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The LIAISON® Anti-HAV assay is an in vitro chemiluminescent immunoassay intended for the qualitative detection of total antibodies to hepatitis A (anti-HAV) in human serum and sodium heparin plasma samples using the LIAISON® Analyzer family. The assay is indicated as an aid in the laboratory diagnosis of current or previous HAV infections in conjunction with other serological and clinical information and to determine the presponse to HAV in vaccine recipients.

The assay is not intended for screening blood or solid or soft tissue donors.

The method for qualitative determination of anti-HAV is a competitive sandwich chemiluminescence immunoassay (CLIA) based on neutralization. The assay uses magnetic particles (solid phase) coated with IqG antibodies to HAV (mouse monoclonal), and a mouse monoclonal anti-HAV antibody conjugate linked to an isoluminol derivative (isoluminol-antibody conjuqate). The first incubation step consists of adding the HAV antigen to calibrators, samples or controls, during which anti-HAV present in calibrators, samples or controls binds to a fixed and limited amount of HAV. thus forming an HAV-anti-HAV immune complex. After this step the second incubation follows and it involves addition of magnetic microparticles and conjugate into the cuvette, during which the antibody conjugate and the solid-phase antibody compete with anti-HAV present in the specimen for HAV. This allows the conjugate to bind to the solid phase and to form a sandwich. If all HAV added is sequestered in an HAV-anti-HAV immune complex during the first incubation, no sandwich is formed during the second incubation. After the second incubation, the 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 inversely indicative of anti-HAV present in calibrators, samples or controls.

Here's an analysis of the provided text regarding the DiaSorin Inc. LIAISON® Anti-HAV device, outlining acceptance criteria and study details:

Acceptance Criteria and Device Performance

The provided document describes two main performance studies: a Method Comparison study and a Reproducibility study. The "acceptance criteria" are implied by the reported agreement percentages and coefficient of variation (%CV) values, which are generally expected to be high for agreement and low for variation in diagnostic assays.

Table of Acceptance Criteria and Reported Device Performance

Study Details for LIAISON® Anti-HAV

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

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

• Method Comparison Test Set: 100 frozen serum samples.

• Data Provenance: Samples were "either selected or prepared by DiaSorin Inc." The text does not explicitly state the country of origin or if the samples were retrospective or prospective, but the selection/preparation by the manufacturer suggests a controlled, potentially retrospective or spiked sample set rather than a purely prospective real-world patient cohort. The testing was performed at "2 external sites and at DiaSorin Inc."

• Reproducibility Study Test Set: A coded precision panel consisting of seven (7) serum specimens manufactured by DiaSorin S.p.A. and two (2) kit controls (a positive and negative from a single control lot). Each sample was run with 4 replicates per day for 12 days at each of the 3 sites, totaling 144 replicates per sample (4 replicates/day * 12 days * 3 sites) for both samples and controls.

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

The studies described are for an in vitro diagnostic (IVD) immunoassay, not an imaging device or AI-driven diagnostic that typically involves human expert interpretation for ground truth. Therefore, no human experts were used to establish ground truth in the traditional sense for these performance studies.

• In the method comparison study, the ground truth for samples was based on the results from a predicate device (LIAISON® Anti-HAV, Reference K082049).
• In the reproducibility study, the "ground truth" for the precision panel samples would be their known or assigned concentration/status based on their manufacturing and characterization, against which the assay's consistency is measured. The text doesn't specify how these concentrations were established, but it would typically be through reference methods or rigorous characterization during manufacturing.

4. Adjudication Method for the Test Set

Given that these are performance studies for an in vitro diagnostic where comparison is primarily against a predicate device or known sample characteristics, no human adjudication method (e.g., 2+1, 3+1) was mentioned or would typically be applicable. The "adjudication" is effectively the direct comparison of results between the new device and the predicate device or the statistical analysis of quantitative measurements against expected values (for reproducibility).

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. MRMC studies are typically performed for medical imaging or AI diagnostics where multiple human readers interpret cases and their performance is compared with and without AI assistance. This document describes an in vitro diagnostic assay that determines the presence of antibodies in serum/plasma, not a technology that human readers interpret.

