Search Results

The Aptiva APS IgG Reagent is an immunoassay utilizing particle-based multi-analyte technology for the semiquantitative determination of anti-cardiolipin (aCL) and anti-beta 2 glycoprotein 1 (all2GPI) IgG autoantibodies in human serum as an aid in the diagnosis of primary antiphospholipid syndrome (APS), when used in conjunction with other laboratory findings.

The Aptiva APS IgG Reagent is intended for use with the Aptiva System.

The Aptiva APS IgM Reagent is an immunoassay utilizing particle-based multi-analyte technology for the semiquantitative determination of anti-cardiolipin (aCL) and anti-beta 2 glycoprotein 1 (aß2GPI) IgM autoantibodies in human serum as an aid in the diagnosis of primary and secondary antiphospholipid syndrome (APS), when used in conjunction with other laboratory findings.

The Aptiva APS IgM Reagent is intended for use with the Aptiva System.

The Aptiva APS IgG and Aptiva APS IgM reagent utilize particle based multi-analyte technology (PMAT) in a cartridge format. Each analyte (anti-cardiolipin [aCL] and anti-B2-Glycoprotein I [aB2GPI]) in the Aptiva APS IgG and Aptiva APS IgM reagent is a solid phase immunoassay utilizing fluorescent microparticles. This technology allows each of the two analytes, along with a human IgG or human IgM capture antibody (IgG or IgM Control Microparticle), to be coated onto three uniquely recognizable paramagnetic microparticles, which are combined into one tube.

The Aptiva 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 two analyte microparticles, along with the control microparticle, are stored in the reagent cartridge under conditions that proteins 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 instrument, where the microparticles are automatically rehydrated using a buffer located within the cartridge.

The Aptiva System dilutes the sample 1:8, then combines an aliquot of diluted sample, and reagent into a cuyette. The mixture is incubated at 37°C. After a wash cvcle, conjugated antihuman IgG or IdM antibodies are added to the particles and this mixture is incubated at 37°C. Excess conjugate is removed in another wash cycle, and the particles are re-suspended in system fluid.

Multiple images are generated by the system to identify and count the two (2) unique analyte particles, as well as determine the amount of coniugate on each particle. Coated with goat anti-human lgG or IdM antibodies, is present as a control to flaq low concentrations of IgG or IgM in the sample as an assay verification step. The median fluorescent intensity (MFI) for each analyte is proportional to the concentration of conjugate bound to human IgG or IgM, which is proportional to the concentration of IgG or IgM antibodies bound to the corresponding particle population. The system uses the MFI from at least 50 particles of each population. The identity of the particles is determined by the unique signature of the particles.

Each analyte in the Aptiva APS IgG Reagent and the Aptiva APS IgM Reagent is assigned a predefined lot specific master curve. The analyte specific master curve is stored on the reagent cartridge RFID label. Based on results obtained by running calibrators (supplied separately), the system creates individual working curves. Working curves are used by the software to calculate Fluorescent Light Units (FLU) for each analyte from the MFI values obtained for each sample.

Aptiva APS IgG and Aptiva APS IgM Calibrators and Aptiva APS IgG and Aptiva APS IgM Controls are sold separately.

The provided text describes the analytical and clinical performance characteristics of the Aptiva APS IgG and Aptiva APS IgM Reagents, which are immunoassays for the semi-quantitative determination of anti-cardiolipin (aCL) and anti-beta 2 glycoprotein 1 (aβ2GPI) IgG/IgM autoantibodies. This information is presented in the context of a 510(k) premarket notification for FDA clearance.

Here's a breakdown of the requested information based on the provided text:

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

The document does not explicitly state "acceptance criteria" as a separate, quantified set of thresholds for each performance metric. Instead, it presents the results of various analytical and clinical studies, implying that these results met the internal criteria for substantial equivalence to predicate devices and overall performance claims for an in vitro diagnostic (IVD) device.

However, we can infer performance targets based on the presented data and the overall context of an FDA submission for an IVD. The primary performance metrics presented are related to precision, detection limits, linearity, interference, and clinical sensitivity/specificity.

Inferred Acceptance Criteria and Reported Device Performance (Summary)

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Clinical Performance Test Set Sample Sizes:

  • Aptiva APS IgG (aCL IgG & aβ2GPI IgG): N=526 (122 APS combined, 404 controls/non-APS)
  • Aptiva APS IgM (aCL IgM & aβ2GPI IgM): N=689 (291 APS combined, 398 controls/non-APS)
  • Normal Population for Expected Values: N=200 apparently healthy blood donors.

• Method Comparison Test Set Sample Sizes:

  • Aptiva APS IgG (aCL IgG vs. QUANTA Flash aCL IgG): N=202
  • Aptiva APS IgG (aβ2GPI IgG vs. QUANTA Lite Beta 2GP1 IgG ELISA): N=108
  • Aptiva APS IgM (aCL IgM vs. QUANTA Flash aCL IgM): N=422
  • Aptiva APS IgM (aβ2GPI IgM vs. QUANTA Flash β2GPI IgM): N=244

• Analytical Performance Test Set Sample Sizes:

  • Precision: 7 samples for IgG, 7 samples for IgM (80 replicates each for within-lab; 75 replicates each for between-site/lot reproducibility from multiple sites/lots).
  • LoB/LoD/LoQ: Blanks (LoB: 4 samples, 60 data points/lot); Low-level samples (LoD/LoQ: 4 samples, 120 data points/assay/lot).
  • Interference: 6 human specimens (negative, cutoff, positive) for each analyte, spiked with various interferents and tested in 5 replicates.
  • Sample Stability: 5 serum samples (IgG), 5 serum samples (IgM) tested in duplicates over time/cycles.
  • In-use Stability: 11 samples (IgG), 7 samples (IgM) tested periodically.

• Data Provenance: The document states that a "cohort of characterized samples, none of which were used for establishing the reference range, was used to validate the clinical performance." It does not explicitly state the country of origin of the data or whether the studies were retrospective or prospective. However, for a 510(k) submission, clinical validation studies typically involve retrospective or prospectively collected clinical samples, but the exact nature (e.g., specific clinical sites, patient populations beyond disease groups) and geographic origin are not detailed here. The studies were likely conducted within a controlled laboratory setting by the manufacturer (Inova Diagnostics, Inc. in San Diego, CA) or its affiliates, using sourced human serum samples.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

The establishment of "ground truth" for IVD devices like these typically relies on well-characterized clinical samples and established diagnostic criteria for the disease (Antiphospholipid Syndrome - APS).

• The document states that the clinical performance validation was performed using "a cohort of characterized samples." The characterization of these samples (i.e., whether they definitively represent APS or control) would serve as the ground truth.
• However, the document does not specify the number of experts or their qualifications (e.g., rheumatologists, clinical immunologists/pathologists) who established the diagnostic status (ground truth) of the clinical samples (APS vs. control) used in the clinical sensitivity and specificity studies. It is implied that these were "characterized samples," meaning their disease status was determined by established clinical and laboratory criteria, likely involving clinical consensus or previous diagnoses.
• For cut-off establishment, the reference population included "apparently healthy subjects," and the "internal APS samples (data not provided)" and "distribution of result values of healthy controls" were used. This suggests clinical characterization of these samples.

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

The concept of "adjudication method" (like 2+1 or 3+1) is typically relevant for interpretative tasks, such as reading medical images, where multiple human readers interpret the same data and their interpretations need to be reconciled to establish a ground truth.

For these types of IVD assays, ground truth for clinical performance is established based on the clinical diagnosis of the patient from whom the sample was collected. This diagnosis is usually a culmination of clinical findings, established criteria (e.g., the revised Sapporo criteria for APS), and other laboratory tests, rather than an "adjudication" of multiple independent interpretations of the test results themselves.

