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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 presence of an antibody response to HAV in vaccine recipients.

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

The DiaSorin LIAISON® XS Analyzer is a fully automated, closed, continuous loading of samples and reagents in vitro diagnostic immunoassay system utilizing chemiluminescent technology to provide rapid sample results. The analyzer uses DiaSorin proprietary reagents in which chemiluminescence of an analyte is measured in a sample by the reaction of a magnetic particle solid phase coated with antigen or antibody and a chemiluminescent tracer. The LIAISON® XS Analyzer is intended for use in professional clinical laboratories only.

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 (isoluminolantibody conjugate).

The provided text describes a 510(k) premarket notification for a modified medical device, the LIAISON® XS Analyzer, used with the LIAISON® Anti-HAV assay. However, the document does not contain specific details about acceptance criteria, reported device performance (in terms of sensitivity, specificity, etc.), sample sizes for test sets, data provenance, number of experts, adjudication methods, MRMC studies, standalone performance, or ground truth details for either test or training sets.

The submission is for a device modification (moving fluid canisters onboard) to an already cleared device (K210272). The focus of the provided text is on demonstrating that these modifications do not negatively impact the device's performance or safety/effectiveness, rather than a full de novo performance study of the Anti-HAV assay itself.

Therefore, most of the requested information cannot be extracted from this document. The "Summary of Performance Data" section states that "Non-clinical verification and validation activities conducted with the LIAISON® XS Analyzer demonstrate that the modified device met predetermined acceptance criteria," but it does not specify what those criteria were or quantitatively report the performance. It merely lists the types of studies conducted.

Here is what can be inferred or stated based on the provided text:

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

The document does not explicitly list the acceptance criteria or quantitative performance results (e.g., sensitivity, specificity, accuracy) for the LIAISON Anti-HAV assay after the modifications. It broadly states: "Non-clinical verification and validation activities conducted with the LIAISON® XS Analyzer demonstrate that the modified device met predetermined acceptance criteria, supporting equivalency of the modified device to the cleared device." And "Testing verified all acceptance criteria were met."

The primary goal of this 510(k) is to demonstrate that the modifications to the analyzer (moving fluid canisters onboard) do not alter the safety and effectiveness of the existing cleared device. The previous clearance (K210272) would have contained the detailed performance data for the LIAISON® Anti-HAV assay itself.

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

Not provided in this document. The document refers to "non-clinical verification and validation activities" which are typically internal testing, not necessarily clinical studies with patient test sets.

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

Not applicable and not provided. This information would be relevant for a de novo clinical study with expert ground truth, which is not the focus of this modification submission.

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

Not applicable and not provided.

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

Not applicable. The LIAISON® XS Analyzer is an in vitro diagnostic immunoassay system, not an AI-assisted diagnostic tool that requires human reader interpretation.

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

The LIAISON® Anti-HAV assay on the LIAISON® XS Analyzer is a standalone diagnostic test. Its performance is evaluated based on its accuracy in detecting antibodies, as indicated by the chemiluminescence signal, and does not involve human interpretation of complex images or signals in the same way an AI algorithm might. The document does not provide the specific performance metrics (e.g., sensitivity, specificity, NPV, PPV) for this standalone device in the context of this specific 510(k) submission, as it refers to these having been established in the previous clearance (K210272).

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

Not explicitly stated in this specific document. For an immunoassay like this, the ground truth for clinical studies would typically be established through a combination of:

• Established reference methods: Usually another FDA-cleared or gold standard HAV antibody test.
• Clinical diagnosis: Based on patient symptoms, epidemiological information, and other laboratory markers.
• Seroconversion panels: Well-characterized samples from individuals demonstrating progression of infection or immune response.

Since this 510(k) is for a modification to an existing device, it relies on the ground truth established during the original clearance of the LIAISON® Anti-HAV assay.

8. The sample size for the training set

Not applicable and not provided. Immunoassays are not "trained" in the same way machine learning models are. Performance characteristics are established through various analytical and clinical studies.

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

Not applicable and not provided (see point 8).

