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Immunoassay for the in vitro qualitative detection of total antibodies (IgG and IgM) to Treponema pallidum in human serum and plasma. The test is intended as an aid in the diagnosis of syphilis infection in conjunction with clinical signs and symptoms.

The Elecsys Syphilis immunoasay is not in screening blood or tissue donors. The effectiveness of this assay in testing blood or tissue donors has not been established.

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

The Elecsys Syphilis immunoassay is a fully automated, qualitative assay that uses a double antigen sandwich format for the detection of IgM and IgG antibodies to T. pallidum.

Recombinant T. pallidum antigens labeled with either biotin or a ruthenium complex bind to T. pallidum-specific IgG or IgM to form a double antigen sandwich complex. The sandwich complex binds to streptavidin-coated microparticles which can be immobilized magnetically to the surface of an electrode. Unbound substances are removed during a wash step using ProCell. A chemiluminescent substrate is then added to the reaction tube. Application of a voltage to the electrode induces a chemiluminescent emission which is measured by a photomultiplier.

The presence or absence of anti-TP antibodies in the specimen is determined by comparing the chemiluminescent signal in the reaction to the cutoff index (COI) determined from an active calibration. The strength of the signal generated is proportional to the amount of bound conjugate and thus the amount of anti-T. pallidum antibodies present in the specimen. If the chemiluminescent signal in the reaction is greater than or equal to the cutoff signal, the specimen is considered reactive for anti-TP antibodies. If the chemiluminescent signal is below the cutoff signal, the specimen is considered nonreactive for the anti-TP antibodies.

The provided text describes the Elecsys Syphilis immunoassay, an in vitro diagnostic device, and its evaluation for substantial equivalence to a predicate device (Elecsys Syphilis K160910) following an update to improve biotin tolerance.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for this 510(k) submission revolve around demonstrating that the updated Elecsys Syphilis assay is as safe and effective as the predicate device, with the added benefit of improved biotin tolerance. The document states that "All performance specifications were met." While specific numerical acceptance criteria for each study (e.g., precision coefficients of variation, acceptable bias for method comparison) are not explicitly detailed as a formal table with pass/fail values, the reported device performance indicates that these criteria were satisfied.

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

• Precision Study:
  • Sample Size: Two aliquots of each of two levels of controls and 7 human serum samples were tested per run. This was done for 2 runs per day for 21 days. (Total of 9 distinct samples tested repeatedly).
  • Data Provenance: Not explicitly stated, but "human serum samples" suggests clinical samples. The text does not specify country of origin or if they were retrospective or prospective, but for precision studies, these factors are usually less critical than for clinical performance studies.
• Biotin Interference Study:
  • Sample Size: Three serum samples (negative, close to cut-off, positive) were used. These were typically pooled samples.
  • Data Provenance: Not explicitly stated, but implies human serum.
• Method Comparison Study:
  • Sample Size: A total of 232 samples from the intended use population.
  • Data Provenance: Not explicitly stated, but "samples from the intended use population" implies clinical samples. The text does not specify country of origin or if they were retrospective or prospective.

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

This information is not provided in the document. The Elecsys Syphilis assay is an in vitro diagnostic device that detects antibodies. Its performance is typically assessed by comparing its results to established reference methods (e.g., other FDA-cleared syphilis tests, Western Blot) or by using samples with a known status (e.g., from syphilis patients or healthy controls). The ground truth for this type of device is usually based on the results of these reference methods or known clinical status, rather than expert adjudication of images or clinical cases.

4. Adjudication Method (for the test set)

Adjudication methods (like 2+1, 3+1) are typically used in studies where human readers interpret complex data (e.g., medical images) to establish a consensus ground truth. This is not applicable to this type of in vitro diagnostic device study, as the ground truth is established through laboratory reference methods or known sample status.

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

This information is not applicable to this device. The Elecsys Syphilis is a fully automated immunoassay, not an AI-powered diagnostic device that assists human readers. Therefore, an MRMC study and analysis of human reader improvement with AI assistance are not relevant to this submission.

