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The CAPI 3 NEONAT Hb kit is intended as a qualitative screen for the detection of normal hemoglobins (F and A) and abnormal hemoglobins (S, C, E, D and Bart's) in blood from human new-born collected on filter paper. This analysis is performed by capillary electrophoresis with the CAPILLARYS 3 DBS instrument.

The CAPILLARYS 3 DBS instrument is a capillary electrophoresis based automated analyzer which performs a complete hemoglobin profile for the qualitative analysis of hemoglobins (A, F, S, C, D, E and Bart's). The assay is performed on the hemolysate of whole blood samples previously collected on filter paper.

The test result must be interpreted in conjunction with other biological and clinical findings. In case of abnormal hemoglobin presence, it should be confirmed by additional tests as per local recommendations. The device is intended for professional use only.

For In Vitro Diagnostic Use only.

The CAPI 3 NEONAT Hb kit is intended for the detection of normal hemoglobins (F and A) and abnormal hemoglobins (S, C, E, D and Bart's) in blood from human new-born collected on filter paper. The resulting electrophoregrams are automatically evaluated for pattern abnormalities with identification of normal and pathological patterns.

The CAPILLARYS 3 DBS instrument uses the principle of capillary electrophoresis in free solution which is the most common form of capillary electrophoresis. With this technique, charged molecules are separated by their electrophoretic mobility in an alkaline buffer with a specific pH. Separation also occurs according to the electrolyte pH and electroosmotic flow.

The CAPILLARYS 3 DBS instrument has silica capillaries functioning in parallel allowing 12 simultaneous analyses. A sample dilution with hemolysing solution is prepared and injected by aspiration at the anodic end of the capillary. A high voltage protein separation is then performed and direct detection of the hemoglobins is made at the cathodic end of the capillary at 415 nm. which is the absorbance wavelength specific to hemoglobins. Before each run. the capillaries are washed with a wash solution and prepared for the next analysis with buffer.

The CAPILLARYS 3 DBS performs all sequences automatically to obtain a complete hemoglobin profile for the qualitative analysis of hemoglobins. The assay is performed on the hemolysate of whole blood samples previously collected on Guthrie filter paper and punched to obtain a paper circle.

By using alkaline pH buffer. normal and abnormal (or variant) hemoglobins are detected in the following order. from cathode to anode: C, A2, E, S, D, F, degraded F, A, degraded A and Bart's. Variants generated by the mutation of the y chain may appear in different zones of the electrophoretic pattern. The carbonic anhydrase is not visualized on the hemoglobin electrophoretic patterns with capillary electrophoresis.

The provided text describes the analytical performance data for the CAPI 3 NEONAT Hb kit using the CAPILLARYS 3 DBS instrument. This device is intended for qualitative screening of normal and abnormal hemoglobins in newborn blood samples.

Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:

Acceptance Criteria and Reported Device Performance

The acceptance criteria for this device are implicitly demonstrated through its performance in various analytical studies, primarily focusing on 100% identification pattern concordance and high positive/negative percent agreement (PPA/NPA) compared to a reference method.

• Between capillaries: 100% (96.2%; 100.0%)
• Between lots: 100% (96.7%; 100.0%)
• Between instruments: 100% (96.7%; 100.0%)
• Between days: 100% (98.0%; 100.0%) |
  | Analytical Specificity/Interference: No significant interference from common endogenous substances. | No interference was detected from conjugated bilirubin (up to 40 mg/dL), unconjugated bilirubin (up to 40 mg/dL), and triglycerides (up to 1500 mg/dL). |
  | Qualitative Method Comparison: High agreement with a commercially available capillary electrophoresis reference procedure. | Internal Study:
• Positive Percent Agreement (PPA): 100% (95% CI: 94.6%; 100.0%)
• Negative Percent Agreement (NPA): 100.0% (95% CI: 94.9%; 100.0%)
  External Study No. 1 (USA):
• PPA: 100.0% (95% CI: 98.1%; 100.0%)
• NPA: 100.0% (95% CI: 98.2%; 100.0%)
  External Study No. 2 (Spain):
• PPA: 100.0% (95% CI: 96.9%; 100.0%)
• NPA: 100.0% (95% CI: 96.9%; 100.0%) |

Study Details Proving Acceptance Criteria

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

   • Precision Studies:

     • Identification Pattern Concordance: 8 different samples (6 newborn whole blood samples with FA, FAS, FAC, FAD, FAE, FA Bart's patterns, and 2 controls with AF, AFSC patterns).
       • Between capillaries: 12 analyses per sample (total 96 analyses).
       • Between lots: 6 analyses per sample (total 114 analyses).
       • Between instruments: 6 analyses per sample (total 114 analyses).
       • Between days: 10 analyses per sample (total 190 analyses).
     • Precision using controls (CLSI EP05-A3): 2 control samples (AF and AFSC patterns).
       • Within-laboratory: 480 analyses per control (total 960).
       • Between-lots: 90 analyses per control (total 180).
       • Between-instruments: 90 analyses per control (total 180).
     • Data Provenance: Not explicitly stated for precision samples' geographic origin, but samples include "new-born whole blood samples" and controls. The CLSI guidelines are international standards.

   • Analytical Specificity/Interference: Not explicitly stated how many samples were used, but the study evaluated common interfering factors at specified concentrations.

