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The D-100™ HbA1c test is intended for the quantitative determination of hemoglobin A1c (IFCC mmol/mol and NGSP %) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC) on the D-100 Hemoglobin Testing System.
Hemoglobin A1c measurements are used as an aid in diagnosis of diabetes mellitus, 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 D-100TM HbA1c test is intended for Professional Use Only.
Calibrators:
The D-100™ HbA1c Calibrator Pack is for the calibration of the D-100 Hemoglobin Testing System used for the quantitative determination of hemoglobin A1c(HbA1c) in human whole blood.
The Bio-Rad D-100™ HbA1c utilizes principles of ion-exchange high-performance liquid chromatography (HPLC). A high-pressure pumping system delivers a buffer solution to an analytical cartridge and detector. Whole blood samples undergo an automatic hemolysis and dilution process before being introduced into the analytical flow path. Prediluted samples are identified based upon the use of a microvial adapter in the sample rack, and the automatic dilution step is omitted.
A programmed buffer gradient of increasing ionic strength delivers the sample to the analytical cartridge where the hemoglobin species are separated based upon their ionic interactions with the cartridge material and the buffer gradient. The separated hemoglobin species then pass through the flow cell where changes in the absorbance are measured at 415 nm and recorded as a digital chromatogram.
The software performs an analysis of the hemoglobin peaks in the chromatogram, recording information including retention time, peak area, and relative are percent. Any peaks that are identified as the target analyte(s) are calibrated before generating a sample report and chromatogram for each sample. The software includes an optional feature (Advisor) that compares the sample report against a set of rules that are programmed to take user-specified actions.
The D-100™ HbA1c test is designed to be used on the D-100™ Hemoglobin Testing System.
This document describes the D-100™ HbA1c test and D-100™ HbA1c Calibrator Pack, intended for the quantitative determination of hemoglobin A1c (HbA1c) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC) on the D-100™ Hemoglobin Testing System. The test is used as an aid in diagnosing diabetes mellitus, identifying individuals at risk for diabetes, and monitoring long-term blood glucose control in diabetic patients. The calibrators are used for the calibration of the system.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are implied through the study designs, particularly the "significant interference" threshold for analytical specificity and the performance demonstrated in linearity and precision studies. For the purpose of this summary, the relevant performance metrics are extracted and presented.
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Precision (NGSP %CV Total Precision) | Not explicitly stated, but results within reasonable analytical variation for diagnostic assays. | < 1.8% for all samples (NGSP%) across all instruments, with combined total precision from 0.9% to 1.8%. |
| Precision (IFCC mmol/mol %CV Total Precision) | Not explicitly stated. | < 3.4% for all samples (IFCC mmol/mol) across all instruments, with combined total precision from 1.1% to 3.1%. |
| Linearity (NGSP % HbA1c) | Maximum measured difference of ±0.09% between 1st and 2nd order results (as shown in Table 11). | Demonstrated linearity from 3.5 - 20.0% HbA1c, with a maximum measured difference of ±0.09% between predicted 1st and 2nd order results. |
| Linearity (IFCC mmol/mol HbA1c) | Maximum measured difference of ±0.9% (or ±0.94 mmol/mol) between 1st and 2nd order results (as shown in Table 12). | Demonstrated linearity from 15 – 195 mmol/mol, with a maximum measured difference of ±0.94 mmol/mol. |
