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The VARIANT™ II TURBO HbA1c Kit- 2.0 is intended for the quantitative determination of hemoglobin A1c (IFCC mmol/mol and NGSP %) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC) on the VARIANT II TURBO Hemoglobin Testing System and VARIANT II TURBO Link Hemoglobin Testing System.

This test is to be used as an aid in diagnosis of diabetes and as an aid in identifying patients who may be at risk for developing diabetes.

The VARIANT II TURBO HbA1c Kit- 2.0 is intended for Professional Use Only.

The Hemoglobin Capillary Collection System (HCCS) is intended for the collection of human whole blood for the percent determination of hemoglobin A1c using Bio-Rad HPLC methods.

The VARIANT™ II TURBO HbA1c Kit - 2.0 utilizes principles of ion-exchange highperformance liquid chromatography (HPLC). The samples are automatically diluted on the VARIANT™ II TURBO Sampling Station (VSS) and injected into the analytical cartridge. The VARIANT™ II TURBO Chromatographic Station (VCS) dual pumps deliver a programmed buffer gradient of increasing ionic strength to the cartridge, where the hemoglobins are separated based on their ionic interactions with the cartridge material. The separated hemoglobins then pass through the flow cell of the filter photometer, where changes in the absorbance at 415 nm are measured. An additional filter at 690 nm corrects for background absorbance.

The VARIANT™ II TURBO Clinical Data Management (CDM™) software performs reduction of raw data collected from each analysis. Two-level calibration is used for adjustment of the calculated HbA1c values. A sample report, including retention times of detected peaks and a chromatogram, is generated by the CDM for each sample. The A1c peak is shaded for ease of identification. The area is calculated using an exponentially modified Gaussian (EMG) algorithm and the result printed in either mmol/mol or % HbA1c format as selected by the user.

The VARIANT™ II TURBO HbA1c Kit – 2.0 is designed to be used on the standalone VARIANT™ II TURBO and the VARIANT™ II TURBO Link Hemoglobin Testing Systems. VARIANT™ II TURBO and the VARIANT™ II TURBO Link Hemoglobin Testing Systems are identical with respect to all operational and system components. Physically, the VARIANT™ II TURBO Link VSS outer case is modified for compatibility with a track Functionality of the VARIANT™ II TURBO Link has not changed, just the system. physical orientation to accommodate sample tube management on a track system.

This document describes the performance of the VARIANT™ II TURBO HbA1c Kit - 2.0, an in vitro diagnostic device used for quantitative determination of hemoglobin A1c.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are derived from the "Special Controls Requirements for HbA1c for Diabetes Diagnosis" as outlined in Table 17 of the document (though it's mislabeled and actually on page 14 of the PDF). The device performance is reported in various sections of the "Summary of Performance Data."

Detailed Study Information:

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

• Precision/Reproducibility Study:
  • Sample Size: 4 EDTA whole blood samples (at ~5%, ~6.5%, ~8%, and ~12% HbA1c) and 5 quality control materials. Each sample had 720 measurements (run in duplicate, 2 runs/day, for 20 days across 3 instruments).
  • Data Provenance: Not explicitly stated regarding country of origin, but it involves patient samples and quality control materials, which are typically retrospective or derived from clinical settings.
• Method Comparison Study:
  • Sample Size: 130 variant-free whole blood EDTA samples.
  • Data Provenance: Not explicitly stated regarding country of origin. The samples ranged from 3.4% to 20.0% HbA1c, suggesting prospective collection covering a diagnostic range. It mentions comparison to a "secondary NGSP SRL reference laboratory," implying real-world clinical samples.
• Linearity Study:
  • Sample Size: Low (3.4%HbA1c) and high (20.6%HbA1c) EDTA whole blood patient samples mixed at varying ratios, creating 11 distinct levels (Level 1 to Level 11).
  • Data Provenance: Patient samples, likely retrospective.
• Analytical Specificity (Interference) Studies:
  • Endogenous Interference: Two EDTA whole blood sample pools (~6.5%HbA1c and ~8.0%HbA1c) were used. 10 replicates of each pool with test and control samples.
  • Drug Interference: Two EDTA whole blood sample pools (~6.5%HbA1c and ~8.0%HbA1c) were used. 10 replicates of each drug with test and control samples.
  • Hemoglobin Derivatives Interference: Low (~6.5%HbA1c) and high (~8.0%HbA1c) whole blood EDTA samples. Ten replicates each.
  • Hemoglobin Variant Study: Specific variant samples (HbS, HbC, HbD, HbE, HbA2, HbF), with n=21-29 for each variant (e.g., 26 for HbS, 25 for HbC). Tested in duplicate.
  • Data Provenance: Not explicitly stated regarding country of origin. "Patient samples" were used for some, and pure substances/serum samples for others.