   • Qualitative Method Comparison:

     • Internal Study: 138 different newborn whole blood samples (71 normal and 67 pathological with variants S, C, D, E, and Bart's).
       • Data Provenance: Samples provided by 5 laboratories in France, Thailand, and Panama. This study was likely retrospective, using banked samples.
     • External Study No. 1: 411 different newborn whole blood samples (210 normal samples and 201 pathological samples with variants S, C, D, E, and Bart's).
       • Data Provenance: Samples analyzed in a laboratory based in the United States of America. This study was likely retrospective.
     • External Study No. 2: 240 different newborn whole blood samples (120 normal samples and 120 pathological samples with variants S, C, D, E, and Bart's).
       • Data Provenance: Samples analyzed in a laboratory based in Spain. This study was likely retrospective.

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

   • The document implies that the ground truth for the test set (qualitative method comparison) was established by a "commercially available capillary electrophoresis procedure for hemoglobin analysis (reference)." It does not mention the use of human experts for ground truth establishment. This suggests the reference method itself serves as the "gold standard" for comparison, not human interpretation in this context.

3. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

   • No human adjudication method is described. The comparison is directly between the candidate device and the "reference procedure."

4. 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:

   • No MRMC or human-in-the-loop study involving human reader improvement with AI assistance was performed or reported. This device is an in vitro diagnostic (IVD) instrument that provides qualitative results directly, not an AI-assisted diagnostic imaging tool requiring human interpretation improvement studies.

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

   • Yes, the performance data presented (precision, analytical specificity, method comparison) reflects the standalone performance of the CAPI 3 NEONAT Hb kit and CAPILLARYS 3 DBS instrument, as it is an automated IVD device. The results are automatically evaluated for pattern abnormalities with identification of normal and pathological patterns.

6. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

   • The ground truth for the qualitative method comparison studies was established by a "commercially available capillary electrophoresis procedure for hemoglobin analysis (reference)." This is an established laboratory method serving as the analytical gold standard.

7. The sample size for the training set:

   • This document describes analytical performance studies of a medical device, not a machine learning or AI algorithm development. Therefore, there is no mention of a "training set" in the context of machine learning. The device's underlying technology is capillary electrophoresis, and its performance is validated through traditional IVD analytical studies, not typically through machine learning training and testing paradigms that would involve a distinct "training set."

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

   • As this is not an AI/ML device in the sense of requiring a "training set" for model development, this question is not applicable to the information provided.

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The Premier Resolution System is an automated High Performance Liquid Chromatography (HPLC) system which performs the separation of hemoglobin species in venous whole blood samples for the quantitative analysis of normal hemoglobin (A, A2, and F), and the qualitative detection of major variant hemoglobin S, C, D-Los Angeles, and E in adult, adolescent, children and infant populations. The assays are performed on venous whole blood samples collected in tubes containing K2EDTA as anticoagulant.

The Premier Resolution System is intended for Professional Laboratory Use only.

The Premier Resolution System is intended for use with analytical components and reagents provided by Trinity Biotech.

The Premier Resolution System is intended to be used in conjunction with other laboratory and clinical findings.

For In Vitro Diagnostic Use.

The Premier Resolution System consists of a high performance liquid chromatographic analyzer, reagents, analytical column and software which allows for the fractionation and quantitation of fetal hemoglobin (Hb F), and hemoglobin A2 (Hb A2), and with fractionation and presumptive identification of abnormal hemoglobin variants. This is accomplished using the principles of ion-exchange (IEX) high performance liquid chromatography (HPLC).

This document describes the performance data for the "Premier Resolution System," an automated High Performance Liquid Chromatography (HPLC) system for hemoglobin analysis. The study aims to demonstrate that the device is substantially equivalent to a predicate device, the Bio-Rad Variant II ß-thalassemia (K991127).

1. Acceptance Criteria and Reported Device Performance:

The document outlines comparative performance against a predicate device (Bio-Rad Variant II ß-thalassemia) and precision studies. The acceptance criteria are implicitly defined by demonstrating comparability and acceptable precision, rather than explicit thresholds for each metric. The reported device performance includes:

2. Sample Size and Data Provenance (Test Set):

• Correlation (Method Comparison): A total of 780 unique patient samples were collected and analyzed. The data provenance is described as being collected and analyzed at three (3) professional external laboratory sites. It is implicit that these were retrospective real-world samples, as they are referred to as "patient samples" used for method comparison against an existing device. The country of origin is not explicitly stated, but given the FDA submission, it is likely the US.
• Precision (Single Site): The sample size for each analyte was 80 data points, generated by a 20x2x2 study design over 20 days, with two runs per day and two replicates per run. These were "samples of varying concentrations" and not explicitly patient samples.
• Precision (Multisite): The sample size for each analyte was 75 data points (3x5x5 study design across three external sites, over five days with five replicates per day). These were "precision samples."
• Limits of Detection: 60 determinations of low-level samples for each hemoglobin type. These were "human whole blood samples" with varying levels of hemoglobins.

3. Number of Experts and Qualifications for Ground Truth (Test Set):

This device is an in-vitro diagnostic (IVD) instrument for quantitative and qualitative analysis of hemoglobin species. The ground truth for such devices is typically established by well-characterized reference methods or by comparison to a legally marketed predicate device. In this submission, the primary method for establishing the device's performance is:

• Correlation (Method Comparison): Comparison against the Bio-Rad Variant II ß-thalassemia, which serves as the "ground truth" or reference for establishing substantial equivalence. No human experts are described as establishing ground truth for the test set, as the ground truth is the measurement from the predicate device.

