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The Atellica® CH Enzymatic Creatinine 3 (ECre3) assay is for in vitro diagnostic use in the quantitative determination of creatinine in human serum, plasma (lithium heparin and dipotassium EDTA), and urine using the Atellica® CH Analyzer. Such measurements are used in the diagnosis and treatment of renal diseases and in monitoring renal dialysis.

The Atellica CH ECre3 assay measures the concentration of creatinine through a series of coupled enzymatic reactions and is based upon the method developed by Masaru and Mitsutaka. The Atellica CH ECre3 assay uses a series of coupled enzymatic reactions. In a "pretreatment" reaction, endogenous creatine and sarcosine are removed from a test sample by creatinase and sarcosine oxidase. The level of creatinine in a test sample is then determined through coupled enzymatic reactions. First, creatinine is enzymatically converted by creatininase into creatine. Creatine is then enzymatically converted to sarcosine by creatinase. This is followed by the oxidation of sarcosine by sarcosine oxidase to produce hydrogen peroxide. In the presence of peroxidase, the hydrogen peroxide allows for the oxidative condensation of 4-aminoantipyrine and N-ethyl-N-(3-methylphenyl)-N'-succinyl-ethylenediamine to produce a reddish purple quinone pigment. The absorbance of this quinone pigment is measured as an endpoint reaction at 545/694 nm.

This document describes the performance of the Atellica® CH Enzymatic Creatinine 3 (ECre3) assay, a new in vitro diagnostic device for quantitative determination of creatinine. The information provided is for a 510(k) Premarket Notification to the FDA, demonstrating substantial equivalence to a predicate device. Therefore, the "acceptance criteria" here refers to the performance thresholds that the new device must meet to show it functions as intended and is comparable to the predicate device. The "study" refers to the analytical performance validation studies conducted.

Here's the breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance & 2. Sample Sizes and Data Provenance

Since this is an in vitro diagnostic (IVD) device, the "acceptance criteria" are typically defined as performance specifications that demonstrate the device's analytical accuracy, precision, linearity, and freedom from interferences. These are not clinical acceptance criteria in the sense of diagnostic accuracy to a specific disease state, but rather analytical performance metrics. The document compares the new device (candidate) to a predicate device and established standards.

Data Provenance (General): The document does not explicitly state the country of origin for the patient samples used in method comparison or specimen equivalency studies. It also does not specify if the studies were retrospective or prospective, though for IVD analytical performance, they are typically prospective analytical studies using characterized samples (pooled, spiked, or real patient samples collected for the study).

Regarding items 3-9 for this IVD document:

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

• For an IVD device like this, "ground truth" for analytical performance studies is established by reference methods (e.g., Isotope Dilution Mass Spectrometry - IDMS, as seen in the assay comparison) or against a legally marketed predicate device (ADVIA Chemistry ECRE_2 assay). It is not established by human experts (like radiologists reading images) for diagnostic accuracy or consensus in the typical sense for medical imaging or clinical decision support AI. The "experts" would be the metrologists or lab professionals validating the reference methods according to CLSI guidelines.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

• Not applicable in the context of an IVD analytical performance study. Adjudication methods are relevant for subjective interpretations, like radiology image reads or pathological diagnoses, where human variability exists and a consensus "ground truth" needs to be established. Here, the "truth" is quantitative measurement by reference methods.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done:

• Not applicable. MRMC studies are used to assess the comparative effectiveness of different diagnostic methods (often involving human readers and AI) where subjectivity and reader variability are factors. This submission is for an in vitro diagnostic assay, which provides quantitative values, not an imaging-based AI or a system that aids human interpretation in a subjective setting.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done:

• This is inherently a "standalone" device in the sense that it is an automated laboratory assay. Its performance is measured directly (algorithm only) against reference methods or the predicate, as presented in the analytical performance section. There isn't a "human-in-the-loop" component in its operation or interpretation beyond the lab professional running the analyzer and reviewing results.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

• The ground truth for this device's performance evaluation is established by:
  • Reference Methods: Specifically, Isotope Dilution Mass Spectrometry (IDMS) for creatinine measurements, which is a highly accurate and precise chromatographic-mass spectrometric method. This is considered the "gold standard" for creatinine measurement.
  • Comparison to a Legally Marketed Predicate Device: The ADVIA® Chemistry Enzymatic Creatinine_2 (ECRE_2) assay. The performance against the predicate is used to demonstrate "substantial equivalence."
  • Internal analytical validation: Using controlled samples (e.g., spiked samples, control materials) for precision, linearity, interference studies, where the "ground truth" is the known concentration or expected behavior of the sample.

8. The sample size for the training set:

• This document describes the validation of the device's performance, not its development or "training." For an IVD assay (like a chemical reagent and analyzer system), there isn't a "training set" in the machine learning sense. The assay is based on established enzymatic reaction principles, not on learned patterns from a "training set" of data. Therefore, this concept is not applicable here.

9. How the ground truth for the training set was established:

• Not applicable, as there is no "training set" for this type of IVD device. The assay's chemical reactions and measurement principles are intrinsically defined, not learned from data.

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The Atellica™ CH Creatinine 2 (Crea 2) assay is for in vitro diagnostic use in the quantitative determination of creatinine in human serum, plasma (lithium heparin), and urine using the Atellica™ CH Analyzer, Such measurements are used in the diagnosis and treatment of renal diseases, and in monitoring renal dialysis.

The Atellica™ CH Chemistry Calibrator (CHEM CAL) is for in vitro diagnostic use in calibrating the Crea 2 assay using the Atellica™ CH Analyzer.

The Atellica CH Creatinine_2 (Crea_2) assay is based on the reaction of picric acid with creatinine in an alkaline medium as described in the original procedure of Jaffe. Creatinine reacts with picric acid in an alkaline medium to produce a red-colored creatinine-picrate complex. The rate of complex formation is measured at 505/571 nm and is proportional to the creatinine concentration. The Atellica CH Creatinine 2 (Crea_2) assay is a modification of the Jaffe method using rate blanking and intercept correction. Rate blanking is used to minimize bilirubin interference. Also, because nonspecific serum/plasma protein interactions with this reagent have been found to produce a positive bias of approximately 0.3 mg/dL (26.5 umol/L), serum/plasma measurements are automatically corrected by subtracting 0.3 mg/dL (26.5 umol/L) from each result.

The Atellica CH Chemistry Calibrator (CHEM CAL) is a 1 level lyophilized calibrator product prepared from bovine serum base product.

Here's an analysis of the provided text to extract the acceptance criteria and study details for the Atellica CH Creatinine 2 (Crea 2) and Atellica CH Chemistry Calibrator (CHEM CAL) devices:

1. Table of Acceptance Criteria and Reported Device Performance

Detailed Precision Results:

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

• Detection Limit (LoB/LoD):
  • LoB: 4 samples with no analyte, tested 5 times a day for 3 days (60 reps total).
  • LoD: 4 low analyte samples, tested 5 times a day for 3 days (60 reps total).
• Limit of Quantitation (LoQ):
  • Serum: 10 low samples, 5 replicates each, on 3 reagent lots for 3 days, 5 calibrations per day (75 measurements per reagent lot per sample). Total of 2250 determinations.
  • Urine: Similar setup for urine samples. Total of 2250 determinations.
• Linearity Study:
  • Serum/Plasma: 12 samples (high and low concentration mixes). 5 replicates measured for each sample.
  • Urine: 10 samples (high and low concentration mixes). 5 replicates measured for each sample.
• Precision Studies:
  • Controls, serum, and plasma pools: 80 replicates (n=2 replicates, 2 times a day for at least 20 days).
• Interferences:
  • "Fresh sample pools" containing low or high levels of creatinine in serum and urine. Specific count not given, but refers to testing across these pools.
• Method Comparison (Predicate):
  • Serum: 140 remnant de-identified samples.
  • Urine: 109 remnant de-identified samples.
  • Data Provenance: "Remnant de-identified samples" implies retrospective patient data. "No patient history information was obtained." The studies were conducted internally by Siemens Healthcare Diagnostic Inc. R&D personnel.
• Method Comparison (IDMS):
  • Serum: 49 samples.
• Matrix Equivalency:
  • 58 matched serum and lithium heparin plasma samples.

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

This type of device (Creatinine assay system) does not typically involve human expert adjudication for its ground truth. The "ground truth" for a chemical assay is established through highly accurate reference methods or certified reference materials.

• Ground Truth for Method Comparison: The predicate device, ADVIA Chemistry Enzymatic Creatinine_2 (ECRE_2), served as the comparative "ground truth" for the method comparison study. Additionally, "Isotope Dilution Mass Spectrometry (IDMS)" was used as a reference method for a subset of samples, which is a highly accurate and precise method for determining analyte concentrations and is recognized as a gold standard in clinical chemistry.
• Ground Truth for Calibration/Standardization: The device uses "IDMS Reference Method" for standardization, and the predicate uses "SRM967" (Standard Reference Material 967, which is a NIST standard for creatinine in human serum, often value-assigned by IDMS). These are highly precise and accurate methods, not typically involving human expert consensus in the same way an imaging device would.

4. Adjudication Method for the Test Set

Not applicable for this type of in-vitro diagnostic device. Ground truth is established by quantitative measurement or comparison to a reference method, not by expert adjudication of human interpretations.

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 chemical analysis, not an AI-assisted diagnostic imaging or interpretation device that would involve human readers.

6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done

The device itself is a standalone, automated analytical system (Atellica CH Analyzer) that performs the creatinine assay. The performance results reported (LoB, LoD, LoQ, Linearity, Precision, Interference, Method Comparison) represent the standalone performance of the assay on the analyzer. There is no human-in-the-loop component for the measurement of creatinine by this system.

7. The Type of Ground Truth Used

• Reference Methods:
  • The predicate device (ADVIA Chemistry Enzymatic Creatinine_2) was used as a reference for method comparison.
  • Isotope Dilution Mass Spectrometry (IDMS) was used as a highly accurate reference method for a subset of serum samples. This is considered a gold standard for creatinine measurement.
• Reference Materials: Standardization mentions "IDMS Reference Method," which implies traceability to primary reference materials. The predicate mentions SRM967, a certified reference material.
• Defined Protocols: CLSI (Clinical and Laboratory Standards Institute) protocols (EP17-A2, EP05-A3, EP06-A, EP7-A2, EP09-A3, EP28-A3c) were followed for various performance evaluations, which define how to establish performance characteristics against expected statistical and analytical metrics.

8. The Sample Size for the Training Set

Not explicitly mentioned in the provided text as a "training set" in the context of machine learning, which is typically what this question implies. For an IVD assay, method development and initial optimization would involve numerous experiments and samples, but these are typically not referred to as a "training set" in the AI sense. The text focuses on the validation studies performed to demonstrate performance.

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

As above, the concept of a "training set" with established ground truth as used in AI/ML is not directly applicable here. The development of an IVD assay involves extensive R&D, where analytical methods are refined to accurately measure the analyte. The "ground truth" during this development phase would be established by reference methods or gravimetric/volumetric preparations of known concentrations, similar to how the validation ground truth is established.

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