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The Roche Elecsys Anti-HAV immunoassay is used for the in vitro qualitative detection of total antibodies (IgM and IgG) to hepatitis A virus in human serum and plasma (K2-EDTA). The assay is intended for use as an aid in the laboratory diagnosis of past or acute/recent hepatitis A infection.

Assay results, in conjunction with other laboratory results and clinical information, may be used to provide presumptive evidence of infection with hepatitis A virus in persons with signs or symptoms of hepatitis and in persons at risk for hepatitis A infection, or used as an aid to determine the presence of antibody response to HAV in vaccine recipients.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassav analyzers.

Elecsys PreciControl Anti-HAV is used for the quality control of the Elecsys Anti-HAV immunoassay on the Elecsys and cobas e immunoassay analyzers.

The Elecsys anti-HAV test is a qualitative assay based on electrochemiluminescence immunoassay "ECLIA" technology. The Elecsys anti-HAV test utilizes a competitive immunoassay format in which sample anti-HAV antibody competes with biotinylated and ruthenvlated anti-HAV monoclonal antibodies for a limited amount of cell culture-derived HAV antigen. The sample antibody and the HAV antigen react in the first incubation. The biotinylated antibodies and ruthenium complex® -labeled antibodies specific for HAV antigen are added in the second incubation together with streptavidin-coated magnetic microparticles. The unbound HAV antigen reacts with the modified antibodies and the resulting immune complexes are bound to the solid phase through a biotinstreptavidin interaction. If all HAV antigens are complexed by sample anti-HAV antibody during the first incubation, no modified/labeled immune complexes are formed and captured during the second incubation.

Following the second incubation, the reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are removed by elution with ProCell. Application of a voltage to the electrode induces chemiluminescent emission from the captured immune complexes which is measured by a photomultiplier. The level of signal detected by the system decreases as the concentration of the anti-HAV antibody target present in a patient sample increases.

Results are determined via a calibration curve which is generated by 2-point calibration on the instrument and a master curve provided via the reagent barcode. The calibration process converts the output so that low levels of sample anti-HAV antibodies are expressed by low output and high levels of antibody are expressed by high output. These outputs are finally interpreted on a qualitative basis around the established cut-off output.

Here's a breakdown of the acceptance criteria and study information for the Elecsys® Anti-HAV Assay, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the performance metrics reported, as the submission concludes that the information "supports a substantial equivalence decision." This means the reported performance met the FDA's expectations for equivalence to the predicate device.

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

• Clinical Performance Study (Comparison with Predicate):
  • Total Samples: 1050 samples (after excluding one concordantly equivocal sample).
  • Cohort Breakdown:
    • Subjects for whom routine hepatitis A testing had been ordered.
    • Hospitalized patients.
    • Subjects at increased risk for hepatitis.
    • Subjects with signs and symptoms of hepatitis.
    • Subjects characterized with acute hepatitis A.
    • Subjects below the age of 21 years (pediatric/adolescents).
    • Specific numbers per cohort are detailed in the tables (e.g., 197 for Routine HAV Testing, 219 for Hospitalized, etc., summing to the overall total).
  • Data Provenance: Multi-center study conducted in the U.S. (across 3 sites: BW, WU, JH). Samples were a mix of prospective and retrospective collections. All samples stored frozen before shipment.
• Analytical Specificity (Cross-reactivity): 177 samples from 15 potentially cross-reactive subgroups.
• Analytical Specificity (Interference): Native human serum pools, and 18 commonly used pharmaceuticals and folic acid.
• Prevalence Study (Expected Values): 602 patients (300 from high prevalence region, Western U.S. (New Mexico); 302 from low prevalence region, Eastern U.S. (Indiana)). This was a prospective study.
• Seroconversion Sensitivity: 3 seroconversion panels.
• Method Comparison (between platforms): 202 samples (100 non-reactive from prevalence cohort, 53 reactive from clinical cohorts, 49 reactive from Roche R&D archive).

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

This information is not explicitly provided in the summary. The "ground truth" for clinical performance is established by comparing the Elecsys Anti-HAV assay results against an "FDA-cleared reference method" (the predicate device, Abbott AxSym HAVAB® 2.0). However, the summary does not specify if or how many human experts were involved in interpreting results from either the new device or the predicate to establish a "ground truth" in cases of discordance, or to confirm clinical status. The study relies on the predicate device's established performance and classification of samples.

4. Adjudication Method for the Test Set

The summary does not explicitly describe an adjudication method involving human experts for the test set. The clinical performance section states that the assay's performance was determined by agreement with the predicate device, which indicates a direct comparison rather than a human adjudication process to "resolve" discordant results. For "borderline" results from the Elecsys Anti-HAV assay (18.0 < IU/L < 22.0), the protocol involves retesting in duplicate and interpreting based on the majority of the three results (initial + 2 retests). This is an internal retesting protocol, not an external expert adjudication.

