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The Alegria Flash CTD Screen kit is a chemiluminescent immunoassay (CLIA) for the qualitative screening of IgG autoantibodies to SSA-60, SSA-52, SS-B, Jo-1, Scl-70, SmRNP, Sm, dsDNA, Ribosomal P, Nucleosome, and Centromere-B in human serum. The presence of these autoantibodies is intended for use as an aid in the diagnosis of the connective tissue diseases (CTD): Sjogren's syndrome (SS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Limited Cutaneous Systemic Sclerosis (CREST Syndrome), polymyositis, and dermatomyositis along with other laboratory and clinical findings. The test must be performed on the Alegria Flash instrument.

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The Alegria Flash ENA Screen kit is a chemiluminescent immunoassay (CLIA) for the qualitative screening of IgG autoantibodies to Jo-1, SSA-52, SSA-60, SS-B, Scl-70, Sm, or SmRNP in human serum. The presence of these autoantibodies is intended for use as an aid in the diagnosis of the connective tissue diseases (CTD) Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Limited Cutaneous Systemic Sclerosis (CREST Syndrome), polymyositis, and dermatomyositis along with other laboratory and clinical findings. The test must be performed on the Alegria Flash instrument.

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The Aptiva CTD Essential Reagent consists of 10 multiplexed immunoassays utilizing particle-based multi-analyte technology for the quantitative determination of IgG autoantibodies against dsDNA, and semi-quantitative determination of IgG autoantibodies against RNP, Sm, Ro52, Ro60, SS-B, Scl-70, Jo-1, centromere, and Ribo-P in human serum:

· The presence of dsDNA antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of systemic lupus erythematosus.

· The presence of RNP antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of mixed connective tissue disease and systemic lupus erythematosus.

· The presence of Sm antibodies, in conjunction with clinical findings and other laboratory tests, is an ad in the diagnosis of systemic lupus erythematosus.

· The presence of Ro52 antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the

diagnosis of systemic lupus erythematosus, Sjögren's systemic scleross, and idiopathic inflammatory myositis. · The presence of Ro60 antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the

diagnosis of systemic lupus erythematosus and Sjögren's syndrome.

· The presence of SS-B antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of systemic lupus erythematosus and Sjögren's syndrome.

· The presence of Scl-70 antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of systemic sclerosis.

· The presence of Jo-1 antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of idiopathic inflammatory myositis.

· The presence of centromere antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of systemic sclerosis.

· The presence of Ribo-P antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of systemic lupus erythematosus.

The individual assays included in the Aptiva CTD Essential Reagent are intended for use with the Inova Diagnostics Aptiva System.

The Aptiva CTD Essential reagent utilizes particle based multi-analyte technology (PMAT) in a cartridge format. Each analyte (dsDNA, RNP, Sm, Ro60, Ro52, SS-B, Scl-70, Jo-1, Centromere and Ribo-P) in the Aptiva CTD Essential reagent is a solid phase immunoassay utilizing fluorescent microparticles. This technology allows each of the ten analytes, along with a human anti-lgG capture antibody (IgG Control Microparticle), to be coated onto eleven uniquely recognizable paramagnetic microparticles, which are combined into one tube.

The Aptiva Multi-Analyte 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 ten unique populations of microparticles coated with dsDNA, RNP, Sm, Ro60, Ro52, SS-B, Scl-70, Jo-1, Centromere and Ribo-P, along with the one for the control microparticle, are stored in the reagent cartridge under conditions that preserve the autoantigens 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 Multi-Analyte Instrument, where the microparticles are automatically rehydrated using buffer located within the cartridge.

A patient's serum is diluted 1:44.4 fold with Aptiva system rinse by the instrument in a disposable cuvette. A small amount of the diluted sample is combined with assay buffer and the microparticle suspension in a second cuvette, and mixed (final serum dilution: 1:230). This reaction cuvette is incubated for 9 ½ minutes at 37°C. The cuvette is then exposed to a magnet that retains the microparticles in place. The liquid is aspirated, and the microparticles are resuspended as system rinse is added to the cuvette and the magnet is removed. This wash cycle is repeated. During the third wash, no system rinse is added after the aspiration step. After the third wash, phycoerythrin conjugated polyclonal anti-human lgG (known as PE Tracer IgG) is added to the cuvette with microparticles, and mixed. Again, the cuvette is incubated for 9 ½ minutes at 37°C. Three wash steps, as described above, are performed on the microparticles. Following the wash steps, the microparticles are transferred to the optical module of the instrument, where a charge coupled device (CCD) camera takes multiple images to identify and count the twelve unique microparticle regions, as well as determine the amount of conjugate on the microparticles. A twelfth particle, coated with goat anti-human IgG, is present in the reagent as a control to flag low concentrations of IgG in the patient serum sample as an assay verification step. The median fluorescent intensity (MFI) is proportional to the amount of PE Tracer that is bound to the human IgG, which is proportional to the amount of IgG antibodies bound to the corresponding microparticle regions.

For quantitation, the ten assays (together as part of the Aptiva CTD Essential Reagent) each utilizes a predefined lot specific Master Curve that is uploaded onto the instrument through the RFID tag on the reagent cartridge. The first time a reagent cartridge of a new lot of Aptiva CTD Essential is placed in the instrument, it must be calibrated. The Aptiva CTD Essential Calibrators are sold separately. The calibration process utilizes the 6 Calibrators that are included in the Calibrators kit to adjust the predefined lot specific dsDNA, RNP, Sm, Ro60, Ro52, SS-B, Scl-70, Jo-1, Centromere and Ribo-P Master Curves into instrument specific Working Curves. These Working Curves are used to calculate FLU (or IU/mL for dsDNA) values from the measured MFI. The Working Curves are lot and instrument specific and stored in the system for use with any reagent cartridge from that lot. The lot specific calibration expires 6 months from the last time the calibration was performed, and re-calibration is required.

Aptiva CTD Essential Calibrators and Aptiva CTD Essential Controls are sold separately.

The Aptiva CTD Essential Reagent kit contains the following materials:

One (1) Aptiva CTD Essential Reagent Cartridge contains the following materials to process 250 determinations:

• a. dsDNA, RNP, Sm, Ro60, Ro52, SS-B, Scl-70, Jo-1, Centromere and Ribo-P, and Control paramagnetic particles, preserved.
• b. Assay Buffer clear liquid, containing protein stabilizers and preservatives.
• c. PE Tracer IgG PE labeled anti-human IgG antibody, containing buffer, protein stabilizers and preservative.
• d. Rehydration Buffer containing protein stabilizers and preservatives.

This document describes the analytical and clinical performance characteristics of the Aptiva CTD Essential Reagent, a multiplexed immunoassay system, and its comparison to predicate devices.

Here's an analysis of the acceptance criteria and study proving device performance:

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

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

• Clinical Validation Study (Test Set for Clinical Sensitivity and Specificity):

  • Sample Size: 1269 samples in total. This included 141 patients with Sjögren's syndrome (SjS), 230 with systemic lupus erythematosus (SLE), 217 with systemic sclerosis (SSc), 91 with mixed connective tissue disease (MCTD), 200 with idiopathic inflammatory myopathy (IIM), and 390 control samples from patients with various types of autoimmune and infectious diseases.
  • Data Provenance: The document does not explicitly state the country of origin. It indicates that the samples were "from patients," implying clinical samples. The study describes them as a "cohort of characterized samples," and it's mentioned that these were "none of which were used for establishing the reference range." This typically suggests retrospective collection for validation purposes.

