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The IDS iSYS 25-Hydroxy Vitamin DS Assay (IDS-iSYS 250HD*) is intended for the quantitative determination of 25-hydroxyvitamin D (25OHD) and other hydroxylated metabolites in human serum on the IDS iSYS Multi-Discipline Automated System. Results are to be used in conjunction with other clinical and laboratory data to assist the clinician in the assessment of vitamin D sufficiency in an adult population.

The IDS-iSYS 25-Hydroxy Vitamin DS (250HDS) Control Set is used for quality control of the IDSiSYS 25-Hydroxy Vitamin DS assay on the IDS-iSYS Multi-Discipline Automated System.

The IDS-iSYS 25-Hydroxy Vitamin DS assay consists of a reagent cartridge and one set of calibrators (Calibrators A & B or CAL A & CAL B). The reagent cartridge contains multiple reagents: MPV1 (Magnetic particles coated with 25-OH D in a phosphate buffer containing methanol with sodium azide as preservative), CONJ (Anti- 25-OH D sheep polyclonal antibody labelled with an acridinium ester derivative, in buffer containing bovine, sheep, rabbit and mouse proteins with sodium azide as preservative), NaOH (Sodium hydroxide solution <0.5 M), and BUF (Assay buffer containing proprietary displacing compounds, methanol, and sodium azide as preservative). Calibrators A and B contain horse serum in a buffer matrix with two defined concentrations of 25-OH D and sodium azide as a preservative. The IDS-iSYS 25-Hydroxy Vitamin DS Control Set contains horse serum in a buffer matrix with three defined concentrations of 25-OH D and sodium azide as a preservative.

This is an analysis of a 510(k) summary for the IDS-iSYS 25-Hydroxy Vitamin Dˢ Assay and IDS-iSYS 25-Hydroxy Vitamin Dˢ Control Set.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally established by internal specifications of the manufacturer, often guided by CLSI (Clinical and Laboratory Standards Institute) guidelines or regulatory precedents. The document presents the reported performance without explicitly stating pre-defined acceptance criteria for each measurement, but rather implies acceptability by presenting results typically expected for such assays. For some sections, such as precision/reproducibility and interference, the acceptable range is mentioned within the text (e.g., ±10% bias for interference).

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

• Precision/Reproducibility: 6 serum samples, 80 measurements each (total = 480 measurements across 3 lots, 2 internal replicates, 2 external replicates, 20 days, 3 analyzers). Data provenance: Not explicitly stated, but typically internal studies.
• Linearity/Assay Reportable Range: 11 concentration levels from a high and low serum sample dilution, each assayed in duplicate from one manufacturing batch (total 22 concentration levels). Data provenance: Not explicitly stated, typically internal studies.
• Detection Limit:
  • LoB: Zero calibrator assayed as 10 replicates over 10 assays on 10 separate days (total of 100 measurements).
  • LoD: 10 samples (native and/or diluted) with very low vitamin D concentrations, in duplicate over 12 assays spanning multiple days (total of 240 data points).
  • LoQ: 13 low samples (native and/or diluted) in duplicate over 7 individual assays spanning multiple days (total of 182 data points).
    Data provenance for all detection limits: Not explicitly stated, typically internal studies.
• Analytical Specificity (Cross-reactivity): Not explicitly stated numbers of samples per cross-reactant, but uses vitamin D serum samples, some spiked. Data provenance: Not explicitly stated, typically internal studies.
• Interference: Not explicitly stated numbers of samples per interfering agent, but uses test vs. control samples, and in one case, 26 measurements for each condition. Data provenance: Not explicitly stated, typically internal studies.
• Method Comparison with Predicate Device (vs. ID-LC-MS/MS RMP): 99 samples. Data provenance: Not explicitly stated, but implies connection to CDC VDSP program for traceability.
• Method Comparison with Internal Predicate Device: 283 European-sourced serum samples. Data provenance: European, retrospective.
• Expected Values/Reference Range: 275 apparently healthy adults (light skin and dark skin, male and female, aged 21-77 years) from geographically diverse regions of the United States. Data provenance: Prospective, United States.

