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The Bio-Rad VARIANT™nbs Sickle Cell Program is intended as a qualitative screen for the presence of hemoglobins F, A, S, D, C, and E in eluates of neonatal blood collected on filter paper by high-performance liquid chromatography (HPLC).

The Bio-Rad VARIANT™nbs Sickle Cell Program is intended for Professional Use Only. For In Vitro Diagnostic Use.

The Bio-Rad VARIANT™nbs Sickle Cell Program is for use only with the Bio-Rad VARIANT™nbs Newborn Screening System.

The presence of hemoglobin S (HbS) in a patient blood sample is indicative of sickle cell disease or sickle cell trait. Diagnosis of sickle cell disease prior to the age of four months allows for the administration of a prophylactic treatment with penicillin. Prophylactic treatment with penicillin has shown to decrease morbidity and mortality.

The VARIANTnbs Newborn Screening System uses the principles of high-performance liquid chromatography (HPLC). The VARIANTnbs Sickle Cell Program is based on the chromatographic separation of hemoglobins F, A, S, D, C, and E on a cation exchange cartridge.

The new feature in this submission is the upgrade of the Genetic Data Management (GDM) software. The current software (GDM 2.01) requires Microsoft Windows NT. This product is nearing the end of its lifecycle. GDM 3.0 software is needed to transfer the GDM software to the Microsoft Windows XP Operating System.

Acceptance Criteria and Study Details for Bio-Rad VARIANT™nbs Sickle Cell Program with GDM 3.0

This document outlines the acceptance criteria and the study conducted to demonstrate that the Bio-Rad VARIANT™nbs Sickle Cell Program run on the VARIANT™nbs Newborn Screening System using Genetic Data Management (GDM) 3.0 Software meets these criteria.

1. Table of Acceptance Criteria and Reported Device Performance

The primary acceptance criteria for the new GDM 3.0 software update was to maintain 100% agreement with the predicate device (GDM 2.01) in identifying the presence of specific hemoglobins.

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

• Sample Size: The provided document does not explicitly state the total number of patient samples used in the correlation study. It lists categories of hemoglobin types (FA, FAS, FAC, FAD, and an unspecified "H" type) and indicates 100% agreement for each. While a total count of samples is not given, the implicit message is that all samples tested within these categories showed agreement.
• Data Provenance: The study was conducted "at an external site". The country of origin is not specified but is presumably the United States, given the FDA submission. The study compared results from the predicate device and the new device ran on the same samples on the same day, suggesting it was a prospective comparison of the new software's performance on existing samples, rather than entirely retrospective data analysis.

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

The document describes a "method correlation study" where samples run on the predicate device (GDM 2.01) were repeated on the GDM 3.0 platform. The "ground truth" in this context is established by the results obtained from the predicate device (GDM 2.01). There is no mention of external human experts establishing a separate ground truth for this correlation study, as the comparison is specifically between the two software versions and their agreement.

4. Adjudication Method for the Test Set

No explicit adjudication method is described. The study directly compares the results of the two software versions. Since the goal was to demonstrate 100% agreement, any discrepancy would inherently require investigation. However, with 100% agreement reported, no further adjudication process for conflicting results was needed or mentioned.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic system for qualitative screening of hemoglobins using HPLC and software for data management, not an AI-assisted diagnostic imaging or interpretation tool for human readers. The change is an upgrade to the operating system and features of the data management software.

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

The study described is a standalone performance comparison between the GDM 3.0 software and the predicate GDM 2.01 software. It assesses the algorithm's (software's) ability to produce the same qualitative results as the older version when processing the same samples. While human operators are involved in running the HPLC system, the software's output is the focus of the comparison, making it a standalone assessment of the software's correlation with its predecessor.

7. The Type of Ground Truth Used

The ground truth used for this study was the results generated by the predicate device (VARIANT™nbs Sickle Cell Program with GDM 2.01). The objective was to demonstrate that the new GDM 3.0 software produced identical qualitative results to the previously cleared and established predicate device.

8. The Sample Size for the Training Set

The provided summary does not mention a training set in the typical sense for machine learning or AI models. The GDM 3.0 is a software upgrade to an existing HPLC system, primarily focusing on operating system compatibility and usability enhancements, not a new algorithm requiring a training phase from scratch. Therefore, the concept of a "training set" for the algorithm itself is not directly applicable in this context. The development process would have involved internal testing and validation, but this information is not part of the public summary provided.

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

As explained above, a dedicated "training set" for an AI algorithm is not applicable to this software upgrade. The "ground truth" for ensuring the functionality of the GDM 3.0 software during its development would have been established through rigorous software testing against known sample profiles and expected outputs, confirming its accuracy in processing the chromatographic data according to the established scientific principles of HPLC for hemoglobin separation. This typically involves using reference materials and clinically characterized samples.

