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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 Aptiva APS IgG Reagent is an immunoassay utilizing particle-based multi-analyte technology for the semiquantitative determination of anti-cardiolipin (aCL) and anti-beta 2 glycoprotein 1 (all2GPI) IgG autoantibodies in human serum as an aid in the diagnosis of primary antiphospholipid syndrome (APS), when used in conjunction with other laboratory findings.

The Aptiva APS IgG Reagent is intended for use with the Aptiva System.

The Aptiva APS IgM Reagent is an immunoassay utilizing particle-based multi-analyte technology for the semiquantitative determination of anti-cardiolipin (aCL) and anti-beta 2 glycoprotein 1 (aß2GPI) IgM autoantibodies in human serum as an aid in the diagnosis of primary and secondary antiphospholipid syndrome (APS), when used in conjunction with other laboratory findings.

The Aptiva APS IgM Reagent is intended for use with the Aptiva System.

The Aptiva APS IgG and Aptiva APS IgM reagent utilize particle based multi-analyte technology (PMAT) in a cartridge format. Each analyte (anti-cardiolipin [aCL] and anti-B2-Glycoprotein I [aB2GPI]) in the Aptiva APS IgG and Aptiva APS IgM reagent is a solid phase immunoassay utilizing fluorescent microparticles. This technology allows each of the two analytes, along with a human IgG or human IgM capture antibody (IgG or IgM Control Microparticle), to be coated onto three uniquely recognizable paramagnetic microparticles, which are combined into one tube.

The Aptiva instrument is a fully automated, random-access analyzer. This platform is a closed system with continuous load and random-access capabilities that processes the samples, runs the reagent and reports results. It includes liquid handling hardware, optical module (OM), and integrated computer with proprietary software and touch screen user interface.

The two analyte microparticles, along with the control microparticle, are stored in the reagent cartridge under conditions that proteins in their reactive states. When the assay cartridge is ready to be used for the first time, the reagent tube seals are pierced using the cartridge lid. The reagent cartridge is then loaded onto the Aptiva instrument, where the microparticles are automatically rehydrated using a buffer located within the cartridge.

The Aptiva System dilutes the sample 1:8, then combines an aliquot of diluted sample, and reagent into a cuyette. The mixture is incubated at 37°C. After a wash cvcle, conjugated antihuman IgG or IdM antibodies are added to the particles and this mixture is incubated at 37°C. Excess conjugate is removed in another wash cycle, and the particles are re-suspended in system fluid.

Multiple images are generated by the system to identify and count the two (2) unique analyte particles, as well as determine the amount of coniugate on each particle. Coated with goat anti-human lgG or IdM antibodies, is present as a control to flaq low concentrations of IgG or IgM in the sample as an assay verification step. The median fluorescent intensity (MFI) for each analyte is proportional to the concentration of conjugate bound to human IgG or IgM, which is proportional to the concentration of IgG or IgM antibodies bound to the corresponding particle population. The system uses the MFI from at least 50 particles of each population. The identity of the particles is determined by the unique signature of the particles.

Each analyte in the Aptiva APS IgG Reagent and the Aptiva APS IgM Reagent is assigned a predefined lot specific master curve. The analyte specific master curve is stored on the reagent cartridge RFID label. Based on results obtained by running calibrators (supplied separately), the system creates individual working curves. Working curves are used by the software to calculate Fluorescent Light Units (FLU) for each analyte from the MFI values obtained for each sample.

Aptiva APS IgG and Aptiva APS IgM Calibrators and Aptiva APS IgG and Aptiva APS IgM Controls are sold separately.

The provided text describes the analytical and clinical performance characteristics of the Aptiva APS IgG and Aptiva APS IgM Reagents, which are immunoassays for the semi-quantitative determination of anti-cardiolipin (aCL) and anti-beta 2 glycoprotein 1 (aβ2GPI) IgG/IgM autoantibodies. This information is presented in the context of a 510(k) premarket notification for FDA clearance.

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

1. A table of acceptance criteria and the reported device performance

The document does not explicitly state "acceptance criteria" as a separate, quantified set of thresholds for each performance metric. Instead, it presents the results of various analytical and clinical studies, implying that these results met the internal criteria for substantial equivalence to predicate devices and overall performance claims for an in vitro diagnostic (IVD) device.

However, we can infer performance targets based on the presented data and the overall context of an FDA submission for an IVD. The primary performance metrics presented are related to precision, detection limits, linearity, interference, and clinical sensitivity/specificity.

Inferred Acceptance Criteria and Reported Device Performance (Summary)

• aCL IgG: 5.6% - 9.5% (generally decreasing with higher FLU)
• aβ2GPI IgG: 6.9% - 11.7% (generally decreasing with higher FLU)
• aCL IgM: 4.3% - 9.7% (generally decreasing with higher FLU)
• aβ2GPI IgM: 5.5% - 10.2% (generally decreasing with higher FLU)

Between-Site Reproducibility CV% (3 sites):

• aCL IgG: 5.2% - 9.3%
• aβ2GPI IgG: 6.4% - 10.0%
• aCL IgM: 5.4% - 10.0%
• aβ2GPI IgM: 5.9% - 10.5%

Between-Lot Reproducibility CV% (3 lots):

• aCL IgG: 6.6% - 13.3%
• aβ2GPI IgG: 8.5% - 12.1%
• aCL IgM: 6.1% - 11.4%
• aβ2GPI IgM: 6.0% - 10.5% |
  | Limit of Blank (LoB) | Very low, close to zero, ensuring no signal from blank samples. | aCL IgG: 0.00 FLU
  aβ2GPI IgG: 0.02 FLU
  aCL IgM: 0.01 FLU
  aβ2GPI IgM: 0.03 FLU |
  | Limit of Detection (LoD)| Low, indicating ability to detect small amounts of analyte. | aCL IgG: 0.07 FLU
  aβ2GPI IgG: 0.09 FLU
  aCL IgM: 0.04 FLU
  aβ2GPI IgM: 0.06 FLU |
  | Limit of Quantitation (LoQ)| Low, defining the lowest concentration that can be reliably quantified. | aCL IgG: 0.29 FLU
  aβ2GPI IgG: 0.21 FLU
  aCL IgM: 0.06 FLU (set to 0.10 FLU for AMR lower limit)
  aβ2GPI IgM: 0.09 FLU (set to 0.10 FLU for AMR lower limit) |
  | Analytical Measuring Range (AMR)| Wide enough to cover relevant clinical concentrations, with demonstrated linearity. | aCL IgG: 0.29 - 328.94 FLU
  aβ2GPI IgG: 0.21 - 256.70 FLU
  aCL IgM: 0.10 – 114.68 FLU
  aβ2GPI IgM: 0.10 – 95.86 FLU