4. Adjudication Method for the Test Set:

Not applicable. The study design involves direct comparison of quantitative measurements from two analytical instruments (device under review vs. predicate device), and precision of the device itself. There is no subjective interpretation requiring adjudication by experts.

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

Not applicable. This is an in-vitro diagnostic device that provides quantitative and qualitative measurements, not an image-based diagnostic system requiring human interpretation with or without AI assistance. Therefore, an MRMC study is not relevant.

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

Yes, the entire study focuses on the standalone performance of the "Premier Resolution System" as an automated HPLC system. There is no human-in-the-loop component described for its routine operation or for the performance studies presented. The device performs the analysis and provides results independently.

7. Type of Ground Truth Used:

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

• Comparison to a legally marketed predicate device: The Bio-Rad Variant II ß-thalassemia, for method comparison (correlation).
• Internal consistency and statistical measures: For precision (repeatability, within-laboratory, reproducibility) and limits of detection/quantitation. This relies on the inherent analytical capabilities and controls of the new device itself.

8. Sample Size for the Training Set:

The document does not explicitly describe a "training set" in the context of machine learning or AI models. This device is an automated HPLC system, where performance is based on chemical separation principles, not a learning algorithm that requires a separate training phase with labeled data in the AI sense. Its "training" or development would involve chemical and engineering optimization.

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 model for this device. The development of an HPLC system involves instrument design, reagent formulation, and software development, which are validated through analytical performance studies like those presented (precision, linearity, method comparison, etc.).

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The V8 Nexus Hemoglobin UltraScreen method is designed for the separation of normal hemoglobins (A, A2, and F) in human blood samples, and for the detection of major hemoglobins variants (S and C) by using a capillary zone electrophoresis (CZE) buffer with the V8 instrument. The V8 Nexus Hemoglobin UltraScreen test is indicated for use in patients 2 years of age and older. This test is designed for in-vitro diagnostic use only in conjunction with other laboratory and clinical findings.

The V8 instrument is an automated analyzer which performs a complete hemoglobin profile for quantitative analysis of the normal hemoglobin fractions A, A2 and F and for the detection of major hemoglobin variants S and C. The assay is performed on the hemolysate of venous whole blood collected in tubes containing K2EDTA as the anticoagulant. The V8 Nexus Hemoglobin UltraScreen method uses capillary zone electrophoresis (CZE) buffer with the V8 instrument for the separation of normal hemoglobins (A, A2, and F) and detection of major hemoglobin variants (S and C). The V8 AFSA2 Hemo Control is a control material derived from whole blood used as a quantitative and/or qualitative control for the Hemoglobin UltraScreen on the V8 Capillary Electrophoresis (CE) system.

The V8 Nexus Hemoglobin UltraScreen is a medical device for the separation of normal hemoglobins (A, A2, and F) and the detection of major hemoglobin variants (S and C) in human blood samples. The device uses capillary zone electrophoresis (CZE) and is indicated for in-vitro diagnostic use in patients 2 years of age and older.

Here's an analysis based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly derived from the precision/reproducibility and comparison studies. For the precision studies, the acceptance criteria would be the measured standard deviation (SD) and coefficient of variation (CV) of the hemoglobin fractions. For comparison studies, the acceptance criteria are generally an R-value close to 1, a slope close to 1, and an intercept close to 0, along with acceptable confidence intervals.

Linearity Acceptance Criteria and Performance:

Limit of Detection (LOD) and Limit of Quantitation (LOQ) Acceptance Criteria and Performance:

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

The "test set" in this context refers to the clinical samples used for the comparison studies with the predicate device.

• Sample Size for Comparison Studies (Test Set): A total of 439 patient samples were used across three external sites.
  • Hb A quantitation: 320 samples
  • Hb A2 quantitation: 412 samples
  • Hb F quantitation: 175 samples
  • Presumptive Hb S: 143 samples
  • Presumptive Hb C: 33 samples
• Data Provenance: The data comes from three external sites, suggesting a multi-center study setup. The samples were "fresh venous K2-EDTA-anticoagulated whole blood," indicating that these were prospective or recently collected samples for analysis. The country of origin is not explicitly stated, but given the submitter's address (Beaumont, Texas, USA) and FDA submission, it is likely the studies were conducted in the USA.

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

The document does not mention the use of experts to establish ground truth for the test set. Instead, the "ground truth" for the comparison studies was the results obtained from the predicate device, the Sebia CAPILLARYS Hemoglobin(E) Test (K112491).

4. Adjudication Method for the Test Set

No adjudication method is described for the test set. The comparison studies directly compared the performance of the V8 Nexus Hemoglobin UltraScreen to the predicate device.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of Human Reader Improvement

No MRMC comparative effectiveness study was done. This device is an in-vitro diagnostic assay for analyzing blood samples, not an image-based diagnostic that involves human readers.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, the studies presented are standalone (algorithm only) performance assessments of the V8 Nexus Hemoglobin UltraScreen instrument. These are bench-top studies and comparison studies demonstrating the device's analytical performance on its own, without direct human intervention in the interpretation of the capillary electrophoresis data beyond routine laboratory procedures. The instrument is described as an "automated analyzer."