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

The LIAISON® Anti-HAV assay itself is a standalone in vitro diagnostic device, meaning its performance is evaluated based on its own output (chemiluminescence signal leading to qualitative detection of antibodies) without direct human interpretation of complex patterns or images. The "algorithm" in this context refers to the assay's chemical and instrumental process, which produces results independently. The provided studies directly assess this standalone performance (e.g., agreement with a predicate, and reproducibility).

7. The Type of Ground Truth Used

• Method Comparison Study: The ground truth for the test set was established by the predicate device (LIAISON® Anti-HAV, Reference K082049) results. This is a common practice for demonstrating substantial equivalence for IVDs.
• Reproducibility Study: The ground truth, in terms of expected values for precision, was based on the known characteristics of the manufactured serum specimens and kit controls. This is not "expert consensus" or "pathology" but rather scientifically characterized samples.

8. The Sample Size for the Training Set

The document does not specify a training set sample size. This is expected because the LIAISON® Anti-HAV assay is a chemiluminescent immunoassay, which is a traditional laboratory diagnostic method based on biochemical reactions, not a machine learning or AI algorithm that requires a "training set" in the context of model development. The development of such an assay involves extensive R&D, reagent optimization, and analytical validation but not a "training set" in the computational sense.

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

Since there is no "training set" in the AI/ML sense, this question is not applicable based on the provided information. The development of the assay would have relied on established scientific principles, method validation, and characterization of reagents and controls.

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The LIAISON® Anti-HAV assay is an in vitro chemiluminescent immunoassay intended for the qualitative detection of total antibodies to hepatitis A (anti-HAV) in human serum and sodium heparinized plasma samples using the automated LIAISON® Analyzer. The assay is indicated as an aid in the laboratory diagnosis of current or previous HAV Infections in conjunction with other serological and clinical information and to determine the presence of an antibody response to HAV in vaccine recipients.

This assay is not intended for screening blood or solid or soft tissue donors. Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients. The user is responsible for establishing their own assay performance characteristics in these populations.

The LIAISON® Control Anti-HAV (negative and positive) is intended for use as assayed quality control samples to monitor the performance of the LIAISON® Anti-HAV assay.

The method for qualitative determination of anti-HAV is a competitive sandwich chemiluminescence immunoassay (CLIA) based on neutralization. The assay uses magnetic particles (solid phase) coated with IgG antibodies to HAV (mouse monoclonal), and a mouse monoclonal anti- HAV antibody conjugate linked to an isoluminol derivative (isoluminol-antibody conjugate).

The first incubation step consists of adding the HAV antigen to calibrators, samples or controls, during which anti-HAV present in calibrators, samples or controls binds to a fixed and limited amount of HAV, thus forming an HAV-anti-HAV immune complex.

After this step the second incubation follows and it involves addition of magnetic microparticles and conjugate into the reaction module, during which the antibody conjugate and the solid-phase antibody compete with anti-HAV present in the specimen for HAV. This allows the conjugate to bind to the solid phase and to form a sandwich. If all HAV added is sequestered in an HAV-anti-HAV immune complex during the first incubation, no sandwich is formed during the second incubation. After the second incubation, the 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 isoluminolantibody conjugate, is measured by a photomultiplier as relative light units (RLU) and is inversely indicative of anti-HAV present in calibrators, samples or controls.

The provided text describes the performance data for the DiaSorin LIAISON® Anti-HAV assay. However, it does not explicitly state specific acceptance criteria (e.g., "Positive agreement must be >= 95%"). Instead, it reports the observed performance (percent agreement and confidence intervals) which implies these results were deemed acceptable by the regulatory body for 510(k) clearance based on substantial equivalence to a predicate device.

Therefore, the table below will present the reported device performance, and the description will elaborate on the various studies conducted to demonstrate this performance.