Therefore, the document does not mention any adjudication method in the context of establishing ground truth for the test samples, as it's not applicable in the same way it would be for an AI-medical imaging device. The "ground truth" for the samples (APS vs. non-APS) is assumed to be pre-established 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 MRMC study was conducted or is applicable here.

This device is an in vitro diagnostic (IVD) immunoassay, not an AI-powered image analysis or diagnostic aid that assists human readers (e.g., radiologists interpreting images). The device directly measures biomarker levels in a sample, and its output is a quantitative value (FLU) which then determines a semi-quantitative result (Positive/Negative/Indeterminate based on cut-offs). Human "readers" (laboratory personnel) operate the instrument and interpret the final quantitative results based on predefined cut-offs, but they are not subjectively interpreting complex data that AI would assist with, in the sense of an MRMC study.

Therefore, an MRMC comparative effectiveness study, and an effect size related to human reader improvement with AI assistance, are not relevant for this type of device and are not mentioned in the document.

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

This is a "standalone" device in terms of its core functionality, but the term "algorithm only" or "human-in-the-loop" isn't directly analogous.

• The Aptiva System is a fully automated, random-access analyzer (page 6). This means the instrument itself, with its integrated software and optical module, processes the samples, runs the reagents, and reports results independently after the sample is loaded and the assay initiated.
• The "performance" described here (sensitivity, specificity, precision, linearity, etc.) is the device's performance (including its internal algorithms and mechanics) in generating quantitative results. There isn't a separate "algorithm only" performance that needs to be differentiated from a "human-in-the-loop" performance, because the device is the automated system determining the FLU values. The human interaction is primarily in sample loading, reagent handling, and result review/reporting, not in interpreting raw data that the device itself would also interpret in an unassisted mode.

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

The ground truth for the clinical performance studies (sensitivity and specificity) was established based on "characterized samples" representing patients with Antiphospholipid Syndrome (APS) and various control groups (patients with other autoimmune/infectious diseases, apparently healthy subjects).

While the document doesn't explicitly state "expert consensus," it's highly implied that the "characterization" of these samples as APS or control would be based on:

• Clinical findings: Presenting symptoms, medical history.
• Other laboratory findings: Beyond the novel antibodies, other relevant diagnostic tests.
• Established diagnostic criteria: For APS, this would typically be the revised Sapporo classification criteria, which combine clinical and laboratory criteria.

So, it's a combination of established clinical diagnoses and potentially other laboratory data, which implicitly would involve the consensus or findings of medical experts involved in patient diagnosis. It is not based on pathology (e.g., tissue biopsy) or outcomes data (e.g., long-term disease progression as the sole ground truth).

8. The sample size for the training set

The document describes the submission of a "new device" and its performance characteristics. It does not explicitly mention or quantify a "training set" in the context of machine learning.

For IVD devices, a "training set" isn't a standard concept unless the device incorporates adaptive algorithms or AI that learns from data. In this case, the device is an immunoassay with predefined master curves and calibrated reagents. The master curves are generated "at Inova for each reagent lot, where in-house Master Curve Standards with assigned FLU values are run multiple times." These "in-house Master Curve Standards" could be considered analogous to a "training" or calibration process, but it's not a dataset for training a generalized AI model but rather for calibrating each reagent lot of a classical assay.

The sample sizes provided in the document are for:

• Analytical performance (precision, LoB/LoD/LoQ, linearity, interference, stability).
• Clinical validation (sensitivity/specificity studies).
• Method comparison studies.
• Reference range establishment.

None of these are explicitly labeled as a "training set."

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

As there is no explicitly defined "training set" for a machine learning model, the concept of establishing ground truth for such a set is not applicable here.

However, if we consider the "Master Curve Standards" as analogous to calibration/training data for the assay, their "ground truth" (assigned FLU values) would be established through a rigorous internal process by the manufacturer (Inova Diagnostics) based on:

• Carefully prepared and characterized aliquots (standards) with known or assigned concentrations of the target antibodies.
• Repeat measurements and statistical analysis for consistent and accurate assignment of FLU values.
• This is a standard practice for calibrating quantitative IVD assays, ensuring the device outputs accurate and traceable results.

Ask a specific question about this device

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.

Ask a specific question about this device

The Aptiva Celiac Disease IgG Reagent is an immunoassay utilizing particle-based multi-analyte technology for the semiquantitative determination of anti-tissue transglutaminase IgG autoantibodies and anti-deamidated gliadin peptide IgG autoantibodies in human serum. The presence of these antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of celiac disease and dermatitis herpetiformis, particularly in patients with selective IgA deficiency.

The Aptiva Celiac Disease IgG Reagent is intended for use with the Inova Diagnostics Aptiva System.

The Aptiva Celiac Disease IgG reagent utilizes particle based multi-analyte technology (PMAT) in a cartridge format. Each analyte (tissue transglutaminase [tTG] and deamidated gliadin peptide [DGP]) in the Aptiva Celiac Disease IgG reagent is a solid phase immunoassay utilizing fluorescent microparticles. This technology allows each of the two analytes, along with a human IgG capture antibody (IgG Control Microparticle), to be coated onto three uniquely recognizable paramagnetic microparticles, which are combined into one tube.

The Aptiva 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 two analyte microparticles, along with the control microparticle, are stored in the reagent cartridge under conditions that preserve the proteins 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 instrument, where the microparticles are automatically rehydrated using buffer located within the cartridge.

A patient's serum is diluted 1:23 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 small magnet that holds 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 one more time. 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 microparticles in the cuvette, and mixed. Again, the cuvette is incubated for 9 ½ minutes at 37℃. Three wash steps, as described above, are performed on the microparticles. Following the wash steps, the microparticles are transferred to the of the instrument, where a charge coupled device (CCD) camera takes multiple images in order to identify and count the three unique microparticle regions, as well as determine the amount of conjugate on the microparticles. The control microparticle, a third particle, coated with goat anti-human IgG, is included in the reagent in as a control to flag low concentrations of IgG 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 DGP IgG and tTG IgG assays (together as part of the Aptiva Celiac Disease IgG Reagent) each utilizes a predefined lot specific Master Curve that is uploaded onto the instrument through the reagent cartridge RFID tag. Every new lot of reagent cartridge must be calibrated before first use with the reagent specific calibrators. Based on the results obtained with the calibrators included in the Aptiva Celiac Disease IgG Calibrator kit (sold separately), an instrument specific Working Curve is created for each assay, which is used to calculate reported fluorescent light units (FLU) from the median fluorescent intensity (MFI) instrument signal obtained for each sample, on each of the two assays within the reagent.

Aptiva Celiac Disease IgG Calibrators and Aptiva Celiac Disease IgG Controls are sold separately.

The Aptiva Celiac Disease IgG Reagent kit contains the following materials:

One (1) Aptiva Celiac Disease IgG Reagent Cartridge, containing the following reagents for 200 determinations:

• a. Aptiva Celiac Disease IgG microparticle containing 3 unique microparticle regions coated with recombinant tissue transglutaminase, deamidated gliadin peptide, or goat antihuman IgG antibody.
• b. Assay buffer - colored pink, containing protein stabilizers and preservatives.
• C. PE Tracer IgG - phycoerythrin (PE) labeled anti-human IgG antibody, containing buffer, protein stabilizers and preservative.
• ð. Rehydration Buffer - containing protein stabilizers and preservatives.

This document describes the analytical and clinical performance of the Aptiva Celiac Disease IgG Reagent, an immunoassay for the semi-quantitative determination of anti-tissue transglutaminase IgG autoantibodies (tTG IgG) and anti-deamidated gliadin peptide IgG autoantibodies (DGP IgG) in human serum. This device is intended as an aid in the diagnosis of celiac disease and dermatitis herpetiformis.