Linearity demonstrated across these ranges with R2 values mostly ≥ 0.98. |
| High Concentration Hook Effect| No hook effect within or above the AMR. | Confirmed no hook effect up to theoretically calculated values: aCL IgG: 2645.36 FLU, aβ2GPI IgG: 1790.48 FLU, aCL IgM: 167.25 FLU, aβ2GPI IgM: 126.13 FLU. |
| Interference | No significant interference from common endogenous or exogenous substances at specified concentrations. | No interference detected for aCL IgG, aβ2GPI IgG, aCL IgM, and aβ2GPI IgM with tested interferents (bilirubin, hemoglobin, triglycerides, cholesterol, RF IgM, human IgG, ibuprofen, warfarin, prednisone, acetaminophen, aspirin, hydroxychloroquine, omeprazole, simvastatin, heparin) at their respective tested concentrations. Percent recoveries or FLU differences were within acceptable ranges (generally close to 100% recovery for spiked samples, or low FLU difference for negative samples). |
| Sample Stability | Samples should be stable for specific storage conditions and freeze/thaw cycles. | Samples stable up to 48 hours at room temperature, up to 14 days at 2-8°C, and for up to 5 freeze/thaw cycles. |
| Reagent Stability | Reagent shelf-life and in-use stability should be established. | Shelf-life: 9 months for Aptiva APS IgG Reagent, 7 months for Aptiva APS IgM Reagent (based on accelerated stability, verified by ongoing real-time studies).
In-use (onboard) stability: 28 days for both, with 14-day recalibration. |
| Clinical Sensitivity & Specificity| High sensitivity to detect disease (APS) and high specificity to correctly identify non-disease states (controls/non-APS). | Aptiva APS IgG:

• aCL IgG: Sensitivity 54.1% (95% CI: 45.3–62.7%), Specificity 99.5% (95% CI: 98.2–99.9%)
• aβ2GPI IgG: Sensitivity 53.3% (95% CI: 44.5-61.9%), Specificity 99.0% (95% CI: 97.5-99.6%)

Aptiva APS IgM:

• aCL IgM: Sensitivity 27.5% (95% CI: 22.7–32.9%), Specificity 97.5% (95% CI: 95.4–98.6%)
• aβ2GPI IgM: Sensitivity 24.7% (95% CI: 20.1–30.0%), Specificity 98.5% (95% CI: 96.8–99.3%) |
  | Predicate Method Comparison (Percent Agreement)| High agreement with legally marketed predicate devices. | Aptiva APS IgG (aCL IgG) vs. QUANTA Flash aCL IgG: PPA: 81.6%, NPA: 95.7%, TPA: 93.1% (N=202)
  Aptiva APS IgG (aβ2GPI IgG) vs. QUANTA Lite Beta 2GP1 IgG ELISA: PPA: 88.0%, NPA: 89.7%, TPA: 88.9% (N=108)
  Aptiva APS IgM (aCL IgM) vs. QUANTA Flash aCL IgM: PPA: 87.0%, NPA: 90.2%, TPA: 89.8% (N=422)
  Aptiva APS IgM (aβ2GPI IgM) vs. QUANTA Flash β2GPI IgM: PPA: 88.9%, NPA: 84.3%, TPA: 84.8% (N=244) |

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Clinical Performance Test Set Sample Sizes:

  • Aptiva APS IgG (aCL IgG & aβ2GPI IgG): N=526 (122 APS combined, 404 controls/non-APS)
  • Aptiva APS IgM (aCL IgM & aβ2GPI IgM): N=689 (291 APS combined, 398 controls/non-APS)
  • Normal Population for Expected Values: N=200 apparently healthy blood donors.

• Method Comparison Test Set Sample Sizes:

  • Aptiva APS IgG (aCL IgG vs. QUANTA Flash aCL IgG): N=202
  • Aptiva APS IgG (aβ2GPI IgG vs. QUANTA Lite Beta 2GP1 IgG ELISA): N=108
  • Aptiva APS IgM (aCL IgM vs. QUANTA Flash aCL IgM): N=422
  • Aptiva APS IgM (aβ2GPI IgM vs. QUANTA Flash β2GPI IgM): N=244

• Analytical Performance Test Set Sample Sizes:

  • Precision: 7 samples for IgG, 7 samples for IgM (80 replicates each for within-lab; 75 replicates each for between-site/lot reproducibility from multiple sites/lots).
  • LoB/LoD/LoQ: Blanks (LoB: 4 samples, 60 data points/lot); Low-level samples (LoD/LoQ: 4 samples, 120 data points/assay/lot).
  • Interference: 6 human specimens (negative, cutoff, positive) for each analyte, spiked with various interferents and tested in 5 replicates.
  • Sample Stability: 5 serum samples (IgG), 5 serum samples (IgM) tested in duplicates over time/cycles.
  • In-use Stability: 11 samples (IgG), 7 samples (IgM) tested periodically.

• Data Provenance: The document states that a "cohort of characterized samples, none of which were used for establishing the reference range, was used to validate the clinical performance." It does not explicitly state the country of origin of the data or whether the studies were retrospective or prospective. However, for a 510(k) submission, clinical validation studies typically involve retrospective or prospectively collected clinical samples, but the exact nature (e.g., specific clinical sites, patient populations beyond disease groups) and geographic origin are not detailed here. The studies were likely conducted within a controlled laboratory setting by the manufacturer (Inova Diagnostics, Inc. in San Diego, CA) or its affiliates, using sourced human serum samples.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

The establishment of "ground truth" for IVD devices like these typically relies on well-characterized clinical samples and established diagnostic criteria for the disease (Antiphospholipid Syndrome - APS).

• The document states that the clinical performance validation was performed using "a cohort of characterized samples." The characterization of these samples (i.e., whether they definitively represent APS or control) would serve as the ground truth.
• However, the document does not specify the number of experts or their qualifications (e.g., rheumatologists, clinical immunologists/pathologists) who established the diagnostic status (ground truth) of the clinical samples (APS vs. control) used in the clinical sensitivity and specificity studies. It is implied that these were "characterized samples," meaning their disease status was determined by established clinical and laboratory criteria, likely involving clinical consensus or previous diagnoses.
• For cut-off establishment, the reference population included "apparently healthy subjects," and the "internal APS samples (data not provided)" and "distribution of result values of healthy controls" were used. This suggests clinical characterization of these samples.

