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The Access Syphilis assay is a paramagnetic particle, chemiluminescent immunoassay for the qualitative detection of total antibodies to Treponema pallidum in human serum and plasma using the Access lmmunoassay Systems. It is intended to be used as an aid in the diagnosis of syphilis or in conjunction with a nontreponemal laboratory test and clinical findings to aid in the diagnosis of syphilis infection. The Access Syphilis assay is not intended for blood and tissue donor screening.

The Access Syphilis assay is a two-step enzyme immunoassay. A sample is added to a reaction vessel with buffer, paramagnetic particles coated with recombinant Treponema pallidum antigens Tp17 and Tp47, and Tp47, and biotinylated Treponema Tp17 & Tp47 antigens. After incubation in a reaction vessel, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Alkaline phosphatase conjugates are added, and the conjugates bind to the immunoglobulin captured on the particles. A chemilyminescent substrate is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is proportional to the amount of Treponema pallidum antibodies in the sample. The light quantity measured for a sample allows a determination of the presence of the analyte by comparison with a cut-off value defined during the assay calibration on the instrument. The Access Syphilis reagents are provided in liquid ready-to-use format designed for optimal performance on the Beckman Coulter Access Immunoassay Systems. Each reagent kit contains two reagent packs.

The Access Syphilis assay is a qualitative immunoassay for detecting total antibodies to Treponema pallidum in human serum and plasma, used as an aid in diagnosing syphilis. The device was evaluated for its clinical performance on two systems: the Access 2 Immunoassay System and the Dxl 9000 Access Immunoassay Analyzer. The acceptance criteria and performance data are primarily based on percent agreement with a composite reference method.

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance:

The document does not explicitly state pre-defined acceptance criteria values for Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA). However, the results presented are implicitly the "performance" that aims to demonstrate substantial equivalence. The following table summarizes the reported performance in key clinical evaluation cohorts:

*Note on NPA for Retrospective Specimens: The low NPA for retrospective specimens is due to a very small number of non-reactive specimens in the comparator (only 4), making the percentage highly sensitive to a single misclassification. The 31 reactive results from Access Syphilis where the comparator was nonreactive need further investigation, which the document attributes to "3 specimens were reactive by treponemal immunoassay and nonreactive by RPR and TPPA". This suggests potential discordance with the composite comparator definition for these few cases rather than a broad failing of the device's negative detection.

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

The study involved a total of 1,910 specimens for clinical performance evaluation. These specimens were broadly characterized as:

• 1,104 prospectively collected specimens from the intended use population. The age range was 12 to >89 years, with 63.8% female and 36.2% male. This cohort included:
  • 399 patients sent for syphilis testing
  • 405 pregnant women
  • 300 HIV positive patients
• 402 retrospective specimens from patients (including 22 from pregnant females).
• 204 prospectively collected specimens from apparently healthy individuals.
• 150 retrospective specimens from patients with medically diagnosed syphilis (primary, secondary, and latent stages).
• 50 retrospective specimens from individuals at high-risk of sexually transmitted disease.

The provenance of the data is multicenter, meaning specimens were collected from multiple clinical sites. Both retrospective and prospective data were used. The document does not explicitly state the country of origin, but the submission to the U.S. FDA suggests a U.S. or international clinical setting adhering to FDA standards.

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

The document does not mention the use of human experts to establish the ground truth for the test set in the traditional sense (e.g., radiologists interpreting images). Instead, the "final comparator result" (ground truth) was established using a composite testing algorithm of multiple FDA-approved laboratory assays, which is standard practice for in vitro diagnostic devices.

4. Adjudication Method for the Test Set:

The adjudication method used a composite testing algorithm as the "final comparator result." This algorithm consisted of:

• An FDA-approved predicate treponemal immunoassay.
• A non-treponemal assay (RPR - Rapid Plasma Reagin).
• A second treponemal assay (TPPA - Treponema Pallidum Particle Agglutination).

The document does not detail a specific "2+1" or "3+1" adjudication process involving human review for discordant results beyond the internal algorithmic comparison. However, for discordant results in the HIV positive patient subpopulation (where the Access Syphilis assay showed lower NPA), an additional FDA-cleared electrochemiluminescent immunoassay was used to further evaluate 28 discordant specimens.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done:

No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic assay, not an imaging AI device that involves human readers interpreting images with or without AI assistance. The performance is assessed by comparing the device's output to established laboratory reference methods, not human interpretation.

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

Yes, the clinical performance study is a standalone performance evaluation. The Access Syphilis assay is an automated immunoassay system that provides results independently. Its performance (reactive/non-reactive) is directly compared against the composite reference standard without human interpretation of the assay's raw output.

7. The type of ground truth used:

The ground truth was established using a composite testing algorithm consisting of results from:

• An FDA-approved predicate treponemal immunoassay.
• A non-treponemal assay (RPR).
• A second treponemal assay (TPPA).

This acts as a "reference standard" or "expert consensus" in the context of laboratory diagnostics, where consensus among multiple established tests determines the final disease status. In some cases, "medically diagnosed syphilis" for specific retrospective cohorts also contributed to the understanding of the samples.

8. The sample size for the training set:

The document does not specify a separate training set size for the Access Syphilis assay. As a chemiluminescent immunoassay, it is a biochemical test, not an AI/machine learning algorithm that typically requires a discrete "training set" in the same way. The assay's parameters would have been optimized during its development phase using internal studies, but these are not referred to as a "training set" in the context of typical AI device submissions.

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

Since a distinct "training set" in the AI/ML sense is not described, the method for establishing its ground truth is not applicable in the document. The development of an immunoassay involves extensive analytical and clinical validation, which ensures the reagents and system accurately detect the target antibodies. This process implicitly refines the assay's performance against known positive and negative samples, similar to how a training set might function for an algorithm.

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For the qualitative determination of total (IgG and IgM) antibodies to Treponema pallidum (TP) specific antigens in human serum and plasma using the VITROS 5600 Integrated System.

The presence of antibodies to Treponema pallidum (TP) specific antigens, in conjunction with non-treponemal laboratory tests and clinical findings may aid in the diagnosis of syphilis infection.

The VITROS Syphilis test is not intended for blood and tissue donor screening.

The VITROS Immunodiagnostic Products Syphilis test is performed using the VITROS Immunodiagnostic Products Syphilis Reagent Pack and VITROS Immunodiagnostic Products Syphilis Calibrator on the VITROS 5600 Integrated System.