• Method Comparison Study (Test Set for Agreement with Predicate):

  • Sample Size: The sample sizes vary by analyte due to comparisons against different predicate devices. Examples include:
    • dsDNA: 428 samples
    • RNP: 480 samples
    • Sm: 418 samples
    • Ro52: 1028 samples
    • Ro60: 551 samples
    • SS-B: 550 samples
    • Scl-70: 435 samples
    • Jo-1: 416 samples
    • Centromere: 449 samples
    • Ribo-P: 387 samples
  • Data Provenance: "Samples for the method comparison analysis included the samples from the clinical validation study." Therefore, the provenance is the same as the clinical validation study: clinical samples, likely retrospectively collected, and country of origin not specified.

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

The document states that the ground truth for the clinical validation samples (test set) was established using a "cohort of characterized samples" from patients with specific autoimmune diseases (SjS, SLE, SSc, MCTD, IIM) and control samples. It does not specify:

• The number of experts
• The qualifications of those experts (e.g., radiologist with 10 years of experience)
• The method by which the characterization/diagnosis was made.

The characterization is implied to be clinical diagnosis (e.g., "patients with systemic lupus erythematosus"), which generally would involve medical professionals, but specifics are missing.

4. Adjudication method for the test set

The document does not describe any formal adjudication method (like 2+1 or 3+1) for establishing the ground truth of the clinical validation test set. The samples are referred to as "characterized samples," suggesting that their disease status was determined prior to the study by 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 such MRMC comparative effectiveness study is described in the provided text. The device is an immunoassay (a diagnostic test for autoantibodies), not an AI-powered image analysis tool that assists human readers. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable here.

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

Yes, a standalone performance evaluation was done. The entire document focuses on the performance of the Aptiva CTD Essential Reagent (the immunoassay system) itself. The reported sensitivity, specificity, precision, reproducibility, linearity, interference, and stability data are all measures of the device's performance in isolation, without an explicit human-in-the-loop component beyond standard laboratory operation.

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

For the clinical validation study, the ground truth was based on the clinical diagnosis of patients belonging to specific disease groups (e.g., Systemic Lupus Erythematosus, Sjögren's Syndrome, Systemic Sclerosis, etc.) and control groups with other autoimmune or infectious diseases. This implies that the ground truth was established by medical professionals through clinical findings and other laboratory tests, representing a form of "expert diagnosis/characterization" rather than specific pathology or outcomes data.

For establishing the cut-offs, for several analytes (dsDNA, Sm, Ribo-P, RNP, Ro60, SS-B, Scl-70, Centromere, Ro52, Jo-1), the cut-off was established based on the 95th percentile of results from "reference subjects" (presumably healthy or non-diseased controls) and results from patients with the relevant disease (e.g., SLE patients for dsDNA) "to ensure optimal differentiation." This is a statistical approach tied to distinguishing patient populations.

8. The sample size for the training set

The document does not explicitly use the term "training set" in the context of machine learning. However, for establishing the cut-offs and calibrators for the assays:

• Reference population for cut-offs: 120 samples from reference subjects (various autoimmune and infectious diseases, but generally considered "controls" for the target diseases), plus specific numbers of diseased patient samples (e.g., 13 SLE samples for dsDNA, 7 SLE and 5 MCTD samples for RNP, etc.). These samples were used to define the diagnostic thresholds.
• Master Curves/Calibrators: These were generated "in-house" using "in-house Master Curve Standards" with assigned values. The document states that these standards were run "multiple times" to create the 4-parameter logistic curve for each analyte. The exact number of runs or distinct samples used to define these master curves is not provided with an aggregate number.

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

• For the reference population used to establish cut-offs: The ground truth was established by clinical diagnosis of the subjects ("patients with celiac disease," "patients with systemic lupus erythematosus," etc.). These diagnoses serve as the reference standard for defining what constitutes a positive or negative result for the assay.
• For the Master Curve Standards (calibrators): These standards have "assigned values" (e.g., IU/mL or FLU), indicating that their "ground truth" (concentration) was determined by an internal, established method at Inova Diagnostics. This is a common practice for calibrators in immunoassay development.

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EliA SymphonyS is intended for the in vitro, qualitative measurement of antibodies in human serum and plasma (Li-heparin, EDTA). EliA SymphonyS is based on human recombinant U1RNP (RNP 70, A, C), SS-A/Ro (60 kDa, 52 kDa), SSB/La, Centromere B, Scl-70, Jo-1 proteins and a synthetic SmD3 peptide as antigen and is useful as an aid in the clinical diagnosis of patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren's syndrome, scleroderna and polymyositis, in conjunction with other laboratory and clinical findings. EliA SymphonyS uses the EliA IgG method on the instrument Phadia 250.

EliA SymphonyS is intended for the in vitro, qualitative measurement of antibodies in human serum and plasma (Li-heparin, EDTA). EliA SymphonyS is based on human recombinant U1RNP (RNP 70, A, C), SS-A/Ro (60 kDa, 52 kDa), SSB/La, Centromere B, Scl-70, Jo-1 proteins and a synthetic SmD3 peptide as antigen and is useful as an aid in the clinical diagnosis of patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren's syndrome, scleroderma and polymyositis, in conjunction with other laboratory and clinical findings. EliA SymphonyS uses the EliA IgG method on the instrument Phadia 2500/5000.

The method specific reagents on Phadia® 250 and Phadia® 2500/5000 are identical; they are only filled in different containers. Each device consists of:

• EliA Symphony® Wells are coated with human recombinant U1RNP (RNP70, A. -C). SS-A/Ro (60 kDa. 52 kDa). SS-B/La. Centromere B. Scl-70. Jo-1 proteins and synthetic SmD3 peptide - 4 carriers (16 wells each), ready to use;
• EliA Sample Diluent: PBS containing BSA, detergent and 0.095% sodium azide --6 bottles, 48 mL each, ready to use; or 6 bottles, 400 mL each, ready to use;
• EliA IgG Conjugate 50 or 200: ß-Galactosidase labeled anti-IgG (mouse monoclonal antibodies) in PBS containing BSA and 0.06% sodium azide -6 wedge shaped bottles, 5 mL each, ready to use; or 6 wedge shaped bottles, 19 mL each, ready to use
• EliA ANA Positive Control 250 or 2500/5000: Human serum containing lgG antibodies to dsDNA, RNP, Sm, Ro. La. Scl-70. CENP and Jo-1 in PBS containing BSA, detergent and 0.095% sodium azide - 6 single use vials, 0.3 mL each, ready to use;
• -EliA Negative Control 250 or 2500/5000: Human sera from healthy donors in PBS containing BSA, detergent and 0.095% sodium azide - 6 single-use vials, 0.3 mL each, ready to use;
• EliA IgG Calibrator Strips: Human IgG (0, 4, 10, 20, 100, 600 µg/L) in PBS containing BSA, detergent and 0.095% sodium azide - 5 strips, 6 single-use vials per strip, 0.3 mL each, ready to use;
• -EliA IgG Curve Control Strips: Human IgG (20 µg/L) in PBS containing BSA, detergent and 0.095% sodium azide - 5 strips, 6 single-use vials per strip, 0.3 mL each, ready to use;
• EliA IgG Calibrator Well: Coated with mouse monoclonal antibodies 4 carriers (12 wells each), ready to use.

The Phadia EliA Immunodiagnostic System is an automated system for immunodiagnostic testing. The EliA reagents are available as modular packages, each purchased separately. Apart from the EliA ANA Positive Control 250 or 2500/5000 and the EliA IqG/IqM/IgA Neqative Control 250 or 2500/5000, all packages listed above are required to carry out an EliA SymphonyS Test.

