The iDart™ Lyme IgM ImmunoBlot Kit is an immunoblot assay intended for the in vitro qualitative detection of IgM antibodies to Borrelia burgdorferi in human serum. The iDart™ Lyme IgM ImmunoBlot Kit is intended to detect antibodies to Lyme Screen Antigen (LSA) and multiple other B. burgdorferi antigens following a modified two-tier test methodology. Positive results from the iDart™ Lyme IgM ImmunoBlot Kit are supportive evidence for the presence of antibodies and exposure to B. burgdorferi. Negative results do not preclude infection with B. burgdorferi. iDart™ Lyme IgM ImmunoBlot Kit is intended to aid in the diagnosis of Lyme disease and the test kit should only be used on samples from patients with clinical history, signs and symptoms consistent with Lyme disease. The iDart™ Lyme IgM Immunoblot Kit is not intended as a screen for asymptomatic patients.

Test results are to be used in conjunction with information obtained from the patient's clinical evaluation and other diagnostic procedures.

The iDart™ Lyme IgM ImmunoBlot tests are line immunoblot assays. Antigenic proteins specific for Borrelia species that cause Lyme Disease are produced by recombinant DNA technology in Escherichia coli. The purified proteins are then applied as discrete lines on a nitrocellulose membrane along with two control proteins. The iDart™ Lyme IgM ImmunoBlot Kit contains IgM ImmunoBlot strips and the proteins are applied in the following order: C1 (IgG/IgM – conjugate control), C2 (Protein L – calibrator/serum control), P93, P41 (2 antigen bands), P39 (2 antigen bands), P23 (9 antigen bands), P31 (9 antigen bands), P34, C10 and LSA (a chimeric VlsE peptide termed the Lyme Screen Antigen).

Here's an analysis of the acceptance criteria and study detailed in the provided FDA 510(k) clearance letter for the iDart™ Lyme IgM ImmunoBlot Kit.

Note: The provided text details the performance characteristics but does not explicitly state "acceptance criteria" in a separate section with numerical thresholds. Therefore, the "Acceptance Criteria" column in the table below is inferred from the achieved "Reported Device Performance" and common expectations for such devices (e.g., high agreement, specificity, and sensitivity). The "study that proves the device meets the acceptance criteria" refers to the clinical and analytical performance studies conducted.

1. Table of Acceptance Criteria and Reported Device Performance

Study Proving Device Meets Acceptance Criteria

The studies detailed in the "PERFORMANCE CHARACTERISTICS" section of the 510(k) summary are designed to prove that the iDart™ Lyme IgM ImmunoBlot Kit meets the necessary performance standards for its intended use. These include:

• Reproducibility Study: Tested consistency across multiple sites, operators, and runs.
• Analytical Specificity Studies: Evaluated performance in healthy endemic and non-endemic populations, and cross-reactivity with various non-Borrelia pathogens and autoantibodies.
• Interference Study: Assessed impact of common endogenous substances.
• Method Comparison with STTT: Compared the device's accuracy (PPA and NPA) against the Standard Two-Tier Test methodology, which is a recognized approach for Lyme disease diagnosis.
• CDC Serum Panel Study: Evaluated sensitivity and specificity across different disease stages and in various control groups using a well-characterized reference panel.
• Fresh and Frozen Samples Comparison Study: Demonstrated stability of samples under different storage conditions.
• Antibody Class Specificity Study: Confirmed the specific detection of IgM antibodies.

Additional Information:

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

• Reproducibility: A panel of coded samples with different levels of anti-B. burgdorferi IgM (negative, high negative, low positive, moderate positives, and high positive samples). 90 replicates per sample were generated. The specific number of distinct samples in this panel is not explicitly stated beyond "a panel of coded samples".
• Analytical Specificity (Endemic): 177 samples from apparently healthy individuals in the US from endemic areas (CDC and Bay Area Foundation NY, MA, WI).
• Analytical Specificity (Non-Endemic): 127 samples from apparently healthy individuals in the US from non-endemic areas (CDC and IGeneX, Inc.).
• Cross-Reactivity Study: 243 serum samples from patients with bacterial or viral infections, as well as sera from patients with diagnoses that could be confused with Lyme disease (CDC, IGeneX, Inc., New York Biologics (NY), Kamineni Life Sciences Pvt. Ltd, Hydrabad (India), Warde Medical Laboratory (MI)).
• Interference Study: One positive, one low positive, and one negative Borrelia IgM samples (tested in singlicate with various spiked interfering agents).
• Method Comparison with STTT: 997 prospectively collected serum samples procured from IGeneX, Inc.
• CDC Serum Panel: 258 serum samples from the CDC panel. These included patients with Lyme disease at different stages and Lyme disease look-alike infections, and healthy controls.
• Fresh and Frozen Samples Comparison Study: 63 fresh samples and 63 frozen samples.
• Antibody Class Specificity: 8 previously tested patient samples (4 negatives, 4 positives).

Data Provenance: The data appears to be a mix of retrospective and prospective. Samples from "apparently healthy individuals" and "patients with bacterial or viral infections" can be either. The "Method Comparison with STTT" explicitly states "Prospectively collected serum samples" from IGeneX, Inc. The CDC Serum Panel is a reference panel, usually well-characterized retrospectively. Locations include the US (CDC, Bay Area Foundation NY, MA, WI, IGeneX, Inc., New York Biologics (NY), Warde Medical Laboratory (MI)) and India (Kamineni Life Sciences Pvt. Ltd, Hydrabad).