7. The Type of Ground Truth Used

• For the precision/reproducibility studies, the ground truth was the known composition/percentages of hemoglobin fractions in the controls (AFSA2 and AFSC hemoglobin controls) and patient samples.
• For the comparison studies, the ground truth was the results obtained from the predicate device, the Sebia CAPILLARYS Hemoglobin(E) Test (K112491). This is a common approach for 510(k) submissions, where substantial equivalence to a legally marketed predicate device is demonstrated.

8. The Sample Size for the Training Set

The document does not explicitly describe a "training set" in the context of a machine learning algorithm. This device is a quantitative assay using capillary zone electrophoresis (CZE), a well-established analytical technique. While the term "training" might apply to calibration or method development, a distinct "training set" with established ground truth as would be used for AI/ML validation is not detailed here. The studies focus on analytical validation (precision, linearity, LOD/LOQ, analytical specificity) and comparison to a predicate.

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

As no specific "training set" for an AI/ML algorithm is described, the method for establishing its ground truth is not applicable in this document. The device's performance is validated against established laboratory standards, controls, and a predicate device.

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The CAPI 3 HEMOGLOBIN(E) kit is designed for the separation of the normal hemoglobins (A. A2 and F) in human venous blood samples, and for the detection of the major hemoglobin variants (S, C, E and D), by capillary electrophoresis in alkaline buffer (pH 9.4) with the SEBIA CAPILLARYS 3 TERA instrument.

The CAPILLARYS 3 TERA instrument is an automated analyzer which performs a complete for the quantitative analysis of the normal hemoglobin fractions A. A2 and F and for themoglobin variants S. C. E and D. The assay is performed on the hemolysate of whole blood samples collected in tubes containing K2EDTA or K3EDTA as anticoagulant. The CAPI 3 HEMOGLOBIN(E) is intended to be used in conjunction with other laboratory and clinical findings.

For In Vitro Diagnostic Use

The CAPILLARYS 3 instrument uses the principle of capillary electrophoresis in free solution which is the most common form of capillary electrophoresis. With this technique, charged molecules are separated by their electrophoretic mobility in an alkaline buffer with a specific pH. Separation also occurs according to the electrolyte pH and electroosmotic flow.

The CAPILLARYS 3 instrument has silica capillaries functioning in parallel allowing 12 simultaneous analyses for hemoglobin quantification in a whole blood sample. A sample dilution with hemolysing solution is prepared and injected by aspiration at the anodic end of the capillary. A high voltage protein separation is then performed and direct detection of the hemoglobins is made at the cathodic end of the capillary at 415 nm, which is the absorbance wave length specific to hemoglobins. Before each run, the capillaries are washed with a wash solution and prepared for the next analysis with buffer.

Direct detection provides accurate relative quantification of individual hemoglobin fraction, and the resulting electrophoregrams are also evaluated visually for pattern abnormalities. In addition, the high resolution of this procedure should allow the identification of hemoglobin variants, in particular, to differentiate hemoglobins S from D, and E from C. The hemoglobin A2 quantification can also be performed when hemoglobin E is present. A2 hemoglobin quantification may be used with other clinical and laboratory findings for ß thalassemia detection.

By using alkaline pH buffer, normal and abnormal (or variant) hemoglobins are detected in the following order, from cathode to anode: δΑ'2 (A2 variant). C. A2, E. S. D. F. and A.

The carbonic anhydrase is not visualized on the hemoglobin electrophoretic patterns by capillary electrophoresis, this permits to identify hemoglobin A2 variants in this migration zone.

NOTE : the name "CAPILLARYS 3" is used for the SEBIA CAPILLARYS 3 TERA automated instrument.

The hemoglobins are reported in % units along with an electrophoresis scan.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided FDA 510(k) summary:

Device: CAPI 3 HEMOGLOBIN(E) kit used with SEBIA CAPILLARYS 3 TERA instrument.

Intended Use: For the separation of normal hemoglobins (A, A2, F) in human venous blood and for the detection of major hemoglobin variants (S, C, E, D) by capillary electrophoresis. It provides quantitative analysis of fractions A, A2, F and detection of variants S, C, E, D.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a separate section with specific numerical thresholds for all performance metrics. Instead, it demonstrates performance through various studies and implies that the observed performance (e.g., correlation coefficients close to 1, low CVs for precision) is acceptable for substantial equivalence to a predicate device.

However, based on the provided performance data, we can infer the implied acceptance criteria from the reported excellent results, particularly for method comparison:

• Hb A Total CV: 0.0% - 1.3%
• Hb A2 Total CV: 1.3% - 6.5%
• Hb F Total CV: 2.5%
• Hb S Total CV: 0.6%
• Hb C Total CV: 1.4%
• Hb D Total CV: 1.4%
• Hb E Total CV: 1.6%
  20-days Reproducibility (1 instrument, 1 lot):
• Hb A Total CV: 0.0% - 0.8%
• Hb A2 Total CV: 1.4% - 6.0%
• Hb F Total CV: 0.7%
• Hb S Total CV: 1.0%
• Hb C Total CV: 1.7%
• Hb D Total CV: 0.6%
• Hb E Total CV: 1.1% |
  | Linearity | Demonstrated linearity across the clinically relevant range for all hemoglobin fractions. | Determined to be linear within the entire range studied for:
• Hb A (1.0 - 97.3%)
• HbS (1.1 - 89.7%)
• Hb A2 (0.2 - 9.1%)
• Hb F (0.5 - 83.1%)
• Hb C (0.3 - 82.0%)
• Hb D (1.1 - 43.5%)
• Hb E (0.3 - 86.9%) |
  | Limit of Blank (LOB) | Very low LOB values. | Hb A, Hb A2, Hb F, Hb S, Hb C, Hb D, Hb E: All 0.1% or 0.2% |
  | Limit of Detection (LOD) | Low LOD values indicating sensitivity to detect low concentrations. | Hb A: 1.0%, Hb A2: 0.2%, Hb F: 0.4%, Hb S: 0.9%, Hb C: 0.3%, Hb D: 0.7%, Hb E: 0.3% |
  | Limit of Quantitation (LOQ) | Low LOQ values indicating ability to accurately quantify at low concentrations. | Hb A: 1.0%, Hb A2: 0.2%, Hb F: 0.5%, Hb S: 1.1%, Hb C: 0.3%, Hb D: 1.1%, Hb E: 0.3% |
  | Analytical Specificity (Interference) | Insignificant interference from common substances like bilirubin and triglycerides at elevated levels. | Interference studies showed that Bilirubin (20.6 mg/dL) and Triglycerides (2.2 g/dL) did not significantly interfere with the analytical performance. (The document states studies were "conducted" and lists maximum concentrations without giving specific results of non-interference, but the conclusion implies acceptability). |
  | Method Comparison (Correlation) | Very high correlation coefficients (close to 1.000) for all hemoglobin fractions and variants when compared to a reference method, along with slopes near 1 and y-intercepts near 0 in regression analysis, demonstrating strong agreement. | Site 1:
• Hb A: 1.000 (Slope ~1.01, Y-intercept ~-1.0 to -0.7)
• Hb A2: 0.998 (Slope ~1.00, Y-intercept ~0.0 to -0.05)
• Hb F: 1.000 (Slope ~1.00-1.01, Y-intercept ~-0.008 to 0.05)
• Hb S, C, D, E: All 1.000 (Slopes ~1.01-1.02, Y-intercepts close to 0)
  Site 2:
• Hb A: 1.000 (Slope ~1.01-1.02, Y-intercept ~-1.9 to -1.4)
• Hb A2: 0.987 (Slope ~1.00-1.01, Y-intercept ~0.0 to -0.005)
• Hb F: 0.999 (Slope ~0.96-1.00, Y-intercept ~-0.12 to 0.0)
• Hb S, C, E: All 0.997 - 1.000 (Slopes ~1.00-1.06, Y-intercepts close to 0 or small variations) |
  | False Positives (Variant Detection) | No false positives in the detection of abnormal hemoglobin bands or abnormal levels of normal bands. | "There was no case observed of false positive, i.e., detection of an abnormal band or abnormal level of a normal band where no such abnormality existed." This statement is made for both Site 1 and Site 2 studies. |

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

• Sample Size for Test Set (Method Comparison): A total of 304 samples were used across two sites.
  • Site 1: 153 samples (64 with hemoglobin variants)
  • Site 2: 151 samples (60 with hemoglobin variants)
• Data Provenance: The samples were "provided by hospitals and laboratories international and United States." The study design is implied to be retrospective, as samples were collected and then analyzed by both the candidate and reference methods.

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

• The document does not explicitly state the number of experts used to establish ground truth or their specific qualifications (e.g., "radiologist with 10 years of experience").
• The "reference procedure" used for comparison is described as "a commercially available capillary electrophoresis technique for hemoglobin analysis." This implies that the ground truth for quantitative values and variant identification was established by a previously validated and accepted clinical laboratory method. For abnormal hemoglobin detection, the agreement with "clinical diagnosis" is also mentioned, suggesting that expert clinical assessment contributed to the overall understanding of the ground truth.

4. Adjudication Method (for the test set)

• The document does not explicitly describe an adjudication method (e.g., 2+1, 3+1).
• The comparison studies directly compare the quantitative results and variant detection of the candidate device against a "reference procedure." Any discrepancies would typically be investigated, but the method for their resolution is not detailed. The statement of "no observed false positives" implies a direct agreement determination.

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

• No, an MRMC comparative effectiveness study was not done.
• This device is an in-vitro diagnostic (IVD) for laboratory use that provides quantitative measurements and detects specific analytes. It does not involve human readers interpreting images or data for diagnosis in a way that would typically warrant an MRMC study to assess AI-assisted human performance improvement. The performance is assessed by comparison to a reference laboratory method.

6. Standalone Performance Study (algorithm only without human-in-the-loop performance)

• Yes, the provided performance data primarily represents the standalone performance of the device.
• The CAPI 3 HEMOGLOBIN(E) kit processes samples and provides quantitative results and variant detection via the automated CAPILLARYS 3 TERA instrument. The precision, linearity, LOB/LOD/LOQ, and analytical specificity studies, as well as the method comparison studies, evaluate the device's inherent analytical performance without direct human intervention in the result generation or interpretation (beyond standard laboratory procedures for running the instrument and reviewing results, which is inherent to any IVD). The measurements and variant identifications are generated by the instrument's software.