Here's a breakdown of the acceptance criteria and study information for the EliA SymphonyS Immunoassay, based on the provided FDA 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

Study Details:

2. Sample Size and Data Provenance (Test Set)

• Precision Study (Phadia 250): 5 samples, 252 replicates per sample (totaling 1260 determinations). Data provenance not explicitly stated, but clinical samples are generally used for such studies.
• Precision Study (Phadia 2500/5000): 7 samples, 84 replicates per sample (totaling 588 determinations). Data provenance not explicitly stated.
• Interference Study: 3 serum samples (negative, cut-off, high positive), analyzed in triplicates, repeated twice. Spiked with specific interfering substances. Data provenance not explicitly stated.
• Cut-off Study: 70 apparently healthy blood donor samples from Caucasian individuals (equally distributed by sex and age). 30 ANA positive samples with known reactivities. Data provenance not explicitly stated.
• Method Comparison Study: 633 serum samples from patients with various diagnoses (Mixed Connective Tissue Disease, Poly-/Dermatomyositis, Systemic Sclerosis, SLE, Sjögren's Syndrome, Bacterial Infection, HIV Infection, HCV Infection, HBV Infection, Rheumatoid Arthritis, Cancer). Data provenance not explicitly stated (likely retrospective clinical samples from diverse sources).
• Matrix Comparison Study: 62 patients, serum, lithium heparin plasma, and EDTA plasma collected from the same patients. Data provenance not explicitly stated.
• Instrument Comparison Study: 110 samples (81 positive, 10 equivocal, 19 negative). Data provenance not explicitly stated.
• Clinical Sensitivity and Specificity Study: 444 clinically defined samples with a diagnosis from patients with various autoimmune diseases and control conditions (Mixed Connective Tissue Disease, Poly-/Dermatomyositis, Systemic Sclerosis, SLE, SLE/Lupus nephritis, Sjögren's Syndrome, Bacterial Infection, Viral Infection, Rheumatoid Arthritis, Celiac Disease, Crohn's Disease, Ulcerative Colitis, Graves' Disease, Hashimoto's Disease, primary Antiphospholipid Syndrome, PBC, Autoimmune hepatitis, Granulomatosis with Polyangiitis). Data provenance not explicitly stated (likely retrospective clinical samples from diverse sources).
• Expected Values/Reference Range Study: 558 apparently healthy subjects (Caucasian, African American, Hispanic and Asian population) obtained from a blood bank. This suggests diverse geographic and demographic provenance for the "normal" population.

Most of the studies likely used retrospective clinical samples, given the disease-specific grouping. No specific country of origin is mentioned for individual studies, but the applicant is Phadia AB from Sweden, and the 510(k) contact is in the USA, implying potential multi-site studies or data collection.

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 or qualifications of experts used to establish ground truth for the test set.

• For the "clinically defined samples" in the clinical sensitivity/specificity study, the "diagnosis from patients" would be considered the ground truth, presumably established by treating physicians based on clinical findings and other laboratory tests, but not by a specific panel of experts for the purpose of this device's validation.
• Reference sera (CDC and AMLI) have "target" values, which are established by their respective institutions (Centers for Disease Control and Prevention, and Association of Medical Laboratory Immunologists) and represent a consensus or assigned value, but not necessarily a specific "number of experts" for this study.

4. Adjudication Method for the Test Set

The document does not mention any explicit adjudication method (e.g., 2+1, 3+1) for establishing the ground truth for the test set. Clinical diagnoses are typically made by single treating physicians, and reference materials have predefined target values.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed. This device is an in vitro diagnostic immunoassay, which does not involve human readers interpreting results in the same way an imaging AI might. Its performance is measured directly through analytical and clinical studies against predicate devices or known clinical statuses.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance)

Yes, the device performance described is standalone (algorithm only). The EliA SymphonyS Immunoassay is an automated system that measures antibody levels and provides a qualitative result (negative, equivocal, positive) based on predefined cut-offs, without direct human-in-the-loop interpretation during the measurement process. The "aid in clinical diagnosis" part implies that clinicians interpret the results in conjunction with other findings, but the device itself operates in a standalone manner.

7. Type of Ground Truth Used

The types of ground truth used include:

• Clinical Diagnoses: For the clinical sensitivity/specificity study, the "diagnosis from patients with" various diseases (e.g., SLE, MCTD, Sjögren's syndrome) served as the ground truth. This is based on established clinical criteria for each disease.
• Reference Material Targets: For the evaluation of CDC and AMLI sera, the "Target" reactivity/results defined by these external institutions were used as ground truth.
• Expected Behavior: For precision, interference, carry-over, and cut-off studies, the ground truth is often the expected behavior of the assay (e.g., negative sample should be negative, spiked sample should show no interference, etc.) or statistically derived values from healthy populations.
• Predicate Device Results: For the method comparison study, the results from the legally marketed predicate device (EliA Symphony) served as a comparative ground truth to demonstrate substantial equivalence.

8. Sample Size for the Training Set

The document does not explicitly describe a "training set" in the context of machine learning. This is an immunoassay, which typically relies on established biochemical reactions, calibration curves, and empirically determined cut-offs rather than a machine learning model that requires a discrete training phase with labeled data. The calibration curve is established using calibrator strips (human IgG at known concentrations).

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

As noted above, there isn't a "training set" in the machine learning sense for this immunoassay.

• The calibration curve is established using EliA IgG Calibrator Strips, which contain human IgG at known concentrations (0, 4, 10, 20, 100, 600 µg/L). The "ground truth" for these calibrators is their precisely defined IgG concentrations, which are traceable to the International Reference Preparation (IRP) 67/86 of Human Serum Immunoglobulins A, G and M from WHO.
• The cut-off values (0.7 Ratio and 1.0 Ratio) were established by evaluating 70 apparently healthy blood donor samples and taking into account the 95th percentile, along with testing 30 ANA positive samples with known reactivities. This is a form of empirical ground truth setting based on biological distribution and known positive/negative samples.

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QUANTA Flash HMGCR is a chemiluminescent immunoassay for the semi-quantitative determination of IgG autoantibodies against HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) antigen in human serum. The presence of anti-HMGCR antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of idiopathic inflammatory myopathy (IIM).

The principle of the assay is chemiluminescent microparticle immunoassay, a variation of solid phase immunoassay. The QUANTA Flash® HMGCR 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® HMGCR assay utilizes a reagent cartridge format, which is compatible with the BIO-FLASH® instrument.

HMGCR (3-hydroxy-3-methylglutary)-coenzyme A reductase) antigen is coated on to paramagnetic beads, which are stored in the reagent cartridge lyophilized. When the assay cartridge is ready to be used for the first time, a buffer solution is added to the tube containing the beads, and the beads are resuspended with the buffer. The reagent cartridge is then loaded onto the BIO-FLASH instrument.

A patient serum sample is diluted 1:17 by the instrument in a disposable plastic cuvette. An aliquot of the diluted patient serum, HMGCR-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. lsoluminol conjugated anti-human IgG 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 anti-HMGCR antibodies bound to the antigen on the beads. The QUANTA Flash HMGCR assay utilizes a predefined lot specific Master Curve that is uploaded into the instrument through the reagent cartridge barcode. Based on the results obtained by running two calibrators, an instrument specific Working Curve is created, which is used by the software to calculate chemiluminescent units (CU) from the RLU value obtained for each sample.

QUANTA Flash HMGCR Calibrators and QUANTA Flash HMGCR Controls are sold separately.

