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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 FLC Kappa kit is intended for the quantification of Kappa free light chains in human serum from adults with an Enzyme-Linked Immunosorbent Assay (ELISA) procedure. Measurement of free light chains aids in the diagnosis and monitoring of multiple myeloma and AL amyloidosis. It must be used in conjunction with other laboratory and clinical findings. For In Vitro Diagnostic Use only.

The FLC Lambda kit is intended for the quantification of Lambda free light chains in human serum from adults with an Enzyme-Linked Immunosorbent Assay (ELISA) procedure. Measurement of free light chains aids in the diagnosis and monitoring of multiple myeloma and AL amyloidosis. It must be used in conjunction with other laboratory and clinical findings. For In Vitro Diagnostic Use only.

The FLC Kappa and FLC Lambda test kits are intended for the quantification of free light chains in human serum from adults with an Enzyme-Linked Immunosorbent Assay (ELISA) procedure utilizing specific antibodies targeting anti-Lambda free light chains.

It is carried out in 8 successive steps:

• Incubation of the previously diluted samples and calibrators, in the wells of the microplate, where specific free light chain antibodies are fixed.
• Washing of the wells to remove elements that have not been fixed by the anti-free light chain antiserum.
• Incubation with an anti- light chain antiserum (Kit specific) conjugated to peroxidase.
• Washing of the wells to remove the excess of antiserum conjugated to peroxidase.
• Incubation with peroxidase substrate.
• Stopping of the enzymatic reaction with an acidic solution.
• Reading of the optical density by absorbance spectrophotometry at 450 nm of the colored product.
• Calculation of the free light chain concentration of the sample using a calibration curve obtained with calibrators that have been analyzed on the same microplate.

The provided document is an FDA 510(k) clearance letter and associated summary for the Sebia FLC Kappa and FLC Lambda kits. These kits are in vitro diagnostic (IVD) devices used for quantifying free light chains in human serum. They are immunoassay-based tests, not AI/ML-driven devices.

Therefore, the requested information regarding acceptance criteria and study details for an AI/ML device cannot be extracted from this document. The concepts of "test set," "training set," "experts to establish ground truth," "adjudication methods," "MRMC studies," and "standalone performance" are relevant to AI/ML device evaluations, but they do not apply to the traditional IVD assay described here.

The document discusses analytical and clinical studies for the immunoassay, focusing on performance characteristics such as:

• Clinical Study: Evaluates the concordance of FLC Kappa and FLC Lambda kit results with clinical assessment and other tests for monitoring Multiple Myeloma and AL Amyloidosis.
  • Sample size:
    • Multiple Myeloma: 551 follow-up samples from 235 unique subjects.
    • AL-amyloidosis: 190 follow-up samples from 87 unique subjects.
  • Data Provenance: Subjects had "expanded racial and ethnic diversity (Caucasian, African American, Hispanic, Asian)". No specific country of origin is mentioned, but the manufacturer is based in France and the submission is to the US FDA. The studies appear to be retrospective analyses of follow-up samples.
  • Ground Truth: Clinical assessment and other tests based on criteria from the IMWG (International Myeloma Working Group) for Multiple Myeloma and consensus guidelines (Comenzo et al., 2012; Palladini et al., 2012; Kumar et al., 2022 NCCN guidelines) for AL-Amyloidosis.
  • No mention of experts establishing ground truth or adjudication methods in the context of human readers for an AI system, as this is a laboratory assay.
  • No MRMC study, as this is not an image-based or AI-assisted diagnostic.
  • No separate "standalone" algorithm performance because the device itself is the diagnostic assay.
  • No specific training set or how its ground truth was established is mentioned, as this is a traditional laboratory assay, not a machine learning model.
• Stability Studies: Determined shelf-life for the kits and controls.

In summary, this document describes a traditional immunoassay, not an AI/ML device. Thus, the requested AI/ML-specific information is not applicable and not present.

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The FLC Kappa kit is intended for the quantification of Kappa free light chains in human serum from adults with an Enzyme-Linked Immunosorbent Assay (ELISA) procedure. Measurement of free light chains aids in the diagnosis of multiple myeloma and AL amyloidosis. It must be used in conjunction with other laboratory and clinical findings. For In Vitro Diagnostic Use.

The FLC Lambda kit is intended for the quantification of Lambda free light chains in human serum from adults with an Enzyme-Linked Immunosorbent Assay (ELISA) procedure. Measurement of free light chains aids in the diagnosis of multiple myeloma and AL amyloidosis. It must be used in conjunction with other laboratory and clinical findings. For In Vitro Diagnostic Use.

The FLC Kappa and FLC Lambda test kits are intended for the quantification of free light chains in human serum from adults with an Enzyme-Linked Immunosorbent Assay (ELISA) procedure utilizing specific antibodies targeting anti-Lambda free light chains. It is carried out in 8 successive steps: Incubation of the previously diluted samples and calibrators, in the wells of the microplate, where specific free light chain antibodies are fixed. Washing of the wells to remove elements that have not been fixed by the anti-free light chain antiserum. Incubation with an anti- light chain antiserum (Kit specific) conjugated to peroxidase. Washing of the wells to remove the excess of antiserum conjugated to peroxidase. Incubation with peroxidase substrate. Stopping of the enzymatic reaction with an acidic solution. Reading of the optical density by absorbance spectrophotometry at 450 nm of the colored product. Calculation of the free light chain concentration of the sample using a calibration curve obtained with calibrators that have been analyzed on the same microplate.

Here's a breakdown of the acceptance criteria and study details for the Sebia FLC Kappa and FLC Lambda kits, based on the provided FDA 510(k) summary.

Note: This document describes an in vitro diagnostic (IVD) device, which measures specific analytes (free light chains) in human serum using a laboratory assay (ELISA). The concepts of "AI assistance," "human readers," "radiologist," and "image" are not relevant to this type of device. Therefore, sections pertaining to these concepts (like MRMC studies) are not applicable and will be marked as such. The "ground truth" for an IVD kit is established through various analytical performance studies demonstrating its accuracy and reliability compared to established methods, and clinical studies correlating its results with disease states.