| Method Comparison (Deming Regression Slope for NGSP %) | Close to 1.0 (indicating agreement with reference). | 0.9867 (95% CI: 0.9736 – 0.9999) |
| Method Comparison (Deming Regression y-Intercept for NGSP %) | Close to 0.0 (indicating agreement with reference). | 0.0223 (95% CI: -0.0684 – 0.1131) |
| Method Comparison (Passing-Bablok Regression Slope for NGSP %) | Close to 1.0. | 0.9909 (95% CI: 0.9789 – 1.0026) |
| Method Comparison (Passing-Bablok Regression y-Intercept for NGSP %) | Close to 0.0. | -0.0091 (95% CI: -0.0803 – 0.0763) |
| Total Error (TE) | Not explicitly stated, but calculated values like 4.2% at 5.0% A1c are presented. | Calculated Total Error (TE) values ranging from 3.6% to 4.2% across different HbA1c decision levels. |
| Analytical Specificity (Endogenous Interference) | < ±7% change in %HbA1c value from control. | No significant interference observed for Lipemia (6000 mg/dL), Conjugated bilirubin (60 mg/dL), Unconjugated bilirubin (60 mg/dL), Glucose (2000 mg/dL), Rheumatoid factor (750 IU/mL), Total protein (21 g/dL). |
| Analytical Specificity (Drug Interference) | < ±7% change in %HbA1c value from control. | No significant interference observed at therapeutic levels up to specified concentrations for 15 common drugs (e.g., Acetylcysteine, Ampicillin-Na, Ascorbic acid, Cefoxitin, Heparin, Levodopa, Methyldopa, Metronidazole, Doxycyclin, Acetylsalicylic acid, Rifampicin, Cyclosporine, Acetaminophen, Ibuprofen, Theophylline, Phenylbutazone). |
| Analytical Specificity (Hemoglobin Derivatives Cross-Reactivity) | < ±7% change in HbA1c value from control. | No interference from Acetylated Hb (up to 50 mg/dL), Carbamylated Hb (up to 5%), and Labile A1c (up to 1200 mg/dL of glucose). |
| Analytical Specificity (Hemoglobin Variants) | Not explicitly stated as a percentage bias threshold, but performance is compared against an NGSP reference method. | Relative %Bias from -0.6 to -4.7 for HbS, HbC, HbD, HbE, HbA2, and HbF variants at ~6.5% HbA1c, and from -1.3 to -4.4 at ~9.0% HbA1c. The study indicates the device is free from hemoglobin interferent from a comparable method. |
2. Sample Size Used for the Test Set and Data Provenance
- Precision/Reproducibility:
- Sample Size: Four EDTA whole blood samples at target HbA1c concentrations (~5%, ~6.5%, ~8%, ~12%) and five quality control materials.
- Data Provenance: Not explicitly stated, but typically these samples would be from a clinical setting. Retrospective or prospective is not specified. The study was conducted at "two different sites."
- Linearity:
- Sample Size: Low (3.5% HbA1c) and high (20% HbA1c) EDTA whole blood patient samples, mixed in varying ratios to create 11 sample pools.
- Data Provenance: Not explicitly stated, but these are patient samples. Retrospective or prospective is not specified.
- Method Comparison:
- Sample Size: 129 variant-free whole blood EDTA samples.
- Data Provenance: Patient samples. Retrospective or prospective is not specified.
- Analytical Specificity (Endogenous Interference):
- Sample Size: Two EDTA whole blood sample pools (one at ~6.5% HbA1c and one at ~8.0% HbA1c) for each interferent, with 10 replicates per test and control sample.
- Data Provenance: Whole blood samples. Serum samples were used for Rheumatoid factor, lipemia, and total protein (with known high concentrations), then mixed with whole blood. Retrospective or prospective is not specified.
- Analytical Specificity (Drug Interference):
- Sample Size: Two EDTA whole blood sample pools (one at ~6.5% HbA1c and one at ~8.0% HbA1c) for each drug, with 10 replicates per test and control sample.
- Data Provenance: Whole blood samples. Retrospective or prospective is not specified.
- Analytical Specificity (Hemoglobin Derivatives Cross-Reactivity):
- Sample Size: Low (~6.5% HbA1c) and high (~8.0% HbA1c) EDTA whole blood samples for each derivative, with 10 replicates for each sample pool.
- Data Provenance: Whole blood EDTA samples. Retrospective or prospective is not specified.