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

1. Acceptance Criteria and Reported Device Performance

The document presents several analytical performance characteristics and their corresponding acceptance criteria, along with the reported performance values. The primary clinical acceptance criteria are related to sensitivity and specificity, and the agreement with a predicate device.

2. Sample Sizes and Data Provenance

• Test Set (Clinical Validation Set): A total of 515 characterized samples.
  • 171 samples from celiac disease patients.
  • 20 samples from patients with IgA deficient celiac disease.
  • 34 dermatitis herpetiformis patients.
  • 290 control samples from patients with various types of autoimmune and infectious diseases.
• Data Provenance: The document does not explicitly state the country of origin. Given it's an FDA submission, it's typically a mix of US and possibly international data, but this is not specified. The studies are retrospective as they use "characterized samples" from a "cohort."
• Precision and Reproducibility Studies: Between 75 to 80 replicates per sample for repeatability/precision and reproducibility studies. These numbers are for analytical performance, not clinical.
• LoB, LoD, LoQ: 120 data points were generated for each assay on each reagent lot for LoB and LoD studies. For LoQ, 120 data points per assay per reagent lot.
• Linearity: The number of dilutions and duplicates used is stated (e.g., 4 human serum samples for DGP IgG and 3 for tTG IgG serially diluted, assayed in duplicates).
• Interference: 3 human serum specimens (one positive, one near cut-off, one negative) were tested for each assay.
• Sample Stability: 6 samples for DGP IgG, 7 for tTG IgG (tested in duplicates).
• Reagent Stability: 3 lots of microparticle beads and 3 lots of PE Tracer IgG for accelerated stability. Real-time stability data from 2 different lots.
• Reference Range/Cut-off Establishment:
  • Reference Population: 192 subjects from various autoimmune/infectious disease groups (e.g., Crohn's Disease, Autoimmune Thyroid Disease, Rheumatoid Arthritis).
  • Celiac Disease Patients: 11 diagnosed celiac disease (CD) patient specimens were assayed to aid in cut-off determination.
  • Apparently Healthy Donors (Expected Values): 120 blood donors.

3. Number of Experts and Qualifications

• The document does not mention the number of experts used to establish the ground truth for the test set, nor their specific qualifications. It refers to "characterized samples" and "diagnosed celiac disease (CD) patient specimens," implying a pre-existing clinical diagnosis, but the process of how these characterizations were definitively made (e.g., biopsy confirmation, clinical consensus, expert review) is not detailed for the test set.

4. Adjudication Method

• The document does not describe any specific adjudication method for the test set. The samples are described as "characterized," suggesting that their disease status was already established prior to their use in the study, likely through standard clinical diagnostic procedures, but no expert review or consensus process for this specific study's set is detailed.

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

• Not Applicable. This is an in-vitro diagnostic (IVD) device, specifically an immunoassay for determining autoantibodies in serum. MRMC studies are typically performed for imaging diagnostic devices (e.g., AI for radiology) where human readers (e.g., radiologists) interpret images with and without AI assistance. This document describes the performance of a lab test that outputs a quantitative result (FLU) and a qualitative interpretation (positive/negative) and does not involve human interpretation of complex data in the same way an imaging AI device would.

6. Standalone Performance

• Yes, standalone performance was done. The entire study report describes the standalone performance of the Aptiva Celiac Disease IgG Reagent without human intervention beyond performing the test and interpreting the quantitative results per the device's defined cut-offs. The sensitivity, specificity, and agreement with predicate devices are measures of its standalone performance.

7. Type of Ground Truth Used

• The ground truth for the clinical validation was based on clinical diagnosis/characterization of the patient samples.
  • For celiac disease and dermatitis herpetiformis patients, they were "diagnosed" or "characterized." While not explicitly stated, the gold standard for celiac disease diagnosis usually involves intestinal biopsy with characteristic changes, alongside clinical symptoms and serology.
  • For the control group, patients were characterized with "various types of autoimmune and infectious diseases," implying a clinical diagnosis for these conditions to confirm they are not celiac disease.
  • For the cut-off determination, "diagnosed celiac disease (CD) patient specimens" were used in conjunction with a reference population.

8. Sample Size for the Training Set

• The document does not specify a separate "training set" in the context of an AI/machine learning model. This device is an immunoassay, which relies on chemical reactions and optical detection, not on a machine learning algorithm trained on large datasets in the conventional sense. The "training" in this context refers to the development and optimization of the assay's reagents and parameters, and the establishment of master curves and cut-offs. The data used for calibration and master curve generation (e.g., "in-house Master Curve Standards with assigned FLU values run multiple times," "Calibrators included in the Aptiva Celiac Disease IgG Calibrator kit") effectively serve a similar purpose to training/calibration data in general analytical chemistry.

9. How Ground Truth for Training Set was Established

• Given this is an immunoassay, the concept of "ground truth" for a training set (as defined for AI/ML) is not directly applicable. Instead, the assay's performance and "ground truth" are established through:
  • Calibration: Using Master Curve Standards with "assigned FLU values" (likely determined through extensive in-house characterization and reference methods).
  • Controls: Using Aptiva Celiac Disease IgG Controls with "lot specific values assigned."
  • Reference Materials: The development of the assay's antigens (recombinant tTG and deamidated gliadin peptide) and antibodies would have involved rigorous characterization against known reference materials and clinical samples during the assay development stages to ensure they correctly bind to their target autoantibodies.
  • Cut-off determination: As mentioned in point 7, this involved a reference population of 192 subjects and 11 diagnosed celiac disease patients to establish the 5.00 FLU cut-off.

Ask a specific question about this device

The Aptiva Celiac Disease IgA Reagent is an immunoassay utilizing particle-based multi-analyte technology for the semiquantitative determination of anti-tissue transglutaminase IgA autoantibodies and anti-deamidated gliadin peptide IgA autoantibodies in human serum. The presence of these autoantibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of celiac disease and dermatitis herpetiformis. The Aptiva Celiac Disease IgA Reagent is intended for use with the Inova Diagnostics Aptiva System.

The Aptiva Celiac Disease IgA reagent utilizes particle based multi-analyte technology (PMAT) in a cartridge format. Each analyte (tissue transglutaminase [tTG] and deamidated gliadin peptide [DGP]) in the Aptiva Celiac Disease IgA reagent is a solid phase immunoassay utilizing fluorescent microparticles. This technology allows each of the two analytes, along with a human IgA capture antibody (IgA Control Microparticle), to be coated onto three uniquely recognizable paramagnetic microparticles, which are combined into one tube.

The Aptiva 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 two analyte microparticles, along with the control microparticle, are stored in the reagent cartridge under conditions that preserve the proteins 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 instrument, where the microparticles are automatically rehydrated using buffer located within the cartridge.

A patient's serum is diluted 1:46 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 small magnet that holds 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 one more time. During the third wash, no system rinse is added after the aspiration step. After the third wash, phycoerythrin conjugated polyclonal anti-human IgA (known as PE Tracer IgA) is added to the microparticles in the cuvette, and mixed. Again, the cuvette is incubated for 9 ½ minutes at 37℃. Three wash steps, as described above, are performed on the microparticles. Following the wash steps, the microparticles are transferred to the of the instrument, where a charge coupled device (CCD) camera takes multiple images in order to identify and count the three unique microparticle regions, as well as determine the amount of conjugate on the microparticles. A third particle, coated with goat antibodies, is present in the reagent as a control to flag low concentrations of IgA in the 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 IgA, which is proportional to the amount of IgA antibodies bound to the corresponding microparticle regions.

For quantitation, the DGP IgA and tTG IgA assays (together as part of the Aptiva Celiac Disease IgA Reagent) each utilizes a predefined lot specific Master Curve that is uploaded onto the instrument through the reagent cartridge RFID tag. Every new lot of reagent cartridge must be calibrated before first use with the reagent specific calibrators. Based on the results obtained with the calibrators included in the Aptiva Celiac Disease IgA Calibrator kit (sold separately), an instrument specific Working Curve is created for each assay, which is used to calculate reported fluorescent light units (FLU) from the median fluorescent intensity (MFI) instrument signal obtained for each sample, on each of the two assays within the reagent.