7. Type of Ground Truth Used

The ground truth for the test set was established primarily through:

• Reference Procedure/Comparative System: A "commercially available capillary electrophoresis technique for hemoglobin analysis" (predicate device or similar accepted method). This acts as the gold standard for quantitative values and identification of hemoglobin fractions and variants.
• Clinical Diagnosis: For the detection of abnormal hemoglobins, agreement with "clinical diagnosis" is also mentioned, suggesting that patient medical records and expert clinical assessment contributed to confirming the presence or absence of variants.

8. Sample Size for the Training Set

• The document does not explicitly state the sample size for the training set.
• As this is a 510(k) submission for an IVD kit and instrument, it's likely that extensive internal development and validation data would have been generated during the device's creation (which can be likened to a training/development phase), but this specific information is not typically required in the 510(k) summary provided. The focus of the 510(k) is often on the clinical validation/test set performance.

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

• The document does not explicitly describe how the ground truth for a training set was established.
• Given that this is an analytical device, the "training" (development) process would involve optimizing reagents, instrument parameters, and algorithms to accurately measure hemoglobin fractions and identify variants. This would typically involve using well-characterized control materials, spiked samples, and patient samples with known hemoglobin profiles (established by reference methods, genetic testing, or clinical diagnosis) to calibrate and refine the system, but the specifics are not detailed in this summary.

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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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The CAPILLARYS HEMOGLOBIN(E) kit is designed for the separation of the normal hemoglobins (A, A2 and F) in human blood samples, and for the detection of the major hemoglobin variants (S, C, E and D), by capillary electrophoresis in alkaline buffer (pH 9.4) with the SEBIA CAPILLARYS 2 FLEX-PIERCING instrument. The CAPILLARYS HEMOGLOBIN(E) kit is designed for laboratory use.

The CAPILLARYS 2 FLEX-PIERCING instrument is an automated analyzer which performs a complete hemoglobin profile for the quantitative analysis of the normal hemoglobin fractions A, A2 and F and for the detection of major hemoglobin variants S, C, E and D. The assay is performed on the hemolysate of whole blood samples collected in tubes containing K₂EDTA or K3EDTA as anticoagulant.

For In Vitro Diagnostic Use.

The CAPILLARYS 2 FLEX-PIERCING instrument is an automated analyzer which performs a complete hemoglobin profile for the quantitative analysis of the normal hemoglobin fractions A, A2 and F and for the detection of major hemoglobin variants S, C, E and D. The assay is performed on the hemolysate of whole blood samples collected in tubes containing K₂EDTA or K3EDTA as anticoagulant.

This is a 510(k) premarket notification for a medical device, which typically focuses on demonstrating substantial equivalence to a legally marketed predicate device rather than providing extensive details about acceptance criteria and comprehensive study reports as would be found in a Premarket Approval (PMA) application or a detailed clinical study publication.

Based on the provided document, here's an analysis of the information available regarding acceptance criteria and the study:

The document is an FDA 510(k) clearance letter for the Sebia CAPILLARYS HEMOGLOBIN(E) using the CAPILLARYS 2 FLEX-PIERCING instrument. This letter confirms that the FDA has reviewed the submission and determined that the device is "substantially equivalent" to legally marketed predicate devices. This means the device performs at least as well as existing devices on the market for its intended use.

Important Note: The provided document is the FDA's clearance letter and the "Indications for Use" page. It does not include the detailed study reports or the full 510(k) submission where the specific acceptance criteria and detailed study methodology would be found. Therefore, much of the requested information cannot be directly extracted from this document.

However, based on the nature of a 510(k) for an in vitro diagnostic (IVD) device like an abnormal hemoglobin assay, we can infer some general characteristics and make assumptions where specific details are not given.

1. Table of Acceptance Criteria and Reported Device Performance

This information is not provided in the given document. A 510(k) submission would typically include detailed performance data (e.g., accuracy, precision, analytical specificity, analytical sensitivity, linearity, limits of detection/quantification) compared against pre-defined acceptance criteria. The clearance letter only states that the device was found "substantially equivalent."

For an abnormal hemoglobin assay like this, typical acceptance criteria would involve:

• Accuracy/Agreement: Correlation or concordance with a reference method (e.g., HPLC, CE, or a predicate device) for identifying and quantifying hemoglobin fractions (A, A2, F) and variants (S, C, E, D). This might be expressed as a percentage agreement, mean bias, or confidence intervals.
• Precision: Reproducibility and repeatability of measurements (e.g., CV% for quantitative measurements) over various levels of hemoglobin.
• Interference: Lack of significant interference from common substances in blood.
• Analytical Sensitivity and Specificity: Ability to correctly detect and differentiate variants from normal and other variants.

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

This information is not explicitly stated in the provided document.

• Sample Size: While not mentioned, IVD 510(k) studies typically involve a few hundred to a few thousand samples for method comparison, precision, and other analytical performance evaluations. These samples would ideally cover a range of hemoglobin types (normal, various variants) and concentrations.
• Data Provenance: The document does not specify the country of origin. Given Sebia Inc. is in Georgia, USA, and the FDA is a US regulatory body, some data would likely be from the US, but it could also include international study sites. It's highly probable the study was retrospective for clinical samples used in method comparisons and prospective for collecting data during validation studies (e.g., precision, linearity).

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

This information is not provided in the given document.