An immunometric technique is used; this involves a two-stage reaction. In the first stage antibodies to Syphilis TP specific antigens present in the sample bind with biotinylated recombinant Syphilis TP antigens immobilized on streptavidin coated wells. Unbound sample is removed by washing. In the second stage conjugate reagent containing horseradish peroxidase (HRP)-labeled recombinant Syphilis TP antigens is added. The conjugate binds specifically to any antibody to Syphilis TP specific antigens captured on the well in the first stage. Unbound conjugate is removed by washing.

The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system.

Here's a detailed breakdown of the acceptance criteria and the study proving the device meets these criteria, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the clinical performance results meeting high percentage agreements. While explicit numeric acceptance criteria (e.g., "PPA must be >X%") are not directly stated in a dedicated section, the sponsor presents the results and concludes substantial equivalence, indicating that these results were considered acceptable.

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

• Test Set Sample Size:
  • Prospective Specimens: 924 total specimens.
    • 615 subjects for routine syphilis testing (from 6 sites in the United States).
    • 47 pregnant women.
    • 262 HIV positive subjects.
  • Retrospective Specimens: 547 total specimens.
    • 243 samples from pregnant women.
    • 152 HIV positive samples.
    • 152 pre-selected positive samples.
  • Medically Diagnosed Individuals: 151 samples.
  • Apparently Healthy Individuals: 201 prospective specimens (from 3 sites in the United States).
  • Total Clinical Samples: 924 (prospective) + 547 (retrospective) + 201 (apparently healthy) = 1672 specimens for primary clinical evaluation. The medically diagnosed group is a subset likely included within the prospective/retrospective groups or as additional targeted samples.
• Data Provenance:
  • Country of Origin: United States (for prospective and apparently healthy specimens). Retrospective samples are "purchased," implying they may originate from various sources but were tested at sites.
  • Retrospective or Prospective: Both retrospective and prospective clinical studies were conducted.

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

The document does not specify the number of experts or their qualifications for establishing the ground truth. Instead, the ground truth was established using a "composite testing algorithm."

4. Adjudication method for the test set

The adjudication method relied on a composite testing algorithm using:

• A treponemal electrochemiluminescence immunoassay (TP-ECLIA)
• A Rapid Plasma Reagin (RPR) non-treponemal assay
• A Treponema pallidum Particle Agglutination (TP-PA) Treponema-specific assay

Cases were categorized as "Positive for Syphilis" or "Negative for Syphilis" based on the results of these FDA-cleared comparator assays. The document describes specific combinations of results from these three assays that led to a final comparator result. For example, "Non-reactive TP-ECLIA + Non-reactive RPR" was deemed "Negative," while "Reactive TP-ECLIA + Reactive RPR (and N/A TP-PA)" was "Positive." Discordant results with the final comparator were further analyzed (e.g., 14 discordant prospective samples were found reactive by another FDA-cleared TP antibody test).

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

No, an MRMC comparative effectiveness study involving human readers and AI assistance was not conducted or reported. This device is an in vitro diagnostic test (IVD) for laboratory use, not an AI-powered image analysis or diagnostic aid for human readers.

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

Yes, the studies presented are standalone performance evaluations of the VITROS Immunodiagnostic Products Syphilis test (an algorithm-driven instrument/reagent system) without human-in-the-loop performance being a variable in the reported clinical accuracy. The assay itself performs the determination.

7. The type of ground truth used

The ground truth used was a composite testing algorithm based on multiple FDA-cleared comparator assays (TP-ECLIA, RPR, and TP-PA). This is a form of clinical surrogate ground truth derived from established diagnostic tests, rather than direct pathology, biopsy, or long-term outcomes data, which are typically used for definitive diagnosis in some other medical fields.

8. The sample size for the training set

The document does not provide information on the sample size for a training set. This is because the device described is an immunoassay, a biochemical test, not a machine learning or AI algorithm that typically requires a separate training set. The reported studies evaluate the locked-down analytical and clinical performance of the manufactured diagnostic kit.

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

Since there is no training set mentioned for an AI/machine learning algorithm, the concept of establishing ground truth for a training set is not applicable here. The assay's internal calibration and optimization would have been performed during product development, but this is distinct from "training" an AI model in the context of imaging or predictive analytics.

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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.

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The BioPlex Syphilis Total & RPR kit is a multiplex flow immunoassay intended for the qualitative detection of total (IgG/IgM) antibodies to Treponema pallidum and the qualitative detection and/or titer determination of non-treponemal reagin antibodies in human serum or plasma. The Syphilis Total or RPR assays may be used to supplement a previously determined reactive treponemal or non-treponemal test. The test system should be used in conjunction with other laboratory tests and clinical findings to aid in the diagnosis of syphilis infection.

The BioPlex 2200 Syphilis Total & RPR kit is not intended for use in screening blood or plasma donors

The BioPlex 2200 Syphilis Total & RPR kit is intended for use with the Bio-Rad BioPlex 2200 System.

The BioPlex 2200 Syphilis Total & RPR Control Set is intended for use as an assayed quality control to monitor the performance of the BioPlex 2200 Instrument and BioPlex 2200 Syphilis Total & RPR assay in the clinical laboratory. The performance of the BioPlex 2200 Syphilis Total & RPR Control Set has not been established with any other Syphilis Total & RPR assays.

The BioPlex 2200 Syphilis Total & RPR Calibrator Set is intended for the BioPlex 2200 Syphilis Total & RPR Reagent Pack.

BioPlex 2200 Syphilis Total & RPR kit includes the following components:

• One (1) 10 mL vial, containing dyed beads coated with recombinant Syphilis ● rTP47/rTP17 fusion protein, a cardiolipin antigen, an Internal Standard Bead (ISB) and a Serum Verification Bead (SVB) in MOPS (3-[N-Morpholino] propanesulfonic acid) buffer containing bovine proteins with protein stabilizers. ProClin 300 (≤ 0.3%), sodium benzoate (≤ 0.1%) and sodium azide (

Here's an analysis of the provided text, extracting the acceptance criteria and study details as requested:

BIO-RAD BioPlex 2200 Syphilis Total & RPR Kit Evaluation

1. Table of Acceptance Criteria and Reported Device Performance

The document describes internal precision and reproducibility acceptance criteria implicitly through the reported values for %CV within CLSI guidelines. For clinical performance, acceptance criteria are not explicitly stated as numerical thresholds (e.g., minimum sensitivity/specificity), but agreement percentages are reported. The provided tables are direct results from the studies and serve as the reported performance against assumed internal/regulatory acceptance ranges.