The QUANTA Flash HMGCR Reagents kit contains the following materials:

• a. One (1) QUANTA Flash HMGCR Reagent Cartridge
• b. One (1) tube of Resuspension Buffer
• One (1) transfer pipette

The QUANTA Flash HMGCR reagent cartridge contains the following reagents for 50 determinations:

• a. HMGCR coated paramagnetic beads, lyophilized.
• b. Assay buffer colored pink, containing protein stabilizers and preservatives.
• c. Tracer IgG Isoluminol labeled anti-human IgG antibody, containing buffer, protein stabilizers and preservative.

The provided information describes the analytical and clinical performance characteristics of the QUANTA Flash HMGCR Reagents for the semi-quantitative determination of IgG autoantibodies against HMGCR antigen in human serum. This device aids in the diagnosis of idiopathic inflammatory myopathy (IIM).

Here's an breakdown of the acceptance criteria and the study that proves the device meets those criteria:

1. Table of Acceptance Criteria and Reported Device Performance

The document provides specific acceptance criteria for analytical performance studies, along with the results.

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

• Clinical Performance Validation Set (Test Set):
  • Sample Size: A total of 723 characterized samples were included in the validation set.
  • Data Provenance: The document does not explicitly state the country of origin of the data. It refers to a "cohort of characterized samples" and "a panel of 100 apparently healthy blood donors." The nature of the "characterized samples" suggests they were sourced from clinical settings, likely retrospective or a collection of previously diagnosed samples, as they include various patient groups (e.g., infectious diseases, autoimmune diseases, cancers, and IIM subgroups). The "apparently healthy blood donors" would typically be prospective healthy volunteers.
  • Retrospective/Prospective: The text does not explicitly state "retrospective" or "prospective" for the 723 characterized samples, but the use of "characterized samples" that were "none of which were used for establishing the reference range" implies they were pre-existing samples used for validation. The 100 healthy donors for expected values are likely prospective or from a biobank of healthy individuals.

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

• The document states that the IIM patient samples were classified based on "revised EULAR/ACR classification criteria" and "European Neuromuscular Center criteria (ENMC) 2003 for IMNM."
• The determination of patient groups (e.g., Infectious, SLE, SSc, MCTD, different myositis subgroups) implies a clinical diagnosis.
• The document does not specify the number of experts used or their specific qualifications (e.g., "radiologist with 10 years of experience") for establishing the ground truth. It relies on the widely accepted EULAR/ACR classification criteria and ENMC criteria, which are expert consensus guidelines used by clinicians (e.g., rheumatologists, neurologists) to diagnose these conditions. This suggests an reliance on clinical diagnoses made by qualified professionals adherence to these criteria.

4. Adjudication Method for the Test Set

• The document does not describe a specific "adjudication method" in the traditional sense (e.g., 2+1, 3+1 review by multiple readers for an imaging study).
• Instead, the ground truth for the clinical performance validation set was based on established clinical classification criteria (EULAR/ACR, ENMC). This implies that patient diagnoses (the "ground truth") were determined by clinicians following these standardized guidelines, rather than through an adjudication process of multiple independent assessors specifically for this device 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

• No, an MRMC comparative effectiveness study was not done.
• This device is an in vitro diagnostic (IVD) immunoassay; it measures autoantibodies in human serum. It is not an AI-powered image analysis device or a diagnostic tool that would typically involve "human readers" or "AI assistance" in the way described for an MRMC study. The comparison is between the device's output (presence/absence of antibodies) and a clinical diagnosis, not human reader performance with or without AI.

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

• Yes, this was a standalone performance study in the context of an IVD. The QUANTA Flash HMGCR assay measures the presence and semi-quantitative level of IgG autoantibodies in serum. The device, the BIO-FLASH instrument with the QUANTA Flash HMGCR Reagents, operates as a fully automated closed system that processes samples and reports results. The clinical performance study (sensitivity, specificity) evaluated the algorithm (the assay's ability to detect antibodies and classify as positive/negative based on its cutoff) against established clinical diagnoses, without human interpretation of raw assay signals in the loop for classification.

7. The Type of Ground Truth Used

• The ground truth for the clinical performance validation was clinical diagnosis based on established classification criteria.
  • For the IIM patient cohorts, the ground truth was "idiopathic inflammatory myopathy" (IIM), further subclassified into Dermatomyositis (DM), Amyopathic Dermatomyositis, Juvenile Dermatomyositis, Polymyositis (PM), Inclusion Body Myositis, Overlap, and Immune Mediated Necrotizing Myopathy (IMNM), all determined by adherence to EULAR/ACR classification criteria (with a score of 5.5, not considering biopsy) and ENMC criteria for IMNM.
  • For the control groups (e.g., SLE, Scleroderma, RA, various infectious diseases, cancers, healthy donors), the ground truth was the absence of IIM or the presence of a different diagnosed condition.
• This is a form of outcomes data / expert consensus applied through established clinical criteria.

8. The Sample Size for the Training Set

• The document doesn't explicitly refer to a "training set" in the context of a machine learning algorithm.
• However, for the establishment of the cut-off value, a reference population of 145 subjects was used:
  • 23 Apparently healthy donors
  • 22 Infectious Disease Controls (HBV, HCV, Syphilis)
  • 18 Scleroderma Controls
  • 20 Systemic Lupus Erythematosus Controls
  • 48 End Stage Renal Disease Controls
  • 14 False Positive Cohort (high reactivity samples)
• Additionally, 12 diagnosed idiopathic inflammatory myopathy (IIM) patient specimens were assayed to aid in the determination of the cutoff.
• This combined set (145 + 12 = 157 samples) served as the data used to define the diagnostic threshold (cutoff).

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

• For the cut-off establishment:
  • The reference population (145 subjects) consisted of "apparently healthy donors" and "controls" for various other conditions. These are presumed to have established diagnoses or healthy status.
  • The 12 diagnosed IIM patient specimens were identified as having IIM.
• The cut-off was established in accordance with CLSI EP28-A3c: Defining, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition.
• The method involved:
  1. Analyzing the distribution of results from the reference population.
  2. Using the non-parametric percentile method due to non-normal distribution (Shapiro-Wilk p<0.0001).
  3. Considering the distribution of results in the 12 known positive IIM samples.
  4. The cut-off of 30,000 RLU (assigned 20 CU) was set greater than the 99th percentile of the control results to ensure optimal differentiation.

In summary, the study validates an IVD laboratory test for autoantibodies. Its performance is demonstrated through rigorous analytical studies and clinical validation against defined patient cohorts and controls using established clinical diagnostic criteria. The concept of "AI assistance" or "human readers" is not applicable to this type of device.

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QUANTA Flash® Scl-70 is a chemiluminescent immunoassay for the semi-quantitative determination of IgG anti-Scl-70 autoantibodies in human serum. The presence of anti-Scl-70 autoantibodies, in conjunction with clinical findings and other laboratory tests, aids in the diagnosis of systemic sclerosis.

QUANTA Flash® Scl-70 Calibrators are intended for use with the QUANTA Flash® Scl-70 chemiluminescent immunoassay for the determination of IgG anti-Scl-70 autoantibodies in human serum. Each calibrator establishes a point of reference for the working curve that is used to calculate unit values.

QUANTA Flash® Scl-70 Controls are intended for use with the OUANTA Flash® Scl-70 chemiluminescent immunoassay for quality control in the determination of IgG anti-Scl-70 autoantibodies in human serum.

The QUANTA Flash Scl-70 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 Scl-70 assay utilizes a reagent cartridge format, which is compatible with the BIO-FLASH instrument.

