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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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The Gold Standard Diagnostics Borrelia burgdorferi IgM ELISA Test kit is intended as a qualitative presumptive (first step) test for the detection of IgM antibodies to B. burgdorferi sensu stricto in human serum from symptomatic patients or people suspected of infection. Positive and equivocal results must be supplemented by testing with a second-step Western blot assay.

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 450mm.

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 protein 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 Gold Standard Diagnostics Borrelia burgdorferi IgM ELISA Test Kit is intended as a qualitative presumptive (first step) test for the detection of IgM antibodies to B. burgdorferi sensu stricto in human serum from symptomatic patients or people suspected of infection. Positive and equivocal results must be supplemented by testing with a second-step Western blot assay.

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

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state acceptance criteria in terms of specific thresholds for sensitivity, specificity, or agreement percentages for substantial equivalence. However, the performance metrics are compared against a legally marketed predicate device (Trinity Biotech MarDx Borrelia burgdorferi EIA IgM Test Kit). The demonstration of substantial equivalence relies on favorable comparisons to this predicate.

Approximate "Implied" Acceptance Criteria (Based on Predicate Performance and General Expectations) and Reported Performance:

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

• Comparison with Predicate Device (Clinical Study):
  • Sample Size: 531 serum samples.
  • Data Provenance: Prospective samples submitted for Lyme serology testing. Origin not explicitly stated by country, but implies clinical samples from typical patient populations where Lyme serology is performed.
• Analytical Specificity:
  • Sample Size: 208 asymptomatic individual samples (103 from an endemic region, 105 from a non-endemic region).
  • Data Provenance: Not explicitly stated, presumed retrospective acquisition from asymptomatic individuals. No country of origin is mentioned.
• Cross-Reactivity:
  • Sample Size: 277 samples from serum vendors "who confirmed their positivity for each respective marker."
  • Data Provenance: Retrospective acquisition from serum vendors with various infection/disease conditions. No country of origin is mentioned.
• Sensitivity Study (Clinically Characterized Samples):
  • Sample Size: 114 clinically characterized samples (58 Early, 17 Disseminated, 39 Late stages of Lyme disease).
  • Data Provenance: Not explicitly stated, but "clinically characterized" suggests retrospective collection with confirmed diagnoses. No country of origin is mentioned.
• CDC Panel:
  • Sample Size: 280 positive and negative specimens.
  • Data Provenance: Specimens from the Center for Disease Control (CDC). This is a well-characterized, presumably retrospective, panel. The U.S. CDC implies U.S. origin.
• Determination of Assay Cutoff:
  • Sample Size: 208 normal sera (103 from an endemic region, 105 from a non-endemic region) plus an additional 194 samples (114 from different phases of Lyme disease, 8 negative healthy samples, 72 negative Lyme disease samples with other diseases causing cross-reactivity).
  • Data Provenance: Normal sera from endemic/non-endemic regions, and samples representing various Lyme disease phases and other conditions. The provenance is mixed (healthy, disease stages, cross-reactivity).

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

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

• For the Comparison with Predicate Device and Analytical Specificity studies, the ground truth is indirectly established by the performance of the predicate device and the classification of samples as "asymptomatic" or "submitted for Lyme serology testing," rather than via an expert panel.
• For the Cross-Reactivity study, the samples were obtained from "serum vendors who confirmed their positivity for each respective marker." This implies that the ground truth for these samples was based on previous laboratory testing/diagnosis, not explicitly on expert adjudication for this specific study.
• For the Sensitivity Study, the samples were "clinically characterized," suggesting that the gold standard was clinical diagnosis, but the process and experts involved are not detailed.
• For the CDC Panel, the specimens are described as "masked characterized serum panel," implying the CDC has established the ground truth for these samples (e.g., through clinical diagnosis, Western blot, culture, or other validated methods), but the specific method or experts are not detailed.
• The Second Tier Testing uses an "FDA cleared IgM Western blot assay" as a reference standard, which is itself a laboratory test, not expert consensus.

4. Adjudication Method for the Test Set

No explicit adjudication method (e.g., 2+1, 3+1) is mentioned for establishing ground truth for any of the test sets. Ground truth appears to be based on:

• The performance of a predicate device for comparison studies.
• Clinical characterization or diagnosis for sensitivity studies.
• Confirmed positivity by serum vendors or CDC characterization for specificity and panel studies.
• FDA-cleared IgM Western blot for second-tier testing.

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 ELISA (Enzyme-Linked Immunosorbent Assay) Test Kit, which is a laboratory diagnostic assay, not an imaging device or AI-driven diagnostic system involving 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

This device is a standalone laboratory diagnostic kit. Its performance, as reported in the studies (e.g., PPA, NPA, sensitivity, specificity, precision, reproducibility), represents its standalone performance without a human-in-the-loop component beyond the standard laboratory technician performing the assay. The results are based on objective optical density measurements.

7. The Type of Ground Truth Used

The ground truth used for different studies varies:

• Comparison with Predicate Device: The predicate device's results are used as a reference for agreement, not necessarily a true "ground truth" per se but a comparative standard.
• Analytical Specificity: Clinical status (asymptomatic, endemic/non-endemic region) is used.
• Cross-Reactivity: Confirmed positivity for other markers by serum vendors.
• Second Tier Testing: Results from an "FDA cleared IgM Western blot assay."
• Sensitivity Study: "Clinically characterized samples," indicating clinical diagnosis based on symptoms, history, and potentially other lab data.
• CDC Panel: "Masked characterized serum panel" from the CDC, implying predefined positive/negative status likely based on a combination of clinical information and validated laboratory tests.
• Cutoff Determination: Normal sera from endemic/non-endemic regions and samples from different phases of Lyme disease (clinically defined).

8. The Sample Size for the Training Set

• Determination of Assay Cutoff:
  • 208 normal sera: 103 from an endemic region and 105 from a non-endemic region were used to determine the initial cutoff value (mean plus two standard deviations).
  • An additional 194 samples: 114 from different phases of Lyme disease, 8 negative healthy samples, and 72 negative Lyme disease samples with other conditions for cross-reactivity were used for ROC analysis to confirm the cutoff.
  • While not explicitly called a "training set" in the context of machine learning, these samples were used to establish and validate the assay's interpretive criteria (cutoff value), which is analogous to how a training set informs a model's parameters.
• No other explicit training sets for the device's main performance characteristics are described, as ELISA kits do not typically involve iterative machine learning training in the same way an AI device would.

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

For the samples used in cutoff determination (analogous to a training set):

• Normal sera: Presumed to be healthy controls based on their collection from "normal" individuals in endemic and non-endemic regions.
• Disease-phase samples: "Clinically characterized samples" and "samples from different phases of Lyme disease" suggest a ground truth established by clinical diagnosis.
• Cross-reactivity samples: Negative Lyme disease status with confirmed other conditions.

The establishment of ground truth for these samples aligns with the methods described in point 7.

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