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QUANTA Flash RF IgM is a chemiluminescent immunoassay for the quantitative determination of IgM rheumatoid factor (RF) antibodies in human serum. The presence of IgM RF antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of rheumatoid arthritis (RA).

QUANTA Flash RF IgA is a chemiluminescent immunoassay for the semi-quantitative determination of lgA rheumatoid factor (RF) antibodies in human serum. The presence of IgA RF antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of rheumatoid arthritis (RA).

The principle of the assays is chemiluminescent microparticle immunoassay, a variation of solid phase immunoassay. The QUANTA Flash® RF IgM and QUANTA Flash® RF IgA assays are 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® RF IgM and QUANTA Flash® RF IgA assays utilize a reagent cartridge format, which is compatible with the BIO-FLASH® instrument.

Rabbit polyclonal antibodies are coated onto paramagnetic beads, which are stored in the reagent cartridge under conditions that preserve the antibody in its reactive state. When the assay cartridge is ready to be used for the first time, the entire cartridge is inverted several times to thoroughly mix the reagents. The reagent cartridge is then loaded onto the BIO-FLASH instrument.

A patient serum sample is diluted 1:22.7 by the instrument using system rinse in a disposable plastic cuvette. An aliquot of the diluted patient serum, coupled beads, and assay buffer are combined into a second cuvette, and mixed. This cuvette is incubated at 37°C. The beads are then magnetized and washed several times. Isoluminol conjugated anti-human IgM (QUANTA Flash® RF IgM) or anti-human lgA (QUANTA Flash® RF IgA) antibody is then added to the cuvette, and incubated at 37°C. Again, the beads are magnetized and washed repeatedly. The isoluminol conjugate produces a luminescent reaction when "Trigger" reagents are added to the light produced from this reaction is measured as Relative Light Units (RLU) by the BIO-FLASH optical system. RLU values are proportional to the amount of bound isoluminol conjugate, which in turn is proportional to the amount of RF antibodies bound to the antibodies on the beads.

The QUANTA Flash RF IgM and QUANTA Flash RF IgA assays utilize a predefined lot specific Master Curve that is uploaded into the instrument through the reagent cartridge barcode. Based on the results obtained by running the Calibrators, an instrument specific Working Curve is created, which is used by the software to calculate international units per milliliter (IU/mL) (QUANTA Flash® RF IgM) or chemiluminescent units (CU) (QUANTA Flash® RF IgA) from the RLU value obtained for each sample.

QUANTA Flash RF IgM Calibrators, QUANTA Flash RF IgM Controls, QUANTA Flash RF IgA Calibrators and QUANTA Flash RF IgA Controls are sold separately.

The QUANTA Flash® RF IgM Reagents / QUANTA Flash® RF IgA Reagents kit contains the following materials:

One (1) QUANTA Flash RF IgM / RF IgA Reagent Cartridge

QUANTA Flash RF IgM Reagent Cartridge contains the following reagents for 100 determinations:

• a. Rabbit pAb coated paramagnetic beads.
• b. Assay buffer - colored pink, containing protein stabilizers and preservatives.
• Tracer IgM Isoluminol labeled anti-human IgM antibody, containing buffer, protein C. stabilizers and preservative.

QUANTA Flash RF IgA Reagent Cartridge contains the following reagents for 100 determinations:

• a. Rabbit pAb coated paramagnetic beads.
• b. Assay buffer - colored pink, containing protein stabilizers and preservatives.
• Tracer IgA Isoluminol labeled anti-human IgA antibody, containing buffer, protein C. stabilizers and preservative.

The document describes the analytical and clinical performance characteristics of the QUANTA Flash® RF IgM and QUANTA Flash® RF IgA Reagents, which are chemiluminescent immunoassays for the quantitative or semi-quantitative determination of rheumatoid factor (RF) antibodies in human serum. These assays are intended to aid in the diagnosis of rheumatoid arthritis (RA) in conjunction with clinical findings and other laboratory tests.

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

Since this document describes two assays (RF IgM and RF IgA), the acceptance criteria and performance are presented for each. The acceptance criteria for analytical performance studies are generally stated in the document (e.g., %CV < 12% for precision), while clinical performance acceptance is implied by the reported sensitivity and specificity, demonstrating substantial equivalence to the predicate device.

