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The µTASWako AFP-L3 Immunological Test System is an in vitro device that consists of reagents used with the uTASWako i30 Immunoanalyzer to quantitatively measure, by immunochemical techniques, AFP-L3% in human serum. The device is intended for in vitro diagnostic use as an aid in the risk assessment of patients with chronic liver disease for development of hepatocellular carcinoma (HCC) in conjunction with other laboratory findings, imaging studies and clinical assessment. Patients with elevated AFP-L3% values (≥ 10%) have been shown to be associated with an increase in the risk of developing HCC within the next 21 months and should be more intensely evaluated for evidence of HCC according to the existing HCC practice guidelines in oncology.

The uTASWako DCP Immunological Test System is an in vitro device that consists of reagents used with the µTASWako i30 Immunoanalyzer to quantitatively measure, by immunochemical techniques, DCP in human serum. The device is intended for in vitro diagnostic use as an aid in the risk assessment of patients with chronic liver disease for development of hepatocellular carcinoma (HCC) in conjunction with other laboratory findings, imaging studies, and clinical assessment.

The µTASWako i30 Immunoanalyzer is an in vitro diagnostic automated instrument intended for use to quantitatively measure analytes in clinical chemistry by immunochemical techniques. The uTASWako i30 Immunoanalyzer is indicated for use by healthcare professionals. It is intended for assays cleared or approved for use on this instrument.

The Wako uTASWako AFP-L3 Calibrator Set is designed to be used with the Wako µTASWako AFP-L3 Immunological Test System for the quantitative determination of AFP-L3% in human serum.

The Wako µTASWako AFP-L3 Control L is designed to be used as quality control material for the quantitative determination of AFP-L3% in human serum using the Wako µTASWako AFP-L3 Immunological Test System.

The Wako uTASWako AFP-L3 Control H is designed to be used as quality control material for the quantitative determination of AFP-L3% in human serum using the Wako uTASWako AFP-L3 Immunological Test System.

The Wako µTASWako DCP Calibrator Set is designed to be used with the Wako uTASWako DCP Immunological Test System for the quantitative determination of DCP in human serum.

The Wako µTASWako DCP Control L is designed to be used as a quality control material for the quantitative determination of DCP in human serum using the Wako µTASWako DCP Immunological Test System.

The Wako µTASWako DCP Control H is designed to be used as a quality control material for the quantitative determination of DCP in human serum using the Wako uTASWako DCP Immunological Test System.

The µTASWako i30 Immunoanalyzer System is a fully automated immunoassay system that can perform assays of the uTASWako AFP-L3 and µTASWako DCP Immunological Test Systems. This system automatically conducts sampling, mixing, separation, and fluorescence detection on a microfluidic chip to achieve high sensitivity and accuracy. The instrument contains an automated liquid dispenser, temperature controlled reagent container, chip station, analysis compartment, and sample rack station. The outside panel has a printer and a touch panel with a menu to order measurements and to check the availability for reagent, chip, wash solution, and pure water. A chip is used for each test and is disposable. The instrument is designed to automatically and constantly monitor the reagents, chips, dispensing system and the measurement process so that measurement results are not given when an error occurs.

The system is comprised of the following products:
uTASWako i30
uTASWako AFP-L3, Calibrator Set, Control L and Control H
uTASWako DCP, Calibrator Set, Control L and Control H
Instrument and assay accessories as per labeling

The provided text describes the performance data for the µTASWako i30 Immunoanalyzer System and its associated AFP-L3 and DCP immunological test systems. This is a medical device, and the criteria and studies described relate to analytical performance, not clinical diagnostic accuracy or reader studies with human experts.

