(38 days)
The S TEST Reagent Cartridge Total Bilirubin (T-BIL) is intended for the quantitative determination of total bilirubin in serum, lithium heparin plasma, K3 EDTA plasma, and sodium citrate plasma using the Hitachi Clinical Analyzer E40. The S TEST Reagent Cartridge Total Bilirubin is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.
Total Billirubin measurements are used in the diagnosis and treatment of disorders of the liver.
The Hitachi Clinical Analyzer is an automatic, bench-top, wet chemistry system intended for use in clinical laboratories or physician office laboratories. The instrument consists of a desktop analyzer unit, an operations screen that prompts the user for operation input and displays data, a printer, and a unit cover. The analyzer unit includes a single probe, an incubation rotor, carousels for sample cups and reagent cartridges, and a multi-wavelength photometer. The single-use reagent cartridges may be placed in any configuration on the carousel, allowing the user to develop any test panel where the reagent cartridges are available.
The S TEST reagent cartridges are made of plastic and include two small reservoirs capable of holding two separate reagents (R1 and R2), separated by a reaction cell/photometric cuvette. The cartridges also include a dot code label that contains all chemistry parameters, calibration factors, and other production-related information, e.g., expiration dating. The dimensions of the reagent cartridges are: 13.5 mm (W) × 28 mm (D) × 20.2 mm (H).
System operation: After the sample cup is placed into the carousel, the analyzer pipettes the sample, pipettes the reagent, and mixes (stirs) the sample and reagent together. After the sample and reagent react in the incubator bath, the analyzer measures the absorbance of the sample, and based on the absorbance of the reactions, it calculates the concentration of analyte in the sample. The test system can measure analytes in serum or plasma and results are available in approximately 15 minutes per test. This submission is for Reagent Cartridge Total Bilirubin.
Chemistry reaction: Nitrous acid method: Total bilirubin in samples is oxidized to biliverdin by the action of nitrous acid at pH 3.7. The concentration of total bilirubin can be determined by measuring the decrease of absorbance at a wavelength of 450nm .
Here's a breakdown of the acceptance criteria and the study details for the Hitachi S TEST Reagent Cartridge Total Bilirubin (T-BIL), based on the provided document:
1. Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria for all performance characteristics in a single table. Instead, it presents various test results and implicitly suggests that these results are considered acceptable for demonstrating substantial equivalence to the predicate device.
However, based on the intended use and common analytical performance benchmarks for in vitro diagnostics, we can infer some criteria and list the reported performance:
| Performance Characteristic | Acceptance Criteria (Inferred/Implicit) | Reported Device Performance (S TEST T-BIL) |
|---|---|---|
| Analytical Sensitivity | Limit of Blank: 0.1 mg/dL | |
| Limit of Detection: 0.2 mg/dL | ||
| Limit of Quantitation (LoQ): 0.4 mg/dL with ±20%CV | ||
| Linearity | Good correlation (r > 0.99) | Linear regression: y = 1.0136x - 0.0492; r = 0.9998 |
| Range of Linearity: 0.1 to 42.1 mg/dL | ||
| Reportable Range | Defined range of accurate measurements | 0.4 to 40.0 mg/dL |
| Precision (In-house) | Low %CV (e.g., 0.99), slope near 1, intercept near 0 | n=92, r=0.994, Slope=0.94 (0.92 to 0.96 CI), Y-intercept=0.40 (0.23 to 0.57 CI) |
| Method Comparison (External POL) | Good correlation with comparative method (r > 0.98), slopes near 1, intercepts near 0 | Site 1 (n=50): y=0.94x+0.36, r=0.995 |
| Site 2 (n=48): y=0.96x+0.22, r=0.988 | ||
| Site 3 (n=53): y=0.91x+0.35, r=0.993 | ||
| Matrices Comparison | Good correlation (r > 0.99), slope near 1, intercept near 0 compared to serum | Heparinized Plasma: Slope=1.00, y-intercept=0.07, r=0.999 |
| K3 EDTA Plasma: Slope=1.02, y-intercept=0.02, r=0.999 | ||
| Na Citrate Plasma: Slope=1.01, y-intercept=0.02, r=0.999 | ||
| Detection Wavelength | 450/546 nm (Different from predicate: 546/600 nm) | |
| Test Principle | Nitrous acid method | Nitrous acid method (Different from predicate: Diazo method) |
2. Sample Sizes and Data Provenance
- Analytical Sensitivity (LoQ): Not specified for LoB and LoD. For LoQ, "three low level specimens in six runs over three [days] with three instruments."
- Linearity: 15 serial dilutions, plus the zero standard.
- 20-day In-house Precision: Four levels of samples, "each tested in two runs, twice a day, for 20 days." (Total of 80 measurements per level).
