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(243 days)
The ESA Biosciences Inc. Vitamin D HPLC test is for the quantitative determination of 25-hydroxyvitamin D in human serum or EDTA-plasma to be used in the assessment of vitamin D sufficiency. Assay results should be used in conjunction with other clinical or laboratory data to assist the clinician in making individual patient management decisions in an adult population.
The ESA method is a complete kit for measurement of Total 25(OH)D by HPLC with electrochemical (EC) detection. Specific reagents and solid phase extraction columns are included for sample preparation and are employed with user-supplied standard laboratory equipment (centrifuge, test tubes, pipettes, etc.). A 200µL volume of sample (serum or plasma) is mixed with a precipitation reagent, which contains internal standard (IS). The internal standard is a stable vitamin D analogue that is used to correct for variability in extraction recovery and analytical sample volume. After centrifugation, supernatant is poured onto a pre-conditioned SPE column for rapid extraction of 25(OH)D and IS. SPE columns are washed with 2 different reagents and analytes are eluted with a third reagent. The resulting eluent is diluted before analysis. The prepared sample is analyzed with an isocratic HPLC system using an ESA EC detector (Coulochem® III or CoulArray®) equipped with a dual coulometric EC cell. Calibration is accomplished by direct HPLC analysis of authentic standard solutions (i.e. not taken through the extraction step). Analysis requires a specific guard and analytical column, mobile phase and calibration reagents to allow rapid quantitative analysis. A dual EC cell is used with the first, upstream, cell maintained at a specific potential to oxidatively screen possible interfering sample components. The second, downstream cell is maintained at a potential that is optimized for selective 25(OH)D detection. The dual coulometric EC cell is a rugged detector that provides much higher selectivity than commonly used absorbance detectors. This allows the use of lower sample volumes than are typically required with HPLC-UV methods and is less susceptible to interferences. Analytical run time is less than 12 minutes and Total 25(OH)D sample concentration is automatically determined by single-point internal standard quantitation.
Here's an analysis of the provided text, outlining the acceptance criteria and study details for the ESA Biosciences Inc. Vitamin D HPLC Test:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" in a dedicated section with pass/fail thresholds. However, it presents performance characteristics that implicitly serve as the criteria for evaluating the device's suitability. The table below lists these performance metrics and the reported results.
| Performance Characteristic | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Precision (Within-run) | Low %CV for various samples | Sample #1 (Plasma): 2.82% CVSample #2 (Plasma): 2.31% CVSample #3 (Serum): 2.55% CVSample #4 (Serum): 2.16% CVLevel 1: 10.6% CVLevel 2: 6.8% CV |
| Precision (Within-device/Total) | Low %CV for various samples | Sample #1 (Plasma): 6.05% CVSample #2 (Plasma): 5.48% CVSample #3 (Serum): 5.66% CVSample #4 (Serum): 5.43% CVLevel 1: 12.6% CVLevel 2: 8.4% CV |
| Limit of Detection (LoD) | Defined as concentration with ≤ 5% false negative/positive | 5.0 ng/mL |
| Limit of Quantitation (LoQ) | % CV ≤ 20% at this concentration | 7.0 ng/mL |
| Limit of Blank (LoB) | N/A (reported as a baseline metric) | 2.5 ng/mL |
| Linearity Range | Linear from LoQ to 200 ng/mL with specific bias goals | Linear from 7.0 ng/mL (LoQ) to 200 ng/mL (bias goals: ≤ 3ng/mL bias for ≤ 20 ng/mL; ≤ 7.5% bias for 21-200 ng/mL) |
| Recovery | Expected % recovery around 100% for spiked samples | Plasma: 90-107% mean recoverySerum: 93-105% mean recovery |
| Method Comparison (Correlation) | Correlation Coefficient (R) for comparison with reference method (implies r needs to be within an acceptable range, though r < 0.975 was noted as failing an "adequate range test") | R = 0.973 |
| Method Comparison (Bias) | Bias within acceptable limits at different concentrations, especially if correlation is not ideal | At 22.9 ng/mL (LCUV): -2.6 ng/mL (-11.2% bias)At 45.4 ng/mL (LCUV): -5.6 ng/mL (-12.3% bias)At 100.3 ng/mL (LCUV): -3.3 ng/mL (-3.3% bias) |
| Interference (Cholesterol) | Bias < 10% for cholesterol concentrations < 375 mg/dL | 10% positive bias at 500 mg/dL cholesterol; <10% bias for < 375mg/dL |
| Interference (25(OH)epiD3) | Not to be used in populations where significant interference is expected (e.g., neonates) | Interferes; assay not for use in patients < 1 year of age |
| Other Interferences | No interference from tested substances at high concentrations | Triglycerides, Albumin, Bilirubin, Hemoglobin, Paricalcitrol: No interference |
2. Sample Sizes Used for the Test Set and Data Provenance
- Precision:
- "Neat" Samples: 78-80 replicates per sample (4 samples total), run over 20 days.