1. Table of Acceptance Criteria and Reported Device Performance

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

• Sensitivity (LoD): Sample size not specified, but involved distinguishing analytes from blank.
• Linearity/Assay Reportable Range: Sample size not specified.
• High Dose Hook Effect: Sample size not specified.
• Within-Run Precision: Samples with Total AFP 10-950 ng/mL, AFP-L3% 6-80%, DCP 0.2-910 ng/mL. Number of runs/replicates not specified in summary.
• Total Precision: 7 pooled human serum samples and 2 levels of controls. Samples with Total AFP 10-950 ng/mL, AFP-L3% 6-80%, DCP 0.2-910 ng/mL. Measured over 21 days.
• Reproducibility (Instrument to Instrument): 24 instruments were used. Sample details not explicitly stated, but for AFP-L3 and DCP assays.
• Recovery: Sample details not explicitly stated.
• Interference: Tested with known amounts of various interfering substances. Sample details not explicitly stated.
• HAMA Interference: Tested with two types of HAMA interferents. Sample details not explicitly stated.
• Method Comparison/Correlation (AFP-L3 and DCP):
  • Test Set: 200 samples from 100 patients.
  • Additionally:
    • AFP-L3: 40 serum samples spiked with AFP-L1 and AFP-L3.
    • DCP: 20 serum samples spiked with DCP.
  • Data Provenance: Not explicitly stated, but the studies were conducted to support a US FDA 510(k) submission, suggesting a focus on samples relevant to the intended patient population, likely from clinical settings. It is retrospective in the sense that the samples are collected and then tested.

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

This document describes the analytical performance of an in vitro diagnostic (IVD) device. The "ground truth" for these types of studies is based on the quantitative measurement of analytes and comparison to a legally marketed predicate device (LiBASys instrument with LBA AFP-L3 and LBA DCP test systems). Therefore, human expert judgment in the diagnostic sense (e.g., radiologists interpreting images) is not applicable or described in this context. The "ground truth" for the method comparison studies would be the results obtained from the predicate device (LiBASys).

4. Adjudication Method for the Test Set

Not applicable. The studies described are analytical performance studies, not subjective diagnostic interpretations requiring adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance

Not applicable. This is an IVD immunoassay system, not an AI-assisted diagnostic imaging device that involves human readers.

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

The performance data presented is inherently "standalone" in the context of the device's function, as it evaluates the instrument and test systems' analytical capabilities directly. The µTASWako i30 Immunoanalyzer System is a fully automated immunoassay system that performs sampling, mixing, separation, and fluorescence detection. Its output (quantitative measurements of AFP-L3% and DCP) does not involve human interpretation in the same way an AI imaging algorithm would. The method comparison studies compare the new device's automated results directly against a predicate automated device.

7. The Type of Ground Truth Used

The ground truth for the analytical performance studies is largely based on:

• Reference Standards: For sensitivity and linearity, the accurate measurement of known concentrations of analytes.
• Predicate Device Results: For the method comparison/correlation studies, the results obtained from the legally marketed predicate devices (LiBASys instrument with LBA AFP-L3 and LBA DCP test systems) are used as the comparative "ground truth."
• Clinical Cut-off Values: For calculating concordance rates (e.g., 10% for AFP-L3%, 7.5 ng/mL for DCP), these are established clinical values, not derived from a de novo ground truth for the study but rather applied to the measured values.

8. The Sample Size for the Training Set

The document does not describe a "training set" in the context of machine learning or AI development. These are validation studies for an IVD device. The methods described include validation of reagents, calibrators, and system performance through various analytical tests (precision, linearity, recovery, etc.).

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

Not applicable, as there is no mention of a "training set" in the context of an AI/ML algorithm. The studies conducted are for analytical validation of an IVD system against established analytical performance metrics and comparison to a predicate device.

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The Wako AFP-L3% assay is intended as a risk assessment test for the development of hepatocellular carcinoma (HCC) in patients with chronic liver diseases (CLD). Elevated AFPL3% values (≥ 10%) have been shown to be associated with a seven-fold increase in the risk of developing HCC within the next 21 months. Patients with elevated serum AFPL3% should be more intensely evaluated for evidence of HCC according to the existing HCC practice guidelines in oncology.

The Wako AFP-L3% device consists of reagent 1 (LCA and anion 1-conjugated anti-AFP mouse monoclonal antibody), reagent 2 (horseradish peroxidase (POD)labeled anti-AFP mouse monoclonal antibody and anion 2 conjugated anti-AFP mouse monoclonal antibody, substrate 1 (4 acetamidophenol in 2-propanol) and substrate 2 (hydrogen peroxide) and a column. Reagent 1, reagent 2 and the column are ready-to-use. Elution buffers A to C, sample cups, inside and outside cuvettes are sold separately from kit.

The Wako AFP-L3 Calibrator set and Control set are sold separately. The calibrator set consisted of Calibrator 1 and 2. Calibrator 1 contains human AFP -L1 fraction and Calibrator 2 has human AFP-L3 fraction. The control set consisted of Control 1 and 2, each containing different concentrations of human AFP-L1 and L-3.