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The Bio-Rad VARIANT™ II TURBO Link Hemoglobin A1c Program is intended for the percent determination of hemoglobin A1c in human whole blood using ion-exchange high performance liquid chromatography (HPLC).

The VARIANT II TURBO Link Hemoglobin A1c Program is for use with the VARIANT II TURBO Link Hemoglobin Testing System interfaced with an automated sample transport system.

The Bio-Rad VARIANT II TURBO Link Hemoglobin A1c Program is for Professional Use Only.

Measurement of percent hemoglobin A1c is effective in monitoring long-term glucose control in individuals with diabetes mellitus.

The VARIANT II TURBO Link Hemoglobin Testing System uses the principles of high performance liquid chromatography (HPLC). The VARIANT II TURBO Link Hemoglobin A lc Program is based on chromatographic separation of Hemoglobin Alc on a cation exchange cartridge. The reagents in the VARIANT II TURBO Link Hemoglobin A 1c Program have the same formulation as the reagents in the VARIANT II TURBO Hemoglobin A1c Program.

Here's a breakdown of the acceptance criteria and study details for the Bio-Rad VARIANT™ II TURBO Link Hemoglobin A1c Program, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the comparison to the predicate device. The study aims to demonstrate substantial equivalence by showing similar performance.

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

• Test Set Sample Size: 180 EDTA whole blood patient samples for accuracy, and 80 normal and 80 diabetic patient samples for precision.
• Data Provenance: Not explicitly stated, but given the context of a 510(k) submission for a US market, it's highly probable the data was collected in the US. The document does not specify if the data was retrospective or prospective.

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 document. For HbA1c measurements, the "ground truth" is typically the reference method itself (HPLC in this case, specifically traced to DCCT and IFCC, and certified by NGSP), rather than expert consensus on individual samples. The study compares the new device's measurements to those of the predicate device (which is also traceable to these standards).

4. Adjudication Method for the Test Set

This information is not applicable as the ground truth is established by a quantitative analytical method (HPLC traceable to standards), not by human interpretation 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

This question is not applicable. This is a submission for an in vitro diagnostic device (analyzing blood samples) and not an imaging or AI-assisted diagnostic tool that would involve human "readers" or AI assistance in interpretation.

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

This device operates as a standalone analytical instrument. The reported performance metrics (accuracy, precision, linearity) are reflective of its standalone performance without human input influencing the measurement itself, beyond standard laboratory procedures for sample handling and instrument operation. The "algorithm" here refers to the underlying HPLC and data processing, which operate automatically.

7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)

The ground truth for the device's performance is established by:

• Traceability to recognized reference methods: Diabetes Control and Complications Trial (DCCT) reference method and IFCC.
• Certification: via the National Glycohemoglobin Standardization Program (NGSP).
• Comparison to a legally marketed predicate device: The VARIANT II TURBO Hemoglobin A1c Program (K040872 and K063400), which itself would adhere to these traceability and certification standards.

Essentially, the ground truth is anchored by widely accepted analytical reference standards for HbA1c measurement.

8. The Sample Size for the Training Set

This information is not applicable/not provided. This is a regulatory submission for a diagnostic instrument, not a machine learning model that undergoes "training." The device's performance is validated through accuracy, precision, and linearity studies directly comparing it to a predicate and reference standards, rather than by training on a dataset.

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

This question is not applicable for the same reasons as #8.

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This software submission covers three assays with three different intended uses:

Hemoglobin A1c:
The VARIANT II Hemoglobin A1c Program is intended for the percent determination of hemoglobin A1c in human whole blood using ion-exchange high-performance liquid chromatography (HPLC).
The VARIANT II Hemoglobin Alc Program is intended for use only with the Bio-Rad VARIANT II Hemoglobin Testing System. For in vitro diagnostic use.

Beta-thalassemia:
The VARIANT II Beta thalassemia Short Program is intended for the separation and area percent determinations of hemoglobin A2 and F, and as an aid in the identification of abnormal hemoglobins in human whole blood using ionexchange high-performance liquid chromatography (HPLC).
The VARIANT II Beta-thalassemia Short Program is intended for use only with the Bio-Rad VARIANT II Hemoglobin Testing System. For in vitro diagnostic use.

Total GHb:
The VARIANT II Total GHb Program is intended for the separation and area percent determination of total glycated hemoglobin (GHb) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC).
The VARIANT II Total GHb Program with is intended for use only with the Bio-Rad VARIANT II Hemoglobin Testing System. For in vitro diagnostic use.