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

The concept of "adjudication method" (like 2+1 or 3+1) is typically relevant for interpretative tasks, such as reading medical images, where multiple human readers interpret the same data and their interpretations need to be reconciled to establish a ground truth.

For these types of IVD assays, ground truth for clinical performance is established based on the clinical diagnosis of the patient from whom the sample was collected. This diagnosis is usually a culmination of clinical findings, established criteria (e.g., the revised Sapporo criteria for APS), and other laboratory tests, rather than an "adjudication" of multiple independent interpretations of the test results themselves.

Therefore, the document does not mention any adjudication method in the context of establishing ground truth for the test samples, as it's not applicable in the same way it would be for an AI-medical imaging device. The "ground truth" for the samples (APS vs. non-APS) is assumed to be pre-established clinical 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 study was conducted or is applicable here.

This device is an in vitro diagnostic (IVD) immunoassay, not an AI-powered image analysis or diagnostic aid that assists human readers (e.g., radiologists interpreting images). The device directly measures biomarker levels in a sample, and its output is a quantitative value (FLU) which then determines a semi-quantitative result (Positive/Negative/Indeterminate based on cut-offs). Human "readers" (laboratory personnel) operate the instrument and interpret the final quantitative results based on predefined cut-offs, but they are not subjectively interpreting complex data that AI would assist with, in the sense of an MRMC study.

Therefore, an MRMC comparative effectiveness study, and an effect size related to human reader improvement with AI assistance, are not relevant for this type of device and are not mentioned in the document.

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

This is a "standalone" device in terms of its core functionality, but the term "algorithm only" or "human-in-the-loop" isn't directly analogous.

• The Aptiva System is a fully automated, random-access analyzer (page 6). This means the instrument itself, with its integrated software and optical module, processes the samples, runs the reagents, and reports results independently after the sample is loaded and the assay initiated.
• The "performance" described here (sensitivity, specificity, precision, linearity, etc.) is the device's performance (including its internal algorithms and mechanics) in generating quantitative results. There isn't a separate "algorithm only" performance that needs to be differentiated from a "human-in-the-loop" performance, because the device is the automated system determining the FLU values. The human interaction is primarily in sample loading, reagent handling, and result review/reporting, not in interpreting raw data that the device itself would also interpret in an unassisted mode.

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

The ground truth for the clinical performance studies (sensitivity and specificity) was established based on "characterized samples" representing patients with Antiphospholipid Syndrome (APS) and various control groups (patients with other autoimmune/infectious diseases, apparently healthy subjects).

While the document doesn't explicitly state "expert consensus," it's highly implied that the "characterization" of these samples as APS or control would be based on:

• Clinical findings: Presenting symptoms, medical history.
• Other laboratory findings: Beyond the novel antibodies, other relevant diagnostic tests.
• Established diagnostic criteria: For APS, this would typically be the revised Sapporo classification criteria, which combine clinical and laboratory criteria.

So, it's a combination of established clinical diagnoses and potentially other laboratory data, which implicitly would involve the consensus or findings of medical experts involved in patient diagnosis. It is not based on pathology (e.g., tissue biopsy) or outcomes data (e.g., long-term disease progression as the sole ground truth).

8. The sample size for the training set

The document describes the submission of a "new device" and its performance characteristics. It does not explicitly mention or quantify a "training set" in the context of machine learning.

For IVD devices, a "training set" isn't a standard concept unless the device incorporates adaptive algorithms or AI that learns from data. In this case, the device is an immunoassay with predefined master curves and calibrated reagents. The master curves are generated "at Inova for each reagent lot, where in-house Master Curve Standards with assigned FLU values are run multiple times." These "in-house Master Curve Standards" could be considered analogous to a "training" or calibration process, but it's not a dataset for training a generalized AI model but rather for calibrating each reagent lot of a classical assay.

The sample sizes provided in the document are for:

• Analytical performance (precision, LoB/LoD/LoQ, linearity, interference, stability).
• Clinical validation (sensitivity/specificity studies).
• Method comparison studies.
• Reference range establishment.

None of these are explicitly labeled as a "training set."

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

As there is no explicitly defined "training set" for a machine learning model, the concept of establishing ground truth for such a set is not applicable here.

However, if we consider the "Master Curve Standards" as analogous to calibration/training data for the assay, their "ground truth" (assigned FLU values) would be established through a rigorous internal process by the manufacturer (Inova Diagnostics) based on:

• Carefully prepared and characterized aliquots (standards) with known or assigned concentrations of the target antibodies.
• Repeat measurements and statistical analysis for consistent and accurate assignment of FLU values.
• This is a standard practice for calibrating quantitative IVD assays, ensuring the device outputs accurate and traceable results.

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The Access Toxo IgM II assay is a paramagnetic-particle chemiluminescent immunoassay for the qualitative detection of Toxoplasma gondii-specific IgM antibody in adult human serum and plasma using the Access Immunoassay Systems.

The Access Toxo IgM II assay is presumptive for the diagnosis of acute, recent, or reactivated Toxoplasma gondii infection in males and pregnant females. It is recommended this assay be performed in conjunction with a Toxoplasma gondii-specific IgG antibody assay.

Note: This assay has not been cleared/approved by the FDA for the screening of blood or plasma donors in the United States.

The Access Toxo IgM II assay is a paramagnetic-particle chemiluminescent immunoassay for the qualitative detection of Toxoplasma gondii-specific IgM antibody in human serum and plasma using the Access Immunoassay Systems. The Access Toxo IgM II Calibrators are intended for use with the Access Toxo IgM II assay for the qualitative detection of Toxoplasma gondii-specific IgM antibody in adult human serum and plasma using the Access Immunoassay Systems. The Access Toxo IgM II QC is intended for monitoring system performance of the Access Toxo IgM II assay. The Access assay consists of the reagent pack, calibrators and QCs. Other items needed to run the assay include substrate and wash buffer. The Access assay reagent pack, Access assay callorators, Access QCs, along with the UniCel DxI Wash Buffer II are designed for use with the DxI 9000 Access Immunoassay Analyzer in a clinical laboratory setting.

The provided text is a 510(k) premarket notification summary for the Access Toxo IgM II assay, a diagnostic immunoassay, not an AI/ML-driven device. Therefore, many of the requested criteria (e.g., sample size for training set, number of experts for ground truth, MRMC study, AI assistance effect size) are not applicable to this type of medical device submission.

However, I can extract and present the relevant information regarding the device's acceptance criteria and the study proving it meets these criteria based on the provided text.

