The document does not explicitly state the number of experts used or their specific qualifications (e.g., "radiologist with 10 years of experience"). However, it mentions two methods for evaluating performance:

• Direct comparison with IFA: This implies the "ground truth" for this comparison was the results from commercially available or published EA IgG IFA tests. The expertise would lie within the validated methodology and interpretation of those IFA tests.
• Comparison with clinical interpretation: This "ground truth" was based on "serological pattern analysis for each state of infection, including acute, convalescent, Past, Reactivation and Probable Reactivation/past, and Negative." This process would inherently involve expert medical knowledge and clinical judgment (likely from infectious disease specialists or clinical microbiologists) to establish the "stage of infection based on antibody patterns and clinical diagnosis at the time the specimen was drawn."

4. Adjudication Method for the Test Set

The document does not describe an explicit adjudication method (e.g., 2+1, 3+1). For the direct comparison with IFA, it's a direct comparison of results. For the comparison with clinical interpretation, the ground truth was derived from "expected serological pattern analysis" and "clinical diagnosis," which implies a consensus or established criteria for determining the infection stage, rather than individual expert adjudication of each case.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

This section is not applicable to the provided document. The Biotest EA IgG ELISA is an in vitro diagnostic (IVD) device, specifically an immunoassay for detecting antibodies, not an AI-powered diagnostic imaging or decision support tool that assists human readers. Therefore, an MRMC comparative effectiveness study involving AI assistance for human readers was not performed or described.

6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done

This section is not applicable in the context of an immunoassay. The Biotest EA IgG ELISA is itself a standalone diagnostic test. Its performance is evaluated intrinsically through its ability to detect antibodies in patient samples, not as an algorithm separate from human intervention for interpretation in the same way "standalone algorithm performance" is typically discussed for imaging AI. The "algorithm" here is the chemical and enzymatic reaction within the ELISA, and its output (spectrophotometer reading) is directly interpreted.

7. The Type of Ground Truth Used

Two types of ground truth were used for different aspects of performance evaluation:

• Established Diagnostic Tests (IFA): For the relative sensitivity and specificity, the ground truth was derived from the results of commercially available or published EA IgG Immunofluorescence Assay (IFA) tests.
• Expert Clinical Interpretation/Serological Pattern Analysis: For clinical sensitivity and specificity, the ground truth was established by "clinical interpretation (stage of infection based on antibody patterns and clinical diagnosis at the time the specimen was drawn)." This is a form of expert consensus or established diagnostic criteria based on known serological markers and patient presentation.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning. The device is an ELISA kit, which is a biochemical assay, not an algorithm that requires a separate training phase with a distinct dataset. The "development" of the highly purified EBV antigens (EBNA-1 p72, EA-D p64, EA p138) and the optimization of the ELISA system would have involved internal validation and optimization studies by Biotest, but these are not referred to as a "training set" in the sense of AI model development.

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

As noted in point 8, there is no explicit mention of a "training set" as it would be understood in machine learning. The "ground truth" in the development of an immunoassay would be established through:

• Antigen purity and specificity: Ensuring the recombinant antigens (p72, p54, p138) correctly represent the target EBV EA epitopes without undesirable cross-reactivity. This would involve molecular biology techniques, protein characterization, and immunochemical assays.
• Assay optimization: Fine-tuning reagent concentrations, incubation times, and washing steps to achieve optimal signal-to-noise ratio, linearity, and precision using well-characterized positive and negative control samples. These controls would be independently verified (e.g., by reference methods or clinical status).

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The Biotest EA IgM ELISA is an enzyme immunoassay using recombinant antigens for the qualitative detection of IgM antibodies to the Epstein-Barr Virus early antigens (EA) p54 and p138 in human serum or plasma. Results obtained with this test, in conjunction with other clinical and patient data obtained in assays for other Epstein-Barr virus-specific antibodies such as anti-Early Antigen IgG and anti-EBNA-1 IgG, assist in serological diagnosis of EBV infection in pediatric and adult populations.

Using recombinant DNA technology, Biotest has developed three highly purified EBV antigens for use in their ELISA test system.

• EBNA-1 p72: Major antigen of the EBNA complex. The recombinant protein does not contain the glycine-alanine copolymer, a structural feature of EBNA-1, which shows cross-reactivities with certain autoantibodies and CMV (IgM response).
• EA-D p64: Early antigen. Dominant immunogen of the EA-D complex.
• EA p138: Early antigen and major DNA binding protein. This highly reactive antigen is not detectable in EA immunofluorescence assays based on chemically induced Raji cells (deletion within the Raji genome).