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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 presence of an antibody response to HAV in vaccine recipients.

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

The DiaSorin LIAISON® XS Analyzer is a fully automated, closed, continuous loading of samples and reagents in vitro diagnostic immunoassay system utilizing chemiluminescent technology to provide rapid sample results. The analyzer uses DiaSorin proprietary reagents in which chemiluminescence of an analyte is measured in a sample by the reaction of a magnetic particle solid phase coated with antigen or antibody and a chemiluminescent tracer. The LIAISON® XS Analyzer is intended for use in professional clinical laboratories only.

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 information provided pertains to the DiaSorin LIAISON® Anti-HAV assay running on the LIAISON® XS Analyzer. This premarket notification is a "Special 510(k)" for device modifications to the existing LIAISON® XS analyzer (K193532), primarily addressing improvements in reliability related to the reagent pipettor. The LIAISON® Anti-HAV assay component and procedures themselves remain unchanged.

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

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample size used for the test set and the data provenance

The document does not explicitly state the sample size used for the test set for the immunometrical performance assessment.

• Data Provenance: Not specified. It's unclear if the data is retrospective or prospective, or the country of origin.

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

Not applicable for this type of in vitro diagnostic device (immunoassay). Ground truth for these assays is typically established by reference methods or clinical diagnosis, not by experts reviewing images or other data.

4. Adjudication method for the test set

Not applicable for this type of in vitro diagnostic device. Result determination is quantitative or qualitative based on the assay's output measurements against a defined cutoff, not through expert adjudication of individual cases.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done

No, an MRMC comparative effectiveness study was not done. This type of study is typically associated with imaging devices or AI-assisted diagnostic tools where human readers interpret results. The LIAISON® Anti-HAV assay is an automated chemiluminescent immunoassay.

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

Yes, the performance presented in Table 6-3 represents the standalone performance of the LIAISON® Anti-HAV assay on the modified LIAISON® XS Analyzer. This device is an automated immunoassay system, and its output is directly interpreted as a qualitative detection of antibodies.

7. The type of ground truth used

The ground truth for the immunometrical performance assessment:

• Analytical Sensitivity: Established against a "WHO standard preparation."
• Positive/Negative Agreement: Implied to be established against a reference method or clinical diagnosis for Hepatitis A infection, as is standard for serological assays. The document does not explicitly name the specific reference method used for establishing positive and negative agreement.

8. The sample size for the training set

The document does not provide information regarding a separate "training set" or its sample size. For an immunoassay like this, the development likely involves optimization and validation steps, but not a distinct "training set" in the machine learning sense. The performance data presented is for the evaluation of the validated device.

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

As there is no explicit mention of a training set in the context of machine learning, there is no information on how its ground truth was established. The development of such an assay involves careful analytical and clinical validation, ensuring its performance aligns with established diagnostic standards.

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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

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Immunoassay for the in vitro qualitative detection of total antibodies (IgG and IgM) to hepatitis A virus (HAV) in human pediatric (ages 2 through 21 years) and adult serum and plasma (Li-heparin, potassium EDTA, Na-hebarin). The assay, in conjunction with other serological and clinical information, is indicated as an aid in the clinical laboratory diagnosis of acute or past hepatitis A virus infection in persons with signs or symptoms of hepatitis and in persons at increased risk for hepatitis A infection, or as an aid to identify HAV susceptible individuals and to determine the presence of an antibody response to HAV in vaccine recipients.

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

Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients. This assay has not been FDA cleared or approved for the screening of blood or plasma donors.

Elecsys Anti-HAV II is a second generation assay by Roche Diagnostics for the in vitro qualitative detection of total antibodies (IgG and IgM) to the hepatitis A virus (HAV) in human pediatric (ages 2 through 21 years) and adult serum and plasma. It is intended for use on the cobas e 601 immunoassay analyzer. The cobas e family of analyzers employs the electrochemiluminescence "ECLIA" technology. The assay is an 18-minute assay utilizing a competition principle.