For an IVD device like this, ground truth is typically established using:

• An established reference method (e.g., High-Performance Liquid Chromatography (HPLC) or another capillary electrophoresis system that is considered a gold standard).
• In some cases, samples might be characterized by multiple orthogonal methods to confirm the presence and type of hemoglobin variants.
• Less commonly, individual "experts" are used to establish ground truth for quantitative assays unless the ground truth is a subjective clinical interpretation (which is not the case for hemoglobin fractions). If expert review was part of a discrepant analysis, it would typically involve clinical laboratory scientists or pathologists experienced in hemoglobinopathy diagnostics.

4. Adjudication Method for the Test Set

This information is not provided in the given document.

Adjudication methods (like 2+1 or 3+1) are typically used when the ground truth itself is subject to inter-rater variability, often in image-based diagnostic systems or clinical assessments where experts interpret data. For a quantitative assay like hemoglobin electrophoresis, the "adjudication" would more likely involve:

• Statistical analysis of agreement between the device and the reference method.
• Discrepant analysis: Cases where the device result differs from the reference method would be re-tested by both methods, potentially using an additional confirmatory method, to understand the source of the discrepancy. This is more of a technical investigation than an expert adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size

No, an MRMC comparative effectiveness study was almost certainly NOT done for this device.

• Reasoning: MRMC studies are primarily relevant for diagnostic imaging devices or other systems where human readers interpret complex data, and the AI system is intended to assist or replace human interpretation.
• This device, the Sebia CAPILLARYS HEMOGLOBIN(E) system, is an automated in vitro diagnostic (IVD) assay. It performs analytical separation and quantification of hemoglobin fractions. While a human might interpret the final report, the core function of the device is automated analysis, not "reading" in the sense of a radiologist interpreting an image.
• Therefore, there's no "human readers improve with AI vs without AI assistance" scenario applicable to evaluate using an MRMC study for this type of device.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, the primary performance evaluation for this device would be a standalone (algorithm only) performance study.

• Reasoning: As an automated IVD assay, the device's performance (accuracy, precision, etc.) is assessed based on its ability to correctly identify and quantify hemoglobin fractions and variants directly from the blood sample using its internal algorithms and methods.
• The "performance" is the output of the instrument, not dependent on human-in-the-loop interpretation during the measurement process. A human reviews the results generated by the device, but the device's analytical performance is tested independently of that human review. This is the standard for IVD assays.

7. The Type of Ground Truth Used

Based on the device type (automated hemoglobin assay), the ground truth would most likely be established by:

• Reference Methods: Such as a "gold standard" High-Performance Liquid Chromatography (HPLC) system or another well-established and validated capillary electrophoresis (CE) method from a reputable manufacturer, or a combination of methods.
• Potentially, molecular diagnostics (DNA sequencing) for definitive identification of specific hemoglobin variants where biochemical methods might be ambiguous.
• Expert Consensus (less likely as primary ground truth): While a lab director or clinical pathologist would oversee the process, the "ground truth" for the quantitative values and variant identification is typically derived from objective analytical methods rather than expert visual interpretation for this specific type of assay.

8. The Sample Size for the Training Set

This information is not provided in the given document.

• Reasoning: For an automated IVD device like this, which likely uses established biochemical principles and algorithms for peak detection and quantification, a "training set" in the machine learning sense might not be explicitly defined or might be integrated into the algorithm development and validation process rather than being a distinct "training set" for a separate machine learning model from a clinical dataset.
• If any machine learning or signal processing algorithms were fine-tuned, the training data size would depend on the complexity of the algorithm and the variability of the input signal. This data would typically consist of electropherogram patterns with known hemoglobin compositions.

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

This information is not provided in the given document.

• Reasoning: Similar to the training set size, if there was a "training set" for internal algorithm development, the ground truth would be established by analyzing samples with known hemoglobin compositions using established reference methods (HPLC, confirmed CE, perhaps genetic testing). This allows the algorithm to learn to accurately identify and quantify the various peaks corresponding to normal hemoglobins and common variants.

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The CAPILLARYS HEMOGLOBIN(E) kit is designed for the separation of the normal hemoglobins (A, A2 and F) in human blood samples, and for the detection of the major hemoglobin variants (S, C, E and D), by capillary electrophoresis in alkaline buffer (pH 9.4) with the SEBIA CAPILLARYS 2 instrument. The CAPILLARYS HEMOGLOBIN(E) kit is designed for laboratory use.

The CAPILLARYS 2 instrument is an automated analyzer which performs a complete hemoglobin profile for the quantitative analysis of the normal hemoglobin fractions A, A2 and F and for the detection of major hemoglobin variants S, C, E and D. The assay is performed on the hemolysate of packed red blood cells from blood samples collected in tubes containing KoEDTA or KsEDTA as anticoagulant.

For In Vitro Diagnostic Use.

The CAPILLARYS 2 instrument is an automated analyzer which performs a complete hemoglobin profile for the quantitative analysis of the normal hemoglobin fractions A, A2 and F and for the detection of major hemoglobin variants S, C, E and D. The assay is performed on the hemolysate of packed red blood cells from blood samples collected in tubes containing KoEDTA or KsEDTA as anticoagulant.

The provided text describes a 510(k) premarket notification for the "Sebia CAPILLARYS HEMOGLOBIN(E) using the CAPILLARYS 2 instrument." However, this document does not contain the detailed study information, acceptance criteria, or performance data that you requested.