Aptiva Celiac Disease IgA Calibrators and Aptiva Celiac Disease IgA Controls are sold separately.

The Aptiva Celiac Disease IgA Reagent kit contains the following materials:

One (1) Aptiva Celiac Disease IgA Reagent Cartridge, containing the following reagents for 250 determinations:

• a. Aptiva Celiac IgA microparticle containing 3 unique microparticle regions coated with recombinant tissue transglutaminase, deamidated gliadin peptide, or goat anti-human IgA antibody.
• b. Assay buffer - colored pink, containing protein stabilizers and preservatives.
• PE Tracer IgA phycoerythrin (PE) labeled anti-human IgA antibody, containing buffer, C. protein stabilizers and preservative.
• d. Rehydration Buffer - containing protein stabilizers and preservatives.

The provided text is a 510(k) Summary for the Aptiva Celiac Disease IgA Reagent, an in vitro diagnostic device. It describes the analytical and clinical performance of the device to demonstrate its substantial equivalence to predicate devices. It does not describe an AI/ML-based device, a comparative effectiveness study with human readers, or the establishment of ground truth by expert consensus. Therefore, most of the requested information cannot be extracted from this document as it pertains to AI/ML device studies.

However, I can extract the acceptance criteria and reported performance for analytical aspects of this specific in vitro diagnostic device, as well as details regarding sample size, data provenance, and the type of ground truth used for performance evaluation.

Acceptance Criteria and Reported Device Performance

The device under review is an in vitro diagnostic (IVD) test, not an AI/ML-based medical imaging device. As such, the acceptance criteria and performance evaluation are based on typical analytical validation parameters for immunological assays, such as precision, limit of detection, linearity, interference, and clinical sensitivity/specificity against established reference methods or patient diagnoses.

Table of Acceptance Criteria and Reported Device Performance:

Study Details:

1. Sample sizes used for the test set and data provenance:

   • Precision: 9 samples for DGP IgA, 10 samples for tTG IgA (run in duplicates, twice a day, for 20 days).
   • Reproducibility (Between Sites): 7 samples for DGP IgA and 6 samples for tTG IgA.
   • Reproducibility (Between Lots): 6 samples for DGP IgA and 6 samples for tTG IgA.
   • LoB, LoD, LoQ:
     • LoB: 8 blank samples. For each assay (DGP IgA & tTG IgA), on two reagent lots, run in replicates of 5, once per day for 3 days (120 data points per lot).
     • LoD & LoQ: 4 low-level samples for each assay (DGP IgA & tTG IgA). For each assay, on two reagent lots, run in replicates of 5, twice per day for 3 days (120 data points per assay per lot).
   • Linearity: 4 human serum samples for each assay, serially diluted and assayed in duplicates.
   • Interference: 3 human serum specimens (one positive, one near cutoff, one negative).
   • Sample Stability: 8 test samples for DGP IgA, 6 test samples for tTG IgA.
   • Clinical Performance (Validation Set): A total of 495 characterized samples.
     • 171 samples from celiac disease patients.
     • 34 dermatitis herpetiformis patients.
     • 290 control samples from patients with various types of autoimmune and infectious diseases (e.g., Rheumatoid Arthritis, Ulcerative Colitis, Crohn's Disease, Hepatitis C/B, Syphilis, Sjögren's Syndrome, Systemic Sclerosis, Autoimmune Gastritis, HIV, Systemic Lupus Erythematosus, Epstein-Barr Virus).
     • The document does not explicitly state the country of origin but implies data collection from clinical settings. It describes the use of "characterized samples" and "diagnosed celiac disease (CD) patient specimens," indicating that this was likely a retrospective collection of samples with established diagnoses.
   • Expected Values (Normal Population): 120 apparently healthy blood donors.
   • Method Comparison: All 495 samples from the clinical validation study were also used for method comparison against the predicate devices.

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

   • This is an IVD device, not an AI/ML imaging device. The "ground truth" for the test set (clinical validation cohort) was based on patient diagnoses (e.g., "celiac disease patients," "dermatitis herpetiformis," "control samples from patients with various types of autoimmune and infectious diseases"). Therefore, the ground truth was established by clinical diagnosis, which would typically be made by medical doctors/specialists based on relevant clinical findings and other laboratory tests, rather than by a specific number of experts reviewing image data. The document does not specify the number or qualifications of clinicians involved in establishing these diagnoses.

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

   • Not applicable, as this is an IVD test assessing biochemical markers, not an imaging device requiring expert adjudication of interpretations. The "ground truth" is the established clinical diagnosis of the patient.

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 imaging device, and no MRMC study was performed or is relevant to this type of IVD test.

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

   • The "standalone performance" of this device is represented by its analytical performance characteristics (precision, linearity, LoD, etc.) and its clinical sensitivity and specificity, where the device provides a quantitative result (FLU) to aid in diagnosis. There is no "human-in-the-loop" aspect to the performance of the device itself (it's an automated analyzer), though clinicians interpret its results in conjunction with other clinical findings.

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

   • The primary ground truth for the clinical performance evaluation was established clinical diagnoses of patients ("celiac disease patients," "dermatitis herpetiformis patients," and "control samples from patients with various types of autoimmune and infectious diseases"). This implicitly relies on a combination of clinical findings, potentially other laboratory tests, and possibly biopsy results (pathology) for definitive diagnoses like celiac disease. The document states, "The presence of these autoantibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of celiac disease and dermatitis herpetiformis."

7. The sample size for the training set:

   • This device is an immunoassay (particle-based multi-analyte technology) operating on predefined Master Curves and calibrations. It does not use a "training set" in the sense of machine learning algorithms. The Master Curves and calibrations are established by the manufacturer through runs of precisely quantified standards (e.g., "in-house Master Curve Standards," "reagent specific calibrators"). The section "Quantitation and units of measure" describes how these curves are generated. For example, "Aptiva Celiac Disease IgA Master Curve Standards - DGP IgA" lists 6 standards with assigned FLU values. While these could be seen as "training data" for the device's internal quantitation function, it's not a machine learning model.

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

   • Not applicable in an AI/ML context. For this IVD device, the "ground truth" for its internal calibration (analogous to a training set for an AI model) is based on manufacturer-defined standards with assigned known values ("in-house Master Curve Standards with assigned FLU values"). These standards are run multiple times to generate the 4-parameter logistic (4PL) curve that quantifies the analyte concentration.

Ask a specific question about this device

NOVA Lite® DAPI dsDNA Crithidia luciliae is an indirect immunofluorescent assay for the qualitative and/or semi-quantitative determination of anti-double stranded DNA (dsDNA) IgG antibodies in human serum by NOVA View Automated Fluorescence Microscope or manual fluorescence microscopy. The presence of anti-dsDNA can be used in conjunction with other serological and clinical findings to aid in the diagnosis of systemic lupus erythematosus (SLE). All results generated with NOVA View device must be confirmed by a trained operator.

The NOVA Lite DAPI dsDNA Crithidia luciliae Kit is an indirect immunofluorescence assay for the qualitative detection and semi-quantitative determination of Anti-dsDNA Antibodies (IgG) in human serum. Samples are diluted 1:10 in PBS and incubated with the antigen substrate (dsDNA on glass microscope slides). After incubation, unbound antibodies are washed off. The substrate is then incubated with antihuman IgG-FITC conjugate. The conjugate contains a DNA-binding blue fluorescent dye, 4',6-diamidino-2phenylindole (DAPI) that is required for NOVA View use. The blue dye is not visible by traditional fluorescence microscope at the wavelength where FITC fluorescence is viewed. Unbound reagent is washed off. Stained slides are read by manual fluorescence microscope or scanned with the NOVA View Automated Fluorescence Microscope. The resulting digital images are reviewed and interpreted from the computer monitor. dsDNA positive samples exhibit an apple green fluorescence corresponding to areas of the substrate where autoantibody has bound.