QUANTA Flash® RF IgM Reagents

QUANTA Flash® RF IgA Reagents

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

• Test Set (Clinical Validation Study): A total of 706 characterized samples were used.
  • Data Provenance: The document does not explicitly state the country of origin. However, given it's an FDA 510(k) submission, it's generally understood that the studies conform to regulatory requirements for market clearance in the US.
  • Retrospective/Prospective: The document does not explicitly state whether the samples were collected retrospectively or prospectively. It mentions a "cohort of characterized samples, none of which were used for establishing the reference range," suggesting they were pre-existing and evaluated in a retrospective manner.

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

• This information is not provided in the document. The document describes a "cohort of characterized samples" but does not detail how the characterization (diagnosis of RA vs. control conditions) was established, nor does it mention the number or qualifications of experts involved in this process. This study is not an MRMC study or an AI-based diagnostic study requiring expert ground truth for image interpretation. Instead, it's about the performance of an in-vitro diagnostic (IVD) assay where the "ground truth" for clinical performance is the clinical diagnosis of the patient.

4. Adjudication Method for the Test Set

• This concept is not applicable to this type of study. Since the device is an IVD assay measuring biomarkers, there is no "adjudication" in the sense of comparing human reads with an AI output or resolving discrepancies among readers. The assay itself provides a quantitative or semi-quantitative result. The "ground truth" for clinical sensitivity and specificity is the medical diagnosis of rheumatoid arthritis based on various clinical findings and laboratory tests.

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. This document describes an in-vitro diagnostic (IVD) device, not an AI-assisted diagnostic tool that would involve human "readers" or image interpretation. Therefore, this type of study is not relevant to the described device.

6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done

• Yes, the primary study described is a standalone performance study of the assay. The QUANTA Flash® RF IgM and IgA assays provide a quantitative or semi-quantitative result directly from the sample. Their performance in terms of precision, linearity, interference, stability, and clinical sensitivity/specificity is evaluated as the standalone performance of the assay itself, without a human "interpretation" component that would be integrated into the device's output.

7. The Type of Ground Truth Used

• Clinical Diagnosis: For the clinical performance characteristics (sensitivity and specificity), the ground truth was the diagnosis of rheumatoid arthritis (RA) for patient samples and the characterization of control patient groups with other conditions or as apparently healthy donors. This "characterization" implies a pre-existing medical diagnosis, likely based on a combination of clinical findings, medical history, and other standard laboratory tests.
• Reference Values/Spiked Samples: For analytical performance characteristics (e.g., linearity, LoQ, interference), the ground truth involved reference standards, known concentrations, or spiked samples where the target analyte amount was precisely known.

8. The Sample Size for the Training Set

• This document describes the regulatory submission for an IVD reagent kit. The concept of a "training set" is more relevant to machine learning algorithms. For IVD development, the samples used to establish initial parameters like the Master Curve for calibration are distinct from a "training set" in an AI context.
  • Reference Range/Cutoff Establishment:
    • Reference population: 191 subjects (117 apparently healthy donors, plus various infectious disease and autoimmune cohorts).
    • RA patient specimens: 42 diagnosed RA patient specimens.
  • Standards for Master Curve: The Master Curve for each assay (IgM and IgA) consists of 6 different Standards. The document implies these standards are pre-defined and used during manufacturing to create the lot-specific Master Curve. The specific number of runs or samples used to define these initial standards is not detailed, but they are manufactured as high-quality reference materials.

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

• As noted above, "training set" doesn't directly apply in the AI sense. However, for the samples used to establish the reference range and cutoff values:
  • The reference population (191 subjects) was classified based on their underlying health status (e.g., "apparently healthy donors," "Infectious Disease Controls," "Rheumatoid Arthritis"). This classification represents the ground truth for establishing the assay's normal range and discriminating cutoff.
  • The cutoff values were established in accordance with CLSI EP28-A3c: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition.
  • The non-parametric percentile method was used due to the non-normal distribution of results.
  • For QUANTA Flash RF IgM, the cutoff of 5 IU/mL was set based on the distribution of results in the reference population and the (known) positive RA samples to ensure optimal differentiation.
  • For QUANTA Flash RF IgA, the cutoff was established at 6,000 RLU (assigned 20 CU), which was greater than the 95th percentile of control results (3,767 RLU).

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