For Syphilis Total Assay (Treponemal Test):

For RPR Assay (Non-Treponemal Test):

2. Sample Size and Data Provenance for Test Set

• Total Samples for Clinical Studies: 2008 samples.
• Test Set Breakdown:
  • Prospective Samples: 1001 samples.
    • Country of Origin: Approximately 91% US (23.6% Northeast, 18.7% Southwest, 28.4% Southeast, 9.2% Midwest, 10.8% Unknown), 9% outside US (3.5% Argentina, 3.2% France/Europe, 1.4% China, 1.2% Others).
  • Retrospective Samples: 661 samples.
    • Country of Origin: Not explicitly broken down for retrospective samples, but generally stated to be from "multiple commercial suppliers" with the 91% US / 9% outside US split likely encompassing both.
  • Clinically Diagnosed Individuals: 160 individuals (separate cohort from prospective/retrospective samples with specific diagnoses).
• Data Provenance: Both prospective and retrospective samples were used. Prospectively collected samples were from apparently healthy subjects, syphilis/RPR test ordered patients, pregnant women, and HIV positive individuals. Retrospective samples were from known RPR/VDRL positive, clinically diagnosed syphilis, pregnant syphilis positive, and HIV/Syphilis dual positive individuals.

3. Number of Experts and Qualifications for Ground Truth

The document does not explicitly state the number or qualifications of "experts" used for establishing the ground truth directly. Instead, it relies on a "Final Comparator Algorithm Result" for the Syphilis Total assay, which is derived from multiple commercially available syphilis assays (predicate devices). For the RPR assay, the ground truth is primarily based on a commercially available RPR Card Test (Predicate).

• No specific number of human experts is mentioned for adjudicating individual cases or establishing the final ground truth. The "ground truth" seems to be established algorithmically or through established predicate diagnostic tests.

4. Adjudication Method

• For BioPlex 2200 Syphilis Total assay: The ground truth was established using a "2 out of 3" rule from three commercially available syphilis assays:
  1. Treponemal chemiluminescent immunoassay (primary predicate)
  2. RPR Card Test (non-treponemal assay)
  3. Treponema Pallidum Particle Agglutination (TP-PA) (second treponemal assay)
     If at least two of these predicate assays agreed, that was considered the final comparator result. If there was no agreement (e.g., 1 positive, 1 negative, 1 inconclusive), the result was deemed "indeterminate" and excluded from analysis.
• For BioPlex 2200 RPR assay: The ground truth was established by comparing directly to a commercially available RPR Card Test (Predicate). No explicit "adjudication" among multiple assays is described here.

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

• No MRMC or human-in-the-loop study is described in this document. The device is an automated immunoassay system, and its performance is compared to other diagnostic assays (predicate devices), not to human readers. Therefore, there is no effect size reported for human readers improving with or without AI assistance.

6. Standalone Performance Study

• Yes, a standalone performance study was done. The entire document describes the standalone performance of the BioPlex 2200 Syphilis Total & RPR kit. The device is an algorithm only (automated immunoassay) without a human-in-the-loop component in the diagnostic process itself. The clinical performance tables explicitly show the agreement of the BioPlex 2200 with the "Final Comparator Algorithm Result" (for Syphilis Total) or the "Predicate RPR Result" (for RPR).

7. Type of Ground Truth Used

• For Syphilis Total assay: A composite comparator algorithm based on the results of three commercially available diagnostic assays (predicate Treponemal CIA, RPR Card Test, TP-PA). This could be categorized as a form of expert consensus using established diagnostic tests rather than pathology or direct outcomes data for every individual case.
• For RPR assay: A single predicate diagnostic assay (RPR Card Test).

8. Sample Size for Training Set

• The document does not explicitly state the sample size used for the training set. It mentions the "feasibility phase of BioPlex 2200 Syphilis Total & RPR assay development" where cutoff values were established using "native human samples from apparently healthy subjects, patients sent to the laboratory for syphilis testing and patients diagnosed with syphilis infection." However, specific numbers for this development/training phase are not provided.

9. How Ground Truth for Training Set Was Established

• The cutoff values for the Syphilis Total and RPR assays were established "in the feasibility phase" using Native human samples from:
  • Apparently healthy subjects
  • Patients sent to the laboratory for syphilis testing
  • Patients diagnosed with syphilis infection
• The establishment involved Receiver Operating Characteristics (ROC) analysis using "predicate results as standard". This indicates that the ground truth for establishing the cutoffs was derived from existing, legally marketed assays (predicates). Calibrator values were then adjusted based on this analysis to align with the 1.0 AI cutoff. Further confirmation of cutoff values involved comparing BioPlex results from patient samples to commercially available assays, and ultimately, clinical studies validated the cutoff.

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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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Lumipulse G TP-N Immunoreaction Cartridges Set For in vitro diagnostic use. WARNING: Lumipulse G TP-N is not intended for blood and tissue donor screening. United States federal law restricts this device to sale by or on the order of a physician. Lumipulse G TP-N is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the qualitative determination of antibodies (1gG and 1gM) to Treponema pallidum in human serum and plasma (sodium citrate, or dipotassium EDTA) on the LUMIPULSE & System. Lumipulse G TP-N can be used as an initial diagnostic test or in conjunction with a nontreponemal laboratory test and clinical findings to aid in the diagnosis of syphilis infection.

The Lumipulse G TP-N is an assay system, including a set of immunoassay reagents, for the qualitative detection of anti-TP antibodies (IgG and IgM) in specimens based on CLEIA technology by a two-step sandwich immunoassay method on the LUMIPULSE G System.

Here's an analysis of the acceptance criteria and study detailed in the provided document:

Device: Lumipulse G TP-N Immunoreaction Cartridges Set (for qualitative determination of antibodies to Treponema pallidum)

Indications for Use: For in vitro diagnostic use. Can be used as an initial diagnostic test or in conjunction with a nontreponemal laboratory test and clinical findings to aid in the diagnosis of syphilis infection.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a numerical, pre-defined format for PPA/NPA. Instead, it presents the performance results obtained and implicitly compares them to the predicate device's expected performance and clinical utility. For qualitative assays like this, the relevant performance metrics are Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA).

Note: The document states, "The results of these analytical (nonclinical) and clinical studies demonstrate that the performance of the Lumipulse G TP-N assay is substantially equivalent to the performance of the ADVIA Centaur Syphilis (SYPH) assay." This implies that the observed PPA and NPA values were considered acceptable for demonstrating substantial equivalence to the predicate device.