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
The document does not explicitly state the number of experts or their qualifications for establishing ground truth for the clinical study samples. For the "Method Comparison with comparators (STTT)", the comparison is against "FDA-cleared EIA and immunoblot as part of the standard two-tier test methodology (STTT)". This implies the ground truth for these samples was established by the results of the STTT, which is a standardized and accepted diagnostic algorithm, rather than by individual expert interpretation. For the CDC Panel, the samples are "from patients diagnosed with Lyme Disease at different stages" or "Lyme disease look-like infections", suggesting that the CDC provided established diagnoses based on their protocols, which would implicitly involve expert clinical and laboratory evaluation.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:
The document does not describe an explicit adjudication method (like 2+1 or 3+1) for establishing ground truth for the clinical test sets. The ground truth for the method comparison study was the result of the "FDA-cleared EIA and immunoblot as part of the standard two-tier test methodology (STTT)". For the CDC panel, it was based on the provided "diagnosis".

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 an in vitro diagnostic (IVD) kit for laboratory use (an ImmunoBlot assay, specifically evaluating IgM antibodies) rather than an AI-powered image analysis system or a device requiring human-in-the-loop interpretation that would typically necessitate such a study. The "reading" of the immunoblot strips is performed visually but the interpretation criteria are clearly defined, not requiring subjective interpretive discretion usually addressed by MRMC studies.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
This question is not directly applicable in the terms typically used for AI/software devices. The iDart™ Lyme IgM ImmunoBlot Kit is a lab-based immunoassay. Its performance characteristics (sensitivity, specificity, reproducibility) were evaluated as a standalone device (without external assistance like AI or human readers for interpretation, other than the standard visual reading of the bands per the kit's instructions), as demonstrated by the analytical and clinical studies. The results are generated by the chemical reaction on the strip and interpreted based on predefined criteria. It's an "algorithm only" in the sense of the assay's biochemical process and visual interpretation rules, operating without additional "human-in-the-loop" modifications to its fundamental mechanism or output.

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

• Standard Two-Tier Test (STTT) results: For the majority of the clinical method comparison study (N=997), the device was compared against the results from "FDA-cleared EIA and immunoblot as part of the standard two-tier test methodology".
• Clinical Diagnosis from CDC: For the CDC reference panel, samples were from patients "diagnosed with Lyme Disease at different stages" or "Lyme disease look-like infections". This implies a ground truth established through a combination of clinical evaluation, laboratory tests, and expert judgment according to CDC protocols.

8. The sample size for the training set:
Not applicable/Not specified. This is an in vitro diagnostic kit (ImmunoBlot assay), not a machine learning or AI-based device that typically requires a distinct "training set" for model development. The antigens used are recombinant proteins, and the assay's interpretation criteria are rule-based, not learned from a dataset.

9. How the ground truth for the training set was established:
Not applicable. As stated above, this device does not utilize a training set in the context of machine learning. The design and validation of immunoblots are based on known antigen-antibody interactions and assay development methodologies.

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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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The iDart™ Lyme IgG ImmunoBlot Kit is an immunoblot assay intended for the in vitro qualitative detection of IgG antibodies to Borrelia burgdorferi in human serum. The iDart Lyme IgG ImmunoBlot Kit is intended to detect antibodies to LSA and multiple other B. burgdorferi antigens following a modified two-tier test methodology. Positive results from the iDart Lyme IgG ImmunoBlot Kit are supportive evidence for the presence of antibodies and exposure to B. burgdorferi. Negative results do not preclude infection with B. burgdorferi. iDart™ Lyme IgG ImmunoBlot Kit is intended to aid in the diagnosis of Lyme disease and the test kit should only be used on samples from patients with clinical history, signs and symptoms consistent with Lyme disease. The iDart Lyme IgG Immunoblot Kit is not intended as a screen for asymptomatic patients.

Test results are to be used in conjunction with information obtained from the patient's clinical evaluation and other diagnostic procedures.

For in vitro diagnostic use only
For professional use only
For prescription use only

The iDart™ Lyme IgG ImmunoBlot tests are line immunoblot assays. Antigenic proteins specific for Borrelia species that cause Lyme Disease are produced by recombinant DNA technology in Escherichia coli. The purified proteins are then applied as discrete lines on a nitrocellulose membrane along with two control proteins.

The iDart™ Lyme IgG ImmunoBlot Kit contains IgG ImmunoBlot strips and the proteins are applied in the following order: C1 (lgG/lgM - conjugate control), C2 (Protein L - calibrator/serum control), P93, P41, P39, P23, P31, P66, P58, P45, P34, P30, P28, P18 and LSA (a chimeric VISE peptide termed the Lyme Screen Antigen).

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the iDart™ Lyme IgG ImmunoBlot Kit are primarily demonstrated through its analytical performance (reproducibility, analytical specificity, cross-reactivity, interference) and clinical performance (method comparison with STTT, clinical sensitivity/specificity using a CDC panel).

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

• Reproducibility: 90 samples for each of the 6 sample types (High Positive, Moderate Positive, Negative-1, Negative-2, Negative-3, Low Positive). Total of 540 tests performed across 3 sites, 2 operators, 5 days, 2 runs/day. Data provenance is not explicitly stated beyond "blinded and coded samples."
• Analytical Specificity (Healthy Individuals):
  • 313 samples from endemic areas (CDC, Bay Area Lyme Foundation - NY, MA, WI).
  • 112 samples from non-endemic areas (CDC, CA).
• Cross-Reactivity Study: 376 samples from various disease states/infections (CDC, IGeneX (CA), New York Biological (NY), BEI, Kamineni Life Sciences Pvt. Ltd, Hydrabad (India), Warde Medical Laboratory (MI)).
• Interference Study: One positive, one low positive, and one negative Borrelia IgG sample were used for each interference agent and concentration, tested in singlicate.
• Clinical Studies (Method Comparison with STTT): A total of 768 serum samples.
  • Site 1: 290 clinical serum samples from Bay Area Lyme Foundation.
  • Site 2: 37 clinical serum samples (Cohort 2) + 230 clinical serum samples (Cohort 3) from IGeneX Inc.
  • Site 3: 211 clinical serum samples (Cohort 2) from IGeneX Inc.
  • Data provenance: "procured from two vendors" (Bay Area Lyme Foundation and IGeneX Inc.). Samples were "prospective banked samples" or "clinical serum samples."
• Clinical Sensitivity/Specificity (CDC Serum Panel): 280 serum samples from CDC (patients with Lyme disease at different stages, look-alike conditions, healthy controls from endemic and non-endemic regions).
• Fresh and Frozen Samples Comparison Study: 72 decoded left-over patient serum samples.
• Antibody Class Specificity: 10 previously tested patient samples (6 negatives, 4 positives).