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

• No, an MRMC comparative effectiveness study was not done. This document describes the performance of an in vitro diagnostic (IVD) assay, not the performance of human readers using an AI device. Therefore, the effect size of human readers improving with AI vs without AI assistance is not applicable.

6. Standalone Performance

• Yes, standalone performance was done. The entire submission details the performance of the Elecsys Anti-HAV assay (the algorithm/device) as a standalone diagnostic tool for detecting total antibodies to hepatitis A virus. All performance metrics reported (precision, detection limits, analytical specificity, and clinical agreement with the predicate device) reflect the device's performance without human interpretation or intervention in the diagnostic output itself (though a human ultimately uses the result for clinical decision-making).

7. The Type of Ground Truth Used

The primary "ground truth" used for evaluating the clinical performance of the Elecsys Anti-HAV assay was the results from an FDA-cleared reference method: the Abbott AxSym HAVAB® 2.0 assay. The submission explicitly states: "The performance of the Elecsys anti-HAV assay was determined by percent agreement among negative samples and percent agreement among positive samples, against a consensus comparator method. The main predicate (Abbott AxSym HAV AB- 2.0) was used as sole comparator/reference."
For seroconversion, vendor data from the predicate device was also used.

8. The Sample Size for the Training Set

The summary does not explicitly specify a "training set" sample size in the context of an AI/machine learning model. This is an immunoassay, which typically relies on established chemical and biological reactions and calibration curves rather than an iterative learning process with a "training set" in the modern AI sense. The assay uses a master curve provided via a reagent barcode and 2-point instrument calibration. The master standard curve is established by diluting an anti-HAV positive human serum with an analyte free human serum matrix, with concentration values assigned by reading from a reference calibrator curve using multiple instruments and replicates. The "training" in this context would be the development and optimization of the assay itself and its reagents.

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

As noted above, there isn't a "training set" in the AI sense for this immunoassay. However, the calibration process (which is analogous to establishing the basis for decision-making) works as follows:

• The device is standardized against the "Second International Standard for Anti-Hepatitis A, Immunoglobulin, Human, NIBSC code: 97/646" of the NIBSC.
• Calibrators: Two calibrators are used: Calibrator 1 (anti-HAV negative serum) and Calibrator 2 (anti-HAV positive serum with approx. 46 IU/L).
• Master Standard Curve: A reagent lot-specific master standard curve is provided on the barcode. This curve is established by diluting an anti-HAV positive human serum with an analyte free human serum matrix. The concentration value is assigned by reading the concentration from the reference calibrator curve using four Elecsys 2010 and four MODULAR ANALYTICS E170 instruments with 2 runs and 2 replicates per run and per instrument.
• The calibration data ensures the assay's output signal can be accurately converted into a quantitative reading (IU/L) and then interpreted qualitatively (Reactive, Equivocal, Non-Reactive) based on the established cut-off.

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The Roche Elecsys Anti-HAV IgM immunoassay is used for the in vitro qualitative detection of IgM antibodies to hepatitis A virus (anti-HAV IgM) in human serum and plasma (potassium EDTA, lithium or sodium heparin, sodium citrate). The assay is intended for use as an aid in the laboratory diagnosis of an acute or recently acquired hepatitis A virus infection.

Assay results, in conjunction with other laboratory results and clinical information, may be used to provide presumptive evidence of infection with hepatitis A virus in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis A infection.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Elecsys PreciControl Anti-HAV IgM is used for quality control of the Elecsys Anti-HAV IgM immunoassay on the Elecsys and cobas e immunoassay analyzers.

The Elecsys Anti-HAV IgM immunoassay utilizes a u-capture test concept based on a monoclonal h-IgM directed biotinylated antibody, cell culture derived Hepatitis A Virus and a ruthenylated monoclonal antibody directed to HAV. Capture of formed immune complexes from the reaction mixture is based on biotin binding to streptavidin-coated magnetic microparticles which are collected on a measuring cell electrode. Signal generation is triggered by the application of a voltage to the electrode (electrochemiluminescence technology). The level of signal count detected by the system increases as the concentration of the IgM antibody target present in a patient sample increases.

The Elecsys PreciControl Anti-HAV IgM contains control serum based on human serum in the negative and positive concentration range. The controls are used for monitoring the accuracy of the Elecsys Anti-HAV IgM immunoassays.

The Elecsys® Anti-HAV IgM immunoassay is intended for the in vitro qualitative detection of IgM antibodies to hepatitis A virus (anti-HAV IgM) in human serum and plasma. The assay is meant to aid in the laboratory diagnosis of an acute or recently acquired hepatitis A virus infection.

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

1. Table of Acceptance Criteria and Reported Device Performance

The submission does not explicitly state pre-defined acceptance criteria in terms of numerical thresholds for sensitivity, specificity, or agreement. However, the study aims to demonstrate the performance of the Elecsys Anti-HAV IgM immunoassay by comparing it to an FDA-cleared reference method. The implicit acceptance criterion is a high level of agreement with the predicate device across various sample cohorts.

