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The Immunetics® QuickELISA™ Anthrax-PA Kit is intended for use in the qualitative detection of antibodies to the Protective Antigen (PA) protein of B. anthracis in human serum. The assay should be used only on serum samples from individuals with a clinical history, signs or symptoms consistent with anthrax infection as an aid in the diagnosis of anthrax, or from recipients of anthrax vaccine.

• The diagnosis of anthrax infection must be made based on history, signs, symptoms, Exposure likelihood, and when possible other laborative rooults in addition to the presence of antiation from other evidence to exclude anthrax.
• The assay has not been evaluated in individuals without clinical signs on symptoms who were probamou oxposures on information available to interpret cutaneous of innulation antinentive test result for such individuals
• the meaning of a positive of negativens from patients infected by the The assay fluo not boon orded results with such infections are unknown.
• The minimum level of anti-PA antibodies that confers protection following the vaccination is not known. This galue and protective immunity has not been established.
• The affinity and/or avidity of anti-PA IgG and IgM for the rPA antigen have not been determined with this assay.

The Immunetics® QuickELISA Anthrax-PA Kit allows qualitative detection in human serum of total antibodies to the Protective Antigen (PA) protein of B. anthracis, in a non-subtype specific, non-species specific microwell ELISA format. The PA toxin component of B. anthracis has been shown to elicit a detectable IgG response in naturally infected individuals and vaccine recipients. The assay is based on a single binding step, in which serum antibodies are incubated with a mixture of two rPA conjugates: Streptavidin-rPA and rPA-horseradish peroxidase (rPA-HRP). PA-specific, multivalent antibodies are able to form ternary complexes in which streptavidin-TPA and rPA-HRP are bound to different antigen combining sites on a single antibody molecule. The complexes are bound to the biotin-coated microplate via the streptavidin conjugate and detected via the HRP conjugate.

In the assay procedure Sample Diluent, serum samples and Conjugate mixture are added to wells and incubated. Unbound antibodies and Conjugate are removed by wash steps, and bound anti-PA antibodies and HRP Conjugate are detected by adding a chromogenic peroxidase substrate containing tetramethylbenzidine (TMB). A blue product is produced in wells where antibody has been bound to the solid phase. The color development reaction is quenched by addition of an acidic Stop Solution, which causes a change in color from blue to yellow, after which optical Absorbance at 450nm corrected by 620-650mm background subtraction is measured in each well using an ELISA microplate reader. Turn-around time for the test is approximately 35 minutes if agitation is used, or 70 minutes without agitation. While the assay provides a qualitative result when undiluted samples are tested, it may also be used to obtain semi-quantitative anti-PA IgG titer results when serial dilution data are collected for the scrum sample, in similar fashion to that described by U.S. Centers for Disease Control (CDC) Quinn, C.P. et al. Emerging Infectious Diseases 2002; 8(10):1103-1110.

The provided 510(k) summary for the QuickELISA Anthrax-PA Kit describes performance studies, but it does not explicitly define formal acceptance criteria in terms of specific thresholds for sensitivity, specificity, or reproducibility that the device needed to meet. Instead, it presents various performance metrics as "Summary of Performance."

Therefore, the table below will report the observed performance from the studies rather than predefined acceptance criteria.

1. Table of Acceptance Criteria and Reported Device Performance

Note: Formal acceptance criteria (pre-defined thresholds for success) are not explicitly stated in the provided document. The table below presents the reported performance from the studies.