Acceptance Criteria and Device Performance for Sebia FLC Kappa and FLC Lambda Kits

1. Table of Acceptance Criteria & Reported Device Performance

The FDA 510(k) summary does not explicitly present a "table of acceptance criteria" in the format of pass/fail thresholds. Instead, it details various performance studies and their results, which implicitly form the basis for acceptance. The reported device performance is indicated by the successful execution of these studies and the obtained values meeting recognized clinical laboratory standards (e.g., CLSI guidelines).

General Performance Categories and Key Findings:

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The HYDRASHIFT 2/4 isatuximab kit is intended for the qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis. The HYDRASHIFT 2/4 isatuximab kit is to be used in conjunction with the HYDRAGEL IF kit and the semi-automated HYDRASYS 2 electrophoresis apparatus. The electropherograms are evaluated visually for the presence of specific reactions with the suspect monoclonal proteins. The HYDRASHIFT 2/4 isatuximab kit removes isatuximab IgG kappa interference and enables the visual evaluation of the presence of monoclonal proteins on HYDRAGEL IF kits in patients who have received isatuximab therapy.

For In Vitro Diagnostic use. For Prescription Use Only.

HYDRASYS 2 is a semi-automated multi-parameter system for start-to finish agarose gel electrophoresis: application of samples, migration, drying, staining, destaining and final-stage drying.

Abnormal bands in serum protein electrophoregrams, primarily those in the beta globulin and gamma globulin zones, are always suspected to be monoclonal proteins (M-proteins, paraproteins, monoclonal immunoqlobulins) and therefore, an indication of performing an Immunofixation technique to type and confirm the monoclonal gammopathies.

lsatuximab is a human therapeutic IgG kappa monoclonal antibody and as such, during the clinical monitoring of patients treated with isatuximab, this antibody simulates a band detected by serum protein electrophoresis and immunofixation in the gamma region. It can simulate an endogenous IgG kappa paraprotein.

The HYDRASHIFT isatuximab immunofixation procedure, performed on the HYDRAGEL IF 2/4 gel, is based on the creation of an isatuximab / anti-isatuximab antibody complex and shifting it outside the gammaglobulins zone. With the HYDRASHIFT isatuximab procedure, the isatuximab / anti-isatuximab antibody complex is visualized in alpha-1 zone on IgG and Kappa immunofixation tracks and then the interference is removed from the gamma zone.

The provided text describes the performance data for the HYDRASHIFT 2/4 isatuximab kit, which is intended for the qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis, specifically by removing isatuximab IgG kappa interference.

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

Acceptance Criteria and Reported Device Performance

The core acceptance criterion for this device, based on the performance data presented, is 100% concordance in visual evaluation of the presence or absence of monoclonal proteins, particularly after the removal of isatuximab interference.

Study Details Proving Device Meets Acceptance Criteria

1. A table of acceptance criteria and the reported device performance:
(See table above)

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

• Repeatability Study: 10 different serum samples (2 controls, 8 spiked with monoclonal components). 4 runs per sample within the same gel.
• Reproducibility Study: 8 different serum samples with monoclonal components + Normal Control Serum + Isatuximab Control. Each sample analyzed on 9 runs (1 analysis per gel, over 3 working days) on 3 HYDRASYS 2 instruments with 3 lots of HYDRASHIFT 2/4 isatuximab kit.
• Comparative Studies:
  • Internal Study: 53 serum samples (26 normal, 27 pathological).
  • External Study No. 1: 204 serum samples.
  • External Study No. 2: 203 serum samples. (Note: "The same serum samples were analyzed in both external studies with exception of one sample included in external study 1." suggesting ~204 unique samples across external studies.)

Data Provenance:

• Internal Study: Conducted by Sebia (manufacturer).
• External Studies: Performed in the USA.
• Retrospective/Prospective: Not explicitly stated, but the description of "serum samples" and "analyzed with" suggests they were existing or collected samples, making it likely retrospective for the comparative studies. The repeatability and reproducibility studies appear to be prospective experimental designs.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
The document does not specify the number or qualifications of experts used to establish the ground truth. The results are described as "100% concordant" based on detection and characterization of monoclonal proteins, which implies a pre-established or expert-verified classification for each sample. However, the exact process or personnel involved in this ground truth establishment are not detailed. Given it's an in vitro diagnostic (IVD) device for lab use, the "ground truth" would likely be the result of a reference method interpretation by qualified lab personnel.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:
The document does not specify any adjudication method. The outcome measures are presented as "100% concordant results," which suggests a clear, unambiguous read for each test, or that any discrepancies were resolved, though the process for resolution is not described.

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:
No MRMC study was performed or described. This device is an in vitro diagnostic (IVD) kit for immunofixation electrophoresis, not an AI-assisted diagnostic imaging device for human readers. It automates a lab procedure and provides an electropherogram for visual evaluation. The "visual evaluation" mentioned refers to lab personnel interpreting the results of the gel electrophoresis.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
Yes, effectively. This device is an IVD kit. Its performance is evaluated on its ability to process serum samples and produce an electropherogram that then is visually evaluated. The "performance data" sections (repeatability, reproducibility, comparative studies) essentially describe the standalone performance of the kit itself in consistently producing the expected analytical result (i.e., shifting the isatuximab band and allowing for accurate detection/characterization of monoclonal proteins). While the final "reading" is visual, the kit's function is mechanistic/chemical, not algorithmic interpretation requiring human oversight in the AI sense.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
The ground truth appears to be based on the presence and characterization of monoclonal proteins in serum samples, determined by standard laboratory methods and potentially confirmed by expert consensus in a clinical laboratory setting. For the comparative studies, samples were characterized as "normal" or "abnormal with monoclonal components," implying a reference standard or pre-established truth for each sample type. The "native" samples and "spiked" samples with isatuximab served as a form of ground truth for evaluating the device's ability to differentiate between intrinsic monoclonal proteins and isatuximab interference.