All clinical samples were "blinded, re-coded."

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

The document does not explicitly state that experts were used to establish ground truth for the test set derived from clinical samples. Instead, the ground truth for these clinical performance studies appears to be based on:

• STTT (Standard Two-Tier Test Methodology): This is a laboratory-based diagnostic algorithm involving an EIA/IFA screen followed by an immunoblot. Its results serve as the comparator (ground truth) for the method comparison study.
• CDC Reference Panel: For the clinical sensitivity/specificity, the CDC reference panel implicitly has established diagnoses for Lyme disease stages and other conditions. The process by which CDC established these diagnoses (e.g., expert consensus, other gold standards) is not detailed here.

For the reproducibility study, the samples were "blinded and coded" with "expected result" (e.g., High Positive, Negative). It's not specified how these initial categorizations were established.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method involving multiple experts resolving discrepancies for the test set results. The evaluations are primarily against established comparators like STTT or reference panels (CDC). For the reproducibility study, the agreement was 100%, so no adjudication would have been required for discrepancies.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. The performance studies focus on the device's standalone accuracy against existing diagnostic methods/reference panels, rather than how human readers' performance might improve with or without AI assistance. The device is an ImmunoBlot Kit, not an AI-assisted diagnostic imaging or interpretation system.

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

Yes, the studies reflect the standalone performance of the iDart™ Lyme IgG ImmunoBlot Kit. The "Principle of procedures" describes manual interpretation ("A strip reading guide included in each test kit shows the location of specific antigens in the test strip. ... Any band found having a visual intensity equal to or greater than the C2 control band intensity is considered as a significant (positive) band. Depending on the observed bands pattern, one can interpret the presence or absence of Lyme specific IgG antibodies in the patient serum."). The "Result Generation" for the device is listed as "Manual reading" in the comparison table. This indicates the studies assess the kit's performance as a laboratory test, interpreted by a human, but without a "human-in-the-loop" AI system.

7. The Type of Ground Truth Used

• Clinical Performance (Method Comparison): The "ground truth" was established by Standard Two-Tier Test Methodology (STTT), which involves FDA-cleared EIA and immunoblot tests, performed by laboratory personnel.
• Clinical Sensitivity/Specificity: The "ground truth" was established by the CDC Reference Panel, which represents diagnosed cases of Lyme disease at various stages, look-alike conditions, and healthy controls. The methods for establishing these CDC diagnoses are not detailed but likely involve a combination of clinical assessment and established laboratory criteria.
• Analytical Specificity / Cross-reactivity: Ground truth for these samples was "known to contain potentially cross-reactive antibodies to Lyme infection" or "healthy individuals" or specific disease states, implying prior clinical diagnoses or sample characterization.
• Reproducibility: Samples were initially characterized as "High Positive," "Negative," etc., which served as the expected result for comparison. The method for this initial characterization is not specified.
• Fresh/Frozen & Antibody Class Specificity: Ground truth was based on "previously tested patient samples" with known IgG status.

8. The Sample Size for the Training Set

The document does not describe a "training set" in the context of machine learning or AI. The iDart™ Lyme IgG ImmunoBlot Kit is an immunoassay kit, not an AI-based device that requires model training. Therefore, this question is not applicable to the information provided.

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

As the device is not an AI/ML product, there is no "training set" or corresponding ground truth establishment process described in the document.

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The ZEUS Solinas Borrelia VIsE1/pepC10 IgG/IgM Test System uses chemiluminescent immunoassay (CLIA) technology for the qualitative detection of IgGlgM antibodies to Borrelia burgdorferi in human serum. This assay is intended for use on samples from patients with signs and symptoms consistent with or patients suspected of having Lyme disease to assess the presence of IgG/IgM antibodies.

Positive results with the ZEUS Solinas Borrelia VIsE1/pepC10 IgG/IgM Test System should be supplemented with additional testing with a Standard two-tier test (STTT) methodology using an IgG and/or IgM Borrelia burgdorferi immunoblot assay following current guidelines.

Positive supplemental results are supportive evidence of antibodies and exposure to Borrelia burgdorferi and may be used along with patient history, symptoms and other laboratory data to support a clinical diagnosis of Lyme disease.

Negative results by the ZEUS Solinas Borrelia VlsE1/pepC10 IgG/IgM Test System should not be used to exclude Lyme disease. The test must be performed on the ZEUS Solinas instrument.

The ZEUS Solinas Borrelia VIsE1/pepC10 IgG/IgM Control Kit is intended for use as assayed quality control samples to monitor the performance of the ZEUS Solinas Borrelia VlsE1/pepC10 IgG/IgM Test System. The performance characteristics of the ZEUS Solinas Borrelia VIsE1/pepC10 IgG/IgM Control Kit have not been established for any other assays or instrument platforms.

Not Found

This document is an FDA 510(k) clearance letter for the ZEUS Solinas Borrelia VlsE1/pepC10 IgG/IgM Test System. It describes a diagnostic test for Lyme disease. The information provided does not contain details about acceptance criteria, study data, sample sizes, expert qualifications, or ground truth establishment typically found in a clinical study report for an AI/ML medical device.