Results are determined automatically by the software by comparing the electrochemiluminescence signal obtained from the reaction product of the sample with the signal of the cutoff value previously obtained by calibration.

The reagent rackpack working solutions include:

• M: Streptavidin-coated microparticles .
• R1: HAV Ag (cell culture) .
• R2: Biotinylated monoclonal anti-HAV antibody, monoclonal Anti-HAV antibody . labeled with ruthenium complex
• AHAV 2 Cal1: Negative Calibrator 1 (human serum) .
• AHAV 2 Cal2: Positive Calibrator 2 (anti-HAV (human), approximately 60 IU/L in . human serum)

PreciControl Anti-HAV II is a ready-for-use control serum based on human serum both in the negative and positive concentration range. The controls are used for monitoring the performance of the Elecsys Anti-HAV II immunoassay. PreciControl Anti-HAV II is sold separately from the Elecsys Anti-HAV II immunoassay reagent.

The Elecsys Anti-HAV II is an immunoassay for the in vitro qualitative detection of total antibodies (IgG and IgM) to hepatitis A virus (HAV) in human pediatric (ages 2 through 21 years) and adult serum and plasma. Its purpose is to aid in the clinical laboratory diagnosis of acute or past hepatitis A virus infection in persons with signs or symptoms of hepatitis and in persons at increased risk for hepatitis A infection, or as an aid to identify HAV susceptible individuals and to determine the presence of an antibody response to HAV in vaccine recipients.

Here's an analysis of the acceptance criteria and the studies performed:

1. Table of Acceptance Criteria and Reported Device Performance:

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

• Precision (Repeatability and Within-Laboratory Precision): 5 human serum sample pools and 2 PreciControl materials, tested in 2 aliquots per run, 2 runs per day for 21 days (total 84 measurements per sample/control).
• Analytical Sensitivity (Cut-off): 10 serially diluted samples of the 2nd International Standard for Anti-Hepatitis A, Immunoglobulin, Human, NIBSC code: 97/646. Tested fourfold with three different reagent and calibrator lots.
• HAMA Interference: 11 human serum samples, double positive for HAMA and anti-HAV antibodies.
• Endogenous Interferences (Hemoglobin/Bilirubin/Lipemia, Rheumatoid Factor, Serum Albumin/IgG/IgA/IgM): Four human serum samples for each interfering substance, tested in accordance with CLSI EP07-A2.
• Biotin Interference: Five human serum samples.
• Analytical Specificity/Cross-Reactivity: 12 sample pools, each containing 10 samples (total 120 samples) with antibodies to various infectious agents.
• Exogenous Interferences (Drugs): Four human serum samples (native human serum pools) for each of 18 pharmaceutical compounds.
• Sample Matrix Comparison: At least 60 serum/plasma pairs for each anticoagulant type (K2-EDTA, K3-EDTA, Na-Heparin, Li-Heparin, Na-Citrate).
• Analytical Method Comparison to Predicate: A total of 215 modified serum samples (≥100 negative and ≥100 positive samples).
• Reagent Stability:
  • After First Opening: 2 control samples and 7 samples, tested in duplicate.
  • On-Board Reagent Stability: 2 control samples (singleton) and 7 samples (duplicate).
• Calibration Stability:
  • Lot Calibration Stability: 2 control samples (singleton) and 7 human serum samples (duplicate).
  • On-Board Calibration Stability: 2 control samples (singleton) and 7 human serum samples (duplicate).
• Sample Stability:
  • 2-8°C, Room Temperature, -15 to -25°C, Freeze/Thaw Cycles: 6 human serum, K2-EDTA, Li-Heparin, and Na-Citrate plasma samples, and 7 K3-EDTA and Na-Heparin plasma samples.
• Reproducibility (External Testing): Four human serum pools and two PreciControl materials. Tested in 3 replicates per run, 2 runs per day for 5 days (total 90 measurements per sample/control per site).
• Method Comparison Versus Predicate (Clinical): 961 specimens from various cohorts.
  • Routine HAV testing: 91 PPA, 109 NPA
  • Hospitalized: 56 PPA, 144 NPA
  • Increased risk for hepatitis: 119 PPA, 87 NPA
  • Symptomatic: 129 PPA, 91 NPA
  • Characterized acute HAV: 65 PPA, 10 NPA
  • Pediatric: 42 PPA, 18 NPA
• Pre- and Post-HAV Vaccination: Specimens from 49 subjects.
• Prevalence Study: 400 evaluable subjects from a "high prevalence" region (Western US) and 400 evaluable subjects from a "low prevalence" region (Eastern US).