The document mainly focuses on:

• The FDA's decision of substantial equivalence.
• The regulatory classification (Class II, Product Code GKA).
• General information about FDA regulations for medical devices.
• The intended use of the device.

Therefore, I cannot provide the specific details about acceptance criteria, performance, sample sizes, ground truth establishment, or expert qualifications as these are not present in the given text.

To answer your request, I would need a different document, typically a Summary of Safety and Effectiveness or a full clinical study report, which is usually part of the 510(k) submission but not contained within this FDA correspondence letter.

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The CAPILLARYS NEONAT Hb kit is designed for the separation of the normal hemoglobins (F and A) in blood samples from human new-borns, and for the major hemoglobin vanants (S, C, E, D and Bart's), by electrophoresis in alkaline buffer (pH 9.4) with the CAPILLARYS 2 System. The CAPILLARYS NEONAT Hb kit is designed for laboratory use.

The CAPILLARYS 2 is an automated analyzer which performs a complete hemoglobin profile for the qualitative analysis of hemoglobins. The assay is performed on the hemolysate of whole blood samples previously collected on filter paper.

For In Vitro Diagnostic Use.

The Hb AF Control is designed:

• for the migration control before starting a new analysis sequence and for the qualitative quality control, for human hemoglobins A and F with the SEBIA CAPILLARYS NEONAT Hb electrophoresis procedure used with the CAPILLARYS 2 system, and,

• for the quantitative quality control for detection of the human hemoglobins A, F and A2 with the SEBIA electrophoresis procedures : HYDRAGEL HEMOGLOBIN(E) used with the HYDRASYS system, CAPILLARYS HEMOGLOBIN(E) used with the CAPILLARYS system and MINICAP HEMOGLOBIN(E) used with the MINICAP system.

The Hb AF Control is designed for laboratory use. It should be used (with its bar code label for the CAPILLARYS and MINICAP procedures) like a normal human blood. The values obtained must fall within the range provided with each batch of Hb AF Control.

For In Vitro Diagnostic Use.

The CAPILLARYS 2 is an automated analyzer which performs a complete hemoglobin profile for the qualitative analysis of hemoglobins. The assay is performed on the hemolysate of whole blood samples previously collected on filter paper.

The provided text is a 510(k) premarket notification decision letter from the FDA regarding a medical device, specifically the CAPILLARYS NEONAT Hb kit and Hb AF CONTROL. This type of document typically focuses on establishing substantial equivalence to a predicate device rather than detailing extensive clinical study results with specific acceptance criteria, sample sizes for training or test sets, or ground truth establishment methods for an AI/algorithm-based device.

Therefore, the information requested in your prompt regarding acceptance criteria, study details, sample sizes, expert qualifications, and AI-specific metrics (MRMC, standalone performance, training set ground truth) is not present in the provided document.

This document confirms that the device is substantially equivalent to legally marketed predicate devices for its stated indications for use, without delving into the detailed experimental design and results that would be expected for a novel AI-driven diagnostic.

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The MINICAP HEMOGLOBIN(E) kit is designed for the separation of the normal hemoglobins (A, F and A2) and for the detection of the major hemoglobin variants (especially S, C, E or D), by electrophoresis in alkaline buffer (pH 9.4) with the MINICAP System. The MINICAP performs all sequences automatically to obtain a complete hemoglobin profile for qualitative or quantitative anailysis of hemoglobins. The assay is performed on sedimented, centrifuged or washed red blood cells; washing red blood cells is not essential to perform the analysis. For In Vitro Diagnostic Use

The MINICAP HEMOGLOBIN(E) kit is designed for the separation of the normal hemoglobins (A, F and A2) and for the detection of the major hemoglobin variants (especially S, C, E or D), by electrophoresis in alkaline buffer (pH 9.4) with the MINICAP System. The MINICAP performs all sequences automatically to obtain a complete hemoglobin profile for qualitative or quantitative anailysis of hemoglobins. The assay is performed on sedimented, centrifuged or washed red blood cells; washing red blood cells is not essential to perform the analysis.

The provided document is a 510(k) clearance letter from the FDA for a device called "MINICAP HEMOGLOBIN(E) Kit, Model 2207, 2227." This document certifies that the device is substantially equivalent to legally marketed predicate devices.

However, the document does not contain the specific information requested about acceptance criteria and detailed study results. It is a regulatory clearance document, not a scientific study report or clinical trial summary.

Therefore, I cannot extract the following information from the provided text:

1. A table of acceptance criteria and the reported device performance: This document only states that the device is "substantially equivalent" to predicate devices, but doesn't provide specific performance metrics or acceptance criteria used to establish that equivalence.
2. Sample sizes used for the test set and data provenance: Not mentioned.
3. Number of experts used to establish the ground truth for the test set and their qualifications: Not mentioned.
4. Adjudication method for the test set: Not mentioned.
5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, and its effect size: Not mentioned.
6. If a standalone performance study was done: Not explicitly detailed, beyond the claim of substantial equivalence.
7. The type of ground truth used: Not mentioned.
8. The sample size for the training set: Not mentioned.
9. How the ground truth for the training set was established: Not mentioned.

The document primarily focuses on regulatory approval and the device's intended use: "designed for the separation of the normal hemoglobins (A, F and A2) and for the detection of the major hemoglobin variants (especially S, C, E or D), by electrophoresis in alkaline buffer (pH 9.4) with the MINICAP System."

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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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