Here's a breakdown of the acceptance criteria and study details for the NOVA Lite DAPI dsDNA Crithidia luciliae Kit, based on the provided text:

Acceptance Criteria and Reported Device Performance

Study Details:

1. Sample sizes used for the test set and the data provenance:

   • Precision Study: 6 samples (2 negative, 2 borderline, 2 positive), each processed in triplicate across 14 runs (2 runs/day for 7 days), resulting in 42 data points per sample.
   • Reproducibility Studies (Between sites/instruments): 10 samples (3 negative, 7 positive), each tested in triplicate, twice a day for 5 days at each of 3 sites. This results in 30 data points per sample per site, or 90 data points per sample across all sites. Total data points for this study: 10 samples * 30 data points/sample * 3 sites = 900 data points.
   • Reproducibility (Between lots): 20 clinically and/or analytically characterized samples, tested in duplicate.
   • Linearity Study: 3 positive samples (high, medium, low), serially diluted from 1:10 up to 1:5120. (Number of replicates not specified for this part, but results are given for each dilution).
   • Interference Study: 3 specimens (one negative, one positive, one strong positive) for each interferent, with interfering substances spiked at three different concentrations in 10% of total specimen volume. Samples assessed in triplicates.
   • Sample Stability and Handling: 3 samples (negative, cut-off, positive), tested in duplicates for various conditions (up to 21 days at 2-8°C, up to 48 hours at room temperature, up to 3 freeze/thaw cycles).
   • Reagent Stability (Shelf-life): 3 lots of the kit, tested over 4 weeks accelerated stability (each week = 6 months real time). Real-time stability data was available up to 24, 15, and 19 months for the respective lots at the time of submission.
   • Reagent Stability (In-use/Open Vial): Not detailed how many units/tests were performed each week for 8 weeks.
   • Clinical Performance (Initial Study): 766 clinically characterized serum samples (391 SLE, 375 other diseases). No explicit country of origin is stated, but given this is an FDA submission for Inova Diagnostics, Inc. in San Diego, California, it is reasonable to infer a US-centric data provenance. The study appears to be retrospective based on "clinically characterized serum samples."
   • Clinical Performance (3 Sites Study): 269 clinically characterized samples tested at three sites. Total for reporting: 100 positive (SLE) and 169 negative (non-SLE) per site. The samples comprise 300 SLE and 507 non-SLE clinical diagnoses in total across the three sites. The data provenance is likely multi-center, potentially within the US. The description "clinically characterized samples" suggests these were collected and diagnosed prior to the study, implying a retrospective nature.
   • Expected Values: 120 samples from apparently healthy subjects (60 females, mean age 41, range 18-73).
   • Comparison with Predicate Device: The same 744 serum samples used in the initial clinical study (391 SLE, 353 other diseases).
   • SWT Validation: 31 positive samples for initial validation. 7 positive samples in the between-sites reproducibility study.

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

   • For clinical studies: The ground truth for the clinical studies is stated as "clinically characterized serum samples" and "clinical diagnosis." This implies that the samples were obtained from patients with established diagnoses, likely made by medical professionals (e.g., rheumatologists for SLE patients). The text does not specify the number of experts or their exact qualifications (e.g., "Radiologist with 10 years of experience" is not mentioned, as this is an immunoassay, but rather "clinicians" or "diagnosticians").
   • For analytical studies (Precision, Reproducibility, Linearity, Interference, Stability): The ground truth (Expected Result/Expected Grade) for the control samples or known samples was established by the manufacturer, often based on previous characterization or established laboratory practices. The interpretation of "Manual Reading" and "Digital Reading" results are performed by "trained operators."

3. Adjudication method for the test set:

   • For analytical results (Precision, Reproducibility, Linearity, Interference, Stability): The text mentions that "Digital images were interpreted and confirmed" in multiple sections (e.g., Linearity, Interference, Sample Stability). For the "Reproducibility Studies (Between sites/instruments)", manual and digital reading was performed by "two operators at each site, to assess between operator reproducibility." The acceptance criteria then focus on agreement percentages between operators. This implies that if disagreements occurred, they were likely adjudicated to reach the "Summary" percentages. However, a specific formal adjudication method like "2+1" or "3+1" is not explicitly stated.
   • For clinical results: The clinical samples were "clinically characterized," meaning their diagnosis served as the ground truth. There's no indication of an adjudication process for these clinical diagnoses within the context of this device study.

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:

   • This is not a traditional MRMC comparative effectiveness study involving AI assistance improving human readers. The study compares three modes of interpretation:
     • Manual Reading: Human interpretation using a traditional fluorescence microscope.
     • Digital Reading: Human interpretation of NOVA View generated images on a computer monitor.
     • NOVA View (Software): Automated interpretation by the device's software (algorithm only), which is then confirmed by a trained operator.
   • Therefore, the setup is more of a comparison between manual microscopy, human interpretation of digital images, and the device's automated output. The device itself (NOVA View) is not presented as an AI-assistance tool for human readers but as an alternative interpretation method that still requires human confirmation.
   • The "effect size of how much human readers improve with AI vs without AI assistance" is not directly measured in this context because the "NOVA View" results are the algorithm's output, not a human reader assisted by the algorithm. The "Digital Reading" is human interpretation of the images produced by the NOVA View device, which might be considered an "assisted" or "different modality" reading but not in the typical AI-driven improvement sense.

   Let's look at sensitivity/specificity to show the comparison between manual, digital (human on digital images), and NOVA View (algorithm):

   Initial Clinical Study (N=766)

   • Sensitivity (on SLE):
     • Manual: 48.1% (43.2-53.0)
     • Digital: 48.1% (43.2-53.0)
     • NOVA View: 57.0% (52.1-61.8)
   • Specificity:
     • Manual: 91.2% (87.9-93.7)
     • Digital: 92.3% (89.1-94.6)
     • NOVA View: 88.8% (85.2-91.6)

   Clinical Studies 3 Sites (N=807)

   • Sensitivity (on SLE):
     • Manual Reading: 32.7% (27.6-38.2)
     • Digital Reading: 34.0% (28.9-39.5)
     • NOVA View: 40.0% (34.6-45.6)
   • Specificity:
     • Manual Reading: 95.5% (93.3-97.0)
     • Digital Reading: 95.5% (93.3-97.0)
     • NOVA View: 85.4% (82.1-88.2)

   In both clinical studies, the NOVA View algorithm demonstrates higher sensitivity for SLE detection compared to manual or digital human readings, but lower specificity. This highlights a performance difference, not an improvement of human readers with AI assistance.

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

   • Yes, the "NOVA View" performance reported in the tables (e.g., sensitivity, specificity, qualitative agreements in reproducibility studies) represents the standalone algorithm's performance.
   • The text explicitly states: "All results generated with NOVA View device must be confirmed by a trained operator." This indicates that while the software generates automated classifications, the final clinical interpretation includes a human-in-the-loop for confirmation. The reported performance metrics for "NOVA View" specifically reflect the device's automated output.

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

   • Clinical Ground Truth: "Clinical diagnosis" for patient-derived samples (e.g., Systemic Lupus Erythematosus (SLE), Drug Induced Lupus, Infectious Disease, etc.). This is likely based on a combination of clinical findings and serological tests by clinicians. It is stated as "clinically characterized serum samples."
   • Analytical Ground Truth: For the precision, reproducibility, linearity, interference, and stability studies, the "Expected Result" or "Expected Grade" for the tested samples serves as the ground truth. These are typically reference materials or well-characterized samples with known positive/negative status or reactivity grades established by the manufacturer.