8. The sample size for the training set:
Not applicable/Not specified. This is an in vitro diagnostic (IVD) kit, not a machine learning or AI-based device that typically requires a separate "training set" for model development. The development process for such a kit involves chemical and biochemical optimization rather than data-driven learning.

9. How the ground truth for the training set was established:
As above, not applicable. The device is a wet-lab kit, not an AI algorithm.

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The CAPI 3 IMMUNOTYPING kit is designed for the qualitative detection and the characterization of monoclonal proteins (immunotyping) in human urine and serum with the CAPILLARYS 3 TERA instrument, SEBIA, for capillary electrophoresis. It is used in conjunction with the CAPI 3 PROTEIN(E) 6 kit, SEBIA, designed for proteins separation into 6 major fractions in alkaline buffer (pH 9.9).

The CAPILLARYS 3 TERA instrument performs all procedural sequences automatically to obtain a profile for qualitative analysis. Each urine or serum sample is mixed with individual antisera that are specific against gamma (Ig G). alpha (Ig A) and mu (Ig M) heavy chains, and kappa (free and bound) light chains and lambda (free and bound) light chains, respectively.

The proteins, separated in silica capillaries, are directly detected by their absorbance at 200 nm.

The electrophoregrams are evaluated visually to detect the presence of specific reactions with the suspect monoclonal proteins.

For In Vitro Diagnostic Use.

The capillary electrophoresis provides complete automation with fast separation and good resolution. This electrokinetic separation technique is carried out in a silica glass tube (i.e., capillary) with internal diameter lower than 100 um filled with a buffer composed of electrolytes.

The CAPILLARYS 3 TERA instrument uses the principle of capillary electrophoresis in free solution. With this technique, charged molecules are separated by their electrophoretic mobility in an alkaline buffer with a specific pH. Separation occurs according to the electrolyte pH and electroosmotic flow. The CAPILLARYS 3 TERA instrument has silica capillaries functioning in parallel allowing 12 simultaneous analyses.

In capillary electrophoresis, abnormal fractions detected in serum or urine protein electrophoregrams, primarily those in the beta globulin and gamma globulin zones, are always suspect of being monoclonal proteins (M-proteins, paraproteins, monoclonal immunoglobulins). With the CAPI 3 IMMUNOTYPING procedure, the immunotyping procedure uses specific antibodies to identify these abnormal fractions.

In immunotyping a sample dilution is prepared and injected at the anodic end of six capillaries. The reference pattern (ELP pattern), which is a complete electrophoretic pattern of the sample's proteins, is obtained by mixing the sample with the ELP solution and injection into the 1st capillary. The antisera patterns are obtained by sample aspiration into the 5 subsequent capillaries. Previously diluted samples are mixed with specific antisera against gamma (Ig G), alpha (lg A), mu (lg M) heavy chains, and free and bound Kappa and Lambda light chains. Protein separation is performed in a high voltage electrical field. The separated proteins are detected using absorbance at 200 nm at the cathodic end of the capillary. After the analysis, the capillaries are immediately washed with a wash solution and filled with buffer which prepares the capillaries for the next analysis.

The immunotyping is performed in four automated steps:

1. Dilution of serum or urine samples with a specific diluent in the pre-dilution well of the reagent cup. This dilution is made according to the sample's immunoglobulin concentration.
2. Mixing diluted serum sample with specific antisera. The antigen - antibody complex is formed rapidly in liquid medium without the need for extra incubation step or removal of the immune complexes.
3. Injection of the prepared samples with simultaneous aspiration into 6 capillaries at the anodic end. Protein separation occurs when a high voltage field is applied to the alkaline buffer. The separated proteins are detected using absorbance at 200 nm at the cathodic end of the capillary.
4. Overlay of the ELP pattern on the antisera patterns (Ig G, Ig A, Ig M, Kappa and Lambda) allows characterization of suspected monoclonal component.

Here's an analysis of the acceptance criteria and study data for the CAPI 3 IMMUNOTYPING device, based on the provided FDA 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The FDA 510(k) summary does not explicitly list predefined quantitative acceptance criteria with specific numerical thresholds for all performance metrics (e.g., repeatability, reproducibility, accuracy). Instead, for qualitative assessments, the acceptance criterion appears to be "concordant results" or "100% agreement." For sensitivity, the acceptance criterion is implicitly shown by the reported detection limits.