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

For this in vitro diagnostic device (IVD), the "ground truth" is typically established by reference methods or accepted techniques for measuring the analyte. No human expert "adjudication" in the sense of image review is performed.

• For Traceability/Standardization: The device is traceable to the isotope dilution-liquid chromatography/tandem mass spectrometry (ID-LC-MS/MS) 25(OH)D Reference Method Procedure (RMP) which was used in assigning the target value for the VDSP samples. The ID-LC-MS/MS RMP is traceable to the National Institute of Standards and Technology Standard Reference Material (SRM) 2972. This is considered the reference standard, not "expert concensus" in this context.
• For Method Comparison with Predicate Device (vs. ID-LC-MS/MS RMP): The ID-LC-MS/MS RMP serves as the reference method and thus the "ground truth" in this comparison.

4. Adjudication Method for the Test Set

Not applicable. This is an IVD device, and the ground truth is established by chemical reference methods and measurements, not by human expert adjudication of interpretations.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic assay that directly quantifies an analyte in serum, not an imaging device requiring human interpretation, which is where MRMC studies are typically employed. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply here.

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

Yes, the studies presented (precision, linearity, detection limits, specificity, method comparisons) evaluate the standalone performance of the IDS-iSYS 25-Hydroxy Vitamin Dˢ Assay. This device is an automated system designed to provide quantitative results directly from serum samples without direct human interpretation of the assay's output for diagnosis, beyond basic quality control and clinical interpretation of the quantitative value.

7. The Type of Ground Truth Used

The ground truth for the analytical performance studies (e.g., linearity, detection limit, cross-reactivity, interference) is established by the design of the experiments, using known concentrations of analytes, spiked samples, or reference materials.

For the method comparison studies, the ground truth is:

• ID-LC-MS/MS RMP (Reference Method Procedure): This is considered the gold standard or highly accurate reference method for 25(OH)D measurement, traceable to NIST SRM 2972.
• The currently marketed IDS-iSYS 25-Hydroxy Vitamin D (K091849) predicate device: This device's results are used as a comparative "truth" to demonstrate substantial equivalence, although the new device is also aligned with the ID-LC-MS/MS RMP.

8. The Sample Size for the Training Set

The document does not explicitly delineate a separate "training set" in the context of machine learning. For IVD devices like this, method development and optimization phases involve extensive testing with various samples, which could be considered analogous to a training process, but it's not typically formally described as such.

• Calibrator Traceability and Value Assignment: Master calibrators and kit calibrators are developed using stock solutions, and their values are adjusted based on results from running calibrators in multiple assays (minimum of 20 assay runs for kit calibrators) and multiple analyzers. Final values are adjusted for batch-to-batch consistency and alignment to the CDC VDSP program based on multiple correlation assays of an "established patient library panel". The size of this patient library panel is not specified.

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

As noted above, a formal "training set" with ground truth in the machine learning sense is not explicitly described. However, the development and calibration of the assay involve:

• Traceability to U.V. quantification and then ID-LC-MS/MS RMP:
  • Internal stock solutions are prepared, and their potency is initially based on absorbance at 264nm of an ethanolic 25D solution.
  • Master calibrators are prepared, and their final value assignment is based on extensive testing against the assay itself (running them in multiple assays on multiple analyzers).
  • The kit calibrators are tested as unknowns in a minimum of 20 assay runs calibrated with master calibrators, and values are adjusted to ensure consistency and alignment to the CDC VDSP program based on multiple correlation assays of an established patient library panel. This patient library panel's "ground truth" would have been established by the ID-LC-MS/MS RMP.

In summary, for this IVD, the ground truth primarily relies on established analytical standards and reference methods (ID-LC-MS/MS, NIST SRMs), rather than expert consensus or pathology reports. The studies demonstrate the assay's analytical performance and its comparability to both the ID-LC-MS/MS RMP and a predicate device.

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