The questions you've asked are most relevant to AI/ML device approval processes, where the device "learns" from data. This document describes a Chemiluminescent Immunoassay (CLIA) technology, which is a laboratory-based diagnostic test, not an AI/ML algorithm. Therefore, the concepts of training sets, test sets, human readers assisting AI, adjudication methods, and expert consensus for AI ground truth do not directly apply to this type of device.

This clearance is based on substantial equivalence to legally marketed predicate devices, meaning it has similar indications for use and technological characteristics to devices already on the market. The performance of such a device is typically assessed through analytical and clinical performance studies, comparing its results to a reference method or clinical diagnosis, rather than through AI-specific metrics like those you've inquired about.

To directly answer your request based on the provided document, I cannot fill in the table or provide the requested details because the document describes a traditional diagnostic assay, not an AI/ML device.

Here's why each of your points cannot be addressed with the provided text:

• 1. A table of acceptance criteria and the reported device performance: This document is the clearance letter, not the study report. It states the device is substantially equivalent but does not present the raw performance data or acceptance criteria that were met.
• 2. Sample sizes used for the test set and the data provenance: Not present in this document.
• 3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: Not applicable to a CLIA assay in the context typically asked for AI/ML. Ground truth for a diagnostic test usually refers to clinical diagnosis, a gold standard lab test, or patient outcomes, not expert image annotation.
• 4. Adjudication method (e.g. 2+1, 3+1, none) for the test set: Not applicable to a CLIA assay.
• 5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance: Not applicable, as this is not an AI-assisted device for human interpretation.
• 6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: Not applicable, as this is a laboratory test, not an algorithm.
• 7. The type of ground truth used (expert consensus, pathology, outcomes data, etc): While not detailed, for a diagnostic test like this, ground truth would typically be established based on a combination of clinical diagnosis, other established laboratory tests, and possibly follow-up outcomes, not expert consensus in the way it's used for AI image interpretation.
• 8. The sample size for the training set: Not applicable, as this is not an AI/ML device that requires a "training set."
• 9. How the ground truth for the training set was established: Not applicable for the same reason as above.

In summary, the provided document is an FDA 510(k) clearance letter for a traditional in-vitro diagnostic test, not an AI/ML medical device submission. Therefore, the specific questions related to AI/ML study design and performance metrics cannot be answered from this document.

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The Viramed Biotech AG Borrelia All-In-One ViraChip is an in vitro qualitative microarray assay for the detection of IgM and IgG antibodies to Borrelia burgdorferi in human serum. The assay is intended for testing serum samples from symptomatic patients or those suspected of Lyme Disease. It is intended to detect antibodies to VIsE and multiple other B. burgdorferi antigens following a modified two-tier test methodology. Positive results from the Viramed Biotech AG Borrelia All-In-One ViraChip are supportive evidence for the presence of antibodies and exposure to B. burgdorferi, the causative agent for Lyme disease. Negative results do not preclude infection with B. burgdorferi. Test results are to be used in conjunction with information obtained from the patient's clinical evaluation and other diagnostic procedures as an aid in diagnosis of Lyme disease.

The Viramed Biotech AG Borrelia All-In-One ViraChip Test must be used with a ViraChip Reader and the ViraChip Software.

Not Found

This document is an FDA 510(k) clearance letter for a medical device. It does not contain the detailed performance study results, acceptance criteria, or ground truth establishment methods as requested. The letter only states that the device is substantially equivalent to a predicate device and provides its indications for use.

Therefore, I cannot extract the information to complete the table and answer your questions directly from the provided text. The document clearly states "We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent...". This implies that the detailed study information would be in the 510(k) submission itself, not in the clearance letter.

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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 Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit is intended as a qualitative test for the detection of IgG antibodies to B. burgdorferi sensu stricto in human serum from symptomatic patients or people suspected of infection. When used as the first-tier screening test, positive and equivocal results must be supplemented through additional testing by one of the following methods:
· Standard two-tier test methodology (STTT) using an IgG blot test following current interpretation guidelines, OR
• Modified two-tier test methodology (MTT) using the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/ IgM ELISA Test.
The assay can also be used as a second-tier confirmation test using the MTTT methodology when used with the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/IgM ELISA Test as the first-tier screening test.
Positive test results by either the STTT or MTTT methodology are supportive evidence for the presence of antibodies and exposure to Borrelia burgdorferi, the cause of Lyme disease. A diagnosis of Lyme disease should be made based on the presence of Borrelia burgdorferi antibodies, history, symptoms, and other laboratory findings.

The kit includes 12 x 8 well Antigen Coated strips. Conjugate. Substrate, Stop Solution, Wash Buffer, Diluent, Negative Control, Positive Control, and Cutoff Control. The controls are provided to determine if the assay is functioning properly and to determine the antibody level. The reagents are sufficient for 96 determinations.
During the test procedure, antibodies to B. burgdorferi (sensu stricto) if present in the human serum sample will bind to the antigens coated onto the wells forming antigen-antibody complexes. Excess antibodies are removed by washing. A conjugate of goat anti-human IgG antibodies conjugated with horseradish peroxidase is then added, which binds to the antigenantibody complexes. Excess conjugate is removed by washing. This is followed by the addition of a chromogenic substrate, tetramethylbenzidine (TMB). If specific antibodies to the antigen are present in the patients' serum, a blue color will develop. The enzymatic reaction is then stopped with a stopping solution causing the contents of the well to turn yellow. The wells are read photometrically with a microplate reader at 450nm.
The antigens used in the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test kit is a combination of B. burgdorferi sensu stricto strain B31 lysate, B. burgdorferi sensu stricto strain 2591 lysate, and a recombinant VlsE from B. burgdorferi sensu stricto strain B31. The lysates use spirochetes growing in BSK-H complete medium until mid-exponential phase. The recombinant VlsE protein is produced in E. coli SURE2 cells and purified by affinity chromatography. The purity of each antigen is assayed by SDS-PAGE followed by Coomassie staining and/or Western blotting.