• Lambda free: 0.010 g/L (1.0 mg/dL)
• Kappa free: 0.030 g/L (3.0 mg/dL)
• IgG Lambda: 0.004 g/L (0.4 mg/dL)
• Lambda (part of IgG Lambda): 0.004 g/L (0.4 mg/dL) |
  | Sample Stability (2-8 °C) | Results after 1 week storage at 2-8 °C should comply with "acceptance criteria defined by SEBIA." (Specific criteria not detailed in document). | The results obtained complied with the acceptance criteria defined by SEBIA. Conclusion: Urine samples can be stored for 1 week between 2 and 8 °C. |
  | Sample Stability (-70/-80 °C) | Results after 1 month storage at -70/-80 °C should comply with "acceptance criteria defined by SEBIA." (Specific criteria not detailed in document). | The results obtained complied with the acceptance criteria defined by SEBIA. Conclusion: Urine samples can be stored for 1 month between -70 and -80 ℃. |
  | Kit Stability (CAPI 3 IMMUNOTYPING sample diluent) | Stable for 2 years at 2 - 30 °C. (The acceptance criterion is the claimed stability period and conditions). | 2 years at 2 - 30 °C (Reported as claimed stability). |
  | Kit Stability (CAPI 3 IMMUNOTYPING ELP solution) | Stable for 2 years at 2 - 8 °C. (The acceptance criterion is the claimed stability period and conditions). | 2 years at 2 - 8 °C (Reported as claimed stability). |
  | Kit Stability (CAPI 3 IMMUNOTYPING antisera) | Stable for 2 years at 2 - 8 °C. (The acceptance criterion is the claimed stability period and conditions). | 2 years at 2 - 8 °C (Reported as claimed stability). |
  | On-Board Stability (Sample Diluent, ELP, Antisera) | Stable for 2 months on-board the instrument. (The acceptance criterion is the claimed stability period). | 2 months (Reported as claimed stability). |
  | Accuracy/Concordance | 100% agreement between the test technique (CAPI 3 IMMUNOTYPING on CAPILLARYS 3 TERA) and the reference technique (CAPILLARYS IMMUNOTYPING on CAPILLARYS 2) for qualitative results, including presence/absence and type of monoclonal component. | This study demonstrated 100% agreement between the two techniques for all 52 urine samples (8 without, 44 with monoclonal components of various types). This 100% agreement was confirmed for specific monoclonal protein types (IgG Lambda, IgG Kappa, IgG Lambda with Lambda free, IgG Kappa with Kappa free, Lambda free, Kappa free, IgM Kappa with Kappa free, IgA Lambda, IgA Lambda with Lambda free, and without Monoclonal). |

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

• Repeatability: 4 different urine samples with monoclonal proteins (including Bence Jones proteins).
• Reproducibility: 3 different urine samples with monoclonal proteins (including Bence Jones proteins).
• Sensitivity: 3 pathological urine samples, serially diluted in normal urine.
• Sample Stability (2-8 °C): 10 urine samples (normal and pathological).
• Sample Stability (-70/-80 °C): 10 urine samples (normal and pathological).
• Accuracy/Concordance: 52 urine samples (8 without monoclonal component, 44 with monoclonal component including Bence Jones proteins).

Data Provenance: The document does not explicitly state the country of origin of the data or whether it was retrospective or prospective. Given that it's a 510(k) submission from Sebia (manufacturing in France, submitter in USA), and refers to "urine samples," these are likely clinical samples, but details on their origin are not provided. The phrase "analyzed at the beginning of the study (reference) and after X storage (test)" suggests a prospective element for the stability studies on stored samples.

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

The document states: "All electrophoregrams were evaluated visually for the qualitative results." However, it does not specify the number of experts used for ground truth establishment or their qualifications (e.g., "radiologist with 10 years of experience"). This is a significant omission from the perspective of external validation of the ground truth. It is implied that visual evaluation by trained personnel (likely laboratory professionals or experts in electrophoresis interpretation) was the method, but no further details are provided.

4. Adjudication Method for the Test Set

The document does not detail an adjudication method (such as 2+1 or 3+1 consensus) for the visual evaluation of electrophoregrams. It simply states they were "evaluated visually." This implies a single evaluator, or an internal process where disagreement (if any) was resolved, but the process is not described.

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

No multi-reader multi-case (MRMC) comparative effectiveness study was described. The accuracy/concordance study compares the new device's visual interpretation results to an existing, cleared device's visual interpretation results, which is a comparison of two methods, not an assessment of human readers with and without AI assistance. The device itself is a qualitative detection and characterization system, and the evaluation stated is "electrophoregrams were evaluated visually," indicating human interpretation is still involved in the final result.

6. Standalone Performance Study

The studies described (repeatability, reproducibility, sensitivity, stability, accuracy/concordance) evaluate the performance of the integrated system (CAPI 3 IMMUNOTYPING kit on CAPILLARYS 3 TERA instrument). The "electrophoregrams are evaluated visually" suggests human-in-the-loop performance, rather than a purely standalone algorithm. The device produces a "protein profile for qualitative analysis," which is then visually interpreted. Therefore, a standalone (algorithm only) performance study, in the sense of an AI algorithm making a definitive diagnosis without human oversight, does not appear to have been performed or is not directly applicable to the described use case which involves visual evaluation.

7. Type of Ground Truth Used

The ground truth for the test sets (e.g., for accuracy, repeatability, reproducibility studies) appears to be established by the visual evaluation of electrophoregrams performed by an expert or experts using a "reference technique" or the device itself.

• For the accuracy/concordance study, the "reference technique" (CAPILLARYS IMMUNOTYPING URINE procedure performed with the CAPILLARYS 2 instrument) served as the comparator for establishing ground truth, assuming the predicate device's results are considered the established truth.
• For other studies like repeatability and reproducibility, the "ground truth" seems to implicitly be the correct identification of presence/absence and type of monoclonal protein based on the expected outcome for the known pathological samples, assessed by visual evaluation.
• No mention of pathology, outcomes data, or independent gold standard beyond another electrophoretic method is provided.

8. Sample Size for the Training Set

The document does not mention a "training set" or explicitly describe the development of an algorithm that learns from data. This device is an immunodiagnostic test system based on capillary electrophoresis and specific antisera, producing profiles that are then visually interpreted. It is not presented as an AI/ML-driven device requiring a training set in the conventional sense. The "training" for such a system would typically involve its chemical and mechanical design, calibration, and validation against a standard.

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

As no training set is described for an AI/ML algorithm, this question is not applicable. The assay's "truth" is inherent in its biochemical principle (antigen-antibody reaction, electrophoretic separation) and the expertise of interpreting the resulting electrophoregrams.