Data Provenance for Clinical Studies:
The method comparison and prevalence studies were conducted using specimens that are likely from the United States, as they reference "US- and non-US-obtained specimens" and "Western United States" and "Eastern United States" for the prevalence study. These studies appear to be prospective in nature, as they involve specimen collection for specific study purposes (e.g., cohorts for method comparison, pre- and post-vaccination, and prevalence studies with subjects recruited from specific regions).

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

The document does not explicitly state the number or qualifications of "experts" used to establish the ground truth in the traditional sense of consensus reading or clinical adjudication by medical specialists.

• For the method comparison study, the "ground truth" was established by the predicate device, Elecsys Anti-HAV assay (FDA-cleared). This means the predicate device's results were accepted as the reference against which the new device's performance was measured.
• For the Pre- and Post-HAV Vaccination study, the "ground truth" was established by the predicate assay (Elecsys Anti-HAV).
• For the Analytical Specificity/Cross-Reactivity study, samples were defined as "Anti-HAV negative samples containing potential cross-reacting antibodies to other infectious diseases," implying these diagnoses were previously established, likely through standard diagnostic tests.
• For the Prevalence study, the "ground truth" for HAV antibody status was determined by the Elecsys Anti-HAV II assay itself, as the study evaluated its performance in determining prevalence in different populations rather than comparing it to an external gold standard for individual cases.

4. Adjudication Method for the Test Set:

• None explicitly mentioned in the typical sense of expert review for ambiguous cases.
• For the Method Comparison study, discordant results were counted against the Elecsys Anti-HAV II when calculating agreement. Specifically, specimens with results in the borderline range of the predicate device (18.0 ≤ IU/L

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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.

• PC Anti-HAV 1: Repeatability CV 1.8%, Int. Precision CV 3.1%
• PC Anti-HAV 2: Repeatability CV 3.2%, Int. Precision CV 4.5%
• HSP 1, 2, 3: Repeatability CVs 2.5-3.4%, Int. Precision CVs 3.0-4.6%
  MODULAR ANALYTICS E170:
• PC Anti-HAV 1: Repeatability CV 1.5%, Int. Precision CV 5.5%
• PC Anti-HAV 2: Repeatability CV 2.3%, Int. Precision CV 5.8%
• HSP 1, 2, 3: Repeatability CVs 1.1-3.5%, Int. Precision CVs 4.3-5.6%
  Reproducibility (Overall within-site and between-site CVs also provided, e.g., Overall PPA/NPA > 90%) |
  | Detection Limits (LoD) | Lowest amount of analyte detectable with 95% probability, set at 6.00 IU/L. | Elecsys 2010 / cobas e 411: LoD = 5.155 IU/L
  MODULAR ANALYTICS E170 / cobas e 601: LoD = 2.994 IU/L
  Reported in labeling: 6.00 IU/L for both types. |
  | Analytical Specificity (Cross-reactivity) | Minimal false positives with common interfering conditions/diseases. | 177 samples from 15 subgroups tested: 174 non-reactive, 3 discordant with predicate. No HAMA effect found. |
  | Analytical Specificity (Interference) | Recovery of positive samples within ± 20 % of initial value. | Unaffected by icterus (90-95%) with a legally marketed predicate device. | Overall PPA: 98.12% (96.46% to 99.14% CI) |
  | Overall Negative Percent Agreement (NPA) with Predicate | High agreement (e.g., >90-95%) with a legally marketed predicate device. | Overall NPA: 97.37% (95.70% to 98.52% CI) |
  | Seroconversion Sensitivity | Agreement with predicate and vendor data for seroconversion panels. | Elecsys Anti-HAV assay showed similar performance to comparator (Abbott AxSym HAV AB-2.0) based on post bleed day of earliest reactive/last positive result for 3 panels. |
  | Method Comparison (between platforms) | High PPA and NPA (e.g., >95%) between the Elecsys 2010 and MODULAR ANALYTICS E170. | PPA: 96.8% (91.0% to 99.3% CI)
  NPA: 98.0% (93.0% to 99.8% CI)
  Pearson's regression correlation: 0.9951 (slope 1.024, intercept -0.555). |

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

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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.

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The MONOLISA™ Anti-HAV EIA is an in vitro enzyme immunoassay kit intended for use in the qualitative detection of total antibodies (IgG and IgM) to hepatitis A virus (anti-HAV) in human (adult and pediatric) serum or plasma (EDTA, Heparin, Citrate, ACD). This kit can be used as an aid in the diagnosis of acute or past hepatitis A virus (HAV) infection or as an aid in the identification of HAV-susceptible individuals for vaccination. However, any diagnosis should take into consideration the patient's clinical history and symptoms, as well as serological data. The MONOLISA™ Anti-HAV EIA is intended for manual use and with the EVOLIS™ Automated Microplate System in the detection of total antibodies to hepatitis A virus.

Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients, and cord blood or neonatal specimens.

Warning: This assay is not intended for screening blood or solid or soft tissue donors.

The MONOLISA™ Anti-HAV EIA is an enzyme immunoassay (competitive assay format) for the detection of total antibodies to hepatitis A virus. In the assay procedure, patient specimens, a Calibrator and controls are incubated with HAV antigen in microwells that have been coated with mouse monoclonal anti-hepatitis A antibodies to HAV present in a specimen or control will complex with the HAV antigen reagent and with antibodies coated on the microwells. Excess sample and HAV Viral Antigen reagent are removed by a wash step. The Conjugate (containing horseradish peroxidase-labeled mouse monoclonal antibody to HAV) is subsequently added to the microwells and incubated. The Coniugate binds to the HAV antigen bound to the microwell, in the absence of antibodies to HAV from the specimen. Excess Conjuqate is removed by a wash step, and a TMB Chromogen/Substrate solution is added to the microwells and allowed to incubate. If a sample does not contain anti-HAV antibodies, the bound enzyme (HRP) causes the colorless tetramethylbenzidine (TMB) in the Chromogen solution to change to blue. The blue color turns vellow after the addition of a Stopping Solution. If a sample contains anti-HAV antibodies, the Chromogen/Substrate solution in the well remains colorless during the substrate incubation, and after the addition of the Stopping Solution. The color intensity is measured spectrophotometrically. Absorbance value readings for patient specimens are compared to the Cutoff value determined by the mean of the Calibrator absorbance values.

The performance of the MONOLISA™ Anti-HAV EIA was evaluated in conjunction with the EVOLIS™ Automated Microplate System. The EVOLIS™ Automated Microplate System is a fully automated microplate analyzer that performs all functions necessary for the complete processing of microplate assays. Functions include: barcode scanning, sample pre-dilutions, sample and reagent dispensing, plate incubations, plate wash cycles, photometric measurement of completed assay plates and results evaluation. The analyzer instrument is controlled via the EVOLIS™ software, a Windows® 2000 application running on a separate dedicated PC. An operator loads the appropriate microplates, assay reagents, and patient and control samples, then selects assay parameters, loads sample information, initiates instrument processing, and generates result reports.

Here's a summary of the acceptance criteria and study details based on the provided text, focusing on the performance of the MONOLISA™ Anti-HAV EIA when used with the EVOLIS™ Automated Microplate System.

Acceptance Criteria and Device Performance

The acceptance criteria for the MONOLISA™ Anti-HAV EIA with the EVOLIS™ Automated Microplate System are demonstrated by its substantial equivalence to the manual method (K063318). This equivalence is primarily shown through high percent agreement in comparative studies and acceptable precision and reproducibility.