Recombinant Scl-70 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. A patient serum sample is prediluted 1:23.5 by the BIO-FLASH with system rinse in a disposable plastic cuvette. Small amounts of the diluted patient serum, the beads, and assay buffer are all 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(III) coproporphyrin in sodium hydroxide solution) and Trigger 2 (urea-hydrogen peroxide in sodium chloride solution) are added to the cuvette, and 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-Scl-70 antibodies bound to the corresponding Scl-70 on the beads.

For quantitation, the QUANTA Flash Scl-70 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 Scl-70 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)mL from the instrument signal (RLU) obtained for each sample.

Here's a summary of the acceptance criteria and study findings based on the provided text, structured as requested:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Clinical Performance (Validation Set):

  • Sample Size: 498 samples.
  • Data Provenance: The text does not explicitly state the country of origin. It indicates the samples were a "separate set of samples, none of which were used in establishing the reference range." The patient groups include Systemic Sclerosis (SSc) and various control groups (Systemic Lupus Erythematosus, Rheumatoid Arthritis, Idiopathic Inflammatory Myopathy, Mixed Connective Tissue Disease, Celiac disease, Autoimmune thyroiditis, Sjögren's syndrome, Infectious disease, Crohn's disease, Osteoarthritis, COPD, Chronic Kidney Disease, Vasculitis, Raynaud's, Diabetes, Asthma, Skin Disease). The infectious disease samples specify Hepatitis C virus, Epstein-Barr virus, Toxoplasmosis, Cytomegalovirus, Mycoplasma infection, and Borrelia virus. The study is presented as evidence for the device's performance, suggesting prospective collection or a well-characterized retrospective cohort.

• Comparison with Predicate Device:

  • Sample Size: 539 samples (the 498 samples from the Validation Set plus 41 additional contrived samples).
  • Data Provenance: Same as the clinical performance validation set, with additional contrived samples (diluted Scl-70 positive serum with negative serum).

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

The document does not specify the number of experts or their qualifications for establishing the ground truth for the clinical diagnosis of systemic sclerosis (SSc) or other conditions used in the clinical validation set. It simply refers to "Diagnosis" in the tables relating to sensitivity and specificity. Given this is an in vitro diagnostic device, the ground truth for clinical conditions would typically be established by clinical diagnosis by treating physicians, potentially corroborated by other clinical and laboratory findings.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication method (e.g., 2+1, 3+1) for establishing the ground truth diagnoses in the test set.

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

No multi-reader multi-case (MRMC) comparative effectiveness study is mentioned. This device is an automated chemiluminescent immunoassay; therefore, human reader assistance and improvement with AI assistance are not applicable. The comparison is between the new automated device and a predicate ELISA (enzyme-linked immunosorbent assay), not human readers.

6. Standalone Performance Study

Yes, a standalone performance study was done. The entire document describes the standalone performance of the QUANTA Flash® Scl-70 assay system (algorithm/device only without human-in-the-loop performance, as it's an automated immunoassay) across various analytical and clinical characteristics. The clinical sensitivity and specificity are direct measures of this standalone performance.

7. Type of Ground Truth Used

• Clinical Performance (Sensitivity/Specificity): The ground truth was clinical diagnosis. For systemic sclerosis (SSc), this means patients diagnosed with SSc. For control groups, this refers to patients diagnosed with other autoimmune diseases or infectious diseases, or healthy individuals.
• Analytical Performance: Ground truth was established by controlled experimental conditions, such as known concentrations for precision, linearity, and interference studies, or controlled conditions for stability studies.
• Comparison with Predicate Device: The ground truth for this comparison was the result obtained from the legally marketed predicate device, QUANTA Lite® Scl-70 ELISA.

8. Sample Size for the Training Set

• Reference Range Establishment (for Cut-off): 254 subjects were used. The sample groups included individuals with Rheumatoid Arthritis, Systemic Lupus Erythematosus, Hashimoto's Thyroiditis, Hepatitis B Virus, Hepatitis C Virus, Inflammatory Bowel Disease, Drug Induced Lupus, Autoimmune atrophic gastritis, Biliary anastomatic stricture, and Healthy Individuals.
• Cut-off Adjustment: 19 systemic sclerosis samples that were positive on the predicate device were also used to aid in the final determination of the cutoff.
• The document does not explicitly describe a separate "training set" in the context of machine learning, as this is an immunoassay, but rather samples used for establishing the reference range/cut-off.

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

• Reference Range Establishment: The ground truth for the 254 subjects used to establish the reference range was based on their clinical diagnosis (e.g., Rheumatoid Arthritis, Systemic Lupus Erythematosus, or Healthy Individuals).
• Cut-off Adjustment: The additional 19 systemic sclerosis samples had a ground truth based on their positive results on the predicate device (QUANTA Lite® Scl-70 ELISA) and their clinical diagnosis of systemic sclerosis.

The cut-off was established in accordance with CLSI C28-A3c ("Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition") and adjusted based on the results from the SSc samples positive on the predicate device to optimize differentiation.

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QUANTA Flash Jo-1 is a chemiluminescent immunoassay for the semi-quantitative determination of IgG anti-Jo-1 antibodies in human serum. The presence of antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of idiopathic inflammatory myopathy.

QUANTA Flash Jo-1 Calibrators are intended for use with the QUANTA Flash Jo-1 Reagents for the determination of Ig G anti-Jo-1 antibodies in human serum. Each calibrator establishes a point of reference for the working curve that is used to calculate unit values.

QUANTA Flash Jo-1 Controls are intended for use with the OUANTA Flash Jo-1 Reagents for quality control in the determination of IgG anti-Jo-1 antibodies in human serum.

The QUANTA Flash Jo-1 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 Jo-1 assay utilizes a reagent cartridge format, which is compatible with the BIO-FLASH instrument.

Recombinant Jo-1 antigen is coated onto paramagnetic beads, which is stored in the reagent cartridge as a suspension. When the cartridge is ready to be used for the first time, the entire cartridge is inverted several times to thoroughly mix 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 (urea-hydrogen peroxide in sodium chloride solution) are added to the cuvette, and 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-Jo-1 antibodies bound to the corresponding beads.

For quantitation, the QUANTA Flash Jo-1 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 Jo-1 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 Jo-1 kit contains the following materials:

One (1) QUANTA Flash Jo-1 Reagent Cartridge

The QUANTA Flash Jo-1 reagent cartridge contains the following reagents for 50 determinations:

• a. Jo-1 coated paramagnetic beads, in a suspension containing buffer, protein stabilizers and preservative.
• b. Assay buffer - colored pink, containing buffer, 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 Jo-1 Calibrators kit contains two vials of Calibrator 1 and two vials of Calibrator 2:

QUANTA Flash Jo-1 Calibrators:

• І QUANTA Flash Jo-1 Calibrator 1: Two (2) barcode labeled tubes containing 0.3 mL prediluted, ready to use reagent. Calibrators contain human antibodies to Jo-1 in buffer, stabilizer and preservative.
• QUANTA Flash Jo-1 Calibrator 2: Two (2) barcode labeled tubes containing 0.3 mL prediluted, ready to use reagent. Calibrators contain human antibodies to Jo-1 in buffer, stabilizer and preservative.

The QUANTA Flash Jo-1 Controls kit contains two vials of Negative Control and two vials of Positive Control:

QUANTA Flash Jo-1 Controls:

• -QUANTA Flash Jo-1 Negative Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human antibodies to Jo-1 in buffer, stabilizer and preservative.
• QUANTA Flash Jo-1 Positive Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human antibodies to Jo-1 in buffer, stabilizer and preservative.