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HYDRASHIFT 2/4 daratumumab kits are to be used in conjunction with the HYDRAGEL IF kits and the semi-automated HYDRASYS 2 electrophoresis apparatus. HYDRASHIFT 2/4 daratumumab with the HYDRAGEL IF kit are intended for the qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis. The proteins, separated by electrophoresis on alkaline buffered agarose gels, are incubated with individual antisera that are specific against gamma (Ig G), alpha (Ig A) and mu (Ig M) heavy chains, and kappa (free and bound) and lambda (free and bound) light chains, respectively. After removing the non-reacted proteins, the immunoprecipitates are stained with acid violet. The electrophoregrams are evaluated visually for the presence of specific reactions with the suspect monoclonal proteins. The HYDRASHIFT 2/4 daratumumab kits remove the daratumumab Ig G, Kappa interference and enable the visual evaluation of the presence or absence of monoclonal proteins on the HYDRAGEL IF kits in patients who have received daratumumab therapy.

HYDRASYS 2 is a semi-automated multi-parameter system for start-to finish agarose gel electrophoresis: application of samples, migration, incubation, drying, staining, destaining and final-stage drying. Abnormal bands in serum protein electrophoregrams, primarily those in the beta globulin and gamma globulin zones, are always suspected to be monoclonal proteins (M-proteins, paraproteins, monoclonal immunoqlobulins) and therefore, an indication of performing an Immunofixation technique to type and confirm the monoclonal qammopathies. Daratumumab is a human therapeutic Iq G Kappa monoclonal antibody and as such, during the clinical monitoring of patients treated with daratumumab, this antibody simulates a band detected by serum protein electrophoresis and immunofixation in the gamma region. It can simulate an endogenous Ig G Kappa paraprotein. The HYDRASHIFT 2/4 daratumumab test is intended for the qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis. The kits are to be used in conjunction with the HYDRAGEL IF kits and the semi-automated HYDRASYS 2 electrophoresis apparatus. The proteins, separated bv electrophoresis on alkaline buffered agarose gels, are incubated with individual antisera that are specific against gamma (lg G), alpha (lg A) and mu (lg M) heavy chains, and kappa (free and bound) and lambda (free and bound) light chains, respectively. After removing the non-reacted proteins, the immunoprecipitates are stained with acid violet. The electrophoregrams are evaluated visually for the presence of specific reactions with the suspect monoclonal proteins. The HYDRASHIFT 2/4 daratumumab kits remove the daratumumab lg G, Kappa interference and enable the visual evaluation of the presence or absence of monoclonal proteins on the HYDRAGEL IF kits in patients who have received daratumumab therapy.

The provided FDA 510(k) summary describes the HYDRASHIFT 2/4 daratumumab device, which is an in-vitro diagnostic test. It is a modification of a previously cleared device. The acceptance criteria and study details are primarily focused on demonstrating that the modified device performs equivalently to the predicate device.

Here's an breakdown of the information requested:

1. Table of Acceptance Criteria and Reported Device Performance

The core of the study is a comparison between the modified device (HYDRASHIFT 2/4 daratumumab with anti-daratumumab from Chinese Hamster Ovary cells, referred to as 'Candidate/Modified Device' or 'CHO') and the predicate device (HYDRASHIFT 2/4 daratumumab with anti-daratumumab murine, referred to as 'Predicate Device (K172195)' or 'murine').

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

• Sample Size:
  • Concordance Study: A total of 51 human serum samples were used:
    • 9 negative samples (without monoclonals)
    • 21 daratumumab treated patient samples
    • 21 daratumumab spiked samples
  • Sensitivity and Efficiency Study: 3 serum samples were used:
    • 2 normal serum samples
    • 1 serum with an IgG Kappa monoclonal
• Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given it's a 510(k) summary for a modified device, the samples were likely acquired under institutional review board (IRB) approval for research use, but specifics are not provided. The samples referred to as "human serum samples" and "daratumumab treated patient samples" suggest human origin.

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

The document does not provide information on the number of experts used or their qualifications for establishing ground truth. The evaluation method described is "electrophoregrams are evaluated visually for the presence of specific reactions." This implies visual interpretation, likely by trained laboratory personnel, but no explicit details are given about expert panels.

4. Adjudication Method for the Test Set

The document does not specify any formal adjudication method (e.g., 2+1, 3+1). The evaluation is described as "visual," which suggests individual assessment, potentially followed by internal quality control.

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

No, an MRMC comparative effectiveness study was not done. The study focused on demonstrating equivalence in performance characteristics between the modified device and its predicate, specifically around its ability to remove daratumumab interference. It did not involve comparing human reader performance with and without AI assistance.

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

This device is not an AI/algorithm-only device. It is an in-vitro diagnostic test kit (reagents) used in conjunction with an electrophoresis apparatus, where the final evaluation is visual and performed by a human. The "device" in this context refers to the HYDRASHIFT 2/4 daratumumab kits, which are reagents for laboratory testing.

7. The Type of Ground Truth Used

The ground truth for the performance studies appears to be based on:

• Known sample characteristics: Using "negative samples," "daratumumab-treated patient samples" (with known treatment status), and "daratumumab spiked samples" with predetermined concentrations.
• Visual evaluation of electrophoregrams: The presence or absence of specific reactions with monoclonal proteins is visually assessed, likely based on established laboratory protocols and the expected behavior of the predicate device.

It's essentially a performance comparison against known sample statuses and the established performance of the predicate device.

8. The Sample Size for the Training Set

This document does not describe a training set. This device is a reagent kit, not a machine learning or AI-based system that typically requires a training set. The performance studies are validation studies for the modified reagent.

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

As there is no training set mentioned or implied for this type of device, this question is not applicable.

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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 CAPILLARYS Hb A1c kit is intended for separation and quantification of the HbA1c glycated fraction of hemoglobin (in IFCC unit (mmol/mol) and NGSP unit (%)) in venous whole human blood, by capillary electrophoresis in alkaline buffer with the CAPILLARYS 2 FLEX-PIERCING instrument of hemoglobin A1c is used as an aid in diagnosis of diabetes, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus. The CAPILLARYS Hb A 1c kit is intended for in vitro Diagnostic Use Only.