7. The sample size for the training set:

   • The document does not explicitly state the sample size of a training set for the NOVA View algorithm. It describes validation studies (test sets) for the kit and the performance of the NOVA View device, but not how the algorithm itself was developed or trained.
   • What is mentioned is that for the SWT (Single Well Titer) feature, "The SWT function was established using 22 dsDNA positive samples that represent various levels of antibodies." However, this refers to establishing the intensity curves for titer determination, not necessarily a broad 'training set' for the overall positive/negative classification logic or image analysis.

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

   • As the training set size is not stated, neither is the method for establishing its ground truth.
   • For the 22 dsDNA positive samples used to establish SWT intensity curves, it is implied that manual and digital readings (human interpretations) served as comparison points for establishing the LIU (Light Intensity Units) to titer relationship. The validation of SWT compares its output to manual and digital end-point titers.

Ask a specific question about this device

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).

Ask a specific question about this device

The Fecal Extraction Device is a single use tube containing extraction buffer intended for sampling and extracting human stool specimens and subsequent analysis with the QUANTA Flash Calprotectin assay.

The Fecal Extraction Device acquires the amount of stool necessary to perform the QUANTA Flash Calprotectin assay directly from the primary specimen container instead of weighing the sample. The device consists of a tube, containing 2.8 mL of extraction buffer, and a stick shaped with seven grooves for collecting the sample. The upper end of the device is made up of two parts which can be removed with two separate rotations: the white screw cap (connected to the plastic stick with grooves) is removed by twisting counter-clockwise. The red lower part (for retaining the excess material) is removed by twisting clockwise. Once having completed the extraction procedure, remove both the white and red upper parts. The tube containing the extracted sample can be placed directly into the BIO-FLASH instrument sample rack.

The Fecal Extraction Device is intended for sampling and extracting human stool specimens for subsequent analysis with the QUANTA Flash Calprotectin assay. The device underwent several validation studies to demonstrate its performance and substantial equivalence to the predicate device (QUANTA Flash Calprotectin using manual extraction).

1. Table of Acceptance Criteria and Reported Device Performance

Stool Extraction Method Comparison: Fecal Extraction Device vs. Manual Weighing Method

Device Validation (Amount of Fecal Material Collected)

Extraction Reproducibility

Sample Stability and Handling (Extracted Samples)

Fecal Extraction Device Stability (Shelf Life - Real Time Stability)

Stability at Room Temperature (Fecal Extraction Device)

2. Sample Sizes and Data Provenance

• Stool Extraction Method Comparison Test Set: 97 human stool samples.
• Device Validation (Fecal Material Collection): 5 different human stool samples, tested in replicates of five.
• Extraction Reproducibility: 8 samples, with 75 data points per sample (replicates of 5, once a day for 5 days, by 3 independent operators).
• Sample Stability and Handling: 7 human stool samples (n=1 indeterminate, n=2 around cut-off, n=4 positive).
• Fecal Extraction Device Functionality at Expiration: 15 human stool samples (n=11 negative, n=2 indeterminate, n=1 around cut-off, n=1 positive).
• Fecal Extraction Device Stability at Room Temperature: 6 human stool samples (lots 2 and 3: n=1 indeterminate, n=1 around cut-off, n=3 positive; lot 1: n=1 indeterminate, n=1 around cut-off, n=4 positive).

Data Provenance: The document does not explicitly state the country of origin for the human stool samples. Given "Inova Diagnostics, Inc." is located in "San Diego, CA, 92131", it can be inferred that the studies were likely conducted in the United States. The studies are described as analytical performance characteristics, implying they are laboratory-based investigations evaluating the device's technical specifications rather than clinical trials for diagnostic accuracy with patient outcomes. The term "human stool samples" suggests these are clinical specimens, but whether they are retrospective or prospectively collected for the purpose of the study is not specified, though typically such analytical studies would use prospectively collected or banked specimens.

3. Number of Experts and Qualifications

• No information is provided regarding the use of experts to establish a "ground truth" for the test sets in the typical sense of medical image interpretation or clinical diagnosis. The studies focus on analytical performance characteristics (e.g., comparison of extraction methods, precision, stability) where the "ground truth" is typically the measured value from a reference method or a known target value.
• For the reproducibility study, "three independent operators" were involved in performing extractions, but their specific qualifications beyond being "operators" are not detailed.

4. Adjudication Method

• No adjudication method is described as these studies focus on quantitative analytical performance rather than diagnostic interpretation where adjudication by multiple experts would be common. The "Stool Extraction method comparison" uses a statistical method (Passing-Bablok fit) to compare results from the new device against a manual weighing method. Replicates were used for precision studies, but not for settling disputes between reader interpretations.

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

• No MRMC comparative effectiveness study was performed. The document describes a comparison between two extraction methods (Fecal Extraction Device vs. Manual weighing method) and various performance characteristics of the Fecal Extraction Device itself. This is an analytical device for sample preparation, not a diagnostic imaging or interpretative AI device that typically undergoes MRMC studies to assess human reader improvement with AI assistance.

6. Standalone (Algorithm Only) Performance

• The studies described are for the "Fecal Extraction Device," which is a physical device for sample preparation, not a standalone software algorithm or AI. Its performance is evaluated in conjunction with the QUANTA Flash Calprotectin assay. The comparison study directly assesses the performance of the extraction device alone against a reference extraction method.

7. Type of Ground Truth Used

• For the "Stool Extraction method comparison," the ground truth is implicitly the quantitative calprotectin concentration obtained using the "manual weighing method," which serves as the reference method.
• For "Device Validation" (fecal material collection), the ground truth is the measured weight of the collected fecal material, with an expected target range of 56 mg ± 10%.
• For "Reproducibility Studies," the ground truth is the mean calprotectin concentration values of the samples, against which the precision (SD and %CV) of repeated measurements is assessed.
• For "Stability Studies," the ground truth for extracted sample stability is the initial measurement (time zero/zero cycles) or the pH of fresh devices for device stability, against which recovered concentrations or pH values are compared over time/conditions.

8. Sample Size for the Training Set

• The document describes validation studies for a medical device (Fecal Extraction Device), not an AI or machine learning algorithm. Therefore, there is no concept of a "training set" in the context of the provided information.

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

• As there is no training set for an AI/ML algorithm involved, this question is not applicable.

Ask a specific question about this device

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.

Ask a specific question about this device

QUANTA Flash Calprotectin is a chemiluminescent immunoassay for the quantitative determination of fecal calprotectin in extracted human stool samples. Elevated levels of fecal calprotectin, in conjunction with clinical findings and other laboratory tests, can aid in the diagnosis of inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease), and in the differentiation of IBD from irritable bowel syndrome (IBS).

QUANTA Flash Calprotectin Calibrators are intended for use with the QUANTA Flash Calprotectin Reagents for the determination of fecal calprotectin levels in extracted stool samples. Each calibrator establishes a point of reference for the working curve that is used to calculate unit values.

QUANTA Flash Calprotectin Controls are intended for use with the QUANTA Flash Calprotectin Reagents for quality control in the determination of fecal calprotectin levels in extracted stool samples.

QUANTA Flash Calprotectin Extraction Buffer is intended for use with the QUANTA Flash Calprotectin Reagents as sample extraction solution.