This document describes the validation of the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit, including a new proposed Modified Two-tier Testing (MTTT) methodology. The provided text primarily focuses on comparative studies against predicate devices and existing standard methods, rather than defining explicit acceptance criteria in a quantitative table format. However, implied acceptance criteria can be derived from the performance percentages presented.

Based on the provided information, here's a structured response addressing the requested points:

1. Table of Acceptance Criteria (Implied) and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical cutoffs in the document. However, they can be inferred from the reported "Percent Agreement" values in the comparison studies. The studies aim to demonstrate substantial equivalence to established predicate devices and methodologies.

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

• Determination of Assay Cutoff (Nonclinical):

  • Sample Size: 210 normal sera (105 endemic, 105 non-endemic) + 194 samples (114 Lyme disease stages, 8 healthy negative, 72 negative Lyme disease with other conditions). Total = 404 samples.
  • Data Provenance: Not explicitly stated, but "endemic region of Lyme disease" and "non-endemic region of Lyme disease" suggest geographical diversity. Retrospective, as these are "tested" samples for cutoff determination.

• Precision (Nonclinical):

  • Sample Size: 48 runs for each of 4 panel members (negative, high negative, low positive, moderate positive) + kit controls. This is a repetitive testing design, not individual patient samples.

• Reproducibility (Nonclinical):

  • Sample Size: 90 runs (3 sites x 2 runs/day x 5 days x 3 replicates) for each of 4 panel members (negative, high negative, low positive, moderate positive) + kit controls (30 runs for Pos/Neg control, 60 runs for Cutoff control).

• Analytical Specificity:

  • Sample Size: 208 asymptomatic individuals (103 from endemic regions, 105 from non-endemic regions).
  • Data Provenance: Endemic and non-endemic regions. Retrospective (asymptomatic individuals' samples).

• Cross Reactivity:

  • Sample Size: 377 samples.
  • Data Provenance: Samples obtained from "serum vendors who confirmed their positivity for each respective marker," implying retrospective, controlled samples.

• Comparison/Prospective Study (Clinical):

  • STTT Comparison: 523 serum samples.
  • MTTT Comparison: 481 serum samples for the initial screening. 38 positive/equivocal samples were carried forward for second-tier testing comparison.
  • Data Provenance: "Prospective samples submitted for Lyme serology testing" from "three sites (one internal and two external reference laboratories)." This indicates a prospective study design with samples from potentially diverse geographical locations (clinical labs).

• Sensitivity Study (Clinical):

  • STTT: 114 clinically characterized samples.
  • MTTT: 125 clinically characterized samples.
  • Data Provenance: "Clinically characterized samples" from unspecified sources; likely retrospective collection of known patient cohorts.

• CDC Panel (Clinical):

  • Sample Size: 280 positive and negative specimens.
  • Data Provenance: From the "Center of Disease Control (CDC)." These are reference panels, typically collected and characterized over time, so retrospective.

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

The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the test sets.

• For "clinically characterized samples" and "CDC panel" samples, the implication is that these samples have a pre-defined and reliable "clinical diagnosis" or "reference characterization" based on established medical criteria. This often involves consensus from clinical experts (e.g., infectious disease specialists) and/or a combination of clinical presentation, symptoms, and other laboratory findings, but the specifics are not detailed here.
• For the "Second-Tier Testing" comparison, the "FDA cleared IgG blot assay" and "predicate B. burgdorferi IgG blot test" serve as the ground truth. These are approved diagnostic methods, and their interpretation would follow established guidelines.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication method (e.g., 2+1, 3+1) for resolving discrepancies in the test results or for establishing the initial ground truth diagnoses. The comparisons are based on the results of the different assays and against established clinical characterizations or CDC panels.

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 study was performed or described. This device is an ELISA test kit, a laboratory diagnostic assay for detecting antibodies, not an AI or imaging diagnostic tool that involves human readers interpreting images. Therefore, the concept of "human readers improving with AI assistance" is not applicable.

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

Yes, the primary performance evaluation is standalone. The Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit operates as a standalone diagnostic assay. Its performance (sensitivity, specificity, agreement) is measured as the output of the kit itself (optical density readings converted to units and qualitative results) without direct human interpretation of complex visual patterns or AI assistance. The results are quantitative and then interpreted qualitatively (positive, equivocal, negative) based on predefined cutoffs.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The ground truth used varies by study:

• Predicate Devices/Methodologies: For the STTT and MTTT comparison studies, the ground truth for the device's performance is a comparison against the results from legally marketed predicate devices (e.g., Trinity Biotech MarDx Borrelia burgdorferi EIA IgG Test Kit) and/or a FDA cleared IgG blot assay. This is a form of comparative ground truth against established methods.
• Clinical Diagnosis/Characterization: For the Sensitivity Study and CDC Panel, the ground truth is "clinically characterized samples" and "positive and negative specimens from the Centers of Disease Control (CDC)." This implies a clinical diagnosis or consensus diagnosis based on comprehensive patient data (history, symptoms, other laboratory findings) or a reference panel with established disease status.
• Analytical Ground Truth: For non-clinical studies like analytical specificity and cross-reactivity, the ground truth is often the confirmed absence or presence of specific conditions in the tested samples, usually based on prior laboratory testing or sample vendor claims.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning. The term "training set" is usually associated with the development of AI algorithms. For an ELISA kit, development involves:

• Antigen Selection and Optimization: Which antigens to use (e.g., B31 lysate, 2591 lysate, recombinant VlsE).
• Reagent Formulation: Optimizing conjugate, substrate, buffers, etc.
• Cutoff Determination: "The cutoff was determined by testing a total of 210 normal sera..." and "An additional 194 samples..." This process of determining the cutoff could be considered analogous to a 'calibration' or 'training' phase for a traditional diagnostic test, where a dataset is used to define the diagnostic thresholds. In this sense, a total of 404 samples (210 normal + 194 other known samples) were used for cutoff determination.