The EBV immune status will be determined by the detection of specific antibodies directed against EBV proteins according to the principle of the indirect ELISA. The antigens are purified to apparent homogeneity and immobilized on the solid phase (microtest plate, 96 wells). If the patient's serum contains specific antibodies they will bind during the first incubation. Non-specific antibodies are removed by washing steps. During a second incubation the captured IgM antibodies are labeled. This is performed by addition of murine monoclonal anti-human IgM antibody-enzyme-conjugates. The final reaction converts a colorless substrate to a colored product. The concentration of color after a definite time is related to the concentration of antibody in the serum sample.

This appears to be a 510(k) summary for the Biotest Anti-EBV Recombinant EA IgM ELISA test. Let's break down the acceptance criteria and study details.

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined "acceptance criteria" in terms of specific performance thresholds for sensitivity and specificity. Instead, it presents the results of a comparison study against a predicate device and clinical interpretation. However, we can infer the reported performance metrics.

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

• Sample Size for Test Set: 408 patient samples.
• Data Provenance: Clinical study conducted at two geographically distinct locations. Samples were obtained from both pediatric and adult patients (ages 1 to 74). The study is retrospective in the sense that samples were collected and categorized prior to testing with the Biotest ELISA, allowing for comparison to existing diagnostic methods and clinical records. The document doesn't specify countries of origin, but given the US FDA submission, it's highly likely to be within the US.

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

The document does not explicitly detail the number or qualifications of experts used to establish the "ground truth" for the test set.

• For the "direct comparison with VCA IgM/IgG IFA", the predicate device (Gull VCA IGM test kits, which is an Indirect Fluorescent Antibody (IFA) assay) serves as the reference, which itself would have been interpreted by trained laboratory personnel.
• For the "comparison with clinical interpretation," the ground truth was "based on antibody patterns and clinical diagnosis at the time the specimen was drawn." This implies that the initial diagnoses and serological classifications (e.g., acute, past, negative) were made by healthcare professionals and laboratory personnel, but no specific number or qualification of these experts is provided in this summary.

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method for conflicting results.

• For the direct comparison, it appears the results of the Biotest EA IgM ELISA were compared directly to the results of the VCA IgM/IgG IFA, with agreement or disagreement noted.
• For the clinical interpretation, "Result matches Biotest" and "Result does not match Biotest" categories suggest a direct comparison of the Biotest result against an established clinical interpretation for each sample.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance

• No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This document describes the validation of an ELISA diagnostic kit, not an AI-powered image analysis or diagnostic tool that would involve human readers interpreting results with or without AI assistance. Therefore, there is no effect size for human reader improvement with AI.

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

• Yes, a standalone performance evaluation was done. The Biotest EA IgM ELISA is a laboratory diagnostic test. Its performance (sensitivity, specificity, reproducibility, cross-reactivity) was evaluated as a standalone device, meaning the algorithm/assay itself directly produces the result (positive/negative) without human intervention in the interpretation of the assay's output during the performance study itself. Human intervention would be involved in performing the test and interpreting the final clinical significance, but the device's diagnostic output is standalone.

7. The Type of Ground Truth Used

Two types of ground truth were used:

• Predicate Device Comparison: The results of commercially available or published EBV VCA IgM/IgG IFA tests. This serves as a "reference standard" from an established, legally marketed diagnostic method.
• Clinical Interpretation: "Stage of infection based on antibody patterns and clinical diagnosis at the time the specimen was drawn." This combines serological profiles (antibodies against other EBV antigens) with the clinical presentation of the patient. This represents a more comprehensive "clinical ground truth."

8. The Sample Size for the Training Set

The document does not specify a separate "training set" or its sample size. This is typical for traditional immunoassay device submissions. The "clinical study of 408 patient samples" appears to be the primary validation set (test set) for evaluating the device's performance characteristics. Diagnostic kits like this are generally developed and optimized during an internal R&D phase, and the studies presented are for validation rather than training of a machine learning model.

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

As no explicit "training set" is mentioned in the context of machine learning model development, this question is not directly applicable. For the development and optimization of the ELISA kit itself (which would be analogous to "training" in a broad R&D sense), the ground truth would have been established through extensive research using characterized EBV-infected and uninfected samples, likely verified by a combination of established serological methods, PCR, and clinical diagnosis, but these details are not part of this 510(k) summary.

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The Biotest EBNA IgG ELISA is an enzyme immunoassay using a recombinant antigen for the qualitative detection of IgG antibodies to the Epstein-Barr Virus (EBV) EBNA-1 (Nuclear Antigen 1) in human serum or plasma. Results obtained with this test, in conjunction with other clinical and patient data obtained in assays for other Epstein-Barr antigens such as Early Antigen IgG and IgM, assist in serological diagnosis of EBV infection in pediatric and adult populations.

Using recombinant DNA technology, Biotest has developed three highly purified EBV antigens for use in their ELISA test system.