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

• The document does not explicitly state the number or qualifications of experts for establishing ground truth.
• For the Method Comparison Study, the device's results were compared to a "secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay." The NGSP (National Glycohemoglobin Standardization Program) provides certification for laboratories and methods to ensure traceability to the DCCT (Diabetes Control and Complications Trial) reference method. This implies the ground truth is established by a highly standardized and validated reference method in an accredited laboratory, rather than by individual experts' consensus.
• For the Hemoglobin Variant Study, the comparison was against "a NGSP reference method that has been demonstrated to be free from the hemoglobin interferent," again pointing to a high-standard reference method as the ground truth.

4. Adjudication Method for the Test Set

• No explicit adjudication method (like 2+1 or 3+1 consensus) is described. The ground truth relies on established reference methods (NGSP-certified HPLC for HbA1c, and specialized NGSP reference methods for variant studies) as opposed to human adjudication of ambiguous cases. This is typical for quantitative analytical devices where a measurable reference standard exists.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was Done

• No, an MRMC comparative effectiveness study was not done. This type of study typically evaluates the effectiveness of a diagnostic aid (like AI) on physician performance in interpreting medical images or making diagnoses. The VARIANT™ II TURBO HbA1c Kit - 2.0 is an automated in vitro diagnostic device for quantitative chemical analysis, not an image interpretation or diagnostic aid that involves human "readers." Its performance is measured directly against reference methods and statistical criteria.

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

• Yes, the studies evaluate the standalone (algorithm only) performance. The device is an automated system (ion-exchange HPLC) that processes samples and produces quantitative HbA1c results. The performance data presented (precision, linearity, method comparison, interference studies) directly assesses the accuracy and reliability of this automated system in determining HbA1c values, without human intervention in the interpretative step. The "Human-in-the-loop" aspect would primarily involve sample collection and loading the instrument, not interpretation of the results themselves.

7. The Type of Ground Truth Used

• Primarily reference method comparison, traceable to international standards.
  • For HbA1c quantification, the ground truth is established by comparison to NGSP-certified reference methods, which are themselves traceable to the DCCT (Diabetes Control and Complications Trial) reference method and IFCC (International Federation of Clinical Chemistry and Laboratory Medicine) units. This is stated under "Traceability" (Section 8.d) and in the method comparison and variant studies.
  • For interference studies, the ground truth is based on the expected values of spiked samples without the interferent, as measured by the device itself or a control.

8. The Sample Size for the Training Set

• The document does not explicitly mention a "training set" in the context of machine learning or algorithm development. This device is based on established HPLC principles and data reduction algorithms, which are typically designed and validated, rather than "trained" in the machine learning sense. The performance studies described serve as validation/verification of the final device.

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

• As a traditional in vitro diagnostic device based on HPLC, there isn't a "training set" in the machine learning paradigm. The device's underlying principles (ion-exchange chromatography, spectrophotometry, and specific algorithms for peak detection and calculation) are built upon scientific understanding and engineering. The "ground truth" for developing and calibrating such systems would come from well-characterized reference materials and methods, likely through extensive internal R&D and calibration procedures following international standards, but this is not detailed as a "training set" in the document.

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The Bio-Rad VARIANT™ II TURBO HbA1c Kit - 2.0 is intended for the quantitative determination of hemoglobin A1c in human whole blood using ion-exchange high performance liquid chromatography (HPLC) on the VARIANT™ II TURBO Hemoglobin Testing System. Measurement of hemoglobin A1c is effective in monitoring long term glycemic control in individuals with diabetes mellitus. The Bio-Rad VARIANT™ II TURBO HbA1c Kit-2.0 is intended for Professional Use Only.

The VARIANT II TURBO Hemoglobin Testing System uses the principles of high performance liquid chromatography (HPLC). The VARIANT II TURBO HbA12 Kit - 2.0 is based on chromatographic separation of Hemoglobin A10 on a cation exchange cartridge. The VARIANT II TURBO HbA1c Kit - 2.0 contains an analytical cartridge, 5 prefilters, Elution Buffer A and B, Calibrator Level 1, Calibrator Level 2, Whole Blood Primer, sample vials and a CD-ROM with test parameters.