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

As discussed above, for establishing the cutoff (analogous to training/calibration):

• Normal Sera: The 210 normal sera were likely verified as "normal" through standard clinical practice or donor screening, indicating the absence of target antibodies/disease in a healthy population.
• Known Positive/Negative/Other Disease Samples: The additional 194 samples included "different phases of Lyme disease," "negative healthy samples," and "negative Lyme disease samples but do have other diseases that may cause serologic cross-reactivity." The "ground truth" for these samples would be their known clinical status or disease classification, typically established through comprehensive clinical evaluation, follow-up, and/or panels from disease banks. The ROC analysis was used to confirm the chosen cutoff provides the best compromise between sensitivity and specificity, indicating an analytical optimization process based on these known samples.

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The Gold Standard Diagnostics Borrelia burgdorferi IgG/IgM ELISA Test Kit is intended as a qualitative test for the detection of IgG and IgM antibodies to Borrelia burgdorferi sensu stricto in human serum from symptomatic patients or people suspected of infection. When used as the first-tier screening test, positive and equivocal results must be confirmed through additional testing by one of the following methods:

• Standard two-tier test methodology (STTT) using an IgG and/or IgM blot testing following current interpretation guidelines, OR

• Modified two-tier test methodology (MTTT) using the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/ IgM ELISA Test.

The assay can also be used as a second-tier confirmation test using the MTTT methodology when used with the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/IgM ELISA Test as the first-tier screening test.

Positive test results by either the STTT or MTTT methodology are supportive evidence for the presence of antibodies and exposure to Borrelia burgdorferi, the cause of Lyme disease. A diagnosis of Lyme disease should be made based on the presence of Borrelia burgdorferi antibodies, history, symptoms, and other laboratory findings.

The kit includes 12 x 8 well Antigen Coated strips, Conjugate, Substrate, Stop Solution, Wash Buffer, Diluent, Negative Control, Positive Control, and Cutoff Control. The controls are provided to determine if the assay is functioning properly and to determine the antibody level. The reagents are sufficient for 96 determinations.

During the test procedure, antibodies to B. burgdorferi (sensu stricto) if present in the human serum sample will bind to the antigens coated onto the wells forming antigen-antibody complexes. Excess antibodies are removed by washing. A conjugate of goat anti-human IgG/IgM antibodies conjugated with horseradish peroxidase are then added, which binds to the antigen-antibody complexes. Excess conjugate is removed by washing. This is followed by the addition of a chromogenic substrate, tetramethylbenzidine (TMB). If specific antibodies to the antigen are present in the patients' serum, a blue color will develop. The enzymatic reaction is then stopped with a stopping solution causing the contents of the well to turn yellow. The wells are read photometrically with a microplate reader at 450nm.

The antigens used in the Gold Standard Diagnostics Borrelia burgdorferi IgG/IgM ELISA Test kit is a combination of B. burgdorferi sensu stricto strain B31 lysate, B. burgdorferi sensu stricto strain 2591 lysate, and a recombinant VlsE from B. burgdorferi sensu stricto strain B31. The lysates use spirochetes growing in BSK-H complete medium until mid-exponential phase. The recombinant VlsE protein is produced in E. coli SURE2 cells and purified by affinity chromatography. The purity of each antigen is assayed by SDS-PAGE followed by Coomassie staining and/or Western blotting.

The provided document describes the Gold Standard Diagnostics Borrelia burgdorferi IgG/IgM ELISA Test Kit and its performance in various studies. Here's a breakdown of the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance (STTT comparison):

The document does not explicitly state pre-defined acceptance criteria for the comparative studies. Instead, it presents observed performance metrics (Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA)) against a predicate device. For the purpose of this response, I will highlight the reported performance metrics from the comparative study.

1. Table of Acceptance Criteria and Reported Device Performance (MTTT Comparison):

Similar to the STTT comparison, the document reports observed performance metrics for the MTTT protocol against the STTT predicate.

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

For Comparison with Predicate Device (STTT):

• Sample Size: 520 serum samples.
• Data Provenance: Prospective samples submitted for Lyme serology testing. Collected from three sites (one internal and two external reference laboratories).

For MTTT Comparison (Prospective Study):

• Sample Size: 481 serum samples for the initial screening. Of these, 54 positive or equivocal samples were further tested.
• Data Provenance: Prospective samples submitted for Lyme serology testing. Collected from three sites (one internal and two external reference laboratories).

For Sensitivity Study (STTT and MTTT):

• Sample Size: 89 clinically characterized samples for STTT and 125 clinically characterized samples for MTTT.
• Data Provenance: Clinically characterized samples encompassing early, disseminated, and late stages of Lyme disease. The document doesn't specify geographical origin but implies a clinical context.

For CDC Panel (STTT and MTTT):

• Sample Size: 40 samples for STTT and 280 samples for MTTT.
• Data Provenance: Acquired from the Centers for Disease Control (CDC).

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

The document does not provide specific details on the number or qualifications of experts used to establish the ground truth for the test sets. The ground truth appears to be based on:

• "Clinically characterized samples" (for sensitivity studies).
• "Patients diagnosed with Lyme disease" and "healthy individuals" from the CDC panel.
• Comparison with predicate devices (for comparative studies).

4. Adjudication Method for the Test Set:

The document does not describe any specific adjudication method (e.g., 2+1, 3+1) for resolving discrepancies or establishing ground truth within the test sets. For comparative studies, the predicate device results largely serve as the reference, and for sensitivity studies, samples are clinically characterized, implying pre-existing diagnoses.

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 device is an in-vitro diagnostic (IVD) ELISA test kit, not an AI-powered image analysis or diagnostic tool that involves human readers. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable and was not performed.