The CAPILLARYS 2 FLEX-PIERCING instrument uses the principle of capillary electrophoresis in free solution. With this technique, charged molecules are separated by their electrophoretic mobility in an alkaline buffer with a specific pH. Separation occurs according to the electrolyte pH and electroosmotic flow.

The CAPILLARYS 2 FLEX-PIERCING instrument has silica capillaries functioning in parallel allowing 8 simultaneous analyses of HbA1c 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 A1c fraction. In addition, the high resolution of CAPILLLARYS Hb A1c procedure allows the quantification of HbA1c even in the presence of labile HbA1c, carbamylated and acetylated hemoglobins, and major hemoglobin variants.

By using an alkaline pH buffer, normal and abnormal (or variant) hemoglobins are detected in the following order, from cathode to anode: A2/C, E, S/D, F, A0, other Hb (including minor Hb A1) and then A1c.

The HbA1c concentrations are standardized and indicated in %HbA1c (DCCT/NGSP) and in mmol/mol (IFCC) units.

The provided text describes the performance data for the CAPILLARYS Hb A1c device, which is an in vitro diagnostic test for measuring HbA1c. The acceptance criteria and the study proving adherence to these criteria are detailed, primarily focusing on precision, linearity, and interference.

Here's the breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample sizes used for the test set and the data provenance

• Precision Study:
  • Sample Size: Four human blood samples, two controls, and two calibrators were used. Each of these 8 distinct samples was analyzed in duplicate on two capillaries per run, two runs per day over 20 days per lot, using three lots. This results in 1440 results per sample (8 samples * 2 replicates * 2 capillaries * 2 runs * 20 days * 3 lots, though the 1440 figure suggests a different multiplication, it's stated as 1440 results per sample meaning 8 * 1440 total measurements).
  • Data Provenance: Not explicitly stated regarding country of origin. The study was based on CLSI (USA) guidelines. It's a prospective study as specified by the testing methodology (over 20 days, 3 lots, etc.).
• Accuracy (Comparison) Study:
  • Sample Size: 150 variant-free whole blood samples.
  • Data Provenance: Not explicitly stated regarding country of origin. This dataset was collected for the purpose of the comparison study, implying a prospective design for comparing to a reference method. The samples spanned the measuring range and were distributed around clinical decision points.
• Interference Study:
  • Sample Size: For endogenous factors and drugs, two different whole blood samples were used (one near cut-off, one elevated HbA1c). Ten replicates were analyzed. For hemoglobin variants, specific numbers of samples were used for each variant: 20 for Hb A2, 20 for Hb F, 20 for Hb S, 20 for Hb C, 21 for Hb D, and 22 for Hb E.
  • Data Provenance: Not explicitly stated. Assumed to be prospective.

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

The ground truth for this device (a quantitative diagnostic test) is established by reference methods and certified reference materials, not expert consensus.

• Precision: No "ground truth" experts in the conventional sense. The "ground truth" for the mean values (target concentrations) of the blood samples, controls, and calibrators would be established through highly standardized and traceable processes by the manufacturer or a reference lab according to CLSI guidelines.
• Accuracy (Comparison): The comparison was against a "cleared HPLC HbA1c method (Automated Glycohemoglobin Analyzer HLC-712G8) performed at a NGSP reference laboratory." An NGSP (National Glycohemoglobin Standardization Program) reference laboratory adheres to stringent guidelines for HbA1c measurement and provides traceability to the DCCT (Diabetes Control and Complications Trial) reference method and IFCC (International Federation of Clinical Chemistry and Laboratory Medicine). The "ground truth" here is the result from this highly standardized and certified reference method, not an individual expert's reading.
• Interference: "Ground truth" for interference studies is typically based on the known concentration of the interfering substance and the measured value using a validated method. For hemoglobin variants, it was also compared against an NGSP laboratory's reference method.

Therefore, the concept of "experts" in the traditional sense of medical image interpretation (like radiologists) doesn't directly apply here. The "expertise" is embedded in the scientific rigor of the reference methods and standardization programs.

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

Not applicable. This is a quantitative chemical assay, not a qualitative assessment like image interpretation that requires adjudication among human readers. The "ground truth" from the reference method is considered definitive.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This is a medical device for an automated quantitative laboratory test and does not involve human readers, AI assistance, or MRMC studies.

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

Yes, the CAPILLARYS Hb A1c device is an automated in vitro diagnostic instrument. The performance data presented (precision, linearity, accuracy, interference) are all standalone performance characteristics of the algorithm and instrument system without human intervention influencing the measurement result itself once the sample is loaded.

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

The ground truth used for performance evaluation was:

• Reference methods from NGSP certified laboratories: For accuracy (comparison) and hemoglobin variant interference studies, the device's results were compared to those obtained from an NGSP reference laboratory using a cleared HPLC HbA1c method. NGSP certification ensures traceability to the primary international reference methods (DCCT/IFCC).
• Gravimetric/Volumetric preparation and known concentrations: For linearity and interference studies with endogenous substances and drugs, samples were likely prepared to specific, known concentrations, serving as the ground truth.
• Certified calibrators and controls: For precision studies, the 'true' values of the controls and calibrators are established through rigorous certification processes, making them the ground truth for evaluating reproducibility.

8. The sample size for the training set

This document describes premarket notification for a traditional IVD device, not an AI/ML-based device that typically undergoes "training" and "testing" phases in the same way. The instrument and its reagents are designed based on established chemical and electrophoretic principles. Therefore, there isn't a "training set" in the machine learning sense. The development of the assay and the robust validation typically leverage extensive historical data and scientific understanding, but it's not "training data" for a machine learning algorithm.

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

As there isn't a "training set" in the AI/ML context, this question is not applicable. The performance is validated against rigorous clinical laboratory standards and reference methods as described above.