Acceptance Criteria and Device Performance for Access Toxo IgM II Assay

This document describes the validation of the Access Toxo IgM II assay on the DxI 9000 Access Immunoassay Analyzer, demonstrating its substantial equivalence to the previously cleared Access Toxo IgM II assay on the Access 2 Immunoassay System. The primary performance metrics reported are Positive Percent Agreement (PPA), Negative Percent Agreement (NPA), and Imprecision (CV%).

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the results presented, which showed 100% agreement for both positive and negative samples, and the imprecision results were well within the design specification.

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

• Method Comparison Study: 152 samples.
  • Data Provenance: Samples were "collected from the intended use population." The study was "performed at an internal site." No specific country of origin or whether the data was retrospective or prospective is mentioned, but "intended use population" generally implies clinical samples.
• Imprecision Studies (Within-Laboratory & Reproducibility):
  • For each of the 4 samples tested: N = 240 (for within-laboratory precision) and N = 225 (for reproducibility). These represent the number of individual measurements.
  • The study involved testing multiple samples in duplicate (for precision) or in replicates of 5 (for reproducibility) over multiple days, across three reagent/calibrator lots and three analyzers.

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

N/A. This is a laboratory diagnostic immunoassay, not an image-based AI/ML device where expert consensus for ground truth is typically required. The "ground truth" for the method comparison study was the result from the FDA-cleared predicate device (Access Toxo IgM II on the Access 2 Immunoassay System).

4. Adjudication Method for the Test Set

N/A. The comparison was directly between the candidate device (DxI 9000) and the predicate device (Access 2). There was no human adjudication process involved in settling discrepancies between results from different analyzers beyond standard laboratory procedures for confirming unexpected results.

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

No, an MRMC study was not done. This type of study is relevant for imaging devices or AI-assisted diagnostic tools where human reader performance is a key metric. This submission is for an automated immunoassay.

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

Yes, the studies evaluate the standalone performance of the device/assay system (Access Toxo IgM II on the DxI 9000) against a reference standard (predicate device or established precision metrics). The system itself performs the measurement and provides a qualitative (Reactive, Equivocal, Non-Reactive) result. There isn't an "algorithm only" in the AI/ML sense, but the device operates autonomously to produce results.

7. The Type of Ground Truth Used

• Method Comparison: The results obtained from the FDA-cleared predicate device (Access Toxo IgM II on the Access 2 Immunoassay System) served as the reference for determining agreement.
• Imprecision: The consistency of the device's own measurements provided the "ground truth" for precision relative to established statistical methods (CLSI EP05-A3).

8. The Sample Size for the Training Set

N/A. This is not an AI/ML device that requires a distinct "training set." The device is a chemical immunoassay system. The development of such assays involves extensive R&D, reagent formulation, and analytical validation, but not "training data" in the machine learning sense.

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

N/A. As stated above, there is no "training set" or corresponding ground truth establishment in the context of an AI/ML model. The assay's analytical performance relies on validated biochemical reactions and instrument calibration.

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The Alinity i Toxo IgM assay is a chemiluminescent microparticle immunoassay (CMIA) used for the qualitative detection of IgM antibodies to Toxoplasma gondii in human serum, serum separator, and plasma tubes (lithium heparin, lithium heparin separator, and tripotassium EDTA) on the Alinity i system.

The Alinity i Toxo IgM assay is to be used as an aid in the diagnosis of acute or recent Toxoplasma gondii infection in suspected individuals including women of child-bearing age. It is recommended that the assay be performed in conjunction with a Toxoplasma gondii IgG assay.

The Alinity i Toxo IgM assay has not been cleared for use in screening blood, plasma, or tissue donors.

The Alinity i Toxo IgM assay is an automated, two-step immunoassay for the qualitative detection of IgM antibodies to Toxoplasma gondii in human serum and plasma using chemiluminescent microparticle immunoassay (CMIA) technology. The kit includes Reagents (Microparticles and Conjugate), Calibrator, and Controls.

The provided text is a 510(k) Summary for the Abbott Laboratories Alinity i Toxo IgM assay. It details the device's characteristics, intended use, and performance studies to demonstrate substantial equivalence to a predicate device.

Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided document:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly present a "table of acceptance criteria" with predefined thresholds that the device must meet in a comparative format. Instead, it presents various performance studies (precision, analytical specificity, cross-reactivity, matrix equivalency, class specificity, CDC panel agreement, and clinical agreement) and then summarizes the results of these studies. The implicit acceptance criteria are the successful demonstration of performance comparable to a cleared device and FDA guidance documents.

However, we can infer some "acceptance criteria" from the results presented, especially in the CDC Panel Agreement and Clinical Agreement sections. The document highlights the Percentage Positive Agreement (PPA) and Percentage Negative Agreement (NPA) as key metrics.

Here's a table focusing on the performance of the Alinity i Toxo IgM assay as tested against established benchmarks:

Table of Device Performance Metrics

• Negative Control: SD 0.014 (NAc)
• Positive Control: SD 0.104 (3.8% CV)
• High Nonreactive Panel: SD 0.040 (NAc)
• Low Reactive Panel: SD 0.064 (4.7% CV)
• Reactive Panel: SD 0.109 (4.3% CV)

Reproducibility (5-Day, Multi-Site):