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

The device is an ELISA test kit designed to provide a qualitative result (positive, equivocal, negative) based on optical density readings. It functions as a standalone diagnostic assay without a human-in-the-loop component in its primary function. The interpretation of the results by laboratory personnel is part of standard lab practice, but the "standalone performance" in this context refers to the assay's accuracy in detecting antibodies. The reported PPA, NPA, and sensitivity studies reflect this standalone performance.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc):

The ground truth used for different studies varies:

• Comparison Studies with Predicate Device: The results of the legally marketed predicate devices (Trinity Biotech Captia™ Borrelia burgdorferi IgG/IgM ELISA Test Kit and Gold Standard Diagnostics Borrelia burgdorferi IgG/IgM Blot Tests) served as the reference standard.
• Sensitivity Studies: "Clinically characterized samples" and "patients diagnosed with Lyme disease" from the CDC panel. This implies a combination of clinical assessment, symptomology, and potentially other laboratory findings, which can be seen as a form of expert consensus or aggregated clinical data.
• Analytical Specificity and Cross-Reactivity: For analytical specificity, asymptomatic individuals from endemic and non-endemic regions were used. For cross-reactivity, samples confirmed positive for specific disease markers (from serum vendors) were used.

8. The Sample Size for the Training Set:

The document describes the determination of the assay cutoff but does not explicitly mention a "training set" in the context of machine learning or AI. For the cutoff determination:

• Assay Cutoff: 200 normal sera (100 from endemic, 100 from non-endemic regions).
• Verification: 125 characterized Lyme disease samples were used with the 200 normal samples for ROC analysis to verify the chosen cutoff.

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

As noted above, there isn't a "training set" in the typical AI sense. However, for the determination of the assay cutoff:

• Normal Sera: These were identified as "normal" based on their origin from non-diseased individuals in endemic and non-endemic regions.
• Characterized Lyme Disease Samples: These 125 samples were "characterized" for Lyme disease, implying a pre-established clinical diagnosis or a well-defined status as positive Lyme disease samples.

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The Gold Standard Diagnostics Borrelia burgdorferi IgM ELISA Test Kit is intended as a qualitative test for the detection of IgM antibodies to B. burgdorferi sensu stricto in human serum from symptomatic patients or people suspected of infection. When used as the first-tier screening test, positive and equivocal results must be supplemented through additional testing by one of the following methods:

· Standard two-tier test methodology (STTT) using an IgM blot test following current interpretation guidelines, OR

• Modified two-tier test methodology (MTTT) using the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/ IgM ELISA Test.

The assay can also be used as a second-tier confirmation test using the MTTT methodology when used with the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/IgM ELISA Test as the first-tier screening test.

Positive test results by either the STTT or MTTT methodology are supportive evidence for the presence of antibodies and exposure to Borrelia burgdorferi, the cause of Lyme disease. A diagnosis of Lyme disease should be made based on the presence of Borrelia burgdorferi antibodies, history, symptoms, and other laboratory findings.

The kit includes 12 x 8 well Antigen Coated strips. Conjugate. Substrate, Stop Solution, Wash Buffer, Diluent, Negative Control, Positive Control, and Cutoff Control. The controls are provided to determine if the assay is functioning properly and to determine the antibody level. The reagents are sufficient for 96 determinations.

During the test procedure, antibodies to B. burgdorferi (sensu stricto) if present in the human serum sample will bind to the antigens coated onto the wells forming antigen-antibody complexes. Excess antibodies are removed by washing. A conjugate of goat anti-human IgM antibodies conjugated with horseradish peroxidase is then added, which binds to the antigenantibody complexes. Excess conjugate is removed by washing. This is followed by the addition of a chromogenic substrate, tetramethylbenzidine (TMB). If specific antibodies to the antigen are present in the patients' serum, a blue color will develop. The enzymatic reaction is then stopped with a stopping solution causing the contents of the well to turn yellow. The wells are read photometrically with a microplate reader at 450nm.

The antigens used in the Gold Standard Diagnostics Borrelia burgdorferi IgM ELISA Test kit is a combination of B. burgdorferi sensu stricto strain B31 lysate, B. burgdorferi sensu stricto strain 2591 lysate, and a recombinant VlsE from B. burgdorferi sensu stricto strain B31. The lysates use spirochetes growing in BSK-H complete medium until mid-exponential phase. The recombinant VlsE protein is produced in E. coli SURE2 cells and purified by affinity chromatography. The purity of each antigen is assayed by SDS-PAGE followed by Coomassie staining and/or Western blotting.

Here's an analysis of the provided text to extract the acceptance criteria and study details for the Gold Standard Diagnostics Borrelia burgdorferi IgM ELISA Test Kit.

It's important to note that this document describes an In Vitro Diagnostic (IVD) device, not an AI/ML-based medical device. Therefore, many of the typical acceptance criteria and study designs associated with AI/ML, such as MRMC studies, expert adjudication, separate training/test sets with established ground truth protocols, and specific ground truth types (pathology, outcomes data, expert consensus), are not applicable or described in the same manner.

Instead, the acceptance criteria for IVDs typically revolve around analytical performance (sensitivity, specificity, precision, reproducibility, cross-reactivity, interference) and clinical concordance with a predicate device or clinical diagnosis.

Acceptance Criteria and Device Performance (IVD Device)

1. Table of Acceptance Criteria and Reported Device Performance

Since this is an IVD device, not an AI/ML device, the acceptance criteria are generally based on meeting certain performance metrics (e.g., specificity, sensitivity, precision, agreement with a predicate device) that demonstrate its substantial equivalence to a legally marketed device. The document does not explicitly state numerical acceptance thresholds for each metric, but rather presents the performance observed and implies that these results were deemed acceptable for market clearance.

