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Diazyme's HCY POC Test Kit is intended to be used with the SMART analyzer in a Point-of-Care setting for the in vitro quantitative determination of total L-homocysteine in serum or plasma. The assay can assist in the diagnosis and treatment of patients suspected of having hyperhomocysteinemia and homocystinuria. For in vitro diagnostic use only.

Diazyme HCY POC Test Kit contains reagents intended for use with the SMART analyzer for the quantitative determination of Homocysteine (HCY) in human serum or plasma. Diazyme HCY POC Test is based on a novel enzyme cycling method as published in the Journal of Clinical Chemistry. In this assay, oxidized HCY is first reduced to free HCY which then reacts with a co-substrate, S-adenosylmethionine (SAM) catalyzed by a HCY S-methyltransferase to form methionine (Met) and S-adenosylhomocysteine (SAH). SAH is assessed by coupled enzyme reactions including SAH hydrolase, adenosine (Ado) deaminase and glutamate dehydrogenase, wherein SAH is hydrolyzed into adenosine (Ado) and HCY by SAH hydrolase. The formed HCY that is originated from the co-substrate SAM is cycled into the HCY conversion reaction by HCY S-methyltransferase. This forms a co-substrate conversion product-based enzyme cycling reaction system with signification of detection signals. The formed Ado is immediately hydrolyzed into inosine and ammonia which reacts with glutamate dehydrogenase with concomitant conversion of NADH to NAD+. The concentration of HCY in the sample is indirectly proportional to the amount of NADH converted to NAD+ (ΔA340mm).

The Diazyme HCY POC Test system thus consists of the following:

• HCY POC Test Kit. Reagents are provided in prefilled tubes, cuvettes and . cuvette caps. The DRS cuvette and cuvette caps can only work with the SMART analyzer.
• HCY POC Test Control Kit. Controls are provided for quality control of the . HCY POC Test.

Here’s an analysis of the acceptance criteria and study data for the Diazyme HCY POC Test, based on the provided document:

Acceptance Criteria and Device Performance for Diazyme HCY POC Test

1. Table of Acceptance Criteria and Reported Device Performance

• 7.5 µmol/L HCY: 3.2%
• 11.8 µmol/L HCY: 1.8%
• 29.0 µmol/L HCY: 2.8%
  Total CV%:
• 7.5 µmol/L HCY: 3.4%
• 11.8 µmol/L HCY: 3.5%
• 29.0 µmol/L HCY: 3.3% |
  | Precision (POL sites - 1) | "The results indicated good precision..." (Implied generally low CV%) | POL 1 (Sample 1): Within CV% 3.1%, Total CV% 5.2%
  POL 1 (Sample 2): Within CV% 2.8%, Total CV% 3.7%
  POL 1 (Sample 3): Within CV% 2.8%, Total CV% 4.1%
  POL 1 (Sample 4): Within CV% 3.5%, Total CV% 6.0%
  POL 1 (Sample 5): Within CV% 2.6%, Total CV% 3.2% |
  | Precision (POL sites - 2) | "a CV% of less than 8% was obtained at the three POL sites." for 9 serum samples ranging from 10.26 µmol/L to 42.73 µmol/L. | Site 1:
• Sample 1: Total CV 7.0%
• Sample 2: Total CV 5.3%
• Sample 3: Total CV 6.4%
  Site 2:
• Sample 1: Total CV 6.6%
• Sample 2: Total CV% 5.5%
• Sample 3: Total CV% 4.4%
  Site 3:
• Sample 1: Total CV% 6.0%
• Sample 2: Total CV% 6.8%
• Sample 3: Total CV% 5.5% |
  | Linearity/Reportable Range | Implied acceptable linearity and range. Based on R2, often >0.99 for diagnostic assays. | Linear from 3 - 50 µmol/L.
  Regression equation: Recovered HCY = 0.9749 * Expected HCY + 0.751
  Correlation coefficient (R2): 0.9992 |
  | Traceability | Traceable to a higher-order standard. | HCY POC Test calibration is traceable to the higher order NIST SRM 1955. |
  | Stability | Implied acceptable stability duration. | Real-time data showed stability for at least 10 months at 2-8℃ storage. (Testing is ongoing). |
  | LoB, LoD, LoQ | Distinct, measurable limits. | LoB = 0.06 µmol/L
  LoD = 0.32 µmol/L
  LoQ = 3.00 µmol/L |
  | Interference | "produced less than 10% deviation" for common endogenous substances at specified concentrations. | All listed endogenous substances (Ascorbic Acid, Bilirubin, Hemoglobin, Triglyceride, Glutathione, Methionine, Cysteine, Pyruvate, Cystathionine, Hydroxylamine, Carbamezapine, Methotrexate, Phenytoin, 6-azauridine triacetate, S-adenosyl-methionine, Carbamezapine-10, 11-epoxide, Ethosuximide, Primidone, Valporic Acid, Sodium Nitrate) produced less than 10% deviation at the specified concentrations. |
  | Method Comparison (Internal) | Strong correlation and agreement with predicate device (Diazyme HCY Two Reagent Enzymatic Assay on Olympus AU400). Implied R > 0.95. | n: 74
  Slope: 0.9612
  Intercept: 0.5246
  Correlation coefficient (R): 0.9696
  Range of values: 4.17-49.50 µmol/L |
  | Method Comparison (External) | Strong correlation and agreement with predicate device at POL sites. Implied R2 > 0.95. | All 120 samples combined:
  Slope: 1.0552
  Intercept: -0.8860
  R2: 0.9765
  Range: 3.88-49.86 µmol/L (across sites)
• Site 1: Slope 1.0890, Intercept -0.7438, R2 0.9830
• Site 2: Slope 1.0041, Intercept -0.6251, R2 0.9645
• Site 3: Slope 1.0600, Intercept -1.1564, R2 0.9819 |
  | Matrix Comparison | No significant matrix effect between serum, EDTA plasma, and Li Heparin plasma. | EDTA plasma: Slope = 1.0197, R = 0.9889
  Li Heparin plasma: Slope = 0.9632, R = 0.99
  Conclusion: No matrix effect between serum, EDTA plasma and Li Heparin Plasma. |

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

• Precision (Manufacture site): 40 points per HCY level (3 levels). Data provenance is internal (manufacturer site). Prospective data collection for this internal study.
• Precision (POL sites - 1): 20 points for each of 5 samples. Data provenance is external (three Physician Office Laboratories - POLs). Prospective data collection for this external study.
• Precision (POL sites - 2): 20 points for each of 3 samples per site, across 3 sites. Data provenance is external (three POLs with multiple users). Prospective data collection for this external study.
• Linearity/Assay Reportable Range: Ten levels of linearity set, tested in triplicate. Data provenance is internal (manufacturer site). Prospective data collection.
• Interference: 12μM and 29μM HCY serum samples spiked with various concentrations of interferents. Data provenance is internal (manufacturer site). Prospective data collection.
• Method Comparison (Internal): 74 individual serum samples. Data provenance is internal (manufacturer site). Likely prospective/retrospective (spiked samples indicate some manipulation).
• Method Comparison (External): 120 serum specimens total (40 samples at each of three POL sites). Data provenance is external (three POL sites). Prospective data collection.
• Matrix Comparison: 40 sample sets (serum/EDTA plasma/Li Heparin). Data provenance is internal (manufacturer site). Prospective data collection.

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

This type of device (a quantitative in-vitro diagnostic assay) does not typically use human experts to establish "ground truth" for the test set in the way an imaging AI algorithm would. Instead, the "ground truth" for the test samples is established by:

• Reference Methods: The predicate device itself (Diazyme HCY Two Reagent Enzymatic Assay on Olympus AU400 cleared under K071971) serves as the reference method for comparison studies, implicitly providing the "ground truth" values for patient samples. The predicate device itself would have been validated against a higher standard.
• Known Concentrations: For studies like linearity, LoB/LoD/LoQ, and interference, samples with precisely known concentrations of HCY or interfering substances are prepared according to recognized laboratory standards (e.g., CLSI guidelines).
• NIST SRM 1955: For calibrator traceability, the device is linked to a National Institute of Standards and Technology (NIST) Standard Reference Material, which represents a highly accurate and reliable "ground truth" for homocysteine concentration.

Therefore, no information on the number or qualifications of experts establishing ground truth in the context of clinical interpretation or annotations is applicable or provided.

4. Adjudication Method for the Test Set

Not applicable. As a quantitative in-vitro diagnostic test, "adjudication" in the sense of resolving conflicting interpretations (like in imaging studies) is not performed. The results are numerical values that are compared against a reference method or known concentrations.

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 device for quantitative bodily fluid analysis, not an imaging AI or decision-support tool for human interpretation. Therefore, MRMC studies and "human readers improving with AI assistance" are not relevant to this device.

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

Yes, the studies presented are essentially "standalone" performance evaluations of the device (HCY POC Test Kit + SMART analyzer). The device provides a quantitative result directly, without requiring human interpretation of raw data or human modification of the algorithm's output for its primary function. The users (nurses, office assistants) described in the POL precision studies are operating the device, but their "performance" isn't being measured in terms of their diagnostic accuracy, but rather their ability to correctly perform the test yielding consistent results.

7. The Type of Ground Truth Used

The ground truth used depends on the specific performance characteristic being evaluated:

• For Precision, Linearity, LoB/LoD/LoQ: Samples with precisely known concentrations of HCY, prepared in the laboratory or from certified reference materials (like NIST SRM 1955 for traceability).
• For Method Comparison: The values obtained from the predicate device (Diazyme HCY Two Reagent Enzymatic Assay on an Olympus AU400, K071971) were used as the reference "ground truth" for comparison.
• For Interference: Samples with known HCY concentrations spiked with known concentrations of suspected interfering substances.

8. The Sample Size for the Training Set

This document describes a premarket approval (510(k)) submission for an in-vitro diagnostic assay kit. Such submissions typically detail validation studies for the finished product, not the development or training of an algorithm in the machine learning sense. The "SMART analyzer" uses an RFID card with a preprogrammed calibration curve, which is derived from testing 5 levels of calibrators with the reagents.

• The training set for the calibration curve programming on the RFID card involves testing "5 levels of calibrators used in the predicate device (K071971)" with the Diazyme HCY POC Test reagents on SMART analyzers. The exact number of replicates or runs during this programming phase is not specified beyond "mean of absorbance change."

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

The "ground truth" for establishing the calibration curve (which is the "training set" in a functional sense for this IVD) is established by using:

• Reference Diazyme Homocysteine calibrator values (K071971): These calibrators themselves would have assigned values traceable to higher-order standards.
• NIST SRM 1955: The overall calibration is tied to this higher-order standard.

The process involves testing these known calibrators on the SMART analyzer to obtain absorbance changes, and then programming a curve that correlates these absorbance changes to the known HCY concentrations, which constitutes the "ground truth" for the device's measurement function.

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