Indications for Use:
This software submission covers three assays and has two different Indications for Use:

HbA1c & GHb: Measurement of percent hemoglobin A1c is effective in monitoring long-term glucose control in individuals with diabetes mellitus.
HbA2 and HbF: Measurement of the percent hemoglobin A2 and F are effective in screening of β-thalassemia (i.e. hereditary hemolytic anemias characterized by decreased synthesis of one or more types of abnormal hemoglobin polypeptide chains).

The VARIANT II Hemoglobin Testing System uses the principles of high performance liquid chromatography (HPLC). The VARIANT II Hemoglobin A1c and Beta-thalassemia Short Program are based on chromatographic separation of hemoglobins on a cation exchange cartridge. The Total GHb Program is based on principles of boronate affinity high pressure liquid chromatography to separate glycated hemoglobin from non-glycated hemoglobin.

The new feature in this submission is the upgrade in CDM software. The current software (3.5) requires Windows NT and Object Store N.T. These products are nearing the end of their lifecycle. CDM 4.0 software is needed to transfer the CDM software to Microsoft XP Operating System and Object Store version 4.0.

Here's an analysis of the provided text regarding the acceptance criteria and study for the Bio-Rad VARIANTT II Hemoglobin Testing System with CDM 4.0.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria in this submission are implicit, established by demonstrating substantial equivalence to predicate devices (CDM 3.5 versions of the programs). The key performance metrics evaluated are accuracy (method correlation) and precision.

Here's the table:

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

• Hemoglobin A1c Program (Accuracy): 40 EDTA whole blood samples.
• Beta thalassemia Short Program (Accuracy): 40 EDTA whole blood samples.
• Total GHb Program (Accuracy): 40 EDTA whole blood samples.
• Precision Studies (all programs): Although specific sample numbers are sometimes noted as n=40 or n=80 for the combined precision data, it's important to note these refer to the number of individual measurements or patient samples, not necessarily distinct patients. The studies involved analyzing "duplicate aliquots of normal HbA1c and diabetic HbA1c patient samples and controls" over several days.
• Data Provenance: The document states "EDTA whole blood samples" and "patient samples and controls." It does not specify the country of origin or if the data was retrospective or prospective. Given the context of method correlation and precision, it's likely these were carefully selected samples to cover the analytical range, and are prospective in nature for the purpose of the study.

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

This submission is for an in vitro diagnostic device (IVD) that measures specific biomarkers (HbA1c, HbA2, HbF, GHb) using analytical techniques (HPLC). The "ground truth" for such devices is typically established through a reference method or a highly accurate existing method.

In this case, the device's performance is compared against its predicate device (the older CDM 3.5 version of the same program). The predicate device itself would have been validated against a reference method.

• No external human experts were explicitly used to establish "ground truth" for the test set in this particular comparative study. The ground truth is the measurement obtained from the predicate device (CDM 3.5).
• The standardization for HbA1c and GHb is stated as "Traceable to the Diabetes Control and Complications Trial (DCCT) reference method and IFCC. Certified via the National Glycohemoglobin Standardization Program (NGSP) for HbA1c." This indicates that the values obtained by both the new and predicate devices are ultimately traceable to established clinical reference standards, which is how the "ground truth" of the concentration values is ensured.

4. Adjudication Method for the Test Set

Not applicable. This is not a study involving human interpretation of images or data that would require adjudication. It's a quantitative measurement device, and the comparison is statistical (regression and precision).

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

No. This is an in vitro diagnostic device for quantitative measurement, not an AI or imaging device requiring human reader interpretation or MRMC studies.

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

Yes, the studies presented are standalone performance evaluations of the device (system including software) in terms of its analytical accuracy and precision. There is no human-in-the-loop aspect being evaluated here, as the device is designed for automated measurement.

7. The Type of Ground Truth Used

The "ground truth" for the performance evaluation in this 510(k) submission is the measurements obtained from the predicate device (the Bio-Rad VARIANT II Hemoglobin Testing System running CDM 3.5). The new device (CDM 4.0) is compared directly to the predicate to demonstrate substantial equivalence, meaning it performs similarly.

Underlying this, the initial "ground truth" for quantitative values for HbA1c is linked to reference methods (DCCT and IFCC) and certification (NGSP). For HbA2 and HbF, the ground truth is also tied to established quantitative analysis using HPLC.

8. The Sample Size for the Training Set

The document does not describe a "training set" in the context of machine learning or AI. This device is an analytical instrument with associated software. The software (CDM 4.0) is an upgrade to manage the data and system on a new operating system, not a machine learning algorithm that is "trained."

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

Not applicable, as there is no "training set" in the machine learning sense for this device. The software update primarily concerns operating system compatibility and database management, not the underlying analytical algorithm itself.

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