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

• Total Test Set Sample Size: 2,791 subjects were submitted for testing. After exclusions, 1,290 evaluable prospective samples and 1,472 evaluable retrospective samples were used.
• Data Provenance:
  • Prospective Samples: Collected sequentially from patients prescribed a laboratory test for syphilis during a defined period. Collected from 7 sites representing different geographical regions of the US, including both low-prevalence and high-prevalence sites.
  • Retrospective Samples: Pre-selected (enriched population) from various sources:
    • 379 pregnant women (250 without syphilis, 129 with syphilis)
    • 520 HIV positive subjects (298 remnant samples from reference laboratories, 222 collected at a research facility)
    • 130 known to be T. pallidum (TP)-reactive by previous laboratory testing
    • 68 samples from a research facility from patients clinically diagnosed with syphilis
    • 375 samples consisting of remnants of specimens for routine syphilis testing
    • 289 samples from subjects with well-characterized medically diagnosed syphilis (from Argentina (52%) and Florida (48%))
    • 474 samples from apparently healthy subjects (75 pediatric, 399 adult/not pregnant).

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

The ground truth for the test set was not established by individual experts reviewing cases. Instead, it was based on an algorithmic combination of results from other FDA-cleared laboratory tests. Therefore, information regarding "number of experts" and their "qualifications" is not applicable in the traditional sense of image or clinical interpretation.

4. Adjudication Method for the Test Set

The adjudication method was a "2 out of 3 rule" based on the results of three FDA-cleared tests:

1. A treponemal test (EIA)
2. A non-treponemal Rapid Plasma Reagin (RPR) test
3. A second treponemal test, Treponema pallidum particle agglutination (TP-PA)

The "Final Comparator Result" was determined as Positive or Negative if at least two of the three comparator tests yielded a consistent result.

• Example: Positive EIA + Positive RPR + Positive TP-PA = Positive Final Comparator Result.
• Example: Negative EIA + Negative RPR + Negative TP-PA = Negative Final Comparator Result.
• Example: Negative EIA + Positive RPR + Positive TP-PA = Positive Final Comparator Result.
• Indeterminate Results: Cases were considered "Indeterminate" if the EIA was "equivocal" and the TP-PA was "inconclusive". These were excluded from the final analysis.

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

No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic assay for qualitative determination of antibodies. Its performance is evaluated against a pre-established "ground truth" derived from other laboratory tests, not by comparing human reader performance with and without AI assistance in interpreting diagnostic images or clinical data.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, a standalone performance study was done. The entire clinical study presented (comparison against the "Final Comparator Result") represents the standalone performance of the Lumipulse G TP-N assay, as it is an automated laboratory test. There is no human interpretation or "in-the-loop" component in the direct output of this specific device.

7. The Type of Ground Truth Used

The ground truth used was a "Reference Comparator Algorithm" based on the consensus results of three established, FDA-cleared laboratory tests (EIA, RPR, and TP-PA), using a "2 out of 3 rule."

8. The Sample Size for the Training Set

The document describes performance characteristics and clinical comparison studies for the Lumipulse G TP-N. It does not explicitly mention a "training set" in the context of machine learning. For in-vitro diagnostic assays like this, the development typically involves:

• Internal studies for analytical performance (precision, interference, cross-reactivity).
• Clinical validation studies for method comparison to established comparator methods or reference standards.

The closest analogue to initial "training" or development data might be mentioned in the section on "Assay cut-off": "Lumipulse G TP-N was developed in 1997. 312 negative specimens, 99 positive specimens, and 6 intermediate specimens previously assigned using TP-PA were measured with Lumipulse G TP-N in order to establish its cut-off index."

• If this is considered the "training set" for cutoff establishment: 417 samples (312 negative, 99 positive, 6 intermediate).

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

For the establishment of the assay cut-off, the "ground truth" for the 417 samples (312 negative, 99 positive, 6 intermediate) was established using TP-PA (Treponema pallidum particle agglutination), which is described as a previous method for assigning positivity/negativity.

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The ARCHITECT Syphilis TP assay is a chemiluminescent microparticle immunoassay (CMIA) for the qualitative detection of antibodies (IgG and IgM) directed against Treponema pallidum (TP) in human serum and plasma. The ARCHITECT Syphilis TP assay is intended to be used as an initial diagnostic test or in conjunction with a nontreponemal laboratory test and clinical findings to aid in the diagnosis of syphilis infection.

Warning: The ARCHITECT Syphilis TP assay is not intended for use in screening blood, plasma, or tissue donors. The effectiveness of the ARCHITECT Syphilis TP assay for use in screening blood, plasma, or tissue donors has not been established.

The ARCHITECT Syphilis TP Calibrator is for the ARCHITECT iSystem when used for the qualitative detection of antibody to Treponema pallidum (TP) in human serum and plasma.

The ARCHITECT Syphilis TP Controls are for the estimation of test precision of systematic analytical deviations of the ARCHITECT iSystem when used for the qualitative detection of antibody to Treponema pallidum (TP) in human serum and plasma.

The ARCHITECT Syphilis TP assay is a two-step immunoassay for the qualitative detection of antibodies (IgG and IgM) directed against TP in human serum or plasma using CMIA technology with flexible assay protocols, referred to as Chemiflex.

1. Sample, assay diluent, and recombinant TP antigen (TpN15, TpN17 and TpN47) coated microparticles are combined. Anti-TP antibodies present in the sample bind to the TP coated microparticles.
2. After washing, anti-human IgG and IgM acridinium-labeled conjugate is added to create a reaction mixture.
3. Following another wash cycle, Pre-Trigger and Trigger Solutions are added to the reaction mixture.
4. The resulting chemiluminescent reaction is measured as relative light units (RLUs). There is a direct relationship between the amount of anti-TP antibodies in the sample and the RLUs detected by the ARCHITECT iSystem optics.

The presence or absence of anti-TP antibodies in the specimen is determined by comparing the chemiluminescent signal in the reaction to the cutoff signal determined from an active calibration. 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.

Here's a breakdown of the acceptance criteria and study information for the ARCHITECT Syphilis TP Reagent Kit:

1. Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for positive and negative percent agreement. Instead, it presents the calculated percent agreements observed in the clinical study. The FDA's substantial equivalence decision implies that these observed performance metrics were deemed acceptable when compared to the predicate device.

Note: NA (not applicable) for some categories indicates that there were no positive or negative cases, respectively, in that specific subpopulation to calculate the agreement.