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

• Specificity (Normal Human Sera):
  • Sample Size:
    • Table 1.1: 583 samples (578 Negative, 5 Positive)
    • Table 1.2: 100 samples (Stationary incubation), 104 samples (Agitated incubation) - These appear to be subsets or different studies for normal human sera.
  • Data Provenance: "non-endemic normal population" (implied healthy individuals without anthrax). No specific country of origin is mentioned, but "Normal Human Sera" suggests common laboratory sample sources. Retrospective.
• Cross-Reactive Conditions (Interference Study):
  • Sample Size: 225 samples (224 Negative, 1 Positive) - This appears to be the total count for the interference study, with breakdown provided for specific conditions. E.g., ANA (21), EBV (20), HIV (20), RPR (20), etc.
  • Data Provenance: From individuals with specific disease conditions (e.g., ANA, EBV, HIV, H. pylori, Influenza, Legionella, M. pneumoniae, SLE, Rheumatoid Factor, RPR (syphilis), HAV, HBV). Not specified if retrospective or prospective, or country of origin, but generally such panels are commercially sourced or from research cohorts. The note "CDC published results (JEID 2002); archived data on unrelated samples" suggests some samples were previously characterized by the CDC.
• Sensitivity (Positive Serum Panels):
  • Sample Size:
    • AVA Vaccinees: 49 samples (all tested positive)
    • All Patients: 34 samples (all tested positive, but the table shows '19' in the positive column, which suggests an inconsistency or a subset of 19 positive cases among 34, and then "100%" reported for "All Patients" overall for the device. Given the specificity and sensitivity are percentage of correct detections, this would imply 34 actual positive cases were tested and all were detected. This requires clarification beyond the text).
    • Cutaneous Anthrax: 18 samples (all tested positive)
    • Inhalational Anthrax: 16 samples (all tested positive)
  • Data Provenance:
    • AVA Vaccinees: From recipients of the Anthrax Vaccine Adsorbed (AVA).
    • Patients: From individuals with confirmed anthrax infection (cutaneous and inhalational).
    • The note "Sensitivity in CDC PA IgG-specific ELISA = 100 % in all above groups" suggests these samples were characterized by the CDC.
    • Not specified if retrospective or prospective, or country of origin, but likely from US clinical/public health sources given CDC involvement.
• Analytical Sensitivity (PA IgG Reference Dilutions):
  • Sample Size: Not a patient sample size, but a set of reference material dilutions (e.g., 1000 ng/mL down to 0 ng/mL).
  • Data Provenance: The 1.0 ug/mL PA IgG Reference Sample (REF-1) was "prepared from CDC standard serum pool designated AVR414 (described in JEID, 2002)".

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

The document does not provide information on the number or qualifications of experts used to establish the ground truth for the test set.

However, the "Sensitivity in CDC PA IgG-specific ELISA = 100 % in all above groups" for positive samples and the reference to "CDC published results (JEID 2002); archived data on unrelated samples" for cross-reactivity and normal sera analysis strongly suggest that the ground truth for patient samples and reference materials was established by the U.S. Centers for Disease Control (CDC). The CDC, as a leading public health agency, would be considered the authoritative source for anthrax diagnosis and characterization of antibody responses. While specific expert qualifications are not listed, the involvement of the CDC implies a high level of expertise in infectious diseases and serological testing.

4. Adjudication Method for the Test Set

The document does not explicitly describe any adjudication method (e.g., 2+1, 3+1, none) for establishing the ground truth for the test set.

As mentioned above, the ground truth appears to be established by the CDC, likely through their existing laboratory protocols and reference assays (e.g., CDC PA IgG-specific ELISA). This implies a high standard of reference, but the specific process of resolving discordant results among multiple readers or tests is not detailed for the ground truth establishment.

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

No, a multi-reader, multi-case (MRMC) comparative effectiveness study was not done.

This device is an in-vitro diagnostic (IVD) kit designed for laboratory use to detect antibodies, not for interpretation by human readers in the same way as an imaging device might be. Therefore, the concept of human readers improving with AI vs. without AI assistance does not apply to this type of device. The performance is based on the assay's ability to detect antibodies in serum samples.

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

Yes, the provided studies describe the standalone performance of the QuickELISA Anthrax-PA Kit.

The performance metrics (specificity, sensitivity, cross-reactivity, analytical sensitivity, reproducibility) are all measured directly from the kit's output (optical absorbance, then translated into a qualitative positive/negative result) when testing serum samples. This is inherently a standalone performance evaluation of the device itself, without human interpretation as a variable in the core diagnostic result generation. The human "in-the-loop" for this device would be the laboratory technician performing the assay and reading the microplate reader, but this is standard operation for IVDs and not considered "human-in-the-loop performance" in the context of an AI-assisted diagnostic.

7. The Type of Ground Truth Used

The type of ground truth used appears to be a combination of:

• Expert Consensus/Reference Standard Serology: For positive samples (AVA vaccinees, cutaneous anthrax, inhalational anthrax patients), the ground truth was established by the CDC PA IgG-specific ELISA, which is referred to as having 100% sensitivity for these groups. This indicates a high-level reference standard.
• Clinical Diagnosis/Outcomes Data: For anthrax patients, their classification (cutaneous, inhalational) implies a clinical diagnosis confirmed by other means (symptoms, history, exposure, and possibly other laboratory data), consistent with the intended use statement.
• Known Negative Status: For specificity and cross-reactivity studies, the ground truth was "Normal Human Sera" (presumably healthy individuals without anthrax exposure/vaccination) and "Interference Sera" from individuals with documented conditions known not to be anthrax (e.g., HIV, EBV, Influenza).

8. The Sample Size for the Training Set

The document does not provide information on a dedicated training set or its sample size.