The provided text describes the analytical and clinical performance characteristics of the QUANTA Flash® Jo-1 chemiluminescent immunoassay. This device is intended for the semi-quantitative determination of IgG anti-Jo-1 antibodies in human serum to aid in the diagnosis of idiopathic inflammatory myopathy.

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

Acceptance Criteria and Reported Device Performance

Note: The document provides detailed analytical performance characteristics and clinical performance characteristics. For acceptance criteria, the document explicitly states them for:

• Precision (Total %CV: < 10%)
• Reproducibility (Total %CV: < 15%)
• Linearity (Recovery: 80-120% or ± 4 CU; Slope: 0.9-1.1; R^2: ≥ 0.95)
• Interference (Recovery: 85-115% for samples above cutoff; ± 4 CU for samples below cutoff)
• Lot to Lot Comparison (Between lot %CV: < 10%)
• Sample Stability (90-110% average recovery)
• Reagent Shelf Life (Beads: 85-115% recovery at day 14; Controls & Calibrators: 90-110% recovery at day 14)
• In-use (onboard) Calibrator Stability (Calibrator RLU recovery: 90-110%)
• In-use (onboard) Control Stability (Regression line: 85-115% at run 15)
• Real Time Stability (Results within respective QC ranges/acceptable ranges)

The document primarily focuses on demonstrating that the results achieved meet these pre-defined acceptance criteria, rather than stating all criteria first and then presenting results in a consolidated table for every single point. The tables below compile the key numerical performance metrics against the stated acceptance criteria where available in the document.

Table 1: Acceptance Criteria and Reported Device Performance

Study Details

The provided document describes studies conducted to support the substantial equivalence of the QUANTA Flash® Jo-1 device to a predicate device (FIDIS Connective 10). Primarily, this involves analytical and clinical performance testing for an in vitro diagnostic (IVD) immunoassay, not an AI/ML-driven medical device in the typical sense that would involve image analysis or complex algorithms requiring expert readers for ground truth. Therefore, many of the typical questions for AI/ML devices (e.g., number of experts, adjudication methods, MRMC studies) are not applicable here.

1. Sample size used for the Test Set and Data Provenance:

   • Clinical Validation Cohort / Test Set: 487 characterized samples. This was composed of 206 Idiopathic Inflammatory Myopathy (IIM) patients and 281 control subjects (Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Septicacaemia, Mixed Connective Tissue Disease, Sjögren's Syndrome).
   • Method Comparison Test Set: 425 samples from the clinical validation study + 26 additional contrived samples (total 451 samples, analyzed using 105 samples within AMR).
   • Reference Range Establishment: 207 subjects (various conditions including autoimmune diseases, infections, and healthy individuals).
   • Expected Values in Normal Population: 400 apparently healthy blood donors (246 females, 154 males, ages 17-60).
   • Data Provenance: The document does not explicitly state the country of origin or if the data was retrospective or prospective. Given the nature of an IVD submission and clinical laboratory studies, it's typically a mix of retrospectively collected well-characterized samples and prospectively run samples in controlled laboratory settings for performance evaluation.

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

   • Not Applicable in the traditional sense for this IVD immunoassay. Ground truth for this assay is linked to the presence or absence of specific autoantibodies (anti-Jo-1) as determined by clinical diagnosis of Idiopathic Inflammatory Myopathy (IIM) and other clinical findings, along with the performance of the predicate device. The samples used are described as "characterized samples," meaning their disease status would have been established through standard clinical diagnostic procedures, not necessarily through a panel of expert "readers" establishing ground truth in the way it's done for imaging AI.

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

   • Not Applicable. As this is an IVD immunoassay for antibody determination, not an AI/ML system requiring reader adjudication for image interpretation.

4. 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 not an AI/ML device designed to assist human readers in interpretation. It's a laboratory test system producing a biochemical result.

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

   • Applicable, effectively YES for the device test. The "standalone" performance here refers to the analytical and clinical performance of the assay itself (device + instrument) without human interpretive input beyond following the assay procedure and reading quantitative results. The entire analytical performance section (Precision, LoD, Linearity, Interference, etc.) and clinical performance (Sensitivity, Specificity) demonstrate the standalone performance of the assay. The method comparison with the predicate device also serves this purpose.

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

   • Clinical Diagnosis / Clinical Findings / Well-Characterized Samples: For clinical performance, the ground truth was based on the clinical diagnosis of Idiopathic Inflammatory Myopathy (IIM) and other related conditions. The samples were described as "characterized samples," implying their disease status was established through established clinical criteria, which would involve a combination of clinical findings, potentially pathology (e.g., muscle biopsy for myopathy), and other laboratory tests. For the analytical studies, ground truth for some samples was "contrived" by diluting known positive samples to create a range of concentrations.

7. The sample size for the training set:

   • Not provided/Applicable in the AI/ML sense. This is an immunoassay, not an AI/ML model trained on a dataset. The "training" for such a device occurs during its development and optimization, which would involve many samples, but they are not typically referred to as a "training set" in the context of an AI/ML model. The "Master Curve Standards" are used for manufacturing and calibration, but not as a machine learning training set.

8. How the ground truth for the training set was established:

   • Not Applicable in the AI/ML sense. For an immunoassay, the "ground truth" for calibrators and controls is established through rigorous value assignment procedures, often traceable to in-house primary standards and confirmed through extensive testing (e.g., "trial dilutions on small scale," "tested on at least two instruments, on at least two lots of reagent cartridge, in replicates of 10"). The "standards" themselves are assigned values through a manufacturing process.

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Enzyme linked immunoassay (ELISA) for the qualitative and semi-quantitative detection of SS-A (Ro) (52 kD and 60 kD) Ig G antibodies in human serum as an aid in diagnosis of Systemic Lupus Erythematosus (SLE) and Sjögren's Syndrome in conjunction with clinical findings and other laboratory tests.

Enzyme linked immunoassay (ELISA) for the qualitative and semi-quantitative detection of SS-B (La) IgG antibodies in human serum as an aid in diagnosis of Systemic Lupus Erythematosus (SLE) and Sjögren's Syndrome in conjunction with clinical findings and other laboratory tests.

Enzyme linked immunoassay (ELISA) for the qualitative detection of Sm IgG antibodies in human serum as an aid in diagnosis of Systemic Lupus Erythematosus (SLE) in conjunction with clinical findings and other laboratory tests.

Enzyme linked immunoassay (ELISA) for the qualitative and semi-quantitative detection of RNP IgG antibodies in human serum as an aid in diagnosis of Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease (MCTD) in conjunction with clinical findings and other laboratory tests.

Not Found

I am sorry, but the provided text from the FDA 510(k) summary only contains the indications for use for several ImmuLisa Enhanced™ antibody ELISA tests.

It does not include information about:

• Acceptance criteria for device performance.
• The study design, sample sizes (training or test sets), data provenance, number or qualifications of experts, adjudication methods, or ground truth establishment.
• Any multi-reader multi-case (MRMC) comparative effectiveness study or standalone performance study.

Therefore, I cannot fulfill your request for this specific document.

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QUANTA Flash Ro60 is a chemiluminescent immunoassay for the semi-quantitative determination of IgG anti-Ro60 autoantibodies in human serum. The presence of anti-Ro60 autoantibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of Systemic Lupus Erythematosus and Sjögren's Syndrome.

QUANTA Flash Ro60 Calibrators are intended for use with the QUANTA Flash Ro60 Reagents for the determination of Ig G anti-Ro60 autoantibodies in human serum. Each calibrator establishes a point of reference for the working curve that is used to calculate unit values.

