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QUANTA Flash CCP3 is a chemiluminescent immunoassay for the semi-quantitative determination of IgG anti-CCP3 antibodies in human serum. The presence of anti-CCP3 antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of rheumatoid arthritis.

QUANTA Flash CCP3 Calibrators are intended for use with the QUANTA Flash CCP3 chemiluminescent immunoassay for the determination of IgG anti-CCP3 antibodies in human serum. Each calibrator establishes a point of reference for the working curve that is used to calculate unit values.

QUANTA Flash CCP3 Controls are intended for use with the QUANTA Flash CCP3 chemiluminescent immunoassay for quality control in the determination of IgG anti-CCP3 antibodies in human serum.

The QUANTA Flash CCP3 assay is designed to run on the BIO-FLASH® instrument. This platform is a fully automated closed system with continuous load and random access capabilities that automatically processes the samples, runs the assay and reports the results. It includes liquid handling hardware, luminometer and computer with software-user interface. The QUANTA Flash CCP3 assay utilizes a reagent cartridge format, which is compatible with the BIO-FLASH instrument.

Synthetic cyclic citrullinated peptide is coated onto paramagnetic beads. The bead suspension is lyophilized and stored in the bead tube. Prior to use in the BIO-FLASH system, the sealed reagent tubes are pierced with the reagent cartridge lid and the beads are rehydrated and resuspended using resuspension buffer by pipetting up and down with a transfer pipette. The reagent cartridge is then loaded onto the BIO-FLASH instrument. Samples are also loaded onto the instrument in sample racks. Serum samples are diluted by the BIO-FLASH with system rinse in a small disposable plastic cuvette. Small amounts of the diluted patient serum, the beads, and assay buffer are combined into a second cuvette, and mixed. This cuvette is then incubated at 37°C. The beads are magnetized and washed several times. Isoluminol conjugated anti-human IgG antibodies are then added to the cuvette, and again incubated at 37°C. The beads are magnetized and washed repeatedly. The isoluminol conjugate is oxidized when Trigger 1 (Fe(II)coproporphyrin in sodium hydroxide solution) and Trigger 2 (ureahydrogen peroxide in sodium chloride solution) are added to the flash of light produced from this reaction is measured as Relative Light Units (RLU) by the BIO-FLASH optical system. The RLU are proportional to the amount of isoluminol conjugate that is bound to the human IgG, which is in turn proportional to the amount of anti-CCP3 antibodies bound to the corresponding beads.

For quantitation, the QUANTA Flash CCP3 assay utilizes a predefined lot specific Master Curve that is uploaded onto the instrument through the reagent cartridge barcode. Every new lot number of reagent cartridge must be calibrated before first use, with the QUANTA Flash CCP3 Calibrators. Based on the results obtained with the two Calibrators included in the Calibrator Set (sold separately), an instrument specific Working Curve is created, which is used to calculate chemiluminescent units (CU) from the instrument signal (RLU) obtained for each sample.

The QUANTA Flash CCP3 kit contains the following materials:

One (1) QUANTA Flash CCP3 Reagent Cartridge One (1) vial of Resuspension buffer One (1) Transfer pipette

The QUANTA Flash CCP3 reagent cartridge contains the following reagents for 100 determinations:

• a. CCP3 coated paramagnetic beads, lyophilized.
• b. Assay buffer - colored pink, containing Tris-buffered saline, Tween 20, protein stabilizers and preservatives.
• C. Tracer IgG - Isoluminol labeled anti-human IgG antibodies in buffer, containing protein stabilizers and preservative.

The QUANTA Flash CCP3 Calibrators kit contains two vials of Calibrator 1 and two vials of Calibrator 2:

QUANTA Flash CCP3 Calibrators:

• QUANTA Flash CCP3 Calibrator 1: Two (2) barcode labeled tubes containing 0.7 mL prediluted, ready to use reagent. Calibrators contain human antibodies to CCP3 in stabilizer and preservative.

• QUANTA Flash CCP3 Calibrator 2: Two (2) barcode labeled tubes containing 0.7 mL prediluted, ready to use reagent. Calibrators contain human antibodies to CCP3 in stabilizer and preservative.
  The QUANTA Flash CCP3 Controls kit contains two vials of Negative Control and two vials of Positive Control:

QUANTA Flash CCP3 Controls:

• QUANTA Flash CCP3 Negative Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human antibodies to CCP3 in stabilizer and preservative.
• QUANTA Flash CCP3 Positive Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human antibodies to CCP3 in stabilizer and preservative.

The provided text describes the QUANTA Flash® CCP3 chemiluminescent immunoassay and its associated calibrators and controls. The study focuses on establishing the substantial equivalence of the new device to a predicate device (QUANTA Lite® CCP3 IgG ELISA) and demonstrating its analytical and clinical performance characteristics.