- Hemoglobin Variant Study:
- Sample Size: 20 HbS, 20 HbC, 20 HbD, 20 HbE, 25 HbA2, and 30 HbF specific variant samples (total 135 samples). Two whole blood EDTA patient samples (one ~6.5% HbA1c, one ~8% HbA1c) with the appropriate variants tested in duplicate.
- Data Provenance: Patient samples known to contain specific hemoglobin variants. Retrospective or prospective is not specified.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of those Experts
For this in vitro diagnostic device, human experts are not directly used to establish the ground truth for the test set in the way they might be for image-based diagnostic AI. Instead, the ground truth is established through:
- Reference Methods:
- Precision/Reproducibility: No separate "ground truth" establishment by experts listed, as it measures the device's inherent variability.
- Linearity: No separate "ground truth" establishment by experts listed; it assesses the device's response across a range compared to theoretical values.
- Method Comparison: The reference method was a "secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay," implying highly controlled and standardized laboratory procedures.
- Analytical Specificity & Hemoglobin Variant Study: Comparison to "control" samples or an "NGSP reference method that has been demonstrated to be free from the hemoglobin interferent."
The "experts" in this context are the highly trained laboratory professionals and the robust, standardized analytical methods used in the reference laboratories (e.g., NGSP SRL reference laboratory). Specific number or individual qualifications of these professionals beyond "NGSP SRL reference laboratory" are not detailed in this summary.
4. Adjudication Method for the Test Set
Not applicable in the typical sense of expert adjudication (e.g., 2+1, 3+1 for imaging studies). The comparison is against established laboratory reference methods and defined control samples, which serve as the gold standard. Discrepancies would be resolved through re-testing or investigation per standard laboratory quality control protocols, not through a formal expert adjudication panel.
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 an In Vitro Diagnostic (IVD) device, specifically an automated chemical analyzer (HPLC) for quantitative measurement of HbA1c. There are no "human readers" or "AI assistance" in the context of interpreting images or complex data as would be found in traditional MRMC studies for AI-powered diagnostics. The device completely automates the measurement.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the studies presented are all standalone. The D-100™ HbA1c test and its associated system perform the quantitative determination of HbA1c without human intervention during the measurement process itself, beyond initial sample loading and system operation. The performance metrics (precision, linearity, method comparison, analytical specificity) are all measures of the device's inherent analytical capability.
7. The Type of Ground Truth Used
The ground truth used is primarily:
- Reference Method / Standardized Assays: For method comparison, the device's results were compared to "testing performed at a secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay." For the Hemoglobin Variant study, it was compared to an "NGSP reference method that has been demonstrated to be free from the hemoglobin interferent."
- Known Concentrations/Prepared Samples: For linearity, known ratios of low and high concentration samples were used. For analytical specificity studies, interferents were prepared at known concentrations and spiked into samples.
- Certified Materials: The calibrators are traceable to the International Federation of Clinical Chemistry (IFCC) reference method and are NGSP certified.
8. The Sample Size for the Training Set
Not applicable in the context of this device. The D-100™ HbA1c system is an HPLC-based analytical instrument. It is not an "algorithm" in the sense of a machine learning or AI model that requires a training set for model development. Its "training" involves calibration with certified reference materials (the Calibrator Pack), which are part of the overall analytical system.
9. How the Ground Truth for the Training Set Was Established
Not applicable as there is no "training set" for an AI algorithm in the traditional sense. The calibration process (which could be conceptually analogous to "training" for an analytical instrument) uses the D-100™ HbA1c Calibrator Pack. The ground truth for these calibrators is established by:
- Traceability to IFCC Reference Method: "Each Calibrator Pack contains Calibrator values which have been value assigned using secondary calibrators that are traceable to the International federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method."
- NGSP Certification: The assay is NGSP certified, meaning its results correlate to the Diabetes Control and Complications Trial (DCCT) reference method.
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