QUANTA Flash Ro60 Controls are intended for use with the QUANTA Flash Ro60 reagents for quality control in the determination of IgG anti-Ro60 autoantibodies in human serum.

The QUANTA Flash Ro60 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 Ro60 assay utilizes a reagent cartridge format, which is compatible with the BIO-FLASH instrument.

Purified recombinant Ro60 antigen 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 prediluted 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 all 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 cuvette, and 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-Ro60 antibodies bound to the corresponding beads.

For quantitation, the QUANTA Flash Ro60 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 Ro60 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 Ro60 kit contains the following materials:

One (1) QUANTA Flash Ro60 Reagent Cartridge

One (1) vial of Resuspension buffer

One (1) Transfer pipette

The QUANTA Flash Ro60 reagent cartridge contains the following reagents for 50 determinations:

• a. Ro60 antigen 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 Ro60 Calibrators kit contains two vials of Calibrator 1 and two vials of Calibrator 2:

QUANTA Flash Ro60 Calibrators:

• QUANTA Flash Ro60 Calibrator 1: Two (2) barcode labeled tubes containing 0.3 mL ı prediluted, ready to use reagent. Calibrators contain human antibodies to Ro60 in stabilizers and preservatives.
• -QUANTA Flash Ro60 Calibrator 2: Two (2) barcode labeled tubes containing 0.3 mL prediluted, ready to use reagent. Calibrators contain human antibodies to Ro60 in stabilizers and preservatives.

The QUANTA Flash Ro60 Controls kit contains two vials of Negative Control and two vials of Positive Control:

QUANTA Flash Ro60 Controls:

• । QUANTA Flash Ro60 Negative Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human antibodies to Ro60 in stabilizers and preservatives.
• i QUANTA Flash Ro60 Positive Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human antibodies to Ro60 in stabilizers and preservatives.

The document describes the analytical and clinical performance of the QUANTA Flash® Ro60 chemiluminescent immunoassay for the semi-quantitative determination of IgG anti-Ro60 autoantibodies in human serum.

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance:

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

• Precision Study: 10 samples (run in duplicates, twice a day, for 21 days), 84 replicates each.
• Reproducibility Study: 3 samples (run in quadruplicates, two times a day, for 10 days), 80 data points per sample.
• Limit of Detection (LoD) Study: 120 determinations (60 blank, 60 low-level samples) per reagent lot. 4 low-level samples (diluted anti-Ro60 positive samples) for LoD determination.
• Limit of Blank (LoB) Study: 4 blank samples (System Rinse) from two different lots, run in replicates of five per day for 3 days. 60 data points per lot.
• Linearity Study: 3 serum samples (diluted in 10% increments).
• Interference Study: 3 specimens (one near-cutoff negative, one weak positive, one high positive), spiked with interfering substances at three concentrations.
• Cross-reactivity Study: 213 "control" clinical samples from patients with various autoimmune diseases or infectious disease serology.
• Lot to Lot Comparison Study: 21 unique samples and 2 Positive Controls (23 specimens in total).
• Sample Stability Study: 6 samples (negative, around cut-off, positive).
• Accelerated Stability Studies: 3 lots of beads and 3 lots of Calibrators and Controls.
• Onboard Stability (Calibrators): Not explicitly stated, but involved running Calibrators 5 times over 8.5 hours with Controls and a panel of characterized patient specimens.
• Onboard Stability (Controls): 2 vials of each Control, assayed twice a day for a total of 20 runs.
• Reagent Cartridge Onboard Stability: Three lots of cartridges, tested with up to 6 serum specimens and controls.
• Real-time Stability: Not explicitly stated, but involved testing at various time points (3, 6, 9, 12 months for Calibrators/Controls; 2, 5, 8, 12 months for reagent cartridge).
• Reference Range Establishment: 156 subjects (apparently healthy blood donors, viral hepatitis, HIV, syphilis, rheumatoid arthritis patients). Data provenance not specified beyond "commercial sources" for certain materials.
• Clinical Performance (Sensitivity/Specificity): 475 characterized samples for the Validation Set (from Sjögren's Syndrome, SLE, and various control groups). Data provenance not specified, but likely from a clinical setting.
• Method Comparison: 143 samples from SS and SLE patients and disease controls.

The data provenance for most studies is not explicitly stated beyond general descriptions ("human serum," "commercial sources," "characterized samples"). It is not specified whether the studies were retrospective or prospective, or the country of origin for the patient/sample cohorts.

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

The document does not mention the use of experts to establish ground truth for the test set. For the clinical performance, samples were "characterized" and grouped into patient categories (e.g., Sjögren's Syndrome, SLE), but the method of this characterization (e.g., clinical diagnosis by a panel of rheumatologists, specific diagnostic criteria) and the number/qualifications of experts involved are not provided.

4. Adjudication Method:

The document does not describe any adjudication method (e.g., 2+1, 3+1) for the test set.

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

No MRMC comparative effectiveness study is mentioned. This device is an immunoassay, typically read by an instrument rather than human readers, so such a study would not be applicable.

6. Standalone Performance:

Yes, the entire document details the standalone performance of the QUANTA Flash® Ro60 immunoassay. All the analytical and clinical performance characteristics (precision, reproducibility, linearity, interference, stability, sensitivity, specificity, method comparison) are based on the algorithm's (instrument's) output without human intervention in the result interpretation beyond setting the cut-off. The device is described as "a fully automated closed system with continuous load and random access capabilities that automatically processes the samples, runs the assay and reports the results."

7. Type of Ground Truth Used:

• Analytical Studies (Precision, Reproducibility, Linearity, Interference, LoD, LoB, Lot-to-Lot, Sample Stability, Instrument Stability): Ground truth is typically based on pre-defined concentrations, spiked samples, or reference materials. For example, for linearity, expected values were based on dilution factors. For LoD/LoB, the truth was whether a sample was blank or low-level.
• Clinical Performance (Sensitivity, Specificity) and Cross-reactivity: Ground truth was based on clinical diagnoses (e.g., Sjögren's Syndrome, SLE, Graves' Disease, etc.) for the characterized samples. For cross-reactivity, it also included the presence of specific autoantibodies or infectious disease serology.
• Cut-off Establishment: Used a reference population of 156 subjects (apparently healthy, viral hepatitis, HIV, syphilis, rheumatoid arthritis) and also included 12 proficiency testing samples from CAP and UKNEQAS with known consensus/target results.
• Method Comparison: Ground truth was the result from a predicate device (Hycor AUTOSTAT™ II Anti-SS-A Ro ELISA).

8. Sample Size for the Training Set:

The document does not specify a separate "training set" in the context of machine learning. For an immunoassay, the "training" equivalent would be the data used to establish master curves, calibrator values, and cut-offs.

• Master Curve/Calibrator Values: Based on "in-house Standards" and trial dilutions (sample size for these not specified, but implied to be robust enough for value assignment).
• Cut-off Establishment: 156 subjects (reference population) and 12 proficiency testing samples were used to establish the cut-off. This could be considered part of the "training" for the interpretation of results into positive/negative.

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

As explained in point 8, if we consider cut-off establishment and master curve definition as part of "training":

• Master Curves and Calibrator/Control Values: Established internally using "in-house Standards" and extensive testing on multiple instruments and reagent lots.
• Cut-off for Classification: Established by analyzing the results from a reference population of 156 subjects using statistical methods (99th percentile, non-parametric method) and further informed by 12 proficiency testing samples with known consensus/target results from external quality assessment schemes (CAP, UKNEQAS).