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

Calprotectin-specific capture antibodies are coated on to paramagnetic beads, which are stored in the reagent cartridge under conditions that preserve the antibody in its reactive state. Prior to use in the BIO-FLASH® system, the reagent pack containing all the necessary assay reagents is mixed thoroughly by being inverted several times. The sealed reagent tubes are pierced with the reagent cartridge lid, and the reagent cartridge is loaded onto the instrument. Reagents are calibrated when the lot is first used. A patient extracted stool sample is prediluted by the BIO-FLASH® with sample buffer in a disposable plastic cuvette. Small amounts of the diluted patient extracted stool, the beads, and the 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 monoclonal 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 measured RLU is proportional to the amount of bound isoluminol conjugate, which is in turn proportional to the amount of calprotectin antigen captured by the antibodies (anti-calprotectin polyclonal antibodies in this case) on the beads. For quantitation, the QUANTA Flash® Calprotectin will utilize a predefined lot specific Master Curve that is uploaded onto the instrument through the reagent cartridge barcode. The Master Curve is generated by Inova Diagnostics for each reagent pack lot with in-house Standards with assigned unit values (ng/mL). The RLU and assigned ng/mL values of the Standards are used to create a 4 parameter logistic curve. These four parameters are embedded in the reagent pack barcode. When the lot is used the first time, the Calibrators are run, and based on the results obtained on the Calibrators, an instrument specific Working Curve is created; The Working Curve is used to calculate units (ng/mL) based on RLU values obtained on each sample. The obtained ng/mL values will be converted to mg/kg by a calculation that takes into account the dilution of the samples. This unit conversion is calculated automatically by the software.

Here's an analysis of the provided text, extracting the requested information about acceptance criteria and the study proving device performance:

1. Table of Acceptance Criteria and Reported Device Performance

The device is an in vitro diagnostic (IVD) test system, so performance metrics like sensitivity and specificity are evaluated, alongside analytical performance criteria common for laboratory assays.

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

• Clinical Performance Test Set:

  • Sample Size: A total of 165 characterized samples were included in the validation set.
  • Data Provenance: Samples came from studies performed at two different sites (Site A and Site B) and a commercial source.
    • Site A: Samples 1 to 107. Inclusion criteria for IBD patients included suspicion of IBD, a calprotectin test request, and underwent ileocolonoscopy. Patients diagnosed with IBD or without ileocolonoscopy were excluded.
    • Site B: Samples 108 to 175. Sixty-eight consecutive samples requested for a calprotectin determination test by a gastroenterologist. Patients with excessive mucous, unclear diagnosis, or without colonoscopy were excluded.
  • Retrospective/Prospective: The description implies a retrospective collection of "characterized samples" from previously conducted studies or existing cohorts. For Site A, samples were "recruited over a period of 6 months," suggesting prospective collection during that period, but then used retrospectively for this validation. For Site B, "consecutive samples requested" also suggests a retrospective collection from a past clinical workflow.

• Method Comparison Test Set:

  • Sample Size: 137 samples out of the 165 clinical validation study samples. Of these, 77 samples fell within the AMR of both assays.
  • Data Provenance: Same as the clinical performance test set (two sites and commercial source).

• Precision and Reproducibility Studies: Sample numbers are specified per study (e.g., 8 samples for within-laboratory precision, 8 samples for between-sites, 8 samples for between-lots, 5 samples for extraction reproducibility). These are generally manufactured or spiked samples, not from patients.

• LoD/LoQ: 2 low-level samples for LoQ, 60 blank samples and 60 low-level samples (per lot) for LoD.

• Linearity: Three extracted stool samples and three recombinant antigen samples.

• Recovery: Seven extracted stool samples.

• Interference: Six human stool specimens (one high positive, one moderately positive, one low positive, one near cut-off, one indeterminate, one negative).

• Sample Stability: Eight extracted human stool samples (negative, indeterminate, around cut-off, positive) and three extracted stool samples (indeterminate, around cut-off, high positive) for frozen stability.

• Reference Range Establishment: 61 subjects (presumably healthy donors and some with specific benign conditions).

• Expected Values (Normal Population): 164 apparently healthy stool donors.

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

• Clinical Performance Ground Truth:

  • For IBD diagnosis at Site A, "Senior gastroenterologists performed all endoscopies and findings were documented in a computer-based database. The final diagnosis of IBD (i.e. CD and UC) was independently made by a pathologist or gastroenterologist who was blinded for calprotectin results." This indicates multiple Senior Gastroenterologists and Pathologists/Gastroenterologists were involved. Specific years of experience are not mentioned, but "Senior" implies significant experience.
  • For IBD diagnosis at Site B, "Patients were diagnosed after exclusion of organic pathology on the basis of routine blood tests, thyroid function tests, serological screening for coeliac disease, stool examination for bacteria and parasites, ultrasound examination, and eventually colonoscopy using the ROME III criteria. The diagnosis of IBD was made upon clinical, endoscopic and histological findings as described in J Crohn Colitis 2012:6: 965-990 (ulcerative colitis) and J Crohn Colitis 2010:4:7-27 (Crohn's disease)." This implies multiple Gastroenterologists and Pathologists following established diagnostic guidelines.

• Reference Range Establishment: For the 61 subjects used to establish the cut-off, the description indicates they were "apparently healthy donors" or had specific benign conditions (e.g., Squamous Cell Carcinoma, Glandular Polyp, Hyperplastic Polyp, Adenoma). The diagnosis here would be based on standard clinical and pathological evaluations, though specific experts for this ground truth are not detailed.

4. Adjudication Method for the Test Set

• For the IBD diagnosis at Site A, the final diagnosis was "independently made by a pathologist or gastroenterologist who was blinded for calprotectin results." This suggests a consensus-based approach or review by independent experts, but a specific (e.g., 2+1, 3+1) method is not explicitly stated. The term "independently made" implies that the diagnosis of IBD (considered the ground truth) was confirmed by one or more experts who were shielded from the calprotectin results.

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

• No, an MRMC comparative effectiveness study involving human readers with and without AI assistance was not done. This device is an automated in vitro diagnostic test (chemiluminescent immunoassay) for measuring fecal calprotectin, not an AI-powered image analysis or decision support system that directly assists human readers in real-time interpretation. The studies focus on the analytical and clinical performance of the assay itself compared to a predicate device or clinical diagnosis.

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

• Yes, performance metrics like precision, reproducibility, LoD, LoQ, linearity, recovery, interference, and stability are all "standalone" performance measures of the device itself (its reagents and instrument) without human-in-the-loop directly influencing the measurement result.
• The "Clinical Performance Characteristics" (sensitivity, specificity) are also standalone performance data for the device's ability to differentiate IBD from controls, given a clinical ground truth.
• The "Comparison with predicate device" also serves as a standalone comparison of the new device against an existing, legally marketed device.

7. Type of Ground Truth Used

• Clinical Performance / Clinical Validation: The ground truth for IBD diagnosis was established through comprehensive medical work-up, including "clinical findings and other laboratory tests," "endoscopic and histologic analysis, radiologic work-up and laboratory tests including ileocolonoscopy" (Site A), and "exclusion of organic pathology on the basis of routine blood tests, thyroid function tests, serological screening for coeliac disease, stool examination for bacteria and parasites, ultrasound examination, and eventually colonoscopy using the ROME III criteria" (Site B). This is robust clinical diagnosis/outcomes data, supported by pathology and endoscopy.
• Analytical Performance (e.g., LoD, LoQ, Linearity, Recovery, Interference, Stability): The ground truth for these studies involves pre-defined concentrations of calprotectin (e.g., recombinant calprotectin antigen, spiked samples) or known conditions (e.g., specific concentrations of interferents, different storage temperatures/durations). This is essentially known concentrations/states as ground truth.
• Reference Range / Cut-off: The cut-off was established based on a reference population (61 subjects) and further informed by 31 diagnosed IBD patients. The definition of "negative," "indeterminate," and "positive" ranges are based on statistical analysis of these populations and clinical considerations.

8. Sample Size for the Training Set

The document does not explicitly describe a "training set" in the context of an AI/machine learning model. The device is a chemiluminescent immunoassay run on an automated instrument.