Here's a table summarizing the reported device performance, which implicitly represents the met acceptance criteria for this IVD:

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

• Determination of Assay Cutoff: 208 normal sera (103 from endemic region, 105 from non-endemic region). Provenance not explicitly stated but implies a mix of endemic/non-endemic populations, likely within the US.
• Precision (Test Set): A panel of 4 samples (negative, high negative, low positive, moderate positive) + kit controls. Tested in-house.
• Reproducibility (Test Set): A panel of 4 samples (negative, high negative, low positive, moderate positive) + kit controls. Tested at three different sites.
• Analytical Specificity (Test Set): 208 asymptomatic individuals' samples from endemic and non-endemic regions.
• Cross Reactivity (Test Set): 277 samples from serum vendors, confirmed positive for specific markers (e.g., Tick-borne Relapsing Fever IgM, Treponemal Infections, etc.).
• Interfering Substances (Test Set): 3 samples (high negative, equivocal, low positive) spiked with interferents.
• Clinical Studies (Comparison with Predicate Device - STTT):
  • Prospective Samples: 531 serum samples.
  • Provenance: Collected from three sites (one internal, two external reference laboratories) "using prospective samples submitted for Lyme serology testing". This implies real-world, prospectively collected, likely US-based clinical samples.
• Clinical Studies (Sensitivity Study - STTT): 114 clinically characterized samples (early, disseminated, late stages of Lyme disease). Provenance not explicitly stated.
• Clinical Studies (CDC Panel - STTT): 280 positive and negative specimens from the Center of Disease Control (CDC). These are a characterized reference panel. Provenance is CDC, likely multi-site or pooled.
• Clinical Studies (Method Comparison – MTTT IgM, Prospective Study):
  • Prospective Samples: 481 serum samples for the initial screening. 68 positive and equivocal samples carried forward for second-tier testing.
  • Provenance: Collected from three sites (one internal, two external reference laboratories) "using prospective samples submitted for Lyme serology testing". Implies real-world, prospectively collected, likely US-based clinical samples.
• Clinical Studies (Sensitivity Study - MTTT): 125 clinically characterized samples (early, disseminated, late stages of Lyme disease). Provenance not explicitly stated.
• Clinical Studies (CDC Reference Panel - MTTT): 280 positive and negative specimens from the Centers of Disease Control (CDC).

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

For IVD devices like this one, ground truth is typically established by:

• Consensus of clinical diagnosis for disease stages (clinically characterized samples).
• Confirmed status from reference laboratories or biological repositories (e.g., CDC panel, serum vendors for cross-reactivity).
• Comparison to a legally marketed predicate device (as done for the main comparative studies).

The document does not specify a number of experts or their qualifications for establishing ground truth for the test set. Ground truth is derived from the established clinical status of the samples (e.g., clinically characterized samples, CDC panel, confirmed positive from serum vendors). This is standard for IVD submissions, where the "ground truth" often relies on a combination of patient history, symptoms, other laboratory findings, and established reference panels or predicate device results, rather than a panel of independent human readers interpreting medical images.

4. Adjudication Method for the Test Set

Not applicable in the usual sense for an IVD kit. There's no human "reader" adjudication described. The "adjudication" is inherent in the established clinical status of the samples used as ground truth or the comparison to a predicate device. For instances where samples were "clinically characterized," this implies a clinical diagnosis that served as the reference standard, rather than an adjudication process of human interpretations of imaging/data.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not Applicable. This is an IVD (laboratory diagnostic test kit), not an AI/ML-based medical imaging and interpretation device. MRMC studies are used for evaluating AI/ML systems that assist human readers in tasks like image interpretation.

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

Yes, in essence. The performance metrics (PPA, NPA, sensitivity, specificity, etc.) presented in the tables are the standalone performance of the Gold Standard Diagnostics Borrelia burgdorferi IgM ELISA Test Kit itself, analogous to an "algorithm only" performance for an IVD. There is no "human-in-the-loop" component for the performance of this diagnostic test kit once it is run according to its instructions. The interpretation of the overall Lyme disease diagnosis, however, is intended to be made by a clinician based on multiple factors, as stated in the Indications for Use.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc)

The ground truth for this IVD was established using a combination of:

• Clinical Diagnosis / Clinically Characterized Samples: For the "Sensitivity Study" and "CDC Panel," samples were derived from patients with known clinical diagnoses of Lyme disease stages (early, disseminated, late) or from healthy individuals.
• Reference Panels: Specifically, the CDC Panel which consists of "positive and negative specimens... for Lyme disease detection" that are "masked characterized serum panel." This implies a very high confidence in the true status of these samples.
• Confirmed Status from Vendors: For the "Cross Reactivity" study, samples were "obtained from serum vendors who confirmed their positivity for each respective marker."
• Predicate Device/Established Methodology: For the "Comparison with Predicate Device" and "MTTT Comparison" studies, the performance was measured against results obtained from a legally marketed predicate device (Trinity Biotech MarDx Borrelia burgdorferi EIA IgM Test Kit) or an established "Standard two-tier test methodology (STTT)" using the predicate IgM blot test. While the predicate is not "ground truth" in the pathological sense, it serves as the reference standard for substantial equivalence studies for IVDs.

8. The Sample Size for the Training Set

Not applicable for this type of IVD device. This is a laboratory immunoassay kit, not an AI/ML algorithm that undergoes a distinct "training" phase with a large dataset. The "training" in the context of IVD development would be the R&D and optimization process to develop the assay components and parameters (e.g., antigen formulation, antibody concentrations, incubation times, cutoff determination), which are iterative and not typically reported as a "training set" size in an FDA submission. The determination of the assay cutoff involved 208 normal sera, which could be considered part of the assay's "calibration" or optimization, but not a "training set" in the sense of supervised machine learning.

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

Not applicable. As explained in point 8, there isn't a "training set" in the AI/ML context for this IVD device. The assay development and cutoff determination process is a different methodology. The "ground truth" for establishing the assay cutoff was based on 208 normal sera (from endemic and non-endemic regions) and a subsequent ROC analysis to optimize sensitivity and specificity.

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