The document also describes several non-clinical performance acceptance criteria through studies such as:

• Precision: Evaluated within-run, within-laboratory, within-day, between-site, and between-lot variability. Specific SD and %CV values are reported for controls and panels. The implication is that these values demonstrate acceptable precision.
• Interference: Demonstrated that the assay is not susceptible to interference from various substances at specified levels (e.g., conjugated bilirubin ≤ 20 mg/dL, hemoglobin ≤ 500 mg/dL).
• Analytical Specificity: Evaluation against various medical conditions and disease states. While some cross-reactivity was noted for a few specimens in specific categories (e.g., CMV IgG, HIV), the overall performance and context are considered acceptable, with a specific limitation noted for yaws, pinta, and bejel.
• Tube Type Matrix Comparison: Acceptable mean/median S/CO differences and distribution of S/CO differences for different tube types compared to serum.
• Sample On-Board Stability: Up to 3 hours storage on the ARCHITECT i2000SR System.
• Sample Stability: Up to 7 days at 2-8°C, up to 72 hours at room temperature, up to 6 freeze/thaw cycles, and up to 30 days frozen (-10°C or colder).
• High Dose Hook Effect: Determined not to be susceptible.
• Within-Assay Sample Carryover: Determined not to be susceptible.

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

Test Set Sample Sizes:

• Clinical Study Total Specimens: 2220
  • Prospectively-Collected Intended Use Population: 1145 specimens
    • Routine Syphilis Testing: 442
    • Pregnant Females: 304
    • HIV Positive: 399
  • Pre-Selected Positive for TP Antibodies: 406 specimens
  • Apparently Healthy Individuals: 480 specimens
  • Medically Diagnosed (Primary, Secondary, Latent Syphilis): 179 specimens
  • Spiked Pregnant Female Specimens: 10 specimens

Data Provenance:

• Country of Origin: United States. Specimens for the prospectively-collected intended use population were sourced or collected from various locations: Baltimore, Maryland; Colton, California; Fort Lauderdale, Florida; Hyannis, Massachusetts; Los Angeles, California; Miami, Florida; San Antonio, Texas; and Temple, Texas.
• Retrospective/Prospective:
  • Prospectively-collected: 1145 specimens from the intended use population were collected prospectively.
  • Pre-selected: 406 specimens were "pre-selected positive" based on previous laboratory testing, suggesting a retrospective selection criterion based on existing positive results.
  • Medically diagnosed and Apparently healthy: These populations represent specific cohorts selected for the study.

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

This document describes a diagnostic device for syphilis, not an imaging diagnostic AI. Therefore, the "ground truth" is a laboratory-based composite reference, not expert-read interpretations of images.

The ground truth for the clinical studies was established using comparator assays, not human experts interpreting data for a "ground truth" consensus in the way a radiologist would for an imaging study. The comparator results were determined using a "2 out of 3 rule" from the following assays:

• Treponemal Chemiluminescent Immunoassay (TP-CLIA)
• Rapid Plasma Reagin (RPR) - a nontreponemal assay
• Treponema Pallidum Particle Agglutination (TP-PA) - a second treponemal assay

For the "medically diagnosed" category, the diagnosis was made by a licensed physician based on clinical information and serological testing results (e.g., VDRL, RPR, TP-PA). While a physician's input is a form of expert opinion, it's not described as a multi-expert consensus process specifically for establishing ground truth for the algorithm's direct input.

4. Adjudication Method for the Test Set

The adjudication method for the clinical test set (specifically for the final comparator result) was a "2 out of 3 rule" involving the three comparator assays: TP-CLIA, RPR, and TP-PA. If at least two of these assays were concordant (e.g., both positive or both negative), that determined the final comparator result.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in-vitro diagnostic assay, not an AI-powered imaging or interpretation system designed to assist human readers. Therefore, the concept of "human readers improving with AI vs without AI assistance" does not apply here.

6. Standalone Performance Study

Yes, a standalone performance study was done. The entire document describes the performance of the ARCHITECT Syphilis TP assay as a standalone diagnostic device. Its performance metrics (positive percent agreement, negative percent agreement, precision, specificity, etc.) are all measures of the algorithm's (assay's) performance without human-in-the-loop intervention for result interpretation. The assay outputs a qualitative "Reactive" or "Nonreactive" result based on its internal cutoff calculation (S/CO).

7. Type of Ground Truth Used

The primary type of ground truth used was a composite reference standard derived from the results of three established laboratory assays: a treponemal chemiluminescent immunoassay (TP-CLIA), a nontreponemal assay (Rapid Plasma Reagin [RPR]), and a second treponemal assay (Treponema Pallidum Particle Agglutination [TP-PA]), adjudicated by a "2 out of 3 rule."

Additionally, for some categories, clinical context and medical diagnosis by a licensed physician were used to characterize the patient population (e.g., "medically diagnosed individuals with primary, secondary, or latent syphilis").

8. Sample Size for the Training Set

The document does not explicitly state a separate "training set" sample size for the ARCHITECT Syphilis TP assay. For in-vitro diagnostic devices like this, the "development" or "training" of the assay (e.g., selection of antigens, optimization of reagents, determination of cutoff) is often an iterative process using internal studies and samples, rather than a distinct, large "training set" in the machine learning sense.

The "internal study" for selecting and validating the cutoff is mentioned, indicating some data was used for this purpose, but the size is not specified. The clinical studies described are primarily for validation and performance assessment (akin to a test set).

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

Since a distinct "training set" in the machine learning context is not explicitly described, the method for establishing its ground truth is also not detailed. However, based on the general development of such assays, the "ground truth" for optimizing the assay's components and cutoff during development would likely involve:

• Known positive and negative samples: Samples from individuals with confirmed syphilis infections (e.g., by culture, Western blot, or a panel of established treponemal and non-treponemal tests) and samples from healthy individuals.
• Reference standards: Internal or international reference standards for Treponema pallidum antibodies.

The "internal study" for cutoff selection and validation would have used such characterized samples to ensure the assay's sensitivity and specificity met developmental targets before moving to large-scale clinical validation.

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The BioPlex® 2200 EBV IgG kit is a multiplex flow immunoassay intended for the qualitative detection of IgG antibodies to three (3) separate EBV antigens; Epstein-Barr Virus Nuclear Antigen-1 (EBV NA-1), Viral Capsid Antigen (EBV VCA), and Early Antigen diffuse (EBV EA-D) in human serum. The test system can be used in conjunction with the BioPlex 2200 EBV IgM kit as an aid in the laboratory diagnosis of infectious mononucleosis (IM).

