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The ARCHITECT HE4 assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of HE4 antigen in human serum. The assay is to be used as an aid in monitoring recurrence or progressive disease in patients with epithelial ovarian cancer. Serial testing for patient HE4 assay values should be used in conjunction with other clinical methods used for monitoring ovarian cancer.

The ARCHITECT HE4 Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of HE4 antigen in human serum.

The ARCHITECT HE4 Controls are used for the verification of the accuracy and precision of the ARCHITECT i System when used for the quantitative determination of HE4 antigen in human serum.

The ARCHITECT HE4 assay is a two-step immunoassay for the quantitative determination of HE4 antigen in human serum using CMIA technology with flexible assay protocols, referred to as Chemiflex.

In the first step, sample and 2H5 anti-HE4 coated paramagnetic microparticles are combined. HE4 antigen present in the sample binds to the anti-HE4 coated microparticles. After washing, 3D8 anti-HE4 acridinium-labeled conjugate is added to create a reaction mixture in the second step. Following another wash cycle, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs).

A direct relationship exists between the amount of HE4 antigen in the sample and the RLUs detected by the ARCHITECT i System optics.

The ARCHITECT HE4 Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of HE4 antigen in human serum.

The ARCHITECT HE4 Controls are used for the verification of the accuracy and precision of the ARCHITECT i System when used for the quantitative determination of HE4 antigen in human serum.

Here's a summary of the acceptance criteria and the studies that demonstrate the ARCHITECT HE4 Assay meets those criteria, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Method Comparison: 193 serum specimens. Data provenance is not explicitly stated (e.g., country of origin) but implies a clinical laboratory setting for comparison with a commercially available EIA. The study compared the new device against an existing, commercially available HE4 EIA.
• Precision: Not explicitly an independent "test set" in the common sense, but involved assays of controls and panels. Performed at Fujirebio Diagnostics, Inc. and two external sites.
• Linearity: Samples prepared by mixing serum panels.
• Sensitivity (LoB, LoD, LoQ): One zero-level HE4 sample and four low-level HE4 samples.
• Specificity: Not explicitly a patient "test set". Tumor markers were prepared with ARCHITECT HE4 Calibrator A.
• Interference: Sera containing therapeutic agents and endogenous substances (concentration details provided), and clinical specimens positive for HAMA (6 specimens) and Rheumatoid Factor (6 specimens).
• Monitoring of Disease Status: 76 patients, resulting in 430 pairs of observations (serial samples, average 6.7 observations per patient). Data provenance is not explicitly stated (e.g., country of origin, retrospective/prospective). This appears to be a retrospective analysis of serial samples.

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

The document does not explicitly state the number or qualifications of experts used to establish ground truth for any of the studies, particularly for clinical disease progression. For the "Monitoring of Disease Status" study, "changes in disease status" are mentioned, implying a clinical assessment, but the method for determining disease progression or lack thereof (e.g., imaging, pathology, clinical criteria) and who made these assessments is not detailed.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method for establishing ground truth for any of the test sets. For the "Monitoring of Disease Status" study, while "changes in disease status" were used as a reference, the process by which this status was determined (e.g., consensus, single expert, independent review) is not provided.

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

There is no mention of a multi-reader multi-case (MRMC) comparative effectiveness study in the provided text. The device is an immunoassay for quantitative determination of a biomarker, not an imaging device or diagnostic tool that typically involves human interpretation. Therefore, a study comparing human readers with and without AI assistance is not applicable here.

6. Standalone Performance Study

The reported performance characteristics (Method Comparison, Precision, Linearity, Sensitivity, Specificity, Interference) are all standalone (algorithm only) performance studies of the ARCHITECT HE4 assay. These evaluate the analytical performance of the device without human interpretation in the loop, focusing on its ability to accurately measure HE4 antigen levels. The "Monitoring of Disease status" study also represents the standalone performance of the assay in classifying disease changes based on a defined threshold.

7. Type of Ground Truth Used

• Method Comparison: The ground truth was the results from a "commercially available HE4 EIA" (the predicate device, HE4 EIA K072939).
• Precision, Linearity, Sensitivity, Specificity, Interference: The ground truth was based on established analytical standards, spiked samples, or reference materials with known concentrations. For example, "zero-level HE4 sample," "four low-level HE4 samples," "tumor markers prepared with ARCHITECT HE4 Calibrator A," and "sera containing therapeutic agents and endogenous substances at indicated interferent concentrations."
• Monitoring of Disease Status: The ground truth was "changes in disease status" in patients with epithelial ovarian cancer. While not explicitly defined, this would typically involve a combination of clinical assessments, imaging (e.g., CT scans, MRI), and potentially other tumor markers or biopsy results, as determined by clinicians.

8. Sample Size for the Training Set

The document does not specify a training set for the ARCHITECT HE4 assay. This is typical for an immunoassay that operates based on a physically determined chemical reaction and a calibration curve, rather than a machine learning algorithm that requires a separate training phase. The device is calibrated using ARCHITECT HE4 Calibrators, which serve a similar function to a training set by defining the assay's response curve, but are distinct from data used to train a predictive algorithm.

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

As no explicit "training set" in the machine learning sense is described, this question is not directly applicable. For the calibrators (which functionally serve to "train" or calibrate the instrument), their values would be established through a rigorous process of manufacturing, characterization, and validation against reference standards by the manufacturer (Fujirebio Diagnostics, Inc.), ensuring accurate assignment of HE4 concentrations to each calibrator level.

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