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The Cystatin C assay is an in vitro diagnostic test used in the quantitative immunoturbidimetric determination of cystatin C in human serum and plasma on the Alinity c system.

Measurement of cystatin C aids in the diagnosis and treatment of renal diseases.

For laboratory professional use only.

The Cystatin C assay is an automated clinical chemistry assay.

Cystatin C is a particle-enhanced turbidimetric immunoassay (PETIA) developed to accurately and reproducibly measure cystatin C levels in serum and plasma. Latex particles coated with anti-human cystatin C antibody agglutinate when mixed with sample containing human cystatin C. The change in absorbance due to agglutination of the reaction mixture is proportional to the quantity of human cystatin C in the sample.

The provided text is a 510(k) clearance letter for an in vitro diagnostic test (Cystatin C assay), not an AI/ML-driven medical device. Therefore, the information requested for AI/ML device studies (such as MRMC studies, expert adjudication, training set ground truth, etc.) is not applicable to this document.

However, I can extract and present the performance acceptance criteria and reported device performance from the provided document, even though they relate to a traditional laboratory assay rather than an AI/ML model.

Here's an interpretation based on the provided text for a traditional in vitro diagnostic device:

Based on the provided FDA 510(k) clearance letter for the Cystatin C Test System, the device is a quantitative immunoturbidimetric assay for the determination of cystatin C in human serum and plasma. The performance of this device was demonstrated through various nonclinical studies.

1. Table of Acceptance Criteria and Reported Device Performance

For in vitro diagnostic tests like the Cystatin C assay, "acceptance criteria" are typically defined by ranges or thresholds for performance characteristics such as precision, accuracy (bias), linearity, and limits of detection. The document describes the reported performance measured during the studies, and implicitly, these figures met the internal acceptance criteria set by the manufacturer (and approved by the FDA for clearance).

Here's a summary of the reported device performance:

Study Details (Relevant to IVD, not AI/ML)

The following points are addressed as much as possible for an in vitro diagnostic device, noting where the requested AI/ML specific information is not applicable.

2. Sample sizes used for the test set and the data provenance:

   • Precision/Reproducibility:
     • Within-Laboratory Precision: 80 replicates per sample/control (2 replicates/day for 20 days) for 2 controls and 4 human serum panels.
     • Reproducibility: 240 replicates per sample/control (4 replicates, twice/day for 5 days at 3 sites) for 2 controls and 3 human serum panels.
   • Accuracy (Bias): Not specified as a separate sample size, but involved testing across 2 reagent lots and 2 calibrator lots.
   • Linearity: Not specified as a number of distinct samples, but assessed over a range of concentrations.
   • Lower Limits of Measurement (LoB, LoD, LoQ): ≥ 60 replicates of zero-analyte samples for LoB, and ≥ 60 replicates of low-analyte level samples for LoD/LoQ.
   • Analytical Specificity (Interference): Each substance tested at 2 analyte levels.
   • Method Comparison: 161 serum samples.
   • Matrix Comparison: Not specified as a specific number, but evaluated across various tube types.
   • High Dose Hook: Not specified as a specific number of samples, but tested up to 40.00 mg/L.
   • Expected Values (Reference Interval): 250 apparently healthy individuals (105 females, 145 males) with eGFR > 80, aged 18 to 69 years.

   Data Provenance: The document does not explicitly state the country of origin for the clinical samples. The studies are described as "nonclinical performance" studies, meaning they evaluate the analytical performance of the assay itself, rather than diagnostic accuracy in a clinical setting with patient outcomes. These are typically prospective studies conducted in a controlled lab environment.

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

   • Not applicable for this in vitro diagnostic device. Ground truth for analytical performance studies of IVDs is established by the known concentration of analytes in reference materials, calibrators, and characterized control samples, or by comparison to a well-established reference or predicate method. It does not involve expert readers or their consensus.

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

   • Not applicable for this in vitro diagnostic device. Adjudication methods are relevant for subjective image-based assessments or clinical diagnoses where human interpretation varies. This product is a quantitative chemical assay.

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 for this in vitro diagnostic device. MRMC studies are for evaluating the impact of AI on human reader performance, typically in radiology or similar interpretive fields. This device performs automated measurements.

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

   • Analogous concept applies. The performance data presented (precision, accuracy, linearity, limits of detection, etc.) are the standalone performance of the assay on the Alinity c system. It demonstrates the device's ability to measure Cystatin C without human interpretation of the analytical signal.

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

   • For the analytical performance studies, the ground truth was established by:
     • Certified reference materials: Specifically, ERM-DA471/IFCC for assay standardization and accuracy validation.
     • Preparation of known concentrations: Through spiking or dilution of samples to evaluate linearity and limits of measurement.
     • Comparison to a validated comparator assay: For method comparison (Cystatin C on Alinity c vs a Comparator Cystatin C assay).
     • Characterized control materials: For precision and reproducibility studies.
     • Established healthy population studies: For determining the reference interval.

8. The sample size for the training set:

   • Not applicable in the AI/ML sense. This is a traditional chemical assay, not an AI/ML model that undergoes a "training" phase with data. The assay's parameters are developed through conventional analytical chemistry principles and validated through the nonclinical performance studies detailed.
   • Development would involve formulation and optimization studies, but not "training data" in the AI sense.

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

   • Not applicable for this in vitro diagnostic device. As noted above, there is no "training set" in the AI/ML context for a traditional immunoturbidimetric assay. The "ground truth" for developing such an assay would be based on fundamental chemical principles, known concentrations of analytes, and established analytical chemistry standards.

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Cystatin C is intended for quantitative in-vitro diagnostic determination of Cystatin C in human serum or Li-heparin plasma and EDTA plasma by turbidimetry using T60 Clinical Chemistry Analyzers.

Cystatin C measurements in serum and plasma are used as an aid in the diagnosis and treatment of renal diseases.

Cystatin C Calibrator is intended for in vitro diagnostic use on T60 analyzer. Cystatin C Calibrator is used as a calibrator for quantification of Cystatin C in serum and plasma by immunoturbidimetry using methods defined by Thermo Electron Oy.

Cystatin C Control is intended for in vitro diagnostic use on T60 analyzer. Cystatin C Control is used as a quality control to monitor precision of the Cystatin C test using methods defined by Thermo Electron Oy.

Cystatin C Control High is intended for in vitro diagnostic use on T60 analyzer. Cystatin C Control High is used as a quality control serum to monitor precision of the Cystatin C test using methods defined by Thermo Electron Oy.

Not Found

The provided text describes the 510(k) summary for the Thermo Electron Oy CYSTATIN C diagnostic kit. It focuses on demonstrating substantial equivalence to a predicate device rather than detailing a specific study to meet acceptance criteria for a novel device. However, some performance characteristics are reported that can be considered as addressing acceptance criteria.

1. Table of Acceptance Criteria and Reported Device Performance

Based on the provided text, the acceptance criteria are not explicitly stated for individual metrics. Instead, the approach is to demonstrate comparability to a legally marketed predicate device (Dako Cystatin C reagent). The document outlines several performance characteristics, and the implicit acceptance criterion is that the new device's performance should be similar or equivalent to the predicate device.

2. Sample size used for the test set and the data provenance

• Method Comparison: n = 54 samples were used for the method comparison study with the predicate device.
• Precision: The sample sizes for the precision studies (within-run, between-run, total) are not explicitly stated, but results are given for specific "Levels" (e.g., 0.70 mg/L, 1.49 mg/L) and "Controls" (Cystatin C Control, Cystatin C High Control). Typically, precision studies involve running multiple replicates of these samples over several days/runs.
• Interference: No specific sample size is given for interference studies, but it's implied that studies were performed to determine the interference limits for various substances.
• Data Provenance: The document does not specify the country of origin of the data or whether the studies were retrospective or prospective. Given the submitter's address is Finland, the studies were likely conducted there or in collaboration with Finnish institutions.

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

This information is not provided in the document. For an in vitro diagnostic device like this, "ground truth" would typically refer to the true concentration of Cystatin C in the samples. This is usually established through highly accurate reference methods or certified reference materials, not by expert consensus in the same way an imaging device might use radiologists. The document mentions traceability to "a pure recombinant Cystatin C preparation, where the Cystatin C concentration was established by dry mass determination," which serves as the ultimate reference for ground truth in this context.

4. Adjudication method for the test set

This information is not applicable/not provided. Adjudication methods (like 2+1 or 3+1) are typically used in studies involving subjective interpretation (e.g., medical imaging) where human experts determine a "ground truth" or categorize findings. For a quantitative diagnostic like Cystatin C measurement, the ground truth is established analytically (e.g., precise reference methods, dry mass determination).

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

This is not applicable. The device is an in vitro diagnostic assay kit for measuring Cystatin C concentration, not an AI-assisted diagnostic tool that involves human readers or interpretation of complex, multi-case scenarios.

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

Yes, this is a standalone device (algorithm only). The "algorithm" here refers to the immunoassay method itself and the T60 analyzer's processing of samples to yield a quantitative result. There is no human-in-the-loop performance component in the direct measurement process; the device outputs a quantitative value.

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

The ground truth for the Cystatin C calibrator and potentially other samples is established by traceability to a pure recombinant Cystatin C preparation, with its concentration determined by dry mass determination. This is a highly precise analytical method, serving as the "true" concentration for calibration and validation.

8. The sample size for the training set

This information is not provided. The document describes a traditional immunoassay, not a machine learning model, so the concept of a "training set" for an algorithm in the AI sense is not directly applicable. However, analytical studies for establishing assay parameters (e.g., linearity, sensitivity, specificity) would involve a range of samples and controls, but these are not explicitly termed a "training set" here.

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

As noted above, a "training set" in the AI sense is not directly applicable. However, the ground truth for calibrators and control materials used in developing and validating the assay would be established through traceability to pure recombinant Cystatin C preparation with concentration determined by dry mass determination, as mentioned for the overall assay's standardization.

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For In Vitro Diagnostic Use. For Professional Use Only.

Cystatin C Immunoparticles are intended for the quantitative determination of cystatin C in human serum, heparinized plasma and EDTA plasma by turbidimetry and nephelometry. Cystatin C measurements are used as an aid in the diagnosis and treatment of renal diseases.

Cystatin C Control Set is an assayed bi-level control intended to monitor and evaluate the precision and accuracy of the quantitative immunological determination of human cystatin C by turbidimetry or nephelometry.

The Cystatin C Calibrator is intended for establishing calibration curves for the quantitative immunological determination of human cystatin C by turbidimetry or nephelometry.

Cystatin C Immunoparticles are purified immunoglobulin fraction of rabbit antiserum directed against cystatin C covalently coupled to uniform polystyrene particles. The Cystatin C Immunoparticles are provided as a suspension preserved with 15 mmol/L sodium azide and are supplied ready for use. Recombinant human cystatin C produced in E. coli was used as an immunogen for raising the antibody coupled to the polystyrene particles.

In the DakoCytomation Cystatin C Assay, human serum or plasma is mixed with the Cystatin C Immunoparticles. The resulting immune complexes are measured by turbidimetry or nephelometry. The generated signal is correlated with the concentration of cystatin C in the sample. By interpolation on a standard curve, the concentration of cystatin C in the sample is calculated.

Cystatin C Control Set is a bi-level control. The controls are liquid pools of delipidated human serum enriched with recombinant human cystatin C produced in E. coli and preserved with 15 mmol/L sodium azide. Each donor has been tested and found negative for hepatitis B virus surface antigen, antibodies to hepatitis C virus and human immunodeficiency virus 1 and 2. The Cystatin C Control Set is supplied ready for use.

The cystatin C value assignment has been carried out by turbidimetry using the DakoCytomation Cystatin C Calibrator, code No. X 0974, as reference.

Cystatin C Calibrator is a liquid pool of delipidated human serum enriched with recombinant human cystatin C produced in E. coli and preserved with 15 mmol/L sodium azide. Each donor has been tested and found negative for hepatitis B virus surface antigen, antibodies to hepatitis C virus and human immunodeficiency virus 1 and 2. The Cystatin C Calibrator is supplied ready for use.

The cystatin C value assignment has been carried out by turbidimetry using a precise transfer protocol ensuring traceability to a pure recombinant human cystatin C reference preparation, where the cystatin C concentration was established by dry mass determination.

The provided text describes a 510(k) premarket notification for three in vitro diagnostic devices: Cystatin C Immunoparticles, Cystatin C Control Set, and Cystatin C Calibrator. The focus of the submission is to demonstrate substantial equivalence to previously marketed predicate devices rather than proving a new performance characteristic against a fixed set of acceptance criteria. Therefore, the information regarding acceptance criteria and performance studies is presented differently than would be expected for a device with novel performance claims.

Here's an analysis of the provided information:

1. A table of acceptance criteria and the reported device performance

The document does not present a formal table of distinct acceptance criteria with corresponding performance results similar to what might be found for a device with a specific diagnostic accuracy claim (e.g., sensitivity, specificity, AUC). Instead, the performance evaluations were conducted to demonstrate "substantial equivalence" to predicate devices. The performance characteristics studied include:

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

The document does not explicitly state the sample sizes used for the test sets for precision, accuracy, linearity, etc. It mentions human serum or plasma samples being used. There is no information regarding the country of origin of the data or whether the studies were retrospective or prospective.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This type of information (expert review, ground truth establishment) is typically relevant for diagnostic imaging AI devices, rather than for an in vitro diagnostic (IVD) immunoassay like Cystatin C measurement. For IVD devices, the "ground truth" often refers to a reference method or validated standard, not expert human interpretation of an image. The document mentions value assignment for controls and calibrators by turbidimetry and traceability to a pure recombinant human cystatin C reference preparation where the concentration was established by dry mass determination. This constitutes the "ground truth" for the calibrators and controls.

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

Adjudication methods are typically associated with human reader studies for subjective interpretations (e.g., radiology). This concept does not apply to the performance testing of an automated IVD assay where results are quantitative measurements. The "adjudication" in this context would be the validation of the reference methods and calibrator value assignments.

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, an MRMC comparative effectiveness study was not done. These are typically for AI-assisted diagnostic imaging where human readers interpret cases. This device is an in vitro diagnostic reagent and not an AI-assisted imaging device. The device itself is intended to quantitatively determine Cystatin C, and its performance is evaluated against predicate devices and analytical criteria, not human reader performance.

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

This refers to the inherent performance of the assay itself. The performance characteristics listed (precision, accuracy, linearity, sensitivity, specificity, interferences, stability) are all "standalone" performance evaluations of the assay components (Immunoparticles, Control Set, Calibrator) as they would be run on an automated analyzer. The device's primary function is quantitative measurement, not providing AI assistance to a human interpreter.

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

For the DakoCytomation Cystatin C Assay, the "ground truth" for the calibrators and controls was established by:

• Turbidimetry using the DakoCytomation Cystatin C Calibrator (X 0974) as reference for the control set.
• Traceability to a pure recombinant human cystatin C reference preparation, where the cystatin C concentration was established by dry mