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This is an enzyme immunoassay test system for the detection of antinuclear antibodies in human serum. This test system is to be used as an aid in the detection of antibodies associated with systemic rheumatic disease.

This is an enzyme immunoassay for the detection of antinuclear antibodies in human serum.

This document describes the RELISA® ANA Screening Test System, an enzyme immunoassay for the detection of antinuclear antibodies in human serum, intended as an aid in detecting antibodies associated with systemic rheumatic disease.

1. Acceptance Criteria and Reported Device Performance:

The primary acceptance criterion appears to be "overall agreement" with a reference method. The initial comparison to the predicate device set the stage, but a "referee method" (Immuno Concepts HEp-2000® ANA-Ro Test System using indirect fluorescent antibody technique) was ultimately used to clarify "false positive" and "false negative" results.

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

• Sample Size:
  • Initial Comparison (with Predicate device): 214 (Positive) + 46 (Predicate Negative/Test Positive) + 12 (Predicate Positive/Test Borderline) + 105 (Predicate Negative/Test Borderline) + 8 (Predicate Positive/Test Negative) + 787 (Negative) = 1172 samples.
  • Revised Comparison (with Referee Method): The number of samples re-evaluated for the "referee method" was 79 "false positive" (from the initial comparison) and 4 "false negative" samples. The table provided for the revised comparison then summarizes the results for the entire cohort of 1172 samples based on the referee method's classification for the previously discrepant cases.
• Data Provenance: Not explicitly stated, but given context of the submission, it is assumed to be retrospective clinical samples. No country of origin is mentioned.

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

• Number of Experts: Not explicitly stated.
• Qualifications of Experts: The ground truth for the referee method involved use of the "indirect fluorescent antibody technique" and observation of "clearly discernible ANA patterns." This strongly implies interpretation by trained laboratory professionals, likely medical technologists or clinical immunologists with expertise in ANA testing. Specific qualifications (e.g., years of experience, board certification) are not provided.

4. Adjudication Method for the Test Set:

• Adjudication Method: The document describes a specific process for adjudication of discrepant results: "The large number of 'false positive' samples seen with the Immuno Concepts test was troubling, so we tested all of these sera for antinuclear antibodies using Immuno Concepts HEp-2000® ANA-Ro Test System (K944096 & K972145)." This indicates a targeted re-evaluation of initially discrepant samples using a more definitive "referee method" (indirect fluorescent antibody technique), where the results of this referee method were then considered the "true" classification. This is a form of discrepancy resolution with a gold standard.

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

• There is no indication of an MRMC comparative effectiveness study being performed. The study focuses on comparing the new device against a predicate device and a "referee method," not on human reader performance with or without AI assistance.

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

• Yes, a standalone performance study was conducted. The RELISA® ANA Screening Test System is an enzyme immunoassay, and its performance was evaluated directly against other laboratory tests (the predicate device and the indirect fluorescent antibody technique) without explicit human intervention in the interpretation of the RELISA results for the purpose of the study. The results are from the device itself.

7. The Type of Ground Truth Used:

• The initial comparison used the predicate device's results as a reference.
• The refined comparison, which led to the final performance metrics, used the indirect fluorescent antibody technique (IFA) performed with the Immuno Concepts HEp-2000® ANA-Ro Test System as the "referee method" or gold standard for establishing ground truth, especially for discrepant samples. IFA is generally considered a highly sensitive and specific method for ANA detection and pattern recognition, often serving as a reference method in clinical immunology.

8. The Sample Size for the Training Set:

• The document does not explicitly mention a separate training set or its sample size. This type of submission for an in vitro diagnostic (IVD) device typically focuses on clinical validation (test set) for regulatory approval rather than machine learning model training.

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

• As no training set is explicitly described, there is no information provided on how its ground truth might have been established.

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This test system is for in vitro diagnostic use for the detection of antinuclear antibodies in human serum, with specific identification of autoantibodies to the SS-A/Ro antigen. This test system is to be used as an aid in the detection of antibodies associated with systemic rheumatic disease. The results from this assay can be used as an aid in the diagnosis of autoimune diseases.

This is an indirect fluorescent antibody test for the semi-quantitative detection of antinuclear antibody in human serum. The transfected HEP-2 cell line allows for the identification of anti-SS-A/Ro antibodies because of the unique staining pattern that these antibodies show on this cell line.