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

• Test Set Sample Size:
  • Comparative Testing (Clinical Performance): 1087 total samples.
  • Analytical Sensitivity: 3 commercially available HAV seroconversion panels.
  • Expected Values (Prevalence): 602 subjects (208 males, 394 females) from two US regions.
  • Cross-reactivity: 211 specimens representing various disease states.
  • Potentially Interfering Substances: Not explicitly stated, implied to be sufficient for 18 pharmaceuticals and other substances.
  • Serum and Plasma Comparison: 10 positive, 15 borderline, and 20 negative specimens per plasma matrix (Li-heparin, Na-heparin, K2-EDTA, Sodium citrate).
  • Precision/Reproducibility: Human serum pools (3) and controls (2) tested in replicates over multiple days/runs/sites.
• Data Provenance:
  • Clinical Performance: Multi-center study conducted in the U.S. Retrospective (samples were obtained for routine testing, from hospitalized patients, etc.).
  • Expected Values: Prospective study of apparently healthy individuals from New Mexico (high prevalence region) and Indiana (low prevalence region) in the U.S.
  • Other studies (Analytical Sensitivity, Cross-reactivity, Precision/Reproducibility, Interfering Substances, Serum/Plasma Comparison) are likely laboratory-based studies conducted by the manufacturer, with samples possibly sourced from commercial vendors or clinical sites.

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

The ground truth for the clinical performance study was established by an "FDA-cleared reference method." A second FDA-cleared anti-HAV IgM assay was used for discrepant analysis, and for a subset of concordant specimens.

• Number of Experts: Not applicable, as the ground truth was established by laboratory assays (reference methods), not by individual experts or a consensus thereof.
• Qualifications of Experts: Not applicable.

4. Adjudication Method for the Test Set

For the comparative testing (clinical performance):

• The primary comparison was against a "1st reference anti-HAV IgM assay."
• Discrepant Analysis: For discrepant and several concordant samples, a "second FDA cleared anti-HAV IgM assay" was used for additional testing.
• Adjudication Rule: The second predicate agreed with the Elecsys outcome in 7 of 10 discrepant samples and with the first predicate in 2 of 10. No consensus was obtained in the remaining specimen.
• This indicates a form of 2-assay adjudication where a third assay (the Elecsys in this case) is compared against two reference assays. The "ground truth" for the overall agreement calculation appears to be based on the initial primary reference assay, with the secondary assay used to investigate discrepancies.

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

• No, an MRMC comparative effectiveness study was not done.
  • This device is an in vitro diagnostic (IVD) immunoassay, not an imaging or interpretation device that would typically involve multiple human readers. The performance is assessed in terms of agreement with a reference laboratory method.
• Effect Size of Human Readers with/without AI Assistance: Not applicable, as no human reader component or AI assistance is described for the interpretation of this immunoassay.

6. Standalone Performance Study

• Yes, a standalone study was done. The entire clinical performance section, particularly the "COMPARATIVE TESTING" and "ANALYTICAL SENSITIVITY" sections, evaluates the algorithm's (the immunoassay's) performance independently against established reference methods and panels. The reported Positive Percent Agreement and Negative Percent Agreement are measures of the device's standalone performance relative to the chosen reference.

7. Type of Ground Truth Used

• Expert Consensus: Not used for establishing the primary ground truth.
• Pathology: Not applicable.
• Outcomes Data: Not explicitly mentioned as the primary ground truth source.
• Reference Assay/Method: The primary ground truth for the clinical performance was established by an "FDA-cleared reference method" (the Abbott Axsym HAVAB-M 2.0 Assay). For discrepant samples, a second FDA-cleared anti-HAV IgM assay was used for further investigation. For analytical sensitivity, the ground truth was based on commercially available HAV seroconversion panels and comparator assays (Abbott Axym HAVAB-M 2.0 and Abbott HAVAB-M).

8. Sample Size for the Training Set

• Not explicitly stated within the provided document. IVD assays like this immunoassay typically undergo extensive laboratory development and optimization during which various samples might be used for "training" or optimization. However, the document focuses on the validation and performance testing of the finalized assay. Manufacturers often do not disclose specific "training set" sizes for IVD assays in 510(k) submissions, as the development process involves reagent formulation and analytical optimization rather than a distinct "machine learning training set" in the common sense.

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

• Not explicitly stated in the document. Similar to point 8, the specific methodology for establishing ground truth during the assay's development or "training" phase is not detailed. It is reasonable to assume that standard laboratory practices, including the use of well-characterized positive and negative control samples, reference materials, and expert knowledge of HAV infection serology, would have been employed during the optimization and development of the Elecsys Anti-HAV IgM immunoassay.

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