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The HYDRASHIFT 2/4 daratumumab test is intended for the qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis. The kits are to be used in conjunction with the HYDRAGEL IF kits and the semi-automated HYDRASYS 2 electrophoresis apparatus. The proteins, separated by electrophoresis on alkaline buffered agarose gels, are incubated with individual antisera that are specific against gamma (Ig G), alpha (Ig M) heavy chains, and kappa (free and bound) and lambda (free and bound) light chains, respectively. After removing the nonreacted proteins, the immunoprecipitates are stained with acid violet. The electrophoregrams are evaluated visually for the presence of specific reactions with the suspect monoclonal proteins. The HYDRASHIFT 2/4 daratumumab kits remove the daratumumab Ig G, Kappa interference and enable the visual evaluation of the presence of monoclonal proteins on the HYDRAGEL IF kits in patients who have received daratumumab therapy. For In Vitro Diagnostic Prescription Use Only.

The daratumumab Control is designed for quality control of the HYDRASHIFT daratumumab immunofixation procedure performed using the HYDRASYS 2 instrument. The daratumumab Control is designed for laboratory use. It should be used like a human serum. For In Vitro Diagnostic Prescription Use Only.

HYDRASYS 2 is a semi-automated multi-parameter system for start-to finish agarose gel electrophoresis: application of samples, migration, drying, staining, destaining and final-stage drying.

Abnormal bands in serum protein electrophoregrams, primarily those in the beta globulin and gamma globulin zones, are always suspected to be monoclonal proteins (M-proteins, paraproteins, monoclonal immunoglobulins) and therefore, an indication of performing an Immunofixation technique to type and confirm the monoclonal gammopathies.

Daratumumab is a human therapeutic Ig G Kappa monoclonal antibody and as such, during the clinical monitoring of patients treated with daratumumab, this antibody simulates a band detected by serum protein electrophoresis and immunofixation in the gamma region. It can simulate an endogenous Ig G Kappa paraprotein.

Daratumumab CONTROL is a qualitative quality control for the assay.

The HYDRASHIFT daratumumab immunofixation procedure performed on HYDRAGEL IF 2/4 gel is based on the creation of a daratumumab / anti-daratumumab antibody complex and shifting it outside the gammaglobulins zone. With the HYDRASHIFT daratumumab procedure, the daratumumab / anti-daratumumab antibody complex is visualized in alpha-1 zone on Ig G and Kappa immunofixation tracks and then the interference is removed from the gamma zone.

The HYDRASHIFT 2/4 daratumumab device is an immunofixation electrophoresis kit designed to remove daratumumab Ig G, Kappa interference, allowing for the visual evaluation of monoclonal proteins in human serum from patients treated with daratumumab. The study to prove the device meets acceptance criteria involved repeatability, reproducibility, and external comparative studies.

1. Table of Acceptance Criteria and Reported Device Performance

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

• Repeatability Study: 10 different serum samples (1 normal, 9 with monoclonal components).
• Reproducibility Study: 10 different serum samples (1 normal, 9 with monoclonal components).
• External Comparative Study No. 1: 198 serum samples.
• External Comparative Study No. 2: 172 serum samples (noted that the first 172 samples from study 1 were analyzed on both sites, implying potentially shared samples in part).

The data provenance is from "2 external studies performed in the USA." It is not explicitly stated whether the data was retrospective or prospective.

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

The document does not provide information on the number of experts used or their qualifications for establishing ground truth for the test set. The evaluation of electrophoregrams is noted as "evaluated visually," implying human interpretation, but specifics about the interpreters are absent.

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method (such as 2+1, 3+1) for the test set results. The concordance of results is reported without detailing how disagreements, if any, were resolved.

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

No MRMC comparative effectiveness study is reported in the provided text. The studies focus on the technical performance of the device (repeatability, reproducibility, and concordance with existing methods) rather than the improvement of human reader performance with or without AI assistance. The device is a "HYDRASHIFT" kit that removes interference for visual evaluation, not an AI-based interpretation system.

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

No standalone algorithm performance study was done. The device is a diagnostic kit that requires visual evaluation of electrophoregrams by a human. Its purpose is to prepare samples to remove interference for human readability, not to interpret the results automatically.

7. The Type of Ground Truth Used

The ground truth appears to be based on the established clinical characterization of the serum samples (e.g., "normal" or "pathological with monoclonal components"). For normal samples, it's the absence of monoclonal components. For pathological samples, it's the specific type of monoclonal component (e.g., Ig G, L + Ig A, K + Ig M, L). This would typically be confirmed by standard laboratory techniques and expert interpretation of immunofixation electrophoresis. The external comparative studies also use existing methods (HYDRAGEL 4 IF alone) as a comparison baseline.

8. The Sample Size for the Training Set

The document does not mention a "training set" as it is typically understood in the context of machine learning or AI. The studies performed are for device validation, focusing on performance characteristics such as repeatability, reproducibility, and comparison with predicate devices, rather than training a model.

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

Since there is no mention of a training set for an AI/algorithm, there is no information on how its ground truth would have been established. The ground truth for the validation studies (test sets) is based on the known characteristics of the serum samples and comparison with established methods.

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The CAPI 3 Hb A1c kit is intended for separation and quantification of the HbA1c glycated fraction of hemoglobin (in IFCC unit (mmol/mol) and NGSP unit (%)) in venous whole human blood, by capillary electrophoresis in alkaline buffer with the CAPILLARYS 3 TERA instrument of hemoglobin A1c is used as an aid in diagnosis of diabetes, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus. The CAPI 3 Hb A1c kit is intended for in vitro Diagnostic Use Only.

The CAPILLARYS 3 TERA instrument uses the principle of capillary electrophoresis in free solution. With this technique, charged molecules are separated by their electrophoretic mobility in an alkaline buffer with a specific pH. Separation occurs according to the electrolyte pH and electroosmotic flow. The CAPILLARYS 3 TERA instrument has silica capillaries functioning in parallel allowing 12 simultaneous analyses of HbA1c 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 A1c fraction. In addition, the high resolution of CAPI 3 Hb A1c procedure allows the quantification of HbA1c even in the presence of labile HbA1c. carbamylated and acetylated hemoglobins, and major hemoqlobin variants. By using an alkaline pH buffer, normal and abnormal (or variant) hemoglobins are detected in the following order, from cathode to anode: A2/C, E, S/D, F, A0, other Hb (including minor Hb A1) and then A1c. The HbA1c concentrations are standardized and indicated in %HbA1c (DCCT/NGSP) and in mmol/mol (IFCC) units.