- Interference Testing:
- Ascorbic acid and Hemoglobin: Two pools (approx. 1 and 4 mg/dL total bilirubin), spiked samples tested in triplicate.
- Lipids: Three sets of serum samples with differing natural triglyceride levels and similar T-BIL, plus three sets of serum with low TG and similar T-BIL. Tested in triplicate.
- Method Comparison (Internal): 92 clinical specimens.
- Matrices Comparisons: 39 matched serum/plasma samples (sodium citrate, EDTA, lithium heparin).
- External Site Precision Study: Three blinded serum samples (A, B, C). Each sample assayed six times per day for five days, resulting in 30 replicates per level per site. (Total 90 replicates per sample level across 3 sites).
- External Method Comparison Studies: Approximately 50 serum specimens with total bilirubin values ranging from 0.4 to 38.1 mg/dL per site. (Total ~150 specimens across 3 sites).
Data Provenance: The document does not explicitly state the country of origin for the data. Given the address of the applicant (Mountain View, CA, USA) and the context of a 510(k) submission to the FDA, it is highly probable that the studies were conducted in the USA. All studies appear to be prospective as they were specifically designed and executed for this submission to evaluate the device's performance characteristics.
3. Number of Experts and Qualifications for Ground Truth
The document describes performance studies for an in vitro diagnostic device (reagent cartridge for total bilirubin). The "ground truth" in this context is typically established by a reference method or a standard laboratory system, not by human experts interpreting results.
Therefore, the concept of "number of experts used to establish the ground truth" and their "qualifications" as it applies to image analysis or diagnostic interpretation by humans is not applicable to this type of device and study. The comparison is against established chemical measurement techniques.
4. Adjudication Method
As the "ground truth" is established by chemical reference methods rather than human interpretation, an adjudication method (like 2+1 or 3+1 often used in imaging studies) is not applicable. The results are quantitative measurements compared against other quantitative measurements.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
A Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed, nor would it be appropriate for this type of in vitro diagnostic device. MRMC studies are typically used to evaluate diagnostic accuracy and reader performance (e.g., radiologists, pathologists) for devices that involve human interpretation of images or other diagnostic data, often comparing AI-assisted vs. unassisted human performance.
This device, the "S TEST Reagent Cartridge Total Bilirubin (T-BIL)," is an automated chemistry assay that provides a quantitative measurement. There is no human "reader" in the loop whose performance would be improved by AI assistance.
6. Standalone (Algorithm Only) Performance Study
Yes, a standalone performance study was done. All the studies described (analytical sensitivity, linearity, precision, interference, and method comparisons) evaluate the performance of the S TEST Reagent Cartridge Total Bilirubin when used with the Hitachi Clinical Analyzer E40, without human intervention in the result generation beyond operating the analyzer and collecting the samples.
The method comparison studies specifically compare the algorithm-generated result (from the S TEST T-BIL system) against results from a "standard laboratory system" or "comparative method," demonstrating its standalone performance.
7. Type of Ground Truth Used
The ground truth used for the performance studies was comparison against a standard laboratory system (or comparative method). For example:
- Linearity, Precision, Interference: These studies used prepared samples with known concentrations or manipulated matrices where the expected result provides the ground truth benchmark.
- Method Comparison (Internal & External): The results from the S TEST T-BIL system were compared against a "standard laboratory system" or a "comparative method" (implicitly, another cleared and accepted total bilirubin assay).
- Matrices Comparisons: Comparison was made between the T-BIL results in plasma types against serum using the same or an established method.
There is no mention of pathology, outcome data, or expert consensus in the setting of diagnostic interpretation, as this is a quantitative chemical measurement.
8. Sample Size for the Training Set
The document does not provide information on a training set sample size. This is common for traditional in vitro diagnostic devices like reagent cartridges. These devices are developed based on established chemical principles (Nitrous acid method in this case) and tested for performance, rather than being "trained" using a dataset in the way an AI algorithm for image recognition would be.
Thus, the concept of a "training set" in the context of machine learning or AI is not applicable here. The development and validation process focuses on analytical performance characteristics.
9. How the Ground Truth for the Training Set Was Established
Since there is no "training set" as understood in AI/ML, the question of how its ground truth was established is not applicable. The device's performance is validated against established laboratory standards and reference methods as detailed in section 7.
§ 862.1110 Bilirubin (total or direct) test system.
(a)
Identification. A bilirubin (total or direct) test system is a device intended to measure the levels of bilirubin (total or direct) in plasma or serum. Measurements of the levels of bilirubin, an organic compound formed during the normal and abnormal distruction of red blood cells, if used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.(b)
Classification. Class II.