Study Details

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

   • Main Correlation/Method Comparison: 688 retrospective samples. The country of origin is not specified.
   • Combination Plate Testing: 315 samples. The provenance (retrospective/prospective, country) is not specified, but they are compared to the "same samples tested manually."

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

   • The ground truth for the test set was established by the "manual method" of the MONOLISA™ Anti-HAV EIA (K063318). This is a previously cleared assay and not a consensus from human experts. Therefore, the concept of "number of experts" or their "qualifications" is not directly applicable here in the context of human interpretation of a diagnostic outcome. The "ground truth" is the result from the established and cleared manual assay.

3. Adjudication method for the test set:

   • Not applicable as the ground truth is derived from a reference assay's output, not from human interpretation requiring adjudication. For borderline results in the main correlation study, specimens borderline with the reference assay and negative with EVOLIS™ were considered false negative for EVOLIS™, and specimens borderline with the reference assay and reactive with EVOLIS™ were considered false positive for EVOLIS™. This effectively defines how discrepancies were treated for agreement calculations.

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 MRMC comparative effectiveness study was performed. This device is an automated analyzer for an immunoassay, not an AI-assisted diagnostic tool that aids human readers in interpreting complex images or clinical data. The comparison is between an automated system and a manual laboratory method.

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

   • Yes, the performance data presented (correlation, precision, reproducibility) represents the standalone performance of the MONOLISA™ Anti-HAV EIA when run on the EVOLIS™ Automated Microplate System. The system performs all functions including reagent dispensing, incubation, washing, and photometric measurement, and results evaluation (based on optical density readings and cutoff values). The human operator's role is loading samples/reagents and initiating processing, not interpreting the primary assay output or forming a diagnosis from it directly.

6. The type of ground truth used:

   • The ground truth (or reference method) was the MONOLISA™ Anti-HAV EIA tested manually, which is a previously FDA-cleared laboratory assay. This is a form of reference standard comparison against an established assay.

7. The sample size for the training set:

   • The document does not specify a separate "training set" for the EVOLIS™ Automated Microplate System. Automated systems like this typically undergo a development and validation process during which algorithms (e.g., for robotic movements, optical density reading, cutoff calculations) are built and refined. The data presented here are for the performance validation of the final product. It's an assay system, not a machine learning model that requires a discrete "training set" in the conventional sense.

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

   • Not applicable, as a distinct training set (in the machine learning sense) and its ground truth are not detailed in this submission. The ground truth for the performance validation was the previously cleared manual assay.

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The MONOLISA™ Anti-HAV IgM EIA is an in vitro enzyme immunoassay kit intended for use in the qualitative detection of IgM antibodies to hepatitis A virus (anti-HAV IgM) in human (adult and pediatric) serum or plasma (EDTA, Heparin, Citrate, ACD). This assay is indicated for testing specimens from individuals who have signs and symptoms consistent with acute hepatitis. Assay results, in conjunction with other serological or clinical information, may be used for the laboratory diagnosis of individuals with acute or recent hepatitis A. The MONOLISA™ Anti-HAV IgM EIA is intended for manual use and with the Evolis™ Automated Microplate System in the detection of IgM antibodies to hepatitis A virus.

Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients, and cord blood or neonatal specimens.

Warning: This assay is not intended for screening blood or solid or soft tissue donors.