- Plasma Pools: 100 replicates per level (2 levels total), run over 20 days.
- Limit of Detection (LoD): 133 determinations (67 blank, 66 low-level samples).
- Linearity: 13 equally-spaced concentrations, 3 aliquots of each.
- Recovery: 5 EDTA plasma subjects, 6 serum subjects; each spiked to 7 concentration levels (0, 5, 10, 20, 50, 100, 200 ng/mL), with 3 replicates each.
- Method Comparison: 100 individual patient serum samples (85 from UWHC, 15 augmented samples from a single serum pool).
- Interference Studies: High and low (normal) concentrations of each interferent mixed proportionally to produce 5 equally-spaced levels, with 3 replicates each.
- Reference Range: 150 apparently healthy adult human subjects.
Data Provenance:
- Precision: Not explicitly stated regarding geographic origin, but study followed CLSI EP5-A.
- Limit of Detection (LoD): Not explicitly stated regarding geographic origin, but used patient samples and followed CLSI EP17A.
- Linearity: Not explicitly stated regarding geographic origin, but followed CLSI EP6.
- Recovery: Not explicitly stated regarding geographic origin.
- Method Comparison: Serum samples from 85 individual patients collected at the University of Wisconsin Hospitals and Clinics (UWHC). The remaining 15 were augmented from a single serum pool.
- Interference Studies: Not explicitly stated regarding geographic origin, but followed CLSI EP7-A.
- Reference Range: Samples from 150 apparently healthy adult human subjects collected from 3 locations to achieve even North-South geographical distribution within the latitudes of the contiguous 48 US States. All data appears to be retrospective clinical measurements or prospectively collected for validation purposes (e.g., reference range study).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not mention the use of "experts" in the traditional sense of clinicians or radiologists for establishing a ground truth for the test set. Instead, the ground truth for performance characteristics is established through:
- Reference Methods: For method comparison, an LCUV reference method was used. The qualifications of the individuals performing the LCUV method or confirming its accuracy are not detailed.
- Spiking/Augmenting Samples: For recovery and linearity, known concentrations were added to samples.
- Statistical Analysis: CLSI guidelines (EP5-A, EP17A, EP6, EP7-A, EP9-A2, C28-A2) were referenced, implying statistical methods were used to derive performance metrics from direct measurements.
4. Adjudication Method for the Test Set
No adjudication method (e.g., 2+1, 3+1, none) is mentioned as the ground truth was established by reference methods, spiking, or statistical analysis of direct measurements, not by expert consensus on qualitative assessments.
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. The device is a diagnostic test kit for quantitative measurement of vitamin D, not an AI-assisted diagnostic imaging or qualitative assessment tool that involves human readers in that capacity.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, the studies reported are standalone performance evaluations of the assay itself. The results are quantitative measurements from the HPLC system, operating without direct human interpretation of the primary data to establish the diagnostic outcome. Human involvement is in sample preparation, running the instrument, and interpreting the numerical output.
7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)
The ground truth used for various performance characteristics includes:
- Reference Method Measurements: For method comparison, an LCUV reference method served as the ground truth.
- Known Concentrations: For linearity and recovery studies, the "ground truth" was the precisely known concentrations of 25(OH)D added to samples.
- Statistical Definitions/Calculations: For LoD, LoQ, and precision, the ground truth is derived from statistical analysis of repeated measurements and blank samples according to established CLSI guidelines.
- Absence/Presence of Interferents: For interference studies, the ground truth was the known composition and concentration of tested substances in the samples.
8. The Sample Size for the Training Set
The document does not describe a "training set" in the context of machine learning or AI. The development of this HPLC test likely involved extensive method development and optimization, but the reported studies are primarily validation and verification of the finalized method's performance.
9. How the Ground Truth for the Training Set Was Established
As there's no mention of a "training set" in an AI/ML context, this question is not applicable. For the development of the HPLC method, numerous experiments and analytical techniques would have been used to establish the correct parameters and ensure accurate and precise measurement of 25-hydroxyvitamin D. However, these are not described as a formal "training set" with ground truth in the document.
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