Here's an analysis of the acceptance criteria and study as requested:

1. Table of Acceptance Criteria and Reported Device Performance

The document details numerous acceptance criteria for various analytical and clinical performance characteristics. Below is a summary of some key areas:

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

• Test Set for Clinical Performance (Sensitivity/Specificity, Method Comparison):

  • Sample Size: 728 characterized samples (352 Rheumatoid Arthritis (RA) samples and 376 control samples, which include various other diseases and healthy individuals).
  • Data Provenance: Not explicitly stated regarding country of origin. The study implies these are patient samples ("clinical validation study," "cohort of characterized samples"). It's a retrospective analysis of previously collected and characterized samples.

• Test Set for Cross-reactivity:

  • Sample Size: 234 control samples (subset of the 376 total control samples).
  • Data Provenance: Not explicitly stated regarding country of origin, appears to be retrospective.

• Test Set for Precision: 8 samples.

• Test Set for Reproducibility: 8 (3+5) samples.

• Test Set for Linearity: 5 serum samples.

• Test Set for Interference: 3 specimens.

• Test Set for Lot-to-Lot Comparison: 5 unique samples.

• Test Set for Shelf Life (Accelerated, In-Use, Real-time): "up to 9 characterized samples with various reactivity levels," "up to 6 characterized samples," "QC panel samples."

• Test Set for Reference Range (Cut-off): 210 subjects (170 apparently healthy blood donors, 20 viral hepatitis positive, 20 autoimmune thyroid disease).

• Test Set for Expected Values: 146 apparently healthy blood donors (different from the cut-off establishment cohort).

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 or qualifications of experts used to establish the ground truth for the clinical diagnosis of the test set (e.g., confirming RA diagnosis for the 352 RA patients). It refers to the samples as "characterized samples." This suggests that their disease status was determined by standard diagnostic procedures, likely involving clinicians and laboratory specialists, but the specific details are not provided in this summary.

4. Adjudication Method for the Test Set

The document does not describe a formal adjudication method (e.g., 2+1, 3+1) for the clinical diagnosis of the test set samples. The samples are referred to as "characterized samples," implying their diagnosis was already established prior to their use in this study.

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 document describes an in vitro diagnostic (IVD) device, specifically a chemiluminescent immunoassay for semi-quantitative determination of antibodies. It is a laboratory test, not an imaging device or AI algorithm intended for interpretation by human readers. Therefore, an MRMC comparative effectiveness study where human readers (e.g., radiologists) improve with AI assistance is not applicable to this type of device and study.

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

Yes, the study primarily demonstrates the standalone performance of the QUANTA Flash® CCP3 assay. It evaluates the assay's ability to accurately detect anti-CCP3 antibodies in human serum, with the BIO-FLASH® instrument performing the automated processing and reporting. The "human-in-the-loop" aspect is limited to laboratory personnel operating the instrument and interpreting the reported numerical results based on established cut-offs, rather than an interactive AI interpretation.

7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)

The ground truth for the clinical performance characteristics (sensitivity, specificity) relies on the clinical diagnosis of the patient samples:

• Rheumatoid Arthritis (RA) patients: Diagnosed by unspecified clinical criteria, likely rheumatologist diagnosis based on established classification criteria for RA.
• Control samples: Patients with various other diseases or apparently healthy blood donors, where the absence of RA (or other specific autoantibodies/infections for cross-reactivity) serves as the ground truth.

For analytical characteristics (precision, linearity, interference, etc.), the ground truth is often established by reference materials, defined concentrations, or established spiking protocols (e.g., known concentrations of interfering substances).

8. The Sample Size for the Training Set

The document does not explicitly describe a separate "training set" in the context typically used for machine learning algorithms. This is a traditional IVD device, not an AI algorithm that learns from data.

However, the concept of "training" or "calibration" is present in the context of the assay's internal calibration and master curve generation:

• Master Curve Standards: The QUANTA Flash CCP3 assay uses 7 "Master Curve Standards" with assigned CU values (e.g., 4.6 CU to 2776.8 CU) to create a lot-specific Master Curve. This could be considered analogous to a calibration/training data set for the instrument's internal quantitation.
• Calibrators: Two calibrators are used with each new reagent cartridge lot to create an instrument-specific Working Curve.

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

Given that this is an immunoassay, not an AI algorithm, the "ground truth" for its internal calibration (Master Curve Standards and Calibrators) is established through:

• Assigned Values: The 7 Master Curve Standards have "Assigned Values" in CU (Chemiluminescent units), determined during the manufacturing process.
• Traceability: Calibrator and Control values are "directly traceable to the in-house Standards that are used to create the Master Curves."
• Reference Material: Traceability to an external reference material was also established by testing the IUIS-Centers for Disease Control and Prevention (CDC) reference reagent for ACPA, which has an assigned value of 100 U/mL. This allows for conversion between CU and U/mL.

Essentially, the "ground truth" for the device's internal quantitation is derived from a hierarchy of internal standards, calibrated and assigned specific values during manufacturing, and traceable to external reference materials.

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