Given that this is a 510(k) submission for a non-AI/ML in-vitro diagnostic kit (an ELISA), there isn't typically a "training set" in the machine learning sense. The device's components (antigens, antibodies, reagents) and assay protocol are developed through R&D and optimization phases, which would involve internal testing and validation. The data presented in the summary represents the analytic and clinical validation of the final device, effectively acting as the "test set" to demonstrate its performance against established ground truth.

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

As there is no explicit "training set" mentioned in the context of the 510(k) submission for this ELISA kit, the method for establishing its ground truth is not applicable. The data presented is from the validation studies of the final product.

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The QualiCode™ B. burgdorferi IgG Western Blot Kit is an in vitro qualitative assay for the detection of human IgG antibodies reactive with Borrelia burgdorferi antigens present on a membrane strip. The QualiCode™ B. burgdorferi IgG Western Blot Kit is intended for supplemental testing of human serum specimens which yield positive or equivocal results on B. burgdorferi ELISA or IFA screening assays: QualiCode test results can provide additional, specific evidence of infection with B. burgdorferi which may be useful in the diagnosis of Lyme disease. The OualiCode™ B, burgdorferi IgG Western Blot Kit can be used to test human sera at any time following onset of symptoms, and when (1) only IgM antibodies were originally detected: (2) IgG antibodies were detected previously, but were not considered significant by Western Blot; or (3) previously seronegative patients become positive by ELISA or IFA screening tests.

The device is a Western Blot assay. Proteins and other antigenic components of the Borrelia spirochete are fractionated by polyacrylamide gel electrophoresis in the presence of sodium dodecvl sulfate. The separated proteins are electrophoretically transferred from the gel to nitrocellulose membranes, which are subsequently blocked to minimize non-specific binding and cut into strips. These nitrocellulose strips with resolved Borrelia burgdorferi antigens are then reacted with diluted serum and controls (positive and negative sera of defined reactivity).

During the incubation period, human antibodies specific to the B. burgdorferi antigens, if present in the sample or control, will bind to the antigen to which they have affinity. Unbound serum and non-specific antibodies are washed from the strip. Detection of bound IgG antibodies is accomplished by reacting and incubating the strips with a solution containing anti-human IgG antibodies conjugated with alkaline phosphatase. Unbound conjugate antibodies are removed by washing. The qualitative assessment of the detected IgG antibodies is then accomplished by the reaction of the alkaline phosphatase with a chemical substrate, which is cleaved into a colored, insoluble product that can be visualized. The determination of the reactivity of each unknown specimen is accomplished by comparison of the identified, visualized bands to the Band Identifying and Band Intensity Controls.

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Acceptance Criteria and Study to Prove Device Meets Criteria:

1. Table of Acceptance Criteria and Reported Device Performance:

The document does not explicitly state pre-defined acceptance criteria for the device's performance metrics (sensitivity, specificity, reproducibility). Instead, it presents the "Summary of Performance" as the observed outcomes from the clinical trials. Given this, the table below reflects the reported performance as if they were the benchmarks the device met.

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

• Test Set Sample Sizes:
  • Specificity (Normal Control): 430 samples (279 from endemic regions, 151 from non-endemic regions).
  • Specificity (Cross-Reactive Panel): 172 samples.
  • Sensitivity (Lyme Disease Panel): 199 samples (further categorized by draw time).
  • Reproducibility (Panel): 20 specimens.
  • CDC Lyme Disease Serum Panel: Used for "Substantial Equivalence" but specific sample size for this panel within the clinical trials is not explicitly stated.
• Data Provenance:
  • The samples were obtained from patients with a clinical diagnosis of Lyme Disease and from normal donors from endemic and non-endemic regions.
  • "Each of the clinical trial sites provided specimens that were well characterized by the site." This implies data was collected from multiple clinical trial sites.
  • The data appears to be retrospective, as it refers to "archived Lyme Disease specimens" and samples that "had been drawn at different times after onset of disease."

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

• The document does not explicitly state the number of experts used to establish ground truth for the test set.
• Qualifications of Experts: Not specified. However, the ground truth for "clinical diagnosis of Lyme Disease" was based on a "clinical diagnosis… in accordance with the CDC case definition," and some infections were "confirmed by culture of Borrelia from biopsies." This suggests that medical professionals (e.g., physicians, pathologists) were involved in the initial diagnosis and characterization of these samples.

4. Adjudication Method for the Test Set:

• The document does not explicitly mention an adjudication method (e.g., 2+1, 3+1).
• For Inter-reader reproducibility, it states, "each strip interpreted by two independent readers." While this involves multiple readers, it describes a reproducibility assessment rather than a consensus for establishing a definitive ground truth for individual cases.

