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The Hemoglobin Variants System 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 Hemoglobin Variants System is intended for Professional Use Only. For in vitro diagnostic use. The Hemoglobin Variants System is for use only with the Newborn Hemoglobin System (NHS).

This device, consisting of the reagents, controls, apparatus, HPLC instrumentation, software is indicated for professional laboratory IVD use to isolate and identify inherently determined abnormal (S, D, C, E) and normal (F, A) hemoqlobin types in neonatal blood samples.

The instrument, Newborn Hemoglobin System (NHS) utilizes same principles of ionexchange high-performance liguid chromatography (HPLC). The NHS instrument is a fully automated, high-throughput hemoglobin analyzer. It utilizes principles of ion-exchange highperformance liquid chromatography (HPLC). The NHS provides an integrated method for the separation and determination of relative percent of specific hemoglobins of dried blood spots. The dried blood spot collected from neonatal heel stick is punched and eluted with deionized water. The punched disc is removed and eluted sample is transferred into microplate well. The eluted sample is analyzed to identify specific inherently abnormal (S, D, C, E) as well as normal (F, A) hemoglobins through the system.

The NHS consists of two modules — the Newborn Chromatographic Station (NCS) and the Newborn Auto Sampler (NAS). NCS module delivers buffer solutions (See table 4 for kit components) to the Hemoglobin Variants System CE Mini-Columns and the detector. The NAS module through automatic injection introduces eluted sample from microplate wells. Each sample is processed individually. The mini-column contains a cation exchange gel, and the analyzer makes use of a continuous pre-programmed gradient system. The preprogrammed gradient is designed to have the hemoglobins of interest elute from the minicolumn with retention times that fall within pre-determined windows characteristic of known normal and abnormal hemoglobins. The ionic strength of two phosphate buffers passing through the mini-column is changed over three minutes. The eluted hemoglobins introduced through automatic injection are sequentially detected with a dual-wavelength filter photometer. which monitors hemoglobin absorbance at 415 nm and corrects for any gradient induced absorbance changes at 690 nm. Detection is performed at two wavelengths (415 nm and 690 nm) to ensure a stable baseline. Sample of water immediately following a newborn or quality control sample prevents carryover.

A workstation is used to control the Newborn Hemoglobin System using Genetic Disease Management (GDM) software. The GDM software is designed to execute the assay protocol on the NHS instrument using the Hemoglobin Variants System reagent kit components. The software processed HPLC data is outputted in a printed report that contains: 1) sample identification, 2) date and time of analysis, 3) report data (i.e., peak names, retention times, area, relative percent), and 4) chromatogram. Also system assigns a presumptive phenotype "pattern" to each sample result. The pattern is calculated by applying a set of "rules" to the peaks identified in the peak table. The purpose of the pattern rules is to eliminate minor peaks from the pattern, identify system or sample problems, and to focus the operator on the samples that may require further investigation. The pattern rules used by the GDM software were derived from those generated by the Genetic Diseases Laboratory for the state of California, USA, after analysis of 2.5 million newborns by HPLC over a four year period (Eastman, et al., 1996)'. Laboratories using the Newborn Hemoglobin System pattern rules and assignment should perform an internal validation study to confirm the performance of the system for their application. 1.Eastman, J. W.; Wong, R.; Liao, C. L.; Morales, D. R. Automated HPLC Screening of Newborns for Sickle Cell Anemia and Other Hemoglobinopathies. Clin. Chem. 1996, 42 (5), 704—710.

The HbReview Software is to support the review of transmitted result and release of an approved result for each neonate sample analyzed on Hemoglobin Variants System with Newborn Hemoglobin System. A screening site using Newborn Hemoglobin Systems (NHS) transmits results from the Genetic Disease Management (GDM) software to the central site. The central site uses HbReview software to review results, identify samples for retesting, add comments and release results to the reporting site. Features are provided to assist Reviewers and Approvers in their tasks of examining results from the Hemoglobin Newborn Screening test.

The HbReview software is a Client-Server design. The Review process provides a user interface (client) to a relational database, which is located on a separate computer (the server). The Client software permits an authorized user to make changes to the data maintained on the Server.

This submission describes the Bio-Rad Hemoglobin Variants System on Newborn Hemoglobin System with GDM and HbReview Software. This device 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).

Here's an analysis of the provided information:

1. Table of acceptance criteria and the reported device performance:

The document does not explicitly state acceptance criteria or provide a table of performance metrics (like sensitivity, specificity, accuracy) from a validation study for the Hemoglobin Variants System. It focuses on demonstrating substantial equivalence to a predicate device (Bio-Rad VARIANT™nbs Sickle Cell Program).

However, the "Indications for Use" section states: "This device...is indicated for professional laboratory IVD use to isolate and identify inherently determined abnormal (S, D, C, E) and normal (F, A) hemoglobin types in neonatal blood samples." This implies that the device must accurately identify these hemoglobin types.

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

The document does not provide information on the sample size used for a test set or the data provenance (country of origin, retrospective/prospective) for a performance study of the modified device.

It mentions that the "pattern rules used by the GDM software were derived from those generated by the Genetic Diseases Laboratory for the state of California, USA, after analysis of 2.5 million newborns by HPLC over a four year period (Eastman, et al., 1996)." This refers to the historical data used to establish the rules for the GDM software, not a specific test set for the current device's performance validation. It also suggests that laboratories using the system should perform an internal validation.

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 used to establish ground truth for a specific test set for the modified device. The reference to the Genetic Diseases Laboratory in California for establishing GDM pattern rules implies expert involvement in the development of those rules, but not necessarily in evaluating a specific test set for the current submission.

4. Adjudication method for the test set:

The document does not describe an adjudication method for a test set.

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

No, the document does not mention an MRMC comparative effectiveness study for the modified device. The focus is on demonstrating substantial equivalence, not on quantifying the improvement of human readers with AI assistance.

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

The device described is a system that combines instrumentation, reagents, and software for analysis. While the GDM and HbReview software play a role, the system is designed for in vitro diagnostic use by professional laboratories. The HbReview software aids in the review and release of results by human operators. Therefore, it's not a standalone "algorithm only without human-in-the-loop" performance in the context of typical AI device submissions. The "pattern rules" in GDM are an automated algorithmic component, but the overall system involves human oversight for result review and release.

7. The type of ground truth used:

The document implies that the ground truth for identifying hemoglobin types (F, A, S, D, C, E) would be established through laboratory methods that definitively identify these hemoglobins. For the historical data used to derive GDM pattern rules, it was based on HPLC analysis with extensive validation as referenced (Eastman, et al., 1996). For the current device, a robust laboratory gold standard (e.g., confirmatory biochemical or genetic testing) for hemoglobin types would be expected to serve as ground truth in any validation studies.

8. The sample size for the training set:

The document does not explicitly state a sample size for a training set for the modified device.

However, it states that the GDM software's pattern rules were derived from "analysis of 2.5 million newborns by HPLC over a four-year period (Eastman, et al., 1996)" by the Genetic Diseases Laboratory for the state of California. This large dataset effectively served as the "training data" for formulating those rules.

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

For the 2.5 million newborns analyzed that informed the GDM pattern rules, the ground truth was established through HPLC analysis (ion-exchange high-performance liquid chromatography). This method is a standard laboratory technique for identifying and quantifying hemoglobin variants. The implied ground truth relies on the established accuracy and reliability of this HPLC method, likely supported by expert interpretation and potentially confirmatory testing in ambiguous cases over the four-year period mentioned.

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