• Negative Control: SD 0.018 (NAc)
• Positive Control: SD 0.132 (5.1% CV)
• High Nonreactive Panel: SD 0.041 (NAc)
• Low Reactive Panel: SD 0.067 (5.1% CV)
• Reactive Panel: SD 0.136 (5.5% CV)
  (Overall low CVs demonstrate good precision.) |
  | Analytical Specificity (Interfering Substances) | No significant interference from common endogenous substances, other conditions, or drugs at specified concentrations. | Endogenous Substances: No significant interference observed for Unconjugated Bilirubin (40 mg/dL), Conjugated Bilirubin (40 mg/dL), Hemoglobin (1000 mg/dL), Total Protein (15 g/dL), Triglycerides (3000 mg/dL).
  Other Conditions: No significant interference observed for HAMA (800 ng/mL), RF (200 IU/mL).
  Drugs: No significant interference observed for Ascorbic Acid (300 mg/L), Atovaquone (120 mg/L), Beta Carotene (6 mg/L), Biotin (4250 ng/mL), Clindamycin (5.1 mg/dL), Folic Acid (100 nmol/L), Pyrimethamine (15 mg/L), Spiramycine (4.2 mg/L), Sulfadiazine (25.5 mg/dL), Sulfamethoxazole (210 mg/dL), Trimethoprim (4.2 mg/dL). |
  | Cross-Reactivity | Minimal false reactive results from individuals with other medical conditions and high titer Toxoplasmosis IgG. | Out of 177 specimens from individuals with various unrelated conditions (e.g., CMV, EBV, HSV, Flu vaccine recipients, Syphilis, etc.) and high titer Toxoplasmosis IgG, only 1 out of 10 RF (Rheumatoid Factor) specimens resulted in a false reactive result. |
  | Matrix Equivalency | Acceptable performance across different blood collection tube types (serum, serum separator, lithium heparin plasma, lithium heparin plasma separator, and tripotassium EDTA plasma). | All tested blood collection tube types were found acceptable for use with the Alinity i Toxo IgM assay. |
  | Class Specificity | Reactivity only to human anti-Toxoplasma IgM and no reactivity to human anti-Toxoplasma IgG. | Demonstrated reactivity only to human anti-Toxoplasma IgM, with no reactivity to human anti-Toxoplasma IgG. |
  | CDC Panel Agreement | High positive and negative percent agreement with the CDC Toxoplasma 1998 Human Serum Panel. | PPA: 100.00% (32/32) with 95% CI (89.28%, 100.00%)
  NPA: 100.00% (65/65) with 95% CI (94.42%, 100.00%) |
  | Clinical Agreement | High positive and negative percent agreement with an FDA-cleared predicate assay. | Population 1 (n=897):
• PPA: 94.94% (150/158) with 95% CI (90.33%, 97.41%)
• NPA: 94.44% (697/738) with 95% CI (92.55%, 95.88%)
  Population 2 (pregnant women, n=234):
• PPA: 94.74% (18/19) with 95% CI (75.36%, 99.06%)
• NPA: 100.00% (215/215) with 95% CI (98.24%, 100.00%) |

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Cutoff Establishment (Internal Validation): 1219 samples (1053 nonreactive, 166 reactive). Data provenance not specified (likely internal laboratory samples, retrospective).
• Within-Laboratory Precision (20-Day): Not directly a "test set" sample size for diagnostic accuracy, but involves 2 controls and 4 plasma panels tested multiple times (360-360 replicates per control/panel).
• Analytical Specificity (Interference): Samples with target ranges of anti-Toxo IgM (0.60 to 0.99 S/CO and 1.00 to 2.00 S/CO) spiked with interferents. Specific number of samples per substance/condition not given, but refers to CLSI guidance.
• Cross-Reactivity: 177 serum specimens from individuals with other medical conditions and high titer Toxoplasmosis IgG. Data provenance not specified (likely retrospective or collected for study).
• Matrix Equivalency: 43 donors (20 reactive, 23 nonreactive). Samples collected in 5 different tube types. Data provenance not specified.
• Class Specificity: Not specified as a separate sample set size, likely inferred from internal controls or prepared samples.
• CDC Panel Agreement: 97 specimens (32 true positive, 65 true negative) from the CDC Toxoplasma 1998 Human Serum Panel. This is a retrospective, well-characterized panel.
• Reproducibility (5-Day, Multi-Site): Same sample panels as within-laboratory precision (controls and 4 plasma panels) tested across 3 US sites. 360 replicates per sample.
• Clinical Agreement:
  • Population 1: 897 consecutively collected remnant specimens. 169 from the US and 710 from outside the US. This implies a mixture of retrospective and potentially prospective collection depending on "consecutively collected remnant specimens."
  • Population 2: 207 consecutively collected remnant specimens from pregnant women in the US. This implies a mixture of retrospective and potentially prospective collection.
  • Total US specimens in the clinical study: 376 (169 from Pop 1 + 207 from Pop 2).

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

• The document does not mention the use of experts (e.g., radiologists) for establishing ground truth, as this is an in vitro diagnostic (IVD) device for serological testing.
• Ground Truth for IVDs: For IVDs like this, "ground truth" is typically established by:
  • Reference Method/Predicate Device: The clinical agreement study uses an "FDA-cleared, commercially available anti-Toxo IgM assay" (the bioMérieux VIDAS TOXO IgM assay) as the comparator, which serves as the reference standard for clinical performance.
  • Well-Characterized Panels: The CDC Toxoplasma 1998 Human Serum Panel is used, where the "true positive" and "true negative" status of specimens are established by the CDC through their own rigorous characterization processes.
  • Internal Characterization: For studies like cutoff determination, samples are "characterized with a commercially available anti-Toxo IgM assay," implying the use of an existing reference method.

Therefore, the "experts" in this context are the established reference methods and panels from organizations like the CDC, rather than individual human interpretative experts for modalities like radiology.

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

• Adjudication methods like 2+1 or 3+1 are typically used in imaging studies where multiple human readers interpret images, and discrepancies are resolved by an expert panel.
• For an IVD assay like this, the "adjudication" is inherent in the comparison to a predefined reference standard (the predicate device or the CDC panel's established status) or by the assay's internal cutoff determination process.
• The document does not describe any specific human "adjudication" process for the result of the Alinity i Toxo IgM assay beyond its comparison to the comparator assay or CDC panel.

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 was not done.
• MRMC studies are specific to AI/CADe (Computer-Assisted Detection) or CADx (Computer-Assisted Diagnosis) devices that assist human readers in interpreting medical images.
• The Alinity i Toxo IgM assay is an in vitro diagnostic (IVD) device that performs a laboratory test for antibodies; it does not involve human readers interpreting images or AI assistance for such interpretation.

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

• Yes, this device inherently performs as a standalone "algorithm" in the sense that it is an automated laboratory assay. The results (S/CO values) are generated by the instrument based on its chemical reactions and detection system, and then interpreted against predefined cutoffs.
• While a human operator loads samples and manages the instrument, the diagnostic detection (CMIA technology for Toxo IgM antibodies) is fully automated by the device itself, without human interpretation of the primary result (RLU or S/CO). The physician then interprets the qualitative result (Reactive, Grayzone, Nonreactive) in the context of the patient's clinical picture.
• The performance metrics (precision, analytical specificity, cross-reactivity, CDC panel agreement, clinical agreement) are all measures of this standalone analytical performance.

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

The ground truth for this device was established primarily through:

• Reference Standard/Predicate Assay: For the clinical agreement study, the Alinity i Toxo IgM assay results were compared against an FDA-cleared, commercially available anti-Toxo IgM assay (the bioMérieux VIDAS TOXO IgM assay). This predicate device serves as the clinical "ground truth" or reference.
• Well-Characterized Panel: For the CDC Panel Agreement study, the ground truth was the established status of samples within the CDC Toxoplasma 1998 Human Serum Panel (i.e., known true positive or true negative Toxoplasma specimens). This panel's characterization is highly reliable.
• Internal Characterization/Comparator Assay: For cutoff establishment, samples were characterized using a "commercially available anti-Toxo IgM assay."