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QUANTA Flash SS-B is a chemiluminescent immunoassay for the semi-quantitative determination of IgG anti-SS-B autoantibodies in human serum. The presence of anti-SS-B autoantibodies, in conjunction with clinical findings and other laboratory tests is an aid in the diagnosis of Sjögren's Syndrome and Systemic Lupus Erythematosus.

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

QUANTA Flash SS-B Controls are intended for use with the QUANTA Flash SS-B reagents for quality control in the determination of IgG anti-SS-B autoantibodies in human serum.

The QUANTA Flash SS-B 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 SS-B assay utilizes a reagent cartridge format, which is compatible with the BIO-FLASH instrument.

Purified recombinant SS-B antigen 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 prediluted 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 all 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 cuvette, and 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-SS-B antibodies bound to the corresponding beads.

For quantitation, the QUANTA Flash SS-B 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 SS-B 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 SS-B kit contains the following materials:

One (1) QUANTA Flash SS-B Reagent Cartridge One (1) vial of Resuspension buffer One (1) Transfer pipette

The QUANTA Flash SS-B reagent cartridge contains the following reagents for 50 determinations:

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

The QUANTA Flash SS-B Calibrators kit contains two vials of Calibrator 1 and two vials of Calibrator 2:

QUANTA Flash SS-B Calibrators:

• । QUANTA Flash SS-B Calibrator 1: Two (2) barcode labeled tubes containing 0.3 mL prediluted, ready to use reagent. Calibrators contain human antibodies to SS-B in stabilizers and preservatives.
• QUANTA Flash SS-B Calibrator 2: Two (2) barcode labeled tubes containing 0.3 mL - prediluted, ready to use reagent. Calibrators contain human antibodies to SS-B in stabilizers and preservatives.

The QUANTA Flash SS-B Controls kit contains two vials of Negative Control and two vials of Positive Control:

QUANTA Flash SS-B Controls:

• । QUANTA Flash SS-B Negative Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human antibodies to SS-B in stabilizers and preservatives.
• QUANTA Flash SS-B Positive Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human antibodies to SS-B in stabilizers and preservatives.

The document describes the QUANTA Flash® SS-B assay and its performance characteristics. This device is a chemiluminescent immunoassay for the semi-quantitative determination of IgG anti-SS-B autoantibodies in human serum, used as an aid in diagnosing Sjögren's Syndrome and Systemic Lupus Erythematosus.

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

1. Table of Acceptance Criteria and Reported Device Performance

This section focuses on the analytical performance characteristics and clinical performance.

Study Details:

This document primarily describes the analytical and clinical validation studies for the QUANTA Flash® SS-B assay, Calibrators, and Controls. There is no information about an AI component or expert readers in this specific submission. The device is an immunoassay, not an AI-driven diagnostic. Therefore, some requested information related to AI and human readers is not applicable.

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

• Precision Test Set: 10 samples (quantities for each are not specified beyond the number of replicates) for precision, and 7 samples for reproducibility.
• LoB/LoD Test Set: 4 blank samples (System Rinse) and 4 low-level samples for LoB/LoD determination. 60 data points were generated for each lot tested.
• Linearity Test Set: 5 serum samples with various SS-B antibody concentrations.
• Interference Test Set: 3 specimens (near-cutoff negative, weak positive, high positive).
• Cross-reactivity Test Set: 273 control samples from patients with various autoimmune diseases and infectious conditions.
• Clinical Validation Set: A total of 761 characterized samples.
  • Sub-cohort for Clinical Sensitivity/Specificity: Sjögren's Syndrome (n=40), SLE (n=290), Controls (n=431 including various autoimmune/infectious diseases and healthy donors).
  • Sub-cohort for Expected Values: 138 apparently healthy blood donors (118 F, 20 M; ages 17-60).
  • Sub-cohort for Comparison with Predicate Device: 639 samples (from the 761 clinical validation samples) that had predicate ELISA results available. This cohort included Sjögren's syndrome (n=40), SLE (n=240), and relevant disease controls (n=359). No healthy controls were included in this specific comparison cohort.
• Data Provenance: The document does not explicitly state the country of origin but implies the samples are from human patients/donors. The studies are prospective in the sense that the device was tested on these cohorts to establish performance, however, the samples themselves were "characterized samples" meaning they were retrospectively collected with known diagnoses.

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

• Not applicable as the device is an immunoassay. The ground truth (diagnosis of Sjögren's Syndrome or SLE, or specific autoimmune/infectious conditions for control samples) was established clinically rather than by expert review of imaging or similar data. The characterization of the samples is the ground truth.

4. Adjudication method for the test set:

• Not applicable as the device is an immunoassay measuring anti-SS-B autoantibodies. The "ground truth" for clinical samples was their established clinical diagnosis, not a subjective interpretation requiring adjudication. For analytical studies, internal reference standards and external guidelines (CLSI) were used.

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 not an AI-driven device or an imaging diagnostic that involves human readers.

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

• Yes, implicitly. The QUANTA Flash SS-B assay is a diagnostic device that performs the tests and yields results semi-quantitatively. Its performance characteristics (precision, linearity, sensitivity, specificity, etc.) are determined in a standalone mode. Human involvement is in operating the instrument, collecting samples, and interpreting the numerical results in a clinical context, but not in directly influencing the assay's biochemical reaction or signal generation.

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

• Clinical Ground Truth for Clinical Validation: Established clinical diagnoses of Sjögren's Syndrome, Systemic Lupus Erythematosus (SLE), and various other autoimmune/infectious diseases for the control groups. For the reference range and expected values, apparently healthy blood donors were used.
• Analytical Ground Truth: For linearity, LoB/LoD, precision, and interference studies, the ground truth was based on known concentrations, dilutions, or characteristics of the samples, derived from accepted laboratory methods and standards (e.g., CDC ANA reference sera, in-house standards).

8. The sample size for the training set:

• The document mentions that the cut-off value was initially established using 187 subjects (162 apparently healthy blood donors, 10 viral hepatitis, 5 HIV, 5 Syphilis, 5 Rheumatoid arthritis patients). Then, "32 samples characterized as positive for SS-B antibodies by IIF, FIA, and ELISA" were used to "aid in the determination of the cutoff." It also states "One reference sample tested positive at this threshold."
• For the Calibrators and Master Curve Standards, the "target CU is achieved through trial dilutions on small scale" and "Calibrator and Control values are directly traceable to in-house Standards that are used to create the Master Curves for the QUANTA Flash SS-B assay." No specific 'training set' sample size is explicitly defined beyond these descriptions, as the "training" here refers to the development and calibration of the assay itself, rather than training a machine learning model.

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

• For Cut-off Establishment:
  • The "reference population for establishing the reference interval" (187 subjects) was characterized clinically. The distribution of results from these subjects, particularly the 99th percentile (4097 RLU), informed the initial cut-off.
  • Additionally, 32 samples "characterized as positive for SS-B antibodies by IIF, FIA, and ELISA" were used. This indicates that these samples had prior positive results from other established methods, forming a reference "positive" ground truth. The cut-off was adjusted to 12,000 RLU (corresponding to 20 CU) to optimize differentiation based on these known positive samples.
• For Calibrators and Master Curves: The ground truth for these quantitative assignments is based on "in-house Standards," which are the fundamental reference materials used by the manufacturer to ensure consistency and accuracy of the assay. These standards are likely developed and characterized using highly controlled and validated methods, ensuring traceability where possible (though an international standard for SS-B antibodies is noted as not available). The process involves "trial dilutions," testing on instruments, and "final value assignment."

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