Here's an analysis of the provided 510(k) summary, extracting the requested information about acceptance criteria and the supporting study:

Acceptance Criteria and Device Performance for Wako LBA AFP-L3

1. Table of Acceptance Criteria and Reported Device Performance

The 510(k) summary provided does not explicitly define acceptance criteria in a structured table for each performance characteristic. However, it presents measured performance values and, for linearity, implicitly sets criteria within the reported ranges for slope and R². For clinical performance, the intended use statement sets a clear threshold for risk assessment.

Here's an inferred table based on the provided data:

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

The primary clinical study involved 494 evaluable patients from:

• 6 US clinical sites (Lahey (MA), MCV (VA), Miami (FL), Mt. Sinai (NY), UCSF (SF), UPenn (PA))
• 1 Canadian clinical site (Toronto (Canada))

The study was a double-blind, multi-site prospective study. Serum samples were collected and stored frozen, and AFP-L3% tests were performed retrospectively by Wako Chemicals USA, Inc.

For the relative risk calculation, 57 patients from Group 4 (No HCC) were excluded due to less than 21 months of follow-up, resulting in a dataset of 312 patients (39 HCC, 273 No HCC) being used for the primary relative risk calculation.

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

The summary does not explicitly state the number or specific qualifications of experts used to establish the ground truth for the clinical study. However, the diagnosis of HCC for all enrolled patients was made by "at least one or a combination of the following observations," indicating clinical judgment by physician investigators:

• HCC result on a liver biopsy
• Enlarging mass by imaging (ultrasound, CT, MRI) with elevated serum total AFP
• Enlarging mass by CT or MRI in the setting of cirrhosis
• Very high serum total AFP (>400-500 ng/mL) alone
• At least 3 serial blood draws showing rising serum AFP in the setting of a liver mass
• Mass on CT scan enhancing in arterial phase and hypoattenuating in venous phase.

For evaluable subjects without HCC at enrollment, they were categorized by "the physician investigators" based on biopsy, explanted liver histology, and imaging results. This implies that the ground truth was established by the clinical team at each site.

4. Adjudication Method for the Test Set

The adjudication method for the test set is not explicitly described as a formal numerical system (e.g., 2+1, 3+1). Instead, the diagnosis of HCC was based on a combination of clinical observations and confirmatory tests, as determined by the "physician investigators." This suggests a consensus-based or standard clinical practice approach at each site, rather than a centralized, predefined adjudication panel for the study.

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

No MRMC comparative effectiveness study was done. This device is a quantitative immunoassay for a biomarker (AFP-L3%) and is not an imaging device or AI-assisted diagnostic tool that would typically involve human readers. The study focuses on the standalone performance of the test in assessing HCC risk.

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

Yes, a standalone performance study was done. The entire clinical study described is a standalone evaluation of the Wako AFP-L3% assay. The device measures AFP-L3% in serum, and its performance is evaluated based on its correlation with subsequent HCC development (risk assessment). Human intervention in the diagnostic process occurred after the test result was obtained, not as part of the test interpretation itself. The AFP-L3% values and the 10% cutoff are directly used to stratify patient risk.

7. Type of Ground Truth Used

The ground truth for the clinical study was primarily established through clinical diagnosis based on a combination of pathology (liver biopsy, explanted liver histology), imaging results (CT, MRI, ultrasound), and serial biomarker measurements (total AFP), as determined by physician investigators and standard oncology practice guidelines. This represents a robust clinical ground truth.

8. Sample Size for the Training Set

The 510(k) summary does not specify a separate training set for the clinical performance evaluation. The clinical study described appears to be the primary validation study (test set) for the device's intended use claim. For the analytical performance (precision, linearity, etc.), specific samples (control sera, spiked samples, diluted samples) were used, but these are not referred to as a "training set" in the context of machine learning model development. Given this is an immunoassay, the "training" aspect is more about assay optimization and standard curve generation during assay development than a machine learning training phase.

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

As no dedicated "training set" is identified in the context of a machine learning algorithm, this question is not directly applicable. For the analytical studies, the ground truth was inherently established by:

• Known concentrations in spiked samples.
• Reference materials (e.g., 1st International standard for AFP from WHO) for calibrator and control value assignments.
• Manufacturer-defined preparations for control sera (e.g., purified AFP-L1 and L-3 spiked into pooled serum).

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