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For in vitro diagnostic use in the quantitative determination of Hemoglobin A1c, a diabetes marker, in whole blood on the ADVIA Chemistry systems. Such measurements are used for monitoring the long-term care of persons with diabetes. The A1c_3 and total hemoglobin (tHb_3) values generated as part of the ADVIA Chemistry HbA1c% and HbA1cR assays are intended for use in the calculation of the A1c/total hemoglobin ratio, and must not be used individually for diagnostic purposes.

The concentration of A1c and the concentration of total hemoglobin are measured and their ratio is reported. The automated pretreatment assays (ADVIA Chemistry A1c 3 and ADV)A Chemistry tHb_3) use 3 ADVIA Chemistry reagents:

• · A1c 3 Agglutinator/Total Hemoglobin Reagent (A1c 3 R1)
• · A1c_3 Antibody Reagent (A1c_3 R2)
• · A1c_3 Denaturant Reagent (A1c_3 DENAT)

The Siemens Healthcare Diagnostics ADVIA® 1800 Chemistry Hemoglobin A1c_3 (A1c_3) Automated Pretreatment Assay is intended for in vitro diagnostic use in the quantitative determination of Hemoglobin A1c in whole blood on ADVIA Chemistry systems for monitoring the long-term care of persons with diabetes.

Here's an analysis of its acceptance criteria and supporting study:

1. Table of Acceptance Criteria and Reported Device Performance

The provided document describes the performance characteristics without explicitly stating pre-defined "acceptance criteria" through numerical thresholds. However, substantial equivalence is claimed based on acceptable results compared to a predicate device. Based on the data presented, the implied acceptance is that the new device's performance characteristics demonstrate similar or equivalent performance to the predicate device and meet general analytical chemistry standards for precision, linearity, and lack of significant interference.

• Normal Control: Level 5.45%, SD 0.07%, CV 1.3%
• Abnormal Control: Level 8.70%, SD 0.06%, CV 0.7%
  Total Imprecision (NGSP Units %):
• Normal Control: Level 5.45%, SD 0.13%, CV 2.4%
• Abnormal Control: Level 8.70%, SD 0.14%, CV 1.6%
  Within Run Imprecision (IFCC Units mmol/mol):
• Normal Control: Level 36, SD 0.78, CV 2.2%
• Abnormal Control: Level 71, SD 0.67, CV 0.9%
  Total Imprecision (IFCC Units mmol/mol):
• Normal Control: Level 36, SD 1.41, CV 3.9%
• Abnormal Control: Level 71, SD 1.47, CV 2.1% |
  | Linearity/Assay Range | Linear performance across the intended measuring range. | Linear/Measuring Range:
• A1c_3 specific A1c concentrations: 1.0 to 8.83 µmol/L
• tHb_3 total hemoglobin concentrations: 7 to 24 g/dL
• HbA1c% assay: 2.9 to 15.4% HbA1c
• HbA1cR assay: 8 to 144 mmol/mol
  The range of samples tested in the linearity study was 1.13-19.44% A1c. |
  | Limit of Detection (LoD)| LoD sufficiently low for clinical utility. | LoD for HbA1c_3 assays: 0.48 µmol/L (0.91 %HbA1c). |
  | Method Comparison | High correlation and minimal bias compared to the predicate. | Correlation Coefficient: 0.9942 (between new method and predicate device)
  Linear Regression Equation: This method = 1.00 (predicate device) - 2.90 mmol/mol |
  | Analytical Specificity | No significant interference from common interfering substances. | No significant lipemia interference (Intralipid 0-1000 mg/dL).
  No significant unconjugated bilirubin interference (0-60 mg/dL).
  No significant conjugated bilirubin interference (0-60 mg/dL). (Significance criterion >10% variance from control). |

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

• Imprecision Study: 80 replicates for each of two control levels (Normal and Abnormal) for both within-run and total imprecision analyses.
• Linearity Study: Nine intermediate levels were prepared from low and high commercial linearity set solutions. The total number of samples or discrete measurements is not explicitly stated but implies multiple measurements for each of the 9 levels.
• Limit of Detection (LoD) Study: 60 replicates of 0.9% Saline (Blank) and five HbA1c low samples. Data was obtained from a 3-day precision study.
• Method Comparison Study: 98 whole blood samples.
• Analytical Specificity Study: Specific sample numbers for bilirubin and lipid interference are not given, but levels of interferrents were tested in HbA1c samples (e.g., 5.16%, 9.84% HbA1c for lipemia; 5.16%, 9.90% HbA1c for unconjugated bilirubin; 5.03%, 9.78% HbA1c for conjugated bilirubin).

Data Provenance: The document does not specify the country of origin of the data or explicitly state if it was retrospective or prospective. Given the nature of in-vitro diagnostic device testing, it is generally prospective testing conducted in a laboratory setting.

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

N/A. This device is an automated in vitro diagnostic assay. The "ground truth" for the test set values (e.g., A1c percentages, total hemoglobin concentrations, and control values) would be established by reference methods or validated laboratory methods, not by human expert consensus or interpretation of images.

4. Adjudication Method for the Test Set

N/A. Adjudication methods (like 2+1, 3+1) are typically used in studies involving human interpretation (e.g., radiology reads) where discrepancies between readers need to be resolved. This is not applicable to a quantitative in vitro diagnostic assay.

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

N/A. An MRMC study assesses the performance of human readers, typically for image-based diagnostics, with and without AI assistance. This is not relevant to a fully automated Hemoglobin A1c assay.

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

Yes, the studies described (imprecision, linearity, LoD, method comparison, analytical specificity) represent standalone performance of the algorithm/device. The device is designed to be fully automated for the determination of Hemoglobin A1c, without ongoing human intervention in the measurement process itself.

7. Type of Ground Truth Used

The ground truth for the in vitro diagnostic assay is established through:

• Reference materials/methods: For calibration, linearity, and control samples, values are based on established, highly accurate reference methods or certified reference materials traceable to international standards (IFCC and NGSP).
• Predicate device comparison: For the method comparison study, the results from the legally marketed predicate device (ADVIA® Chemistry Hemoglobin A1c Assay, K081895) served as the reference for comparison, indicating that the new device's measurements align with an already accepted method.
• Known concentrations: For studies like linearity and analytical specificity, samples with known concentrations of analyte or interferents are used.

8. The Sample Size for the Training Set

The document does not specify a distinct "training set" or its size. For an in vitro diagnostic device like this, the development process would involve internal validation and optimization, but the provided K110934 summary focuses on the performance characteristics for market submission using test sets, not on algorithmic training data.

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

N/A. As mentioned above, a "training set" in the context of an AI/ML algorithm is not explicitly described for this in vitro diagnostic device. The ground truth for developing and validating the assay's performance would have been established through a combination of:

• Standard laboratory protocols.
• Use of calibrated reference materials and control samples.
• Comparison with established, validated methods.
• Traceability to international standards (IFCC and NGSP).

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