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

The Elecsys Syphilis immunoassay is a standalone device in the sense that it is a fully automated assay that produces a result (Reactive or Nonreactive) without human interpretation steps in the analytical measurement process. Its performance (precision, biotin tolerance, method comparison) reflects its standalone analytical accuracy and reliability. However, its stated "Indications for Use" mention that it is an "aid in the diagnosis... in conjunction with clinical signs and symptoms" and that results "should always be interpreted in conjunction with additional treponemal or non-treponemal serologic test results." This implies that while the assay itself operates standalone, the final diagnosis based on its results involves a human clinician and other diagnostic information. Nevertheless, the performance studies described (precision, biotin tolerance, method comparison) represent the standalone analytical performance of the device.

7. The Type of Ground Truth Used

The ground truth for the test set samples used in the method comparison and potentially the precision studies is implied to be:

• Clinical Status/Reference Method: Samples "from the intended use population" were used, suggesting samples from individuals with known or suspected syphilis status, likely confirmed by a reference method or a panel of tests. The comparison to the predicate device (another immunoassay) also helps establish agreement against a cleared standard.
• Known Concentration/Status: For precision and biotin interference studies, samples might include negative, low positive, and high positive samples, or samples close to the cutoff, where their status or concentration is well-characterized.

The document states that results "should always be interpreted in conjunction with additional treponemal or non-treponemal serologic test results (as appropriate), the patient's clinical symptoms, medical history, and other clinical and/or laboratory findings to produce a diagnosis of syphilis by disease stage." This holistic approach suggests the ultimate ground truth for a diagnosis is a comprehensive clinical assessment, but for assay performance evaluation, it relies on reference methods and known sample characteristics.

8. The Sample Size for the Training Set

This information is not provided. This device is an immunoassay, not a machine learning or AI algorithm in the context of typical "training sets." Immunoassays are developed based on chemical and biological principles (e.g., antibody-antigen binding, chemiluminescence) and calibrated, rather than "trained" with a dataset in the AI sense. Calibration involves using a small set of calibrator materials (Syphilis Cal1 and Cal2 mentioned).

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

As explained above, the concept of a "training set" and "ground truth for a training set" in the AI sense does not directly apply to this immunoassay. The device is calibrated using specific calibrator materials (Syphilis Cal1 and Cal2), which are human serum preparations with known (negative or reactive) anti-TP antibody status, as stated in the device description. These calibrators establish the signal cutoff for reactive vs. nonreactive results.

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Immunoassay for the in vitro qualitative detection of total antibodies (IgG and IgM) to Treponema pallidum in human serum and plasma. The test is intended as an aid in the diagnosis of syphilis infection with clinical signs and symptoms.

The Elecsys Syphilis immunoassay is not intended for use in screening blood or tissue donors. The effectiveness of this assay in testing blood or tissue donors has not been established.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on the cobas e 411 analyzer.

PreciControl Syphilis is intended for the quality control of the Elecsys Syphilis immunoassay on the cobas e 411 analyzer.

The Elecsys Syphilis assay is a fully automated qualitative assay detecting IgG and IgM antibodies to Treponema pallidum, the causative agent of syphilis. Assay results, in conjunction with other laboratory results and clinical information, may be used to provide presumptive evidence of active or previous infection with Treponema pallidum in persons with signs and symptoms of syphilis, as well as in patients at risk for syphilis infection. This assay does not determine the stage of infection or associated disease.

PreciControl Syphilis is a lyophilized control based on human serum. It is used for monitoring the accuracy of the Elecsys Syphilis immunoassay.

Here's a breakdown of the acceptance criteria and study details for the Elecsys Syphilis assay, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state quantitative acceptance criteria for sensitivity and specificity. Instead, it presents the performance of the Elecsys Syphilis assay compared to a "final comparator algorithm" or "medically diagnosed individuals" and implies that "good agreement" and "substantial equivalence" are the overarching criteria.