• EBNA-1 p72: Major antigen of the EBNA complex. The recombinant protein does not contain the glycine-alanine copolymer, a structural feature of EBNA-1, which shows cross-reactivities with certain autoantibodies and CMV (IgM response).
• EA-D p64: Early antigen. Dominant immunogen of the EA-D complex.
• EA p138: Early antigen and major DNA binding protein. This highly reactive antigen is not detectable in EA immunofluorescence assays based on chemically induced Raji cells (deletion within the Raji genome).

The EBV immune status will be determined by the detection of specific antibodies directed against EBV proteins according to the principle of the indirect ELISA. The antigens are purified to apparent homogeneity and immobilized on the solid phase (microtest plate, 96 wells). If the patient's serum contains specific antibodies they will bind during the first incubation. Non-specific antibodies are removed by washing steps. During a second incubation the captured IgG antibodies are labeled. This is performed by addition of murine monoclonal anti-human IgG antibody-enzyme-conjugates. The final reaction converts a colorless substrate to a colored product. The concentration of color after a definite time is related to the concentration of antibody in the serum sample.

Here's a detailed breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text:

Acceptance Criteria and Device Performance

The acceptance criteria for the Biotest Anti-EBV Recombinant EBNA IgG ELISA device primarily revolve around its sensitivity and specificity in detecting IgG antibodies to EBV EBNA-1. The reported device performance is based on direct comparison with a predicate method (ACIF) and clinical interpretation of patient samples.

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document does not explicitly state numerical acceptance criteria thresholds, but rather presents the study results as justification for the device's performance compared to established methods and clinical understanding. The implied acceptance is that the device performs comparably to or better than existing methods for the intended use.

2. Sample Size for the Test Set and Data Provenance

• Sample Size for Test Set: 408 patient samples.
• Data Provenance:
  • Country of Origin: Not explicitly stated, but the study was conducted at "two geographically distinct locations" within the context of a US FDA submission, implying US-based data.
  • Retrospective or Prospective: Not explicitly stated. The description "samples were obtained from both pediatric and adult patients (ages 1 to 74) representing acute (139), late acute (34), recent past (12), past (120), reactivation (22), past/probable reactivation (11), and negative (70) disease stages of EBV infection" suggests these were pre-existing samples categorized by their disease stage, which points towards a retrospective collection and analysis.

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

The document doesn't explicitly state the "number of experts" or their specific "qualifications" for establishing the ground truth. Instead, it refers to:

• For "Direct Comparison": "commercially available or published EBNA anti-complement immunofluorescence (ACIF) tests." This implies that the ground truth for this comparison was established by the ACIF method, which is a recognized laboratory technique, not directly by human experts for each case in the same way a pathologist would review slides.
• For "Clinical Interpretation": "stage of infection based on antibody patterns and clinical diagnosis at the time the specimen was drawn." This suggests that the ground truth here was derived from established clinical diagnostics and antibody profiling done by medical professionals, but not necessarily a panel of "experts" specifically adjudicating each case for the study.

4. Adjudication Method for the Test Set

• None specified. The study utilized two primary comparisons:
  1. Direct comparison with ACIF: This is a direct laboratory test comparison, not a human adjudication process.
  2. Comparison with clinical interpretation: This relies on pre-existing clinical diagnoses and antibody patterns, also not implying an adjudication panel for the study itself.

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

• No. An MRMC study was not done. This device is an in-vitro diagnostic (IVD) ELISA kit, which is typically evaluated for its direct analytical performance and agreement with established reference methods or clinical gold standards, rather than assessing human reader improvement with AI assistance. The concept of "human readers" is not applicable to the performance evaluation of such a diagnostic kit.

6. Standalone (Algorithm Only) Performance

• The study is a standalone performance evaluation of the Biotest Anti-EBV Recombinant EBNA IgG ELISA kit. As an IVD, its performance is assessed independently (without human-in-the-loop assistance for the test itself), by comparing its results to a ground truth (ACIF or clinical interpretation).

7. Type of Ground Truth Used

Two types of ground truth were used:

1. Reference Method (ACIF): For the "direct comparison," the ground truth was "commercially available or published EBNA anti-complement immunofluorescence (ACIF) tests."
2. Clinical Interpretation: For the second evaluation, the ground truth was "clinical interpretation (stage of infection based on antibody patterns and clinical diagnosis at the time the specimen was drawn)." This incorporates a combination of established diagnostic criteria and patient medical history.

8. Sample Size for the Training Set

• Not applicable / Not explicitly mentioned. ELISA kits are laboratory assays, not machine learning algorithms that require a "training set" in the conventional sense. The "development" of the assay (e.g., antigen selection, antibody optimization) would involve extensive R&D, but this is distinct from the concept of a training set for an AI model. The provided document details the validation of the finalized device.

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

• Not applicable. As explained above, this device does not utilize a training set in the machine learning context. The "ground truth" for the analytical performance of the antigens and antibodies used in the kit would have been established during the development phase through biochemical methods, reference panels, and expert characterization of EBV components, but this is an inherent part of IVD development, not a "training set" process for an algorithm.

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