The EBV IgG kit is intended for use with the Bio-Rad BioPlex 2200 System.

Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients, cord blood, neonatal specimens, or infants. Assay performance characteristics have not been established for the diagnosis of nasopharyngeal carcinoma, Burkitt's lymphoma, and other EBV-associated lymphomas.

The BioPlex® 2200 Syphilis IgG kit is a multiplex flow immunoassay intended for the qualitative detection of Treponema pallidum IgG antibodies in human serum. The test system, when used in conjunction with non-treponemal based assays, provides serological evidence of infection with T. pallidum. This test system also confirms reactive test results form non-treponemal based screening assays.

The Syphilis IgG kit is intended for use with the Bio-Rad BioPlex 2200 System.

The BioPlex 2200 Syphilis IgG kit is not intended for use in screening blood or plasma donors

Warning: A positive result is not useful for establishing a diagnosis of Syphilis. In most situations, such a result may reflect prior treated infection; a negative result can exclude a diagnosis of syphilis except for incubating or early primary disease.

The EBV IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional ElA, but permits simultaneous detection and identification of many antibodies in a single tube. Three (3) different populations of beads are coated with E. coli derived recombinant proteins, EBV NA-1 (28kD and 45kD), EBV VCA p18 (40kD), and EBV EA-D (28kD) associated with infectious mononucleosis. The BioPlex 2200 System combines an aliquot of patient sample, sample diluent, and bead reagent into a reaction vessel. The mixture is incubated at 37°C. After a wash cycle, antihuman IgG antibody, conjugated to phycoerythrin (PE), is added to the dyed beads and this mixture is incubated at 37°C. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the fluorescence of the attached PE. Raw data is calculated in relative fluorescence intensity (RFI).

Three additional dyed beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to verify detector response, the addition of serum or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma. Refer to the BioPlex 2200 System Operation Manual for more information. The instrument is calibrated using a set of seven (7) distinct calibrator vials, supplied separately by Bio-Rad Laboratories. A combination of four (4) vials representing four (4) different antibody concentrations are used for semiquantitative calibration. The result for each of these antibodies is expressed as an antibody index (AI).

The Syphilis IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional ElA, but permits simultaneous detection and identification of many antibodies in a single tube. Three (3) different populations of beads are coated with recombinant proteins associated with T. pallidum (15kD. 17kD. and 47kD). The BioPlex 2200 System combines an aliquot of patient sample diluent, and bead reagent into a reaction vessel. The mixture is incubated at 37°C. After a wash cycle, anti-human IgG antibody, conjugated to phycoerythrin (PE), is added to the dyed beads and this mixture is incubated at 37°C. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the fluorescence of the attached PE. Raw data is calculated in relative fluorescence intensity (RFI).

Three additional dyed beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to verify detector response, the addition of serum or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma. Refer to the BioPlex 2200 System Operation Manual for more information.

The system is calibrated using a set of four (4) distinct calibrator vials, supplied separately by Bio-Rad Laboratories. Four (4) vials representing two (2) or three (3) different antibody concentrations are used for calibration. Results are calculated for each of the three (3) antibodies and are compared against their own respective cut-off and are expressed as an antibody index (AI). A single result is reported after completing a composite analysis of all the antibodies (the highest AI value is reported).

This is a 510(k) premarket notification for device modifications to the BioPlex 2200 EBV IgG and Syphilis IgG kits. The modifications are related to reducing the frequency of Quality Control (QC) testing and adding protein stabilizers and protease inhibitors to the particle diluent. The document asserts that the performance of the modified QC test frequency is substantially equivalent to the current cleared kit, meaning no new clinical studies were conducted to prove device performance against acceptance criteria. Instead, a risk analysis was performed.

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

1. Table of Acceptance Criteria and Reported Device Performance

The documents do not provide specific quantitative acceptance criteria or reported device performance metrics (e.g., sensitivity, specificity, accuracy) for the modified devices. The core assertion is that the devices remain substantially equivalent to their predicate devices due to internal design control activities and risk assessment, rather than new performance testing.

The acceptance criteria for the changes are related to the risk management report and ensuring the modified QC procedure fulfills the requirements of the specifications of the design control process. The reported "performance" for the modified components is that they are considered substantially equivalent.

2. Sample Size for the Test Set and Data Provenance

No specific test set sample size, country of origin, or whether data was retrospective or prospective is mentioned for a new study to prove device performance. The modifications were assessed through design control activities and risk analysis rather than new clinical trials or performance studies involving patient samples.

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

Not applicable. No new test set requiring expert ground truth establishment was conducted for the device modifications. The substantial equivalence determination was based on internal risk analysis and FMEA.

4. Adjudication Method for the Test Set

Not applicable. No new test set requiring adjudication was conducted.

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

No MRMC study was performed or mentioned. These devices are in vitro diagnostic kits, not AI-assisted reader systems.

6. Standalone (i.e., algorithm only without human-in-the-loop performance) Study

Not applicable. These are diagnostic kits, not algorithms that operate without human interaction in the diagnostic process (though the instrument automates parts of it, the overall use involves human input and interpretation). The changes relate to QC frequency and reagent formulation, not the core analytical algorithm.

7. Type of Ground Truth Used

Not applicable for new device performance testing. The "ground truth" for the acceptance of these modifications was the internal design control process, FMEA, and risk analysis, which concluded that the modifications maintained substantial equivalence to the predicate devices. The predicate devices themselves would have had their performance validated against clinical ground truth (e.g., clinical diagnosis of infection) in their original 510(k) submissions.

8. Sample Size for the Training Set

Not applicable. The document describes modifications to existing in vitro diagnostic kits and does not involve machine learning algorithms with training sets.

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

Not applicable, as there is no training set mentioned.

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The ADVIA Centaur Syphilis (SYPH) assay is an in-vitro diagnostic immunoassay for the qualitative determination of antibodies to Treponema pallidum in human serum or plasma (EDTA. lithium or sodium heparinized, citrate) using the ADVIA Centaur® and ADVIA Centaur® XP systems as an aid in the diagnosis of syphilis. The ADVIA Centaur Syphilis assay is not intended for blood and tissue donor screening.

ADVIA® Centaur Syphilis Quality Control Materials are for in-vitro diagnostics use to monitor the performance of the Syphilis assay on the ADVIA Centaur® systems. The performance of the SYPH quality control material has not been established with any other Syphilis assay.

The ADVIA Centaur syphilis assay is a fully automated, antigen sandwich assay, using direct chemiluminometric technology. The ancillary pack reagent containing acridinium-ester-labeled T. pallidum recombinant antigens is added to the sample. These T. pallidum antigens complex with the antibodies in the sample. The solid phase containing biotinylated T. pallidum recombinant antigens preformed to streptavidin-coated magnetic latex particles, is then added to the sample. These particles capture the T. pallidum antigen-antibody complexes. Antibody-antigen complexes will form if Syphilis antibodies are present in the sample. A direct relationship exists between the level of antibodies to T. pallidum present in the patient sample and the amount of relative light units (RLUs) detected by the system. A result of reactive, nonreactive, or equivocal is determined according to the Index Value established with the calibrators.

The Syphilis kit contains the following:

• 1 ReadyPack® primary reagent pack containing ADVIA Centaur Syphilis Solid Phase Reagent (20 mL);
• 1 Ancillary pack containing ADVIA Centaur Syphilis Ancillary Reagent (10mL)
• ADVIA Centaur Syphilis Master Curve card
• 2 vials of Syphilis Low Calibrator (2 mL fill volume)
• 2 vials of Syphilis High Calibrator (2 mL fill volume)
• ADVIA Centaur Syphilis Calibrator Assigned Value cards

In addition Syphilis quality control materials (2 vials of negative control and 2 vials of positive control with 7 mL fill volume each) are provided separately.

The provided 510(k) summary describes the ADVIA® Centaur Syphilis Assay, an in-vitro diagnostic immunoassay for the qualitative determination of antibodies to Treponema pallidum.

Here's an analysis of the acceptance criteria and the study proving the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the comparison to the predicate device and the performance metrics required for substantial equivalence. The document primarily focuses on establishing substantial equivalence through performance characteristics like precision, reproducibility, interference, cross-reactivity, and clinical evaluation (method comparison).

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

• Precision Test Set: 5 serum-based samples, 3 plasma-based samples (2 controls, 1 plasma pool), and 2 calibrators. Each assayed in duplicate over 20 days (40 runs, 80 replicates). Data provenance not explicitly stated, but likely from laboratory-prepared pools.
• Reproducibility Test Set: Sample pools and control materials (negative and positive). Assayed over 10 days, 2 runs/day, 4 replicates/run for pools, 8 replicates/run for controls (Negative Control: 480 replicates total, Positive Control: 480 replicates total, Serum Pools: 240 replicates each total). Data collected from three external sites. Provenance of the samples is not explicitly stated beyond being "serum pools" and "control materials."
• Interference Test Set: Three syphilis levels (negative, low positive, high positive) were used as serum pools spiked with interferents. Provenance not explicitly stated.
• Cross-reactivity Test Set:
  • 211 cord blood samples, 15 samples from pregnant women (1st, 2nd, 3rd trimester), 48 pediatric samples, 51 hospitalized samples, and 20 transplant samples.
  • 265 specimens from 20 groups of potential cross-reactant disease states. These were provided by respective vendors and had known activity to the potential cross-reactant (determined by FDA-cleared methods).
  • Provenance is mixed; some are specific clinical categories (cord blood, trimester, hospitalized, pediatric, transplant), others are disease-state specific and sourced from vendors. All samples were likely retrospective clinical samples.
• Clinical Evaluation (Method Comparison) Test Set:
  • All Sites Pooled: 2108 samples.
  • Expected Positive Population: 561 samples (TPPA-Reactive and Medically Diagnosed).
  • Samples Sent for Syphilis Testing: 741 samples.
  • Data collected from three clinical trial sites. The samples are described as "samples from various patient populations." This strongly suggests prospective or retrospective clinical samples collected at these sites.

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

• Precision, Reproducibility, Interference: These studies do not typically involve human experts for establishing ground truth, as they evaluate the analytical performance of the assay based on known concentrations or characteristics of the samples.
• Cross-reactivity: The cross-reactivity samples with known activity to potential cross-reactants had this activity "determined by FDA-cleared methods." For the "all samples that demonstrated a positive result (with the exception of two HAV-positive samples) were also confirmed positive by other tests (TPPA or RRP)," these confirmatory tests serve as the ground truth, implying expert interpretation of these results. No specific number or qualifications of experts are mentioned.
• Clinical Evaluation (Method Comparison):
  • The predicate device results served as the primary comparator.
  • For the "Expected Positive Population," ground truth was established by:
    • TPPA-Reactive: This refers to the Treponema pallidum particle agglutination assay, a highly specific confirmatory test for syphilis. The results of this assay would be considered expert-interpreted or based on established laboratory criteria.
    • Medically Diagnosed: This implies a clinical diagnosis made by healthcare professionals (experts) based on various factors, including clinical signs, symptoms, and other laboratory tests.
  • No specific number or qualifications of individual experts are detailed.

4. Adjudication Method for the Test Set

• For the analytical studies (precision, reproducibility, interference), no adjudication method is relevant.
• For cross-reactivity, samples positive on the new device were cross-referenced with the predicate device and "confirmed positive by other tests (TPPA or RRP)." This implies a form of consensus or confirmatory testing rather than direct human adjudication of discordant results between the new device and the predicate.
• For the clinical evaluation (method comparison), the comparison is directly between the new device and the predicate device. Discordant results are not mentioned as undergoing a formal adjudication process; instead, the overall agreement rates are presented. The "Expected Positive Population" analysis further validates the device against established external criteria (TPPA and medical diagnosis).

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted. This device is an automated in-vitro diagnostic immunoassay, meaning its output is quantitative (Index Value) and then categorized as reactive, non-reactive, or equivocal, directly by the instrument based on established cut-offs. There is no human "reader" independently interpreting the primary output of the device itself. Therefore, the concept of improving human reader performance with or without AI assistance is not applicable here.

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

Yes, the studies presented are essentially standalone performance studies for the device. The ADVIA® Centaur Syphilis Assay is a fully automated immunoassay system. All performance characteristics (precision, reproducibility, interference, cross-reactivity, and method comparison) evaluate the performance of the algorithm/system in determining the presence of T. pallidum antibodies without direct human intervention in the interpretation of each individual test result. The output (reactive, non-reactive, equivocal) is generated solely by the device.