Acceptance Criteria and Study Details for DiaSorin LIAISON® Anti-HAV Assay

1. Table of Acceptance Criteria and Reported Device Performance

As explicit quantitative acceptance criteria (e.g., "The positive agreement must be at least X%") are not stated in the provided document, the table will reflect the reported performance that was found to be sufficient for substantial equivalence. The document presents "Percent Agreement" values along with their 95% Confidence Intervals as the primary performance metrics. The underlying acceptance for these values is implicit through the 510(k) clearance process, which confirms the device is safe and effective as a predicate device.

Note: The low positive agreement for the Pediatric Population (78.6%) with a wide confidence interval (49.2 – 95.3%) indicates a smaller number of positive samples in that specific cohort, but was still accepted for clearance.

2. Sample Sizes and Data Provenance

• Prospective Studies:
  • HAV Testing and At Risk Populations: 739 samples.
    • 500 excess serum samples from individuals in the Northeastern U.S. sent for HAV testing.
    • 239 samples from individuals at risk for viral hepatitis (homosexual males, healthcare workers, commercial sex workers, drug users, prison inmates, dialysis patients, hemophiliacs).
  • Pediatric Population: 108 samples from children in the United States.
  • Vaccine Study: 73 individuals (9 TWINRIX sets, 32 HAVRIX sets, 32 VAQTA sets of pre- and post-vaccine samples).
• Retrospective Studies:
  • Current/Previous HAV Infection (Adults): 109 samples from adults in Eastern U.S. and Egypt.
  • Current HAV Infection (Pediatric): 42 samples from pediatric patients in Egypt.
• Expected Values (Prevalence Study): 802 apparently healthy adults (301 from Western U.S., 501 from Eastern U.S.).

Data Provenance: The data is a mix of prospective and retrospective collections. Geographically, samples were from the Northeastern U.S., other unspecified regions of the U.S. (for at-risk groups and pediatric prospective), Eastern U.S., Western U.S., and Egypt.

3. Number of Experts and Qualifications for Ground Truth

The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the test sets. Instead, the "Comparator ELISA" assay is consistently referred to as the reference method for determining the true positive, negative, or equivocal status of samples. This implies that the accepted clinical standard for Hepatitis A testing at the time (the predicate ELISA assay) served as the ground truth.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method involving multiple experts. The comparator ELISA assay results were the reference. For samples that yielded "Equivocal" or "Borderline" results by the comparator ELISA, these were sometimes retested per the Instructions for Use of the comparator method. Samples that remained equivocal or borderline after retesting were handled as distinct categories in the comparison tables.

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

A multi-reader multi-case (MRMC) comparative effectiveness study comparing human readers with and without AI assistance was not done. This device is an in vitro diagnostic (IVD) assay designed to be read by automated equipment (LIAISON® Analyzer) and interpreted by laboratory professionals, not primarily by human "readers" interpreting images or complex data in the same way an AI for medical imaging would. The performance is compared to a predicate assay, not human interpretation.

6. Standalone (Algorithm Only) Performance

Yes, a standalone performance study was done. The entire performance evaluation section ("Performance Data") describes the performance of the LIAISON® Anti-HAV assay as a standalone algorithm/device, comparing its results directly against those of a predicate ELISA assay on various sample populations. There is no human-in-the-loop component described for these performance evaluations.

7. Type of Ground Truth Used

The ground truth was established by a comparator ELISA assay, which is referred to throughout the document as the reference method. Specifically, the predicate device, DiaSorin Inc. ETI-AB-HAVK Plus assay (PMA #P890019/S05), served as the standard for comparison.

8. Sample Size for the Training Set

The document does not specify a separate "training set" size. For in vitro diagnostic (IVD) assays, the development process typically involves internal method validation and optimization by the manufacturer, rather than a distinct "training set" in the machine learning sense. The samples described in the "Performance Data" section are effectively the "test set" or clinical validation set used to demonstrate performance for regulatory submission.

9. How Ground Truth for the Training Set Was Established

As no explicit training set is mentioned in the context of machine learning, this question is not directly applicable. For the overall assay development and validation, the ground truth was established by comparison to existing, clinically accepted methods, presumably the predicate ELISA assay during earlier stages of development and optimization.

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