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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."

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The EUROIMMUN Anti-LKM-1 ELISA (IgG) test kit is intended for the qualitative detection of IgG class autoantibodies against LKM-1 (cytochrome P450 IID6 of liver-kidney-microsomes) in human serum and plasma. It is used as an aid in the diagnosis of autoimmune hepatitis, type 2, in conjunction with other laboratory and clinical findings.

The EUROIMMUN Anti-LKM-1 ELISA (IgG) consists of a microwell ELISA plate coated with LKM-1 antigen, calibrator, positive and negative control, peroxidase-labelled anti-human IgG conjugate, sample buffer, wash buffer concentrate, TMB chromogen/substrate solution and stop solution.

Here's a summary of the acceptance criteria and study details for the EUROIMMUN Anti-LKM-1 ELISA (IgG) device, based on the provided text:

Acceptance Criteria and Device Performance

Study Details

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

   • Method Comparison with Predicate Device:
     • Sample Size: 196 total samples (167 initial samples + 29 additional samples created by mixing positive and negative samples).
     • Provenance: "A study was performed in cooperation with a university clinical hospital". Country of origin is not specified, but the context implies it's likely within the same regulatory region as the applicant (EUROIMMUN US INC.), possibly the US or Europe. The study type appears to be retrospective, using a pre-existing collection of samples from different patient groups.
     • Sample Breakdown: 58 from AIH patients, 66 from PBC patients, 15 from AIH/PBC overlap syndrome patients, and 28 from patients with viral hepatitis. 30 men and 137 women, age 1-87 years (average 50 years).
   • Matrix Comparison:
     • Sample Size: 16 sample pairs (serum and corresponding plasma for EDTA, Heparin, and Citrate plasma).
     • Provenance: Not explicitly stated, but likely from a laboratory setting as part of an analytical validation. Retrospective.
   • Clinical Studies (Sensitivity and Specificity):
     • Sample Size: 515 clinically characterized samples.
     • Provenance: "Performed in cooperation with several university, hospital and private laboratories". Country of origin not specified, but likely multi-center. Retrospective.
     • Sample Breakdown: 68 from AIH-2 patients, 65 from AIH-1 patients, 15 from AIH/PBC overlap syndrome patients, and 367 from other control groups (Viral hepatitis, Toxic liver damages, Steatohepatitis, PBC, PSC, Other autoimmune diseases: MCTD, celiac disease, Diabetes Type I, Hashimoto, Grave's disease, ulcerative colitis).
   • Expected Values/Reference Range:
     • Sample Size: 150 apparently healthy blood donors.
     • Provenance: Not explicitly stated, but implies a collection from a healthy population. Retrospective.

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

   • The document does not specify the number of experts or their qualifications. The clinical samples were "clinically characterized" and categorized as originating "from AIH-2 patients," "AIH-1 patients," etc., suggesting diagnoses were established by medical professionals, but details about the consensus process or individual qualifications are not provided.

3. Adjudication method for the test set:

   • No explicit adjudication method (e.g., 2+1, 3+1) is mentioned for establishing the ground truth diagnoses. The samples were simply described as "clinically characterized," implying standard clinical diagnostic procedures were followed.

4. If a multi-reader multi-case (MRMC) comparative effectiveness study was done:

   • No, an MRMC comparative effectiveness study was not done. This device is an ELISA kit for detecting autoantibodies, not an imaging device or one that involves human interpretation of output that would typically be assessed in an MRMC study.

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

   • Yes, the performance data presented (precision, analytical specificity, clinical sensitivity, clinical specificity) represent the standalone performance of the ELISA kit itself. The output of the ELISA is a quantitative ratio, which is then interpreted against a fixed cut-off (Ratio 1.0) to yield a qualitative (positive/negative) result. This process does not involve a human "in-the-loop" for the interpretation of the direct output of the device beyond reading the final calculated ratio.

6. The type of ground truth used:

   • Clinical Diagnosis: For the clinical sensitivity and specificity studies, the ground truth was established by "clinically characterized samples" from specific patient groups (e.g., "Autoimmune hepatitis type 2 (AIH-2) patients," "Viral hepatitis," "Primary biliary liver cirrhosis (PBC)"). This implies a ground truth based on established clinical diagnostic criteria, likely involving a combination of clinical findings, histology, and other laboratory tests.
   • Predicate Device/Reference Method: For the method comparison study, the predicate device (Inova Quanta Lite LKM-1 ELISA) served as a reference method for comparison.
   • Serological Status: For cross-reactivity, ground truth was based on samples "serologically positive for antibodies against SLA/LP."

7. The sample size for the training set:

   • The document does not specify a separate "training set" for the ELISA device. ELISA assays are typically developed based on biochemical principles and optimized through analytical validation, rather than being "trained" in the same way machine learning algorithms are. The samples described in the performance characteristics section are for validation and verification of the device's analytical and clinical performance.

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

   • As there's no explicitly defined "training set" in the context of machine learning for this ELISA device, this question is not directly applicable. The development and optimization of the ELISA kit would involve extensive laboratory work, antigen selection, and reagent formulation, with performance evaluated against characterized clinical samples as described in the "Test Set" details.

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