8. The sample size for the training set

• The document does not explicitly describe a separate "training set" in the context of machine learning or AI model development.
• For IVD devices, a "training set" might loosely refer to the samples used during assay development and optimization (e.g., for reagent formulation, instrument parameters, and initial cutoff setting), but this data is not typically reported as a formalized "training set" size in the same way as for AI.
• The closest description of data used for internal calibration/optimization is the 1219 samples used for assay cutoff establishment (1053 anti-Toxo IgM nonreactive samples and 166 anti-Toxo IgM reactive samples). This dataset could be considered analogous to a development/training set for establishing the assay's interpretation rules, although it's crucial to understand this isn't an AI/ML context.

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

• As mentioned above, there isn't a traditional "training set" for an AI model.
• For the 1219 samples used to establish the assay cutoff, the ground truth (reactive/nonreactive) was established by characterizing these samples with a "commercially available anti-Toxo IgM assay." This means the existing, established methods of Toxo IgM detection were used to classify these samples, allowing the Alinity i assay to be "trained" (or its cutoff optimized) to align with those established classifications.

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The ADVIA Centaur EBV-VCA IgM (EBVM) assay is for in vitro diagnostic use in the qualitative detection of lgM antibodies to the viral capsid antigen (VCA) of the Epstein-Barr virus (EBV) in human pediatric (2-21 years old) and adult serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP system. When used in conjunction with other EBV markers, this assay is intended for use as an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis.

The ADVIA Centaur EBV-VCA IgM assay is a fully automated 2-step sandwich immunoassay using acridinium ester chemiluminescent technology. The specimen is incubated with the Ancillary Well Reagent and the Solid Phase, which contains an EBV-VCA IgM specific antigen. Antigen-antibody complexes will form if anti EBV-VCA IgM antibody is present in the specimen. The Lite Reagent contains monoclonal anti-human IgM labeled with acridinium ester and is used to detect EBV-VCA IgM in the specimen.

Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:

Device: ADVIA Centaur EBV-VCA IgM

1. Table of Acceptance Criteria and Reported Device Performance:

The document implicitly defines acceptance criteria through the reported performance metrics. For a diagnostic device intended to aid in the diagnosis of infection, common acceptance criteria would include achieving certain levels of Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to a reference method, especially in relevant clinical populations (e.g., primary acute infection). Precision and reproducibility are also key acceptance criteria for laboratory assays.

2. Sample Size and Data Provenance:

• Clinical Study Test Set:
  • Total Study Population: 1428 leftover samples (Population 1) + 202 samples with known EBV VCA IgM positive result (Population 2). Total = 1630 samples.
    • Population 1: Collected over a contiguous time period from individuals for whom an EBV test was ordered.
    • Population 2: Samples with a known EBV VCA IgM positive result.
  • Pediatric Population: 479 samples (from Population 1) + 155 samples (from Population 2). Total = 634 samples.
  • Data Provenance: The document states "leftover samples were collected over a contiguous time period" and "multisite clinical study," suggesting diverse geographical sources and a real-world setting. It does not explicitly state country of origin but implies a clinical laboratory setting. The samples are retrospective (leftover samples).

3. Number of Experts and Qualifications for Ground Truth:

• This information is not explicitly provided in the document. The comparison is made against an "FDA-cleared EBV VCA IgM reference assay."
• For equivocal reference assay results, the ground truth was "resolved by 2 other comparative assays." This implies an algorithmic or rule-based resolution rather than human expert consensus for these specific cases.

4. Adjudication Method for the Test Set:

• The document states: "Equivocal reference assay results were resolved by 2 other comparative assays." This indicates a form of algorithmic or rule-based adjudication rather than a human expert consensus method (like 2+1 or 3+1). If the two additional comparative assays agreed, that would constitute a form of resolution. If they disagreed, the method for final resolution is not detailed.

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

• No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) assay, not an imaging device or a device requiring human interpretation as part of its primary function where reader performance would be a direct outcome. The performance is assessed by comparing the assay's output to a reference method, not by how human readers improve with or without AI assistance.

6. Standalone (Algorithm Only) Performance:

• Yes, a standalone performance study was done. The entire clinical and analytical performance evaluation describes the ADVIA Centaur EBV-VCA IgM assay's performance independently (as an algorithm/assay) against a reference standard or for its inherent analytical characteristics (precision, reproducibility). There is no "human-in-the-loop" component described for the assay's function itself; it is an automated immunoassay.

7. Type of Ground Truth Used:

• The primary ground truth was established by an "FDA-cleared EBV VCA IgM reference assay."
• For cases where the reference assay was equivocal, "2 other comparative assays" were used for resolution.
• For defining "primary acute infection," the presence of "either EBV IgM or heterophile antibodies, and the absence of EBNA IgG" was used – this relies on a combination of other serological markers/tests.

8. Sample Size for the Training Set:

• The document does not provide information on the training set for the ADVIA Centaur EBV-VCA IgM assay. As a chemical immunoassay, its "training" involves the development and optimization of its chemical components, reagents, and detection parameters, using internal development studies that are typically not detailed as "training sets" in the same way as machine learning models. The reported studies are for validation/testing.

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

• As the document does not mention a "training set" in the context of machine learning, this question is not applicable/not addressed by the provided text. The development process for such an immunoassay typically involves extensive R&D, analytical characterization, and optimization using well-characterized samples, but this is distinct from establishing ground truth for a machine learning training dataset.

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In-vitro diagnostic reagents for the quantitative determination of immunoglobulins (IgG. IgA and IgM) in human serum, heparinized and EDTA plasma, and IgG in human urine and cerebrospinal fluid (CSF) by means of immunonephelometry on the BN II and BN ProSpec® System. Measurements of IgG aid in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents.

The N Antiserum to Human IgG reagent containing animal serum, produced by immunization of rabbits with highly purified human immunoglobulin (

The provided text describes a special 510(k) premarket notification for a modified device, "N Antisera to Human Immunoglobulins (IgG, IgA, and IgM)". The sole modification is the addition of a High Dose Hook (HDH) effect claim for IgG in cerebrospinal fluid (CSF) samples.

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

1. A table of acceptance criteria and the reported device performance

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Sample Size: The study used a "CSF high sample pool." The exact number of individual patient samples contributing to this pool (if multiple were pooled) is not specified. However, the study involved a dilution scheme with twelve (12) individual dilution levels, including the neat sample.
• Data Provenance: Not explicitly stated. The manufacturer is Siemens Healthcare Diagnostics Products GmbH, located in Marburg, Germany, which suggests the study was likely conducted in Germany or a similar geographic region. It is implicitly a prospective study designed to evaluate the HDH effect for the modified device.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This section is not applicable as the device is an in-vitro diagnostic reagent for quantitative determination, not an imaging or interpretive device that would typically require expert ground truth establishment in the described manner. The "ground truth" for this type of test is the quantitatively measured concentration of IgG in a sample, established through laboratory methods and comparison to known standards.

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

This section is not applicable. Adjudication methods like 2+1 or 3+1 are typically used for establishing ground truth in interpretive studies (e.g., radiologists reviewing images). For a quantitative in-vitro diagnostic test, the "ground truth" is determined by the analytical method itself against known standards.

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 is not applicable. The device is an in-vitro diagnostic reagent, not an AI-assisted diagnostic tool or an imaging device requiring human reader interpretation. No MRMC study was performed.

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

This refers to the performance of the analytical system (N Antisera reagent on BN II System) without human intervention in the measurement process. The HDH study performed is a standalone performance evaluation of the reagent/instrument system. The acceptance criteria and performance data in the table above demonstrate this standalone performance.

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

For this in-vitro diagnostic device, the "ground truth" for the High Dose Hook study was established by creating known dilutions of a high-concentration CSF sample, which were then measured by the device. The reported concentrations for these dilutions serve as the reference. The ultimate analytical ground truth for the quantitative measurement itself is tied to international standards like ERM-DA470k/IFCC (as stated in the "Traceability/Standardization" section).

8. The sample size for the training set

This document does not describe the development or training of a machine learning model, so there is no training set in the typical sense. The "training" for such a diagnostic test involves method development, optimization, and validation using various samples and controls, but these are not referred to as a "training set" for an algorithm.

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

As there is no training set for an algorithm, this question is not applicable.

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ACL TOP 970 CL: The ACL TOP 970 CL is a bench top, fully automated, random access analyzer designed specifically for in vitro diagnostic use by health care professionals in a clinical laboratory. The system provides results for both direct measurements and calculated parameters.
HemosIL CL Anti-Cardiolipin IgM: HemosIL CL Anti-Cardiolipin IgM is a fully automated chemiluminescent immunoassay for the semi-quantitative measurement of anti-cardiolipin (aCL) IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACL TOP 970 CL in the laboratory setting by a healthcare professional, as an aid in the diagnosis of Antiphospholipid Syndrome (APS) when used in conjunction with other laboratory and clinical findings. For use with adult population. For prescription use only.
HemosIL CL Anti-ß2 Glycoprotein-I IgM: HemosIL CL Anti-B2 Glycoprotein-I IgM is a fully automated chemiluminescent immunoassay for the semi-quantitative measurement of anti-B2 Glycoprotein-I (anti-B2GPI) IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACL TOP 970 CL in the laboratory setting by a healthcare professional, as an aid in the diagnosis of Antiphospholipid Syndrome (APS) when used in conjunction with other laboratory and clinical findings. For use with adult population. For prescription use only.

ACL TOP 970 CL Instrument: The ACL TOP 970 CL is an instrument that integrates new chemiluminescent test capability similar to the ACL AcuStar, K083518.
HemosIL CL Anti-Cardiolipin IgM: HemosIL CL Anti-Cardiolipin IgM is a chemiluminescent two-step immunoassay consisting of magnetic particles coated with cardiolipin and human purified ß2GPI, which capture, if present, the aCL antibodies from the sample. After incubation, magnetic separation, and a wash step, a tracer consisting of an isoluminol-labeled anti-human IgM antibody is added and may bind with the captured aCL IgM on the particles. After a second incubation, magnetic separation, and wash step, reagents that trigger the luminescent reaction are added, and the emitted light is measured as relative light units (RLU) by the ACL TOP 970 CL optical system. RLUs are directly proportional to the aCL IgM concentration in the sample.
HemosIL CL Anti-ß2 Glycoprotein-I IgM: HemosIL CL Anti-ß2 Glycoprotein-I IgM is a chemiluminescent two-step immunoassay consisting of magnetic particles coated with human purified ß2GPI, which capture, if present, the aß2GPI antibodies from the sample. After incubation, magnetic separation, and a wash step, a tracer consisting of an isoluminol-labeled anti-human IgM antibody is added and may bind with the captured aß2GPI IgM on the particles. After a second incubation, magnetic separation, and wash step, reagents that trigger the luminescent reaction are added, and the emitted light is measured as relative light units (RLUs) by the ACL TOP 970 CL optical system. RLUs are directly proportional to the aß2GPI IgM concentration in the sample.

The provided text describes the 510(k) summary for the ACL TOP 970 CL instrument and two associated immunoassays, HemosIL CL Anti-Cardiolipin IgM and HemosIL CL Anti-β2 Glycoprotein-I IgM. The studies presented focus on analytical performance and comparability to predicate devices, rather than AI model performance or human-in-the-loop studies. Therefore, many of the requested elements pertaining to AI-driven diagnostic devices (such as expert adjudication, MRMC studies, or training set details for AI) are not applicable or cannot be extracted from this document.

However, I can extract information related to the acceptance criteria for the analytical performance of the assays and how that performance was demonstrated.

Here's a breakdown of the available information:

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria for these in vitro diagnostic devices are demonstrated through various analytical performance studies, focusing on precision, linearity, analytical sensitivity (LoD/LoQ), analytical specificity, and method comparison to predicate devices. The document does not explicitly state pre-defined acceptance thresholds for each parameter (e.g., minimum CV for precision, minimum slope for linearity). Instead, it presents the results of these studies, implying that the observed performance met internal or regulatory acceptance.

HemosIL CL Anti-Cardiolipin IgM

• Low Multi-Ab Control: 1.6%
• High Multi-Ab Control: 1.2%
• Plasma Samples A-E: 1.6% - 9.6% |
  | Reproducibility (Low CV across sites/runs)| Reproducibility (% CV):
• Low Multi-Ab Control: 7.0%
• High Multi-Ab Control: 7.4%
• Clinical Samples 1-4: 4.5% - 9.5% |
  | Analytical Sensitivity (LoD/LoQ) | LoD: 1.0 U/mL
  LoQ: 1.0 U/mL |
  | Linearity Range | 2.7 - 500.0 U/mL |
  | Analytical Specificity (No interference) | No interference for: Hemoglobin, Bilirubin, Triglycerides, Heparin (LMW/UF), Rheumatoid Factor, Acetylsalicylic acid, Atorvastatin, Warfarin, Prednisone, Acid Citric Dextrose, Hydroxychloroquine, Rituximab at specified concentrations. |
  | Method Comparison (Strong correlation to predicate) | Slope (95% CI): 1.00 (0.98 - 1.01)
  r: 1.00 |
  | Diagnostic Performance (Sensitivity/Specificity vs. APS Classification - provided for context, not a direct "acceptance criterion" in the same way as analytical measures) | Sensitivity: 40.5% (33.8% - 47.6%)
  Specificity: 91.9% (88.4% - 94.5%) |

HemosIL CL Anti-β2 Glycoprotein-I IgM

• Low Multi-Ab Control: 12.8%
• High Multi-Ab Control: 11.5%
• Plasma Samples A-E: 3.6% - 7.2% |
  | Reproducibility (Low CV across sites/runs)| Reproducibility (% CV):
• Low Multi-Ab Control: 8.3%
• High Multi-Ab Control: 7.7%
• Clinical Samples 1-4: 4.8% - 8.3% |
  | Analytical Sensitivity (LoD/LoQ) | LoD: 2.0 U/mL
  LoQ: 2.0 U/mL |
  | Linearity Range | 1.9 - 400.0 U/mL |
  | Analytical Specificity (No interference) | No interference for: Hemoglobin, Bilirubin, Triglycerides, Heparin (LMW/UF), Rheumatoid Factor, Acetylsalicylic acid, Atorvastatin, Warfarin, Prednisone, Acid Citric Dextrose, Hydroxychloroquine, Rituximab at specified concentrations. |
  | Method Comparison (Strong correlation to predicate) | Slope (95% CI): 0.94 (0.92 – 0.96)
  r: 0.99 |
  | Diagnostic Performance (Sensitivity/Specificity vs. APS Classification - provided for context, not a direct "acceptance criterion" in the same way as analytical measures) | Sensitivity: 33.0% (26.7% - 39.9%)
  Specificity: 94.6% (91.4% - 96.6%) |

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

• Precision Study (Test Set):
  • HemosIL CL Anti-Cardiolipin IgM & Anti-β2 Glycoprotein-I IgM: 5 plasma samples (3 positive, 2 negative) and 2 levels of controls. Each material was run in duplicate, twice per day over 20 days.
• Reproducibility Study (Test Set):
  • HemosIL CL Anti-Cardiolipin IgM & Anti-β2 Glycoprotein-I IgM: 4 plasma samples (3 positive, 1 negative for Anti-Cardiolipin IgM; 3 positive for Anti-β2 Glycoprotein-I IgM) and 2 levels of controls. Each material tested in triplicate, twice a day for 5 days, totaling 30 replicates per level.
• Analytical Sensitivity (LoD/LoQ):
  • Specific sample numbers for LoD/LoQ for new reagent lots are not detailed, but samples prepared by combining Ab-positive and normal donor plasma were used.
• Linearity:
  • For each assay, samples were prepared by diluting a high antibody plasma sample with a negative antibody plasma sample to create required concentrations. Each level was measured in seven replicates.
• Normal Reference Range:
  • 100 citrated plasma normal donor samples.
• Method Comparison:
  • HemosIL CL Anti-Cardiolipin IgM: N = 131 samples.
  • HemosIL CL Anti-β2 Glycoprotein-I IgM: N = 123 samples.
• APS Outcome Study (Diagnostic Performance):
  • HemosIL CL Anti-Cardiolipin IgM: N = 500 samples.
  • HemosIL CL Anti-β2 Glycoprotein-I IgM: N = 503 samples (indicated by the sum of Positive/Negative categories: 63+17+128+295=503).

Data Provenance: The document does not specify the country of origin for the data or whether the studies were retrospective or prospective, though typical clinical performance studies for diagnostic devices are usually prospective or utilize carefully curated samples. Reproducibility studies were conducted at "3 external sites."

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

This information is not provided. For these in vitro diagnostic immunoassays, the "ground truth" for the analytical performance studies (precision, linearity, etc.) is the quantitative measurement itself, validated against established laboratory methods or reference materials. For the "APS Outcome Study," the ground truth is "APS disease classification per 2006 International Consensus Statement from Miyakis et al." This classification is typically based on a combination of clinical and laboratory findings, interpreted by clinicians, but the specific number and qualifications of experts involved in this classification for the study samples are not detailed.

4. Adjudication Method (e.g., 2+1, 3+1, none) for the Test Set

Not applicable, as this is an in vitro diagnostic device measuring analyte concentrations, not an imaging AI relying on expert interpretations or adjudications. The diagnostic performance (sensitivity/specificity) is compared against pre-defined clinical classification criteria (Miyakis et al. 2006).

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 document describes an in vitro diagnostic device (immunoassay and analyzer), not an AI-driven imaging diagnostic device. There is no mention of human readers or AI assistance in diagnostic interpretation.

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

The performance data provided (precision, linearity, sensitivity, specificity, method comparison) is the standalone performance of the device (instrument + assay). The device provides a semi-quantitative measurement of antibodies, which then aids in diagnosis when used "in conjunction with other laboratory and clinical findings." There is no "human-in-the-loop" component in the assay's direct operation or result generation as described beyond the healthcare professional performing the test.

7. The Type of Ground Truth Used

• Analytical Studies (Precision, Linearity, LoD/LoQ, Specificity): The ground truth is inherent to the nature of these highly controlled analytical tests. For example, for linearity, serially diluted samples with known concentrations are used. For interference, samples spiked with known interferents are used.
• Method Comparison: The ground truth is established by the measurements obtained from the predicate (reference) devices: HemosIL AcuStar Anti-Cardiolipin IgM (K092181) and HemosIL AcuStar Anti-β2 Glycoprotein-I IgM (K091556) on the ACL AcuStar (K083518).
• Normal Reference Range: Established by testing 100 samples from "normal donors."
• APS Outcome Study: "APS disease classification per 2006 International Consensus Statement from Miyakis et al." This is a consensus-based clinical classification criteria.

8. The Sample Size for the Training Set

Not applicable, as this is not an AI/machine learning device that requires a distinct training set. The "development" of the assays would involve internal R&D, but not a "training set" in the context of AI.

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

Not applicable, as there is no training set mentioned for an AI model. For the development/validation of the immunoassay itself, the "ground truth" for calibrators and controls would be established through careful analytical procedures, often traceable to international standards or reference materials, under strict quality control.

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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 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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