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

• No, a MRMC comparative effectiveness study comparing human readers with and without AI assistance was NOT done. This device is a diagnostic kit (Western Blot assay), not an AI-powered image analysis or decision support system that would assist human readers in interpretation. The "Inter-reader reproducibility" section assesses consistency between human readers interpreting the device's results, not the impact of an AI on human performance.

6. Standalone Performance Study:

• Yes, a standalone performance study was done. The entire "Summary of Performance" section details the direct performance of the QualiCode™ B. burgdorferi IgG Western Blot Kit (an "algorithm" in a broader sense of a diagnostic protocol) in detecting IgG antibodies against a defined ground truth (Lyme disease diagnosis, normal controls, cross-reactive conditions). The performance metrics (sensitivity, specificity, reproducibility) are reported for the device itself.

7. Type of Ground Truth Used:

• Clinical Diagnosis: For the Lyme disease panel, the ground truth was "clinical diagnosis of Lyme Disease in accordance with the CDC case definition, i.e. based on the presence of EM (erythema migrans) or the presentation of late Lyme clinical manifestations (e.g., arthritic, cardiac, or neurological symptoms)."
• Pathology/Culture: Infection was "confirmed by culture of Borrelia from biopsies in many examples." This provides a strong, direct form of ground truth for a subset of the Lyme disease cases.
• Screening Assay Results: Specimens were "required to have tested positive or indeterminate on a B. burgdorferi screening assay, typically an ELISA." This indicates a level of pre-screening was used to select the Lyme disease panel.
• Normal Donor Status: For the specificity studies, ground truth was based on samples from "Normal population" (from endemic and non-endemic regions) and "samples from patients with diseases other than Lyme disease that may be cross - reactive." The assumption here is that these samples are truly negative for Lyme disease.

8. Sample Size for the Training Set:

• The document does not explicitly mention a separate "training set" for the device. As a Western Blot kit, it's a biochemical assay rather than a machine learning model that typically requires a distinct training phase. The "clinical trials" described here are designed for validation and performance evaluation of the developed assay, not for training it.

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

• Since a separate training set is not indicated in the context of this type of device, this question is not applicable. The device's components (antigens, reagents) are developed based on scientific understanding of B. burgdorferi and immunology, not through a data-driven training process with a specific ground truth dataset like an AI model.

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The QualiCode™ B. burgdorferi IgM Western Blot Kit is an in vitro qualitative assay for the detection of human IgM antibodies reactive with Borrelia burgdorferi antigens present on a membrane strip. The QualiCode™ B. burgdorferi IgM Western Blot Kit is intended for supplemental testing of human serum specimens which yield positive or equivocal results on B. burgdorferi ELISA or IFA screening assays. QualiCode test results can provide additional, more specific evidence of infection with B. burgdorferi which may be useful in the diagnosis of Lyme disease.

The QualiCode™ B. burgdorferi IgM Western Blot Kit can be used to test human sera for IgM antibodies during the acute phase of disease, within one month of infection, in accordance with CDC/ASTPHLD guidelines. During this period, patients may not yet have developed a detectable IgG response. Beyond one month from infection, an IgG Western Blot test is recommended. Patients should not be tested solely for IgM antibodies at this stage due to the higher probability of false-positive results. Symptomatic patients showing IgM but not IgG antibodies at an early stage in infection should be re-tested for IgG antibodies 2-4 weeks later.

The device is a Western Blot assay. Proteins and other antigenic components of the Borrelia spirochete are fractionated by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The separated proteins are electrophoretically transferred from the gel to nitrocellulose membranes. which are subsequently blocked to minimize non-specific binding and cut into strips. These nitrocellulose strips with resolved Borrelia burgdorferi antigens are then reacted with diluted serum and controls (positive and negative sera of defined reactivity).

During the incubation period, human antibodies specific to the B, burgdorferi antigens, if present in the sample or control, will bind to the antigen to which they have affinity. Unbound serum and non-specific antibodies are washed from the strip. Detection of bound IgM antibodies is accomplished by reacting and incubating the strips with a solution containing anti-human IgM antibodies conjugated with alkaline phosphatase. Unbound conjugate antibodies are removed by washing. The qualitative assessment of the detected IgM antibodies is then accomplished by the reaction of the alkaline phosphatase with a chemical substrate, which is cleaved into a colored, insoluble product that can be visualized. The determination of the reactivity of each unknown specimen is accomplished by comparison of the identified, visualized bands to the Band Identifying and Band Intensity Controls.