However, the "Master Curve" for the assay is established during manufacturing using "in-house Standards with assigned unit values". This master curve can be considered analogous to a foundational calibration or "training" for the assay's quantitative functionality.

• Master Curve Standards: Seven calprotectin standards (0.0 ng/mL to 3478.3 ng/mL) are used to create the lot-specific Master Curve. The number of samples for generating this master curve is not explicitly stated beyond "7 Standards", but it is a manufacturing process.
• Calibrators and Controls Value Assignment: Calibrators and controls are assigned values by testing on at least two instruments, on at least two lots of reagent cartridge, in replicates of 5 to obtain a minimum of 10 data points. This process of value assignment, while not for an AI training set, is how the reference values are established for the functional units of the assay.

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

As noted above, there isn't a traditional "training set" for an AI model. For the functional calibration of the assay:

• Master Curve Ground Truth: The "Master Curve Standards" are "in-house Standards with assigned unit values (ng/mL)." This effectively means the ground truth for the Master Curve is based on traceable, pre-assigned concentrations of calprotectin.
• Calibrators and Controls Ground Truth: The "Calibrator and Control values are directly traceable to the in-house Standards that are used to create the Master Curves for the QUANTA Flash Calprotectin assay." This means their ground truth is rooted in the same pre-assigned values of the in-house standards.

Ask a specific question about this device

QUANTA Flash LKM-1 is a chemiluminescent immunoassay for the semi-quantitative determination of IgG anti-liver/ kidney microsome type 1 antibodies in human serum. The presence of anti-liver/kidney microsome type 1 antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of autoimmune hepatitis type 2.

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

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

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

Recombinant cytochrome P450 2D6 (LKM-1) 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 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-LKM-1 antibodies bound to the corresponding beads.

For quantitation, the QUANTA Flash LKM-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 LKM-1 Calibrators. Based on the results obtained with the three 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 LKM-1 Reagents kit contains the following materials:

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

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

• a. LKM-1 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 LKM-1 Calibrators kit contains two vials each of Calibrator 2, and Calibrator 3:

QUANTA Flash LKM-1 Calibrators:

• । QUANTA Flash LKM-1 Calibrator 1: Two (2) barcode labeled tubes containing 0.3 mL prediluted, ready to use reagent. Calibrators contain human antibodies to LKM-1 in stabilizers and preservatives.
• -QUANTA Flash LKM-1 Calibrator 2: Two (2) barcode labeled tubes containing 0.3 mL prediluted, ready to use reagent. Calibrators contain human antibodies to LKM-1 in stabilizers and preservatives.
• -QUANTA Flash LKM-1 Calibrator 3: Two (2) barcode labeled tubes containing 0.3 mL prediluted, ready to use reagent. Calibrators contain human antibodies to LKM-1 in stabilizers and preservatives.

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

QUANTA Flash LKM-1 Controls:

• । QUANTA Flash LKM-1 Negative Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human antibodies to LKM-1 in stabilizers and preservatives.
• । QUANTA Flash LKM-1 Positive Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human antibodies to LKM-1 in stabilizers, and preservatives.

This document describes the regulatory submission for the QUANTA Flash® LKM-1 Reagents, Calibrators, and Controls, a chemiluminescent immunoassay used for the semi-quantitative determination of IgG anti-liver/kidney microsome type 1 antibodies in human serum. This product aids in the diagnosis of autoimmune hepatitis type 2 (AIH-2) when used with clinical findings and other laboratory tests.

1. Table of Acceptance Criteria and the Reported Device Performance

The acceptance criteria are generally implied within the performance studies described in the document, rather than explicitly stated in a single summarized table. The document provides detailed performance data for analytical and clinical characteristics. Here's a partial summary based on the provided information, focusing on quantifiable metrics:

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

• Clinical Performance Validation Set: A total of 633 characterized samples were used. Data provenance is not explicitly stated (e.g., country of origin, retrospective/prospective), but the samples were "characterized."
  • This set included 26 AIH-2 patients and 607 control samples from various patient groups (e.g., AIH-1, PBC, HCV, SLE, rheumatoid arthritis, apparently healthy blood donors).
• Method Comparison Test Set: 334 samples from the clinical validation study, plus an additional 10 pooled samples around the cutoff, totaling 344 samples.
  • Data provenance not explicitly stated, but tied to the clinical validation study.
• Precision Test Set: 8 samples, analyzed over 20 days.
• Reproducibility (Between Sites) Test Set: 5 samples, tested at three different sites.
• Reproducibility (Between Lots) Test Set: 4 samples, tested using three different lots.
• LoD/LoB Test Set: 240 determinations (60 blank, 60 low-level per reagent lot), across 2 reagent lots.
• AMR/Linearity Test Set: 6 serum samples.
• Interference Test Set: 6 specimens (high positive, moderately positive, low positive, two near cutoff, negative) plus 4 additional samples (negative, two around cutoff, low positive) for corticosteroid interference.
• Sample Stability Test Set: 4 samples (negative, around cut-off, positive).
• Reference Range Establishment: 242 subjects (120 apparently healthy, 20 celiac, 31 rheumatoid arthritis, 30 infectious disease, 39 liver diseases, 2 myositis).

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience):

The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the clinical validation or method comparison test sets. It refers to "characterized samples" and "diagnosed AIH-2 patient specimens," implying a pre-existing clinical diagnosis, but details on the diagnostic process or expert involvement are not provided.

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

The document does not mention an adjudication method for establishing ground truth for the test set.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

This device is an in-vitro diagnostic (IVD) immunoassay, not an AI-based imaging or diagnostic tool intended for human reader assistance. Therefore, an MRMC comparative effectiveness study involving human readers with and without AI assistance is not applicable and was not performed.

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

The device (QUANTA Flash® LKM-1 Reagents, Calibrators, Controls) is a fully automated chemiluminescent immunoassay system (BIO-FLASH® instrument) that processes samples and reports results without human intervention in the analytical steps. So, yes, it performs as a standalone algorithm-only system for generating quantitative results from patient samples. The interpretation of these results in a clinical context would involve a physician.

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

The ground truth used for the clinical performance validation was primarily based on clinical diagnoses (e.g., "Autoimmune Hepatitis type 2 (AIH-2)" patients, "Controls" from various disease groups or apparently healthy). For defining the cutoff, diagnosed AIH-2 patient specimens were used in conjunction with a reference population. It is implied that these diagnoses would have been established through a combination of clinical assessment, other laboratory tests, and potentially biopsy/pathology, but the specific details are not provided.

8. The sample size for the training set:

The document does not explicitly mention a "training set" in the context of machine learning or AI algorithm development, as this is an immunoassay kit. However, the development of the assay involved internal "Master Curve Standards" (5 standards) and "Calibrators and Controls" (3 calibrators, 2 controls), which are essentially used to establish the assay's performance characteristics and enable quantitation. The calibrators had their values assigned by testing on "at least two instruments, on at least two lots of reagent cartridge, in replicates of 5 to obtain a minimum of 10 data points."

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

For the "training" equivalent (i.e., assay development and calibration), the ground truth for the LKM-1 Master Curve Standards, Calibrators, and Controls was established internally by the manufacturer.

• Master Curve Standards: The "Master Curve for QUANTA Flash LKM-1 consists of 5 Standards. These Master Curve Standards are used to create the lot specific Master Curve during the manufacturing procedure." They have assigned CU values (0.0, 6.4, 25.6, 102.4, 409.8 CU).
• Calibrators and Controls: These are manufactured by diluting human serum containing high titers of antibodies with stabilizer and preservative. The "target CU is achieved through trial dilutions on small scale. Once a dilution is selected, the Calibrators and Control are bulked, tested, and adjusted." Final value assignment is determined by testing on multiple instruments and reagent lots. "Calibrator and Control values are directly traceable to the in-house Standards that are used to create the Master Curves."

Ask a specific question about this device