Assuming the implicit acceptance criteria are high levels of positive percent agreement (PPA) and negative percent agreement (NPA) with the established comparator, here's a table summarizing the reported performance:

*Note: The document states "good agreement" and "substantially equivalent," which generally implies high sensitivity and specificity for diagnostic assays. The specific quantitative thresholds are not explicitly defined as "acceptance criteria" but are demonstrated by the reported results.

2. Sample Sizes and Data Provenance

• Test Set Sample Sizes:

  • Prospective Cohorts: Total of 2282 samples.
    • Routine Syphilis testing: 1524 subjects
    • HIV positive subjects: 457 subjects
    • Pregnant women: 301 subjects
  • Retrospective Medically Diagnosed Individuals: Total of 169 specimens.
    • Pregnant positive women: 15
    • Subjects medically diagnosed with syphilis at different stages: 154
  • Apparently Healthy Individuals: 209 specimens.
  • Analytical Specificity: 266 human clinical samples from patients with medical conditions unrelated to Syphilis.

• Data Provenance: The document generally refers to "human serum and plasma" samples.

  • Prospective Cohorts: "prospectively collected samples of the intended use population." A multi-center study was conducted in the EU and the US for cut-off validation, implying global data.
  • Retrospective Medically Diagnosed Individuals: "pre-selected retrospective cohort."
  • The "apparently healthy individuals" and "analytical specificity" samples are also clinical.

• Retrospective or Prospective: Both retrospective and prospective data were used for clinical performance evaluation.

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the "number of experts" or their "qualifications" used to establish the ground truth.

4. Adjudication Method for the Test Set

The ground truth for the clinical performance studies was established using a "composite algorithm" rather than expert adjudication.

• Composite Algorithm: For the prospective cohorts, "all samples were tested according to a composite algorithm using FDA-cleared tests that included the predicate Syphilis immunoassay, the Rapid Plasma Reagin (RPR) non-treponemal specific assay and the Treponema pallidum Particle Agglutination, treponemal-specific assay."
• For the retrospective medically diagnosed individuals, the ground truth was based on "medically diagnosed individuals" and the "final comparator results" from the composite algorithm.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study comparing human readers with and without AI assistance was not conducted. This device is an in-vitro diagnostic (IVD) immunoassay, not an AI-assisted diagnostic imaging or interpretation tool for human readers.

6. Standalone (Algorithm Only) Performance

Yes, the studies presented are for standalone (algorithm only) performance. The Elecsys Syphilis assay is an automated immunoassay that provides a qualitative result (reactive or non-reactive) without human interpretation in the loop for the primary result generation. Its performance is measured against established diagnostic algorithms and clinical diagnoses.

7. Type of Ground Truth Used

The primary ground truth used for evaluating clinical performance was a composite algorithm of FDA-cleared tests (predicate immunoassay, RPR, and TPPA). Additionally, a medical diagnosis was used for the retrospective cohort.

8. Sample Size for the Training Set

The document does not explicitly state the sample size for a "training set." This type of IVD immunoassay typically involves extensive assay development and optimization rather than a "training set" in the machine learning sense. The "cut-off determination" process likely utilized a set of samples, but these are not explicitly termed a "training set" with a specified size.

• Cut-off Determination: "native human serum samples were measured with a prototype lot of the Elecsys Syphilis assay and a preliminary cut-off was set."
• Final Validation: "Final validation of the cut-off was done in multi-center studies conducted in the EU and the US."

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

As there's no explicitly defined "training set" in the machine learning context, the ground truth for cut-off determination would have been established through a combination of:

• Known positive and negative samples: These would have been derived from individuals with confirmed syphilis infections (using reference methods or clinical diagnosis) and confirmed non-infected individuals.
• Preliminary cut-off setting: Based on the distribution of results from these known samples.
• Comparability with commercially available assays: Used to refine and validate the cut-off.

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