Here's an analysis of the provided text, outlining the acceptance criteria and study details for the HEp-2000® Fluorescent ANA-Ro Test System:

Acceptance Criteria and Device Performance Study

The provided text describes a submission for a new device, the HEp-2000® Fluorescent ANA-Ro Test System, seeking substantial equivalence to a legally marketed device (RELISA® SS-A/SS-B Antibody Test System, K955603). The study focuses on demonstrating the unique ability of the HEp-2000® cell line to specifically identify anti-SS-A/Ro antibodies and confirming the presence of SS-A/Ro antibodies.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied through the comparisons to existing HEp-2 cells and ELISA testing, specifically highlighting the ability to identify SS-A/Ro antibodies distinctly.

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

The "test set" in this context refers to the samples used to demonstrate the device's performance against the described criteria, likely corresponding to a validation or clinical study set.

• Sample Sizes:
  • Normal Samples: 500 healthy blood donors (242 females, 258 males).
  • Sera from Patients with Only Ro/SS-A Antibodies: 46 patients with SLE or Sjögren's Syndrome.
  • Sera from Patients with Autoantibodies Other Than SS-A/Ro: 230 patients with a variety of rheumatic and non-rheumatic diseases.
  • Titer Reproducibility: 10 samples (CDC controls and in-house sera).
  • Confirmation of SS-A/Ro Antibodies: 349 patients with known positive ANA tests (from a large rheumatology reference laboratory).
  • Total SS-A/Ro containing sera examined across studies: 429 sera.
• Data Provenance: The document does not explicitly state the country of origin. The mention of "CDC controls" (Centers for Disease Control and Prevention) suggests a US origin or at least use of US-standardized materials. Given the FDA submission, it's highly likely the studies were conducted in or accepted by the US regulatory framework. The data is retrospective, as it involves analyzing existing sera.

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 or qualifications of experts used for establishing ground truth, such as interpreting the HEp-2 or HEp-2000 staining patterns. It implies that these interpretations were done by qualified laboratory personnel following established protocols for fluorescent antibody tests. However, the ground truth for the presence of SS-A/Ro antibodies was established through objective methods.

4. Adjudication Method for the Test Set

The document does not explicitly describe a formal adjudication method (like 2+1 or 3+1 consensus) for the interpretation of fluorescent patterns. The interpretation appears to be based on standard laboratory practice, with discrepancies or confirmations being resolved by "ELISA testing and by Western immunoblotting." This suggests a hierarchical approach rather than a consensus among multiple human readers for pattern interpretation.

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

No, a MRMC comparative effectiveness study was not explicitly described. The study compares the performance of the new device (HEp-2000®) against an older method (non-transfected HEp-2 cells) and a predicate ELISA device, but it doesn't involve multiple human readers interpreting cases with and without AI assistance to measure reader improvement. The "device" in this context is primarily an improved assay, not an AI-powered interpretation tool for human readers.

6. Standalone Performance Study

Yes, a standalone performance study was implicitly done. The entire submission describes the performance of the "HEp-2000® Fluorescent ANA-Ro Test System" (the algorithm/device) on its own, independent of human interpretation improvements (as it's a diagnostic test providing a result rather than an interpretative aid). The results presented are the direct output of the test system, compared to ground truth methods.

7. Type of Ground Truth Used

The ground truth for the presence or absence of SS-A/Ro antibodies was established by objective, highly specific laboratory methods:

• ELISA testing (Predicate Device): RELISA® SS-A/SS-B Antibody Test System (K955603)
• Western immunoblotting

For the patterns observed on HEp-2 and HEp-2000 cells, the ground truth is established by the accepted morphological characteristics of these patterns, which implicitly relies on expert consensus in the field for what constitutes a "speckled pattern" or "typical SS-A/Ro staining." However, when a discrepancy arose or confirmation was needed, the more objective ELISA and Western blot results trumped the pattern interpretation for confirming SS-A/Ro antibody presence.

8. Sample Size for the Training Set

The document does not specify a separate "training set" or its sample size. The entire dataset described appears to be used for validation and demonstration of performance. This is typical for a 510(k) submission for an in-vitro diagnostic assay improvement, where the "training" (development) of the cell line happened prior to these validation studies.

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

Since a separate "training set" is not detailed, the method for establishing ground truth for any underlying development of the HEp-2000® cell line is not described in this document. It can be inferred that the development of the transfected cell line was guided by scientific understanding of SS-A/Ro autoantigen expression and its visual manifestation in IF (Immunofluorescence) assays, likely confirmed by similar biochemical and immune-assay methods as used in the validation steps (e.g., ELISA, Western Blot, molecular characterization of the transfection).

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