Here's an analysis of the provided text to extract the requested information about device acceptance criteria and studies:

Immunetics QualiCode™ B. burgdorferi IgM Western Blot Kit (K991062)

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria (e.g., "The device must achieve X% sensitivity and Y% specificity"). Instead, it presents the performance characteristics found during the clinical trials. We can infer the expected performance based on these reported values.

2. Sample Sizes and Data Provenance for the Test Set

• Specificity Test Set:

  • Normal Population: n=430 (279 from Lyme disease endemic regions, 151 from non-endemic regions).
  • Cross-Reactive Panel: n=172 (samples from patients with diseases other than Lyme disease that may be cross-reactive).
  • Total Specificity Samples: 602
  • Provenance: Not explicitly stated by country, but regional (endemic/non-endemic) and from clinical trial sites. The data is retrospective, as these were "well-characterized, archived Lyme Disease specimens" and other pre-existing panels.

• Sensitivity Test Set:

  • Lyme Disease Panel: n=186 (samples from patients with a clinical diagnosis of Lyme disease).
  • Provenance: Not explicitly stated by country, but from clinical trial sites. The data is retrospective, consisting of "well-characterized, archived Lyme Disease specimens." These samples were drawn at different times after onset of disease.

• Reproducibility Test Set:

  • Panel: n=20 specimens (including positive, weakly reactive, and negative sera).
  • Provenance: Not specified, but likely internal or from the clinical trial sites.

3. Number of Experts and their Qualifications for Ground Truth

The document does not explicitly state the number of experts or their specific qualifications for establishing the ground truth for the test set. However, it does refer to:

• "Clinical diagnosis of Lyme Disease in accordance with the CDC case definition, i.e. based on the presence of EM (erythema migrans) or the presentation of late Lyme clinical manifestations (e.g., arthritic, cardiac, or neurological symptoms)." This implies diagnosis by clinicians.
• "Infection was confirmed by culture of Borrelia from biopsies in many examples."
• "Specimens selected for the trial were required to have tested positive or indeterminate on a B. burgdorferi screening assay, typically an ELISA, in accordance with the two-tier testing protocol recommended by CDC/ASTPHLD." This indicates that initial characterization involved standard serological testing overseen by labs or clinicians.
• The "Lyme Disease Serum Panel" from the Centers for Disease Control (CDC) was also used, which would have its own established ground truth.

For the reproducibility studies, "two independent readers" were used for inter-reader reproducibility, but their qualifications are not specified.

4. Adjudication Method for the Test Set

The document does not describe a formal adjudication method (like 2+1 or 3+1) for establishing the ground truth of the test set specifically for this study. Instead, the samples were "well-characterized" based on clinical diagnosis, culture confirmation, and pre-existing serological testing (two-tier protocol) under CDC/ASTPHLD guidelines. The CDC Lyme Disease Serum Panel also likely has its ground truth externally defined and accepted.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not reported. The study focuses on the standalone performance of the device and its reproducibility characteristics (inter-lot, inter-run, and inter-reader agreement), not on comparing human readers with and without AI assistance.

6. Standalone Performance Study (Algorithm Only)

Yes, a standalone performance study was done. The entire "Summary of Performance" section describes the device's performance (sensitivity, specificity, reproducibility) on various sample panels without human interpretation assistance for the core performance metrics. The result interpretations from the device were compared against the established ground truth of the samples.

7. Type of Ground Truth Used for the Test Set

The ground truth for the test set was a combination of:

• Clinical Diagnosis: Based on CDC case definition (erythema migrans or late Lyme clinical manifestations).
• Pathology/Culture Confirmation: Infection confirmed by culture of Borrelia from biopsies in many examples.
• Established Serological Testing: Initial positive or indeterminate results on B. burgdorferi screening assays (ELISA/IFA) following CDC/ASTPHLD two-tier testing protocol.
• Reference Panels: Utilization of the Centers for Disease Control Lyme Disease Serum Panel, which comes with its own established reference status.

8. Sample Size for the Training Set

The document does not provide information on a specific training set or its sample size. The description of "clinical trials" and "characterized samples" refers to the general methodology for assessing the device's performance, but there is no explicit mention of data used to "train" the assay itself in the context of machine learning or AI. This is a traditional in-vitro diagnostic (IVD) device, not an AI/ML-based device.

9. How Ground Truth for the Training Set Was Established

Since there's no mention of a dedicated training set in the context of an AI/ML algorithm, this question is not applicable. The "training" of a traditional IVD device like this is typically through its design, reagent selection, and optimization during development, rather than a data-driven training set used for machine learning. The clinical performance data presented here serves to validate the final device's performance against established ground truths.

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