The VARIANT II TURBO Hemoglobin Testing System provides an integrated method for sample preparation, separation and the quantitative determination of HbAle in EDTA human whole blood. The VARIANT II TURBO Hemoglobin Testing System is a fully automated, high-throughput hemoglobin analyzer. It consists of two modules - the VARIANT II Chromatographic Station (VCS) and the VARIANT II Sampling Station (VSS). There have been hardware updates due to obsolescence of parts and firmware updates to support the replacement hardware components.

A personal computer is used to control the VARIANT II TURBO Hemoglobin Testing System using updated Clinical Data Management (CDM) software version 5.1.1.

Here's an analysis of the provided 510(k) summary, structured to answer your questions about acceptance criteria and the supporting study:

Some of the requested information, such as the specific country of origin for the data, the exact qualifications of experts, and the adjudication method for the test set, are not explicitly detailed in the provided 510(k) summary. This is typical for such regulatory documents, which focus on summarizing key performance data rather than granular study design details.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the "Method Comparison" study were based on a relative bias not exceeding +/- 10% at the decision points of 6% and 9% HbA1c.

The "Analytical Specificity" study aimed to show no significant interference from common hemoglobin variants at specified concentrations.

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

• Sample Size (Method Comparison): 100 EDTA whole blood human samples and 16 samples prepared by mixing EDTA whole blood samples with either purified HbAo or purified HbA1c. Total: 116 samples.
• Sample Size (Analytical Specificity): Not explicitly stated as a number of individual samples, but described as "Two fresh, EDTA non-variant human blood sample pools at 6.5% and 8.0-9.0% HbA1c" and "Fresh, EDTA human homozygous blood samples for each of the 4 hemoglobin variants (e.g. E, D, S, and C)." Series of test sample pools prepared by dilution.
• Data Provenance: The data used for method comparison and analytical specificity were "EDTA whole blood human samples" and "fresh, EDTA human homozygous blood samples." The country of origin is not specified but is implicitly from a clinical laboratory setting. The studies appear to be prospective or concurrent as they involved preparing and running samples specifically for the study.

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

This information is not provided in the summary. The ground truth for the method comparison study was established by the predicate device's software version 4.03. For the analytical specificity, the "true" HbA1c values for the variant samples were likely determined by a reference method or assumed based on the preparation of the samples (e.g., dilution of homozygous variant samples).

4. Adjudication Method for the Test Set

This information is not provided in the summary. For a quantitative assay like HbA1c, adjudication typically involves comparing the device's results against a gold standard or a highly accurate reference method. In the method comparison, the predicate device's results served as the reference for the modified software.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and the effect size of how much human readers improve with AI vs without AI assistance

A Multi-Reader Multi-Case (MRMC) comparative effectiveness study is not applicable here. This document describes a medical device, the Bio-Rad VARIANT™ II TURBO HbA1c Kit - 2.0, which is an automated in vitro diagnostic (IVD) assay to measure HbA1c. It is not an AI-based diagnostic tool that assists human readers/interpreters.

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

The device itself is a standalone automated system for quantitative determination of HbA1c. The evaluation performed (method comparison and analytical specificity) effectively represents its standalone performance because it directly measures HbA1c levels without human interpretation of complex images or signals requiring AI assistance. The study compares the performance of the updated software/system to a previous version, which is a standalone comparison.

7. The Type of Ground Truth Used

• Method Comparison: The ground truth for the method comparison study was established by the predicate device's software version 4.03 (meaning the measurements obtained from the same system running the older software). This is a "comparative ground truth" when assessing software changes.
• Analytical Specificity: For variant interference, the ground truth was effectively implicit in the preparation of the samples (known variant concentrations, and expected HbA1c values in the pools). The goal was to show that the presence of these variants does not interfere with the HbA1c measurement, meaning the device's reading should remain accurate despite the variant's presence.

8. The Sample Size for the Training Set

This information is not provided in the summary. This device is an in vitro diagnostic (IVD) kit using high-performance liquid chromatography (HPLC) and associated software. While software might undergo internal development and validation (which could involve "training" in a broad sense, especially for algorithms identifying peaks), the concept of a "training set" as it applies to machine learning or AI models is not directly relevant or typically disclosed for this type of IVD device in a 510(k) summary. The summary focuses on comparing the new software's performance against the old, representing an update to an established analytical method.

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

As noted above, a "training set" in the context of AI/ML is not directly applicable. If one considers the development of the analytical method and software, the ground truth for establishing parameters would have been derived from extensive analytical chemistry principles and experiments, likely involving reference methods and characterized samples to ensure accurate chromatographic separation and calculation of HbA1c. This foundational work would be part of the product's overall development, not explicitly detailed as a "training set" in this 510(k) summary.

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