7. The Type of Ground Truth Used

The ground truth for the test sets in the clinical evaluation was primarily established by:

• Predicate Device Results: The IMMULITE 2000 Syphilis Screen Test System, a previously cleared device for the same intended use.
• Confirmatory Assays: For cross-reactivity and the "Expected Positive Population," confirmed positive results by established tests like TPPA (Treponema pallidum particle agglutination assay) and RPR (Rapid Plasma Reagin) served as ground truth for true syphilis infection/reactivity.
• Medical Diagnosis: For the "Expected Positive Population," some cases were identified as "Medically Diagnosed," indicating a clinical ground truth established by healthcare professionals.
• Known Activity to Potential Cross-Reactants: For some cross-reactivity samples, the activity was determined by FDA-cleared methods and provided by vendors.

8. The Sample Size for the Training Set

The document does not explicitly mention a separate "training set" or its sample size. For in-vitro diagnostic assays, particularly predicate-based submissions, the focus is typically on validation of the final, locked algorithm/reagent formulation rather than iterative training and testing cycles common in AI/ML software development. The "training" phase would have occurred during the development of the assay by the manufacturer, but details are not provided in this 510(k) summary.

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

Since no explicit "training set" is mentioned, the method for establishing its ground truth is also not specified. It can be inferred that during the development of the assay, the manufacturer would have used panels of well-characterized samples (positive for syphilis, negative for syphilis, and those with various interfering/cross-reacting conditions) to optimize the assay's antigens, reagents, and cutoff values. The ground truth for these development/training samples would likely have been established using reference methods, confirmatory tests (like TPPA), and clinical diagnosis.

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Syphilis Health Check is a qualitative rapid membrane immunochromatographic assay for the detection of Treponema pallidum (syphilis) antibodies in human whole blood, serum or plasma. This product can be used as an initial screening test or in conjunction with a non-treponemal laboratory test and clinical findings, may aid in the diagnosis of syphilis infection. This test is not intended for use in screening blood or plasma donors.

SYPHILIS HEALTH CHECK is a rapid qualitative screening test for detection of human antibodies to TP in serum, plasma or whole blood. The method employs an unique combination of anti-human immunoglobulins gold conjugate and highly purified TP recombinant proteins to specifically detect anti-TP antibodies. The test mainly detects IgG and IgM will also react in case of high concentrations. As the samples flow through the absorbent device, the anti-human immunoglobulins/protein A dye conjugate binds to the human immunoglobulins forming an antigen-antibody complex. This complex binds to the recombinant protein in the positive reaction zone and produces a pink-rose colored band. In the absence of anti TP antibodies, there is no line in the positive reaction zone. The reaction mixture continues flowing through the absorbent device past the reaction and control zones. Unbound conjugate binds to the reagents in the control zone producing a pink-rose color band, demonstrating that the reagents are functioning correctly.

Here's a breakdown of the acceptance criteria and the study details for the Syphilis Health Check device, based on the provided 510(k) summary:

Acceptance Criteria and Reported Device Performance

Note: The predicate device uses Enzyme ImmunoAssay (EIA) with a stated sensitivity and specificity of >97%. The Syphilis Health Check is a rapid immunochromatographic membrane assay, so direct acceptance criteria for RPR comparisons are not explicitly stated for the predicate, but the overall performance values of the new device are provided for both RPR and treponemal comparisons.

Study Information

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

• Total Test Sample Size: 1292 samples
  • Prospective Samples: 880 patient samples
    • Provenance: Collected from five clinical study sites (four STD clinics and one hospital clinic) in the U.S. Patients were suspected positive for syphilis and exhibiting symptoms.
  • Retrospective Samples: 412 frozen samples
    • Provenance: Purchased from outside commercial vendors and blood centers. These included 149 banked RPR and treponemal reactive serum samples, 28 serum samples from primary/secondary patients (treated but symptomatic), and 138 frozen serum/plasma samples.
  • Clinically Diagnosed Samples: 164 well-characterized serum samples (from treated and untreated patients with primary, secondary, and latent syphilis infections).
    • Provenance: Obtained from a clinic serving a population with various infectious diseases.

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

• The document does not specify the number of individual experts or their qualifications (e.g., radiologist with 10 years of experience) used to establish the ground truth for the test set.
• Ground truth was established by "reference methods" such as RPR (Non-Treponemal), TPPA, TPHA, FTA, ELISA, and MHA-TP. These are established laboratory tests, implying that the ground truth was determined by qualified laboratory personnel performing these assays, not necessarily by clinical experts adjudicating cases beyond the initial patient suspicion and clinical diagnosis for the clinically diagnosed samples.

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

• The document does not explicitly describe an adjudication method for conflicting results between reference methods or between the device and reference methods (e.g., 2+1, 3+1).
• For the "Suspected and Known Positive Syphilis Samples" retrospective study, it mentions that some samples with discrepancies between initial RPR/Treponemal results and Syphilis Health Check were "further tested by an outside laboratory for TPPA titer and Syphilis Health Check results." This implies a form of re-testing or confirmatory testing for discordant results but not a structured expert adjudication panel.
• For the "Clinically Diagnosed" samples, a panel of 164 samples was "well-characterized" and tested with RPR, TPPA, and FTA-ABS as reference assays, suggesting these reference methods collaboratively defined the "known clinical 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:

• No MRMC comparative effectiveness study was done. This device is a rapid diagnostic test (immunochromatographic assay) designed for standalone use, not a diagnostic imaging AI tool requiring human-in-the-loop performance measurement or evaluation of human reader improvement. The "readers" of this test are individuals visually interpreting a pink-rose colored band.

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

• Yes, a standalone performance study was done. The entire performance evaluation presents the Syphilis Health Check test's results in isolation, comparing its output directly to that of established reference methods (RPR, TPPA, TPHA, FTA, ELISA, MHA-TP). The visual interpretation of the test result (presence or absence of a colored band) is the direct output of the device, without human interpretive assistance beyond reading the test itself.

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

• The ground truth was established by reference laboratory assays (established Treponemal and non-Treponemal tests). These include RPR, TPPA, TPHA, FTA, ELISA, and MHA-TP.
• For the "clinically diagnosed" samples, the ground truth was based on "well-characterized clinically diagnosed serum samples" using these reference assays to confirm clinical status (primary, secondary, or latent syphilis).

8. The sample size for the training set:

• The document does not specify a training set sample size. As an immunochromatographic rapid diagnostic test, it is a chemical/biological assay and not an AI algorithm that typically undergoes a distinct "training phase" with a labeled dataset in the same way machine learning models do. Its "development" would involve optimization of reagents, concentrations, and assay design rather than data-driven machine learning training.

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

• Since there's no explicit "training set" for an AI algorithm outlined, this question is not directly applicable. The performance characteristics of the device were evaluated against established reference methods, as described in point 7.

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