The MONOLISA™ Anti-HAV IgM EIA is an enzyme immunoassay (IgM antibody capture format) for the detection of IgM antibodies to hepatitis A virus. In the assay procedure, patient specimens, a calibrator, and controls are incubated with antibodies coated on the microwells. If IgM antibodies to HAV are present in a specimen or control, they bind to the antibody. Excess sample is removed by a wash step. The HAV Viral Antigen and the Conjugate (containing horseradish peroxidase - labeled mouse monoclonal antibody to HAV) are successively added to the microwells and allowed to incubate. The presence of anti-HAV IgM in the sample enables the HAV Viral Antigen and the Conjugate to bind to the solid phase. Excess Conjugate and HAV Viral Antigen are removed by a wash step, and a TMB Chromogen /Substrate solution is added to the microwells and allowed to incubate. If a sample contains anti-HAV IgM, the bound enzyme (HRP) causes the colorless tetramethylbenzidine (TMB) in the Chromogen solution to change to blue. The blue color turns yellow after the addition of a Stopping Solution. If a sample does not contain anti-HAV IgM, the Chromogen/Substrate solution in the well remains colorless during the substrate incubation, and after the Stopping Solution. The color intensity is measured spectrophotometrically. Absorbance value readings for patient specimens are compared to the cutoff value.

The performance of the MONOLISA™ Anti-HAV IgM EIA was evaluated in conjunction with the EVOLIS™ Automated Microplate System. The EVOLIS™ Automated Microplate System is a fully automated microplate analyzer that performs all functions necessary for the complete processing of microplate assays. Functions include: barcode scanning, sample pre-dilutions, sample and reagent dispensing, plate incubations, plate wash cycles, photometric measurement of completed assay plates and results evaluation. The analyzer instrument is controlled via the EVOLIS™ software, a Windows® 2000 application running on a separate dedicated PC. An operator loads the appropriate microplates, assay reagents, and patient and control samples, then selects assay parameters, loads sample information, initiates instrument processing, and generates result reports.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample Sizes and Data Provenance

• Test set for Correlation/Method Comparison:
  • Study 1 (EVOLIS™ vs. Manual): 691 retrospective samples.
  • Study 2 (EVOLIS™ Combination Plate vs. Manual): 313 samples.
• Data Provenance: The document does not explicitly state the country of origin. The samples were retrospective.

3. Number of Experts and Qualifications for Ground Truth

• The document does not mention the use of experts to establish ground truth for the test set.
• The "ground truth" for the comparison studies was the result of the MONOLISA™ Anti-HAV IgM EIA tested manually (the predicate device). The assumption is that the manual method itself, having received prior FDA clearance (K063319), represents the established truth for HAV IgM detection.

4. Adjudication Method

• The document does not describe a specific adjudication method using experts.
• For borderline results in the correlation studies, the following rule was applied: "specimens that were borderline with the reference assay and negative with EVOLIS™ were considered as false negative for the EVOLIS™." This represents a specific rule for handling discordant borderline results rather than an expert adjudication process.

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

• No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done.
• This study pertains to the performance of an automated assay system compared to a manual assay method, not a comparison of human readers with and without AI assistance. Therefore, there is no effect size reported for human readers improving with AI.

6. Standalone Performance Study

• Yes, a standalone (algorithm only) performance study was effectively done. The performance studies (correlation/method comparison, precision, reproducibility, carry-over, pipetting accuracy) evaluate the MONOLISA™ Anti-HAV IgM EIA when used with the EVOLIS™ Automated Microplate System as a fully automated system, without direct human intervention in the result determination process itself (beyond loading, selecting parameters, and generating reports). The "algorithm" here refers to the automated system and its integrated processes compared to the manual method.

7. Type of Ground Truth Used

• The ground truth used for the performance comparison studies was the result from the predicate device (Manual MONOLISA™ Anti-HAV IgM EIA assay). This is a comparative ground truth established by another existing, cleared diagnostic method, rather than direct pathology, expert consensus on clinical findings, or outcomes data.

8. Sample Size for the Training Set

• The document does not specify a separate "training set" in the context of an algorithm or AI model development. This submittal is for an automated system running an existing assay, not a novel AI algorithm that requires training on a data set. Therefore, this information is not applicable or provided.

9. How Ground Truth for Training Set Was Established

• As noted above, there is no explicit "training set" for an AI algorithm mentioned. The performance characteristics of the assay itself (MONOLISA™ Anti-HAV IgM EIA) were established through its prior 510(k) clearance (K063319) when used manually. The current submission focuses on demonstrating that combining this assay with the EVOLIS™ Automated Microplate System yields equivalent performance.

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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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