The provided text describes the 510(k) premarket notification for the CAPI 3 Hb A1c kit, a device used for measuring hemoglobin A1c levels. The document outlines the device's indications for use, technological characteristics, and performance data to demonstrate substantial equivalence to a legally marketed predicate device.

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

1. Table of Acceptance Criteria and Reported Device Performance

The "Special Controls for Diabetes Diagnosis Claim" section (Section 6) explicitly lists the acceptance criteria set by the FDA for devices of this type, along with how the device's performance data addresses these. While the document doesn't present a direct "acceptance criteria vs. reported performance" table, I can synthesize one from Section 6 and the preceding "Performance Data" (Section 5).

Acceptance Criteria and Reported Device Performance for CAPI 3 Hb A1c

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

• Precision/Reproducibility Study (Section 5a):

  • Sample Size: Four different whole blood samples at specific targeted HbA1c concentrations (~5%, ~6.5%, ~8%, ~12%) were used. These were analyzed in duplicate on two capillaries per run on 3 instruments. The study used three lots of kits over 24 days, resulting in a total of 1728 individual results.
  • Data Provenance: The document does not explicitly state the country of origin for these samples. It implies they are clinical samples used in a laboratory setting for reproducibility testing within the manufacturer's or contracted facility. The study design (CLSI guidelines EP05-A3) suggests a prospective, experimentally controlled setup.

• Comparison Studies (Accuracy) (Section 5e):

  • Sample Size: 152 variant-free whole blood samples.
  • Data Provenance: The samples covered the measuring range and spanned decision points for diabetes diagnosis. The comparison was against results from an NGSP reference laboratory using a cleared HPLC HbA1c method. The specific origin (e.g., country) or whether these were retrospectively or prospectively collected is not stated, but the nature of a comparison study with a reference method implies a real-world clinical sample set.

• Interference Studies (Section 5g):

  • Sample Size: Two different whole blood samples (one near cut-off, one with elevated HbA1c) were used for endogenous and drug interference testing. For hemoglobin variant interference, a number of specific samples were used (e.g., 20 Hb A2 samples, 19 Hb F samples, 24 each for Hb S, C, D, and E samples).
  • Data Provenance: Not explicitly stated regarding country or retrospective/prospective. The description suggests these were specific, characterized samples obtained for interference testing, likely in a controlled laboratory environment.

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

• For this in-vitro diagnostic device (HbA1c measurement), "ground truth" is typically established by reference methods or standardized laboratory procedures, not by expert consensus in the way imaging AI models are.
• Comparison Study (Section 5e): The ground truth for the 152 samples was established by "testing performed at a NGSP reference laboratory using the cleared HPLC HbA1c method (Automated Glycohemoglobin Analyzer HLC-712G8)." This is the gold standard for HbA1c measurement and implies the highest level of analytical accuracy for the measured values.
• The document does not mention human experts establishing ground truth or their qualifications; it relies on a technical reference standard.

4. Adjudication Method for the Test Set

• Adjudication methods (like 2+1, 3+1) are typically used in subjective interpretation tasks (e.g., radiology image reading) where multiple human readers contribute to a consensus ground truth.
• For quantitative lab tests like HbA1c, adjudication is not applicable in the same sense. The "ground truth" is the result obtained from a single, highly accurate, standardized reference method, which is considered definitive. Any comparison is statistical, typically regressing one device's results against the reference method's results.

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

• No, an MRMC comparative effectiveness study was not done.
• MRMC studies are relevant for medical imaging devices where human readers interpret images, and the AI system is an "assistant" in that interpretive task.
• This device is an automated in-vitro diagnostic assay, meaning it directly measures a biomarker. It's not an AI system designed to assist human interpretation of complex visual data. Therefore, the concept of "human readers improving with AI vs. without AI assistance" does not apply here.

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

• Yes, the primary performance shown is "standalone" performance.
• The CAPI 3 Hb A1c kit, when run on the CAPILLARYS 3 TERA instrument, provides a direct quantitative measurement. The performance data presented (precision, linearity, comparison, total error, interferences) are all reflective of the device's analytical performance on its own, without human real-time intervention for result calculation or interpretation beyond standard laboratory procedures for operating the instrument and reporting results.
• The output is a numerical value (%HbA1c or mmol/mol), not an image or diagnosis requiring human interpretation in the loop with an AI algorithm.

7. Type of Ground Truth Used

• The ground truth for the comparison studies (accuracy) was established by a standardized reference method (HPLC HbA1c) run at an NGSP reference laboratory.
• This is a form of analytical reference standard, considered the most accurate and reliable method for determining true HbA1c concentrations in the samples.
• For precision and interference studies, the "ground truth" is inherent to the specific sample concentrations being tested, often prepared or characterized against
  these same reference methodologies.

8. Sample Size for the Training Set

• This information is not provided because this is not an AI/ML (Artificial Intelligence/Machine Learning) device requiring a "training set."
• The CAPI 3 Hb A1c kit is an in-vitro diagnostic device based on the principle of capillary electrophoresis, a well-established analytical chemistry technique. Its "performance" is governed by its chemical reagents, instrument design, and physical principles, not by a learned algorithm from data.
• Therefore, there is no "training set" in the context of machine learning. The development and validation of such a device involve optimization of reagents, hardware, and software parameters, followed by rigorous analytical performance validation studies (as detailed in Section 5).

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

• Not applicable, as there is no "training set" for this type of device (see point 8 above).

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