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Immunoassay for the in vitro quantitative determination of thyroglobulin in human serum and plasma. Determination of Tg is used as an aid in monitoring for the presence of persistent or recurrent/metastatic disease in patients who have differentiated thyroid cancer (DTC) and have had thyroid surgery (with or without ablative therapy). The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The Tg II immunoassay makes use of a two-step, double antigen sandwich principle using a biotinylated monoclonal Tg-specific antibody and monoclonal Tg-specific antibodies labeled with a ruthenium complex. The Tg II immunoassay is intended for the in vitro quantitative determination of thyroglobulin in human serum and plasma. Determination of Tg is used to aid in monitoring for the presence of persistent or recurrent/metastatic disease in patients who have differentiated thyroid cancer (DTC) and have had thyroid surgery (with or without ablative therapy). It is intended for use on the cobas e immunoassay analyzers. Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode or e-barcode.

The Elecsys Tg II device is an immunoassay intended for the in vitro quantitative determination of thyroglobulin in human serum and plasma, used as an aid in monitoring for the presence of persistent or recurrent/metastatic disease in patients who have differentiated thyroid cancer (DTC) and have had thyroid surgery.

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

1. Table of Acceptance Criteria and Reported Device Performance

The provided document doesn't explicitly list "acceptance criteria" for all performance measures in a comparative table against the reported performance. However, based on the studies conducted and their results, one can infer the implicit acceptance criteria by observing the measured performance and statements like "All deviations from linearity met the specification" or "Non-significant interferences were defined as %interferences within ± 10 %".

Below is a table summarizing the reported device performance, with inferred acceptance criteria where direct ones are not explicitly stated, but are implied by the reported "met specifications" or similar statements.

Study Information:

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

• Clinical Performance Study (Combined Cohorts):

  • Sample Size: 530 samples available for analysis.
  • Data Provenance:
    • Origin: Collected from 9 sites across the U.S.
    • Nature:
      • Longitudinal Cohort: Serum samples collected from subjects 4-12 weeks post-thyroidectomy (with/without radioiodine ablation) and at 4 additional time points (6, 12, 18, 24 months post-surgery/ablation).
      • Cross-sectional Cohort: Samples collected from subjects with structural disease at a single visit. This cohort was used to increase the number of observations from patients with structural disease.

• Reference Range Study:

  • Sample Size: 244 healthy males and 219 healthy females (total 463).
  • Data Provenance: Not explicitly stated (e.g., age range is given, but not country of origin, retrospective/prospective).

• Expected Values in DTC post-thyroidectomy:

  • Sample Size: 127 subjects with differentiated thyroid cancer (100 female; 27 male) with no evidence of disease for 4 or more years post-total/near total thyroidectomy.
  • Data Provenance: Not explicitly stated.

• Precision (Within-laboratory): 84 runs for each sample.

• Reproducibility (Site-to-site): 146-149 runs for each sample.

• LoB, LoD, LoQ, Linearity, Hook Effect, Interference, Cross-reactivity, Stability Studies: Varying number of samples/replicates as described in the respective sections (e.g., LoB/LoD: 5 native samples, 2 replicates/run, 6 runs over 4 days; LoQ: 7 low-level human serum samples, 5 replicates/run, 1 run/day over 5 days).

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

The document does not explicitly state the number of experts or their specific qualifications for establishing the ground truth of "structural disease" in the clinical study. However, the definition of structural disease is provided:

• Ground Truth Definition: "Structural disease was defined as evidence of disease on ultrasound, cross sectional or functional imaging, or biopsy proven disease as determined by the investigator."
• Implied Experts: This definition suggests that the "investigator" (likely a medical professional such as an endocrinologist, radiologist, or pathologist, depending on the type of evidence) determined the presence of structural disease. The number of such investigators involved in determining ground truth per patient or across the study is not specified.

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method (e.g., 2+1, 3+1) for establishing the ground truth of structural disease. It states that structural disease was "determined by the investigator." This implies a single determination rather than a consensus or adjudicated process among multiple experts for each case.

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

No, an MRMC comparative effectiveness study was not explicitly done. The study focuses on the standalone performance of the Elecsys Tg II assay rather than comparing human reader performance with and without AI assistance. The device itself is an immunoassay, not an AI imaging interpretation tool that would typically involve human readers.

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

Yes, the studies presented are primarily standalone (algorithm only) performance evaluations. The Elecsys Tg II is an automated immunoassay system, and its performance (sensitivity, specificity, precision, accuracy, linearity, stability, etc.) is measured directly on biological samples without active human interpretation assistance in the analytical or clinical performance reported here. The "results are determined via a calibration curve which is instrument-specifically generated."

7. The Type of Ground Truth Used

• Clinical Performance Study: The ground truth for the clinical performance study (sensitivity, specificity, NPV, PPV) was based on structural disease (SD+ or SD-). This was determined by:
  • Evidence of disease on ultrasound.
  • Cross-sectional or functional imaging.
  • Biopsy-proven disease.
  • These were "determined by the investigator."
• Analytical Studies: For analytical performance (LoB, LoD, LoQ, linearity, interference, stability), the ground truth generally involved:
  • Reference standards/materials: e.g., CRM 457.
  • Known analyte concentrations: Obtained by spiking or using characterized serum pools.
  • Clinical laboratory standards: (e.g., CLSI guidelines).

8. The Sample Size for the Training Set

The document does not mention a separate "training set" for the Elecsys Tg II device in the context of machine learning or AI algorithms. As an immunoassay, the "training" analogous to an AI system would be the development and optimization of the assay reagents, protocols, and calibration curves. The provided information relates to the validation of the final product. The "calibration curve" is established for the assay, which is a form of internal "training" for the instrument's interpretation of signal to concentration.

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

As noted above, for an immunoassay, there isn't a "training set" in the typical AI sense. The development of the assay relies on establishing accurate measurements against recognized reference standards and materials (e.g., CRM 457, characterized serum pools with known thyroglobulin concentrations). These standards serve as the "ground truth" to ensure the assay accurately quantifies thyroglobulin. The assay is then calibrated using these standards to accurately relate the measured signal (chemiluminescent emission) to the thyroglobulin concentration in patient samples.

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Access Thyroglobulin assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of thyroglobulin levels in human serum using the Access Immunoassay Systems. This device is aid in monitoring for the presence of persistent or recurrent/metastatic disease in patients who have differentiated thyroid cancer (DTC) and have had thyroid surgery (with or without ablative therapy), and who lack serum thyroglobulin antibodies.

Access Thyroqlobulin assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of thyroglobulin levels in human serum using the Access Immunoassay Systems. This device is intended to aid in monitoring for the presence of persistent or recurrent /metastatic disease in patients who have differentiated thyroid cancer (DTC) and have had thyroid surgery (with or without ablative therapy), and who lack serum thvroglobulin antibodies.

The Access Tg assay consists of the reagent pack and calibrators. Other items needed to run the assay include the Access Tg sample diluent substrate and wash buffer. The Access Tg assay along with the Access wash buffer and substrate are designed for use with the Access Immunoassay Systems in a clinical laboratory setting.

The device modification described in this submission impacts the Access Thyroqlobulin reagent pack only; the change does not impact or change the other components that are used with this reagent pack. The modification does not affect the intended use or indications of the device or alter the fundamental scientific technology of the device.

A description of the reagent pack is provided below.

The provided text describes the Beckman Coulter Access Thyroglobulin assay, a chemiluminescent immunoassay for the quantitative determination of thyroglobulin levels in human serum. This device is intended to aid in monitoring for persistent or recurrent/metastatic differentiated thyroid cancer (DTC) in patients who have undergone thyroid surgery and lack serum thyroglobulin antibodies.

Here's a breakdown of the acceptance criteria and the studies that prove the device meets these criteria:

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

The document does not explicitly present a table of acceptance criteria alongside reported performance for all aspects. Instead, acceptance criteria are generally mentioned within the description of each study. Below is a compilation of the criteria and reported performance for key studies.

Note: For Imprecision and Reproducibility, specific acceptance criteria (e.g., maximum allowable %CV) are not explicitly stated. The tables provide the observed performance metrics (SD, %CV) and imply that these are acceptable.

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

• Method Comparison: 102 serum samples.
• Imprecision: Not explicitly stated as a general sample count; involved multiple samples (6 different samples with varying concentrations) run in duplicate over 20 days.
• Reproducibility:
  • Study 1: 2 samples run in 3 replicates.
  • Study 2: 3 samples run in 5 replicates.
• High-dose Hook Effect: Not specified how many samples or what types were used, but concentrations up to 40,000 ng/mL were tested.
• Linearity: Serum samples were used across the assay range.
• Dilution Recovery: Serum samples were used across and above the assay range.
• Limit of Blank (LoB), Limit of Detection (LoD), Limit of Quantitation (LoQ): Not explicitly stated how many individual samples were used for these studies, but they were determined based on specific testing procedures.
• Analytical Specificity (Cross-reactivity): Serum patient samples at two thyroglobulin concentrations (approx. 20 ng/mL and 100 ng/mL) were used. The number of unique patient samples is not specified.
• Analytical Specificity (Interference): Patient serum samples containing two levels of Thyroglobulin (approx. 25.0 ng/mL and 100.0 ng/mL) were used. The number of unique patient samples is not specified.

Data Provenance: The document does not specify the country of origin for the data or whether the samples were collected retrospectively or prospectively. It consistently refers to the use of "human serum" or "patient serum samples."

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

This information is not applicable to this type of device (an in-vitro diagnostic immunoassay). The ground truth for such assays is established by the intrinsic biochemical properties and analytical performance of the assay itself (e.g., accuracy against reference methods, precision, detection limits using reference standards or well-characterized samples), rather than expert interpretation of images or clinical cases.

4. Adjudication method for the test set

This information is not applicable to this type of device. Adjudication methods like 2+1 or 3+1 are typically used in studies involving expert interpretation (e.g., radiology for AI-assisted diagnosis), where there might be disagreement among experts. For an immunoassay, the results are quantifiable and objective measurements, not subject to subjective adjudication.

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 information is not applicable to this device. An MRMC study is relevant for imaging devices or AI-assisted diagnostic tools where human readers are interpreting cases. The Access Thyroglobulin assay is an automated laboratory test that directly measures a biomarker, without a "human reader" component in the interpretation of the primary data within the context of an MRMC study.

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

The Access Thyroglobulin assay is a standalone device in the sense that it performs the measurement algorithmically via its chemiluminescent immunoassay system without direct human interpretation of the raw signal output. The "algorithm only" performance is what these analytical studies (imprecision, linearity, LoD, etc.) demonstrate. Human involvement is in sample preparation, loading, and interpretation of the final quantitative result.

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

The ground truth for this device is based on analytical performance characteristics established through:

• Reference methods or predicate device comparison (for method comparison study).
• Use of well-characterized samples or reference materials (e.g., for LoB, LoD, LoQ, linearity).
• Known concentrations of potential cross-reactants and interferents (for analytical specificity studies).
• Statistical analysis of repeated measurements (for imprecision and reproducibility).

8. The sample size for the training set

This document describes the performance studies for a modificated device that is compared to a previously cleared predicate and is not a new AI/machine learning device that typically involves a distinct "training set." The studies mentioned are validation studies, not training. Therefore, a specific "training set sample size" is not applicable in the context of this submission. The development and optimization of the immunoassay reagents and protocols would have occurred during the assay's development, but this document focuses on its validation.

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

As there is no "training set" in the context of an AI/machine learning model for this immunoassay submission, the question of how its ground truth was established is not applicable. The "ground truth" for the performance studies described in this document is derived from established analytical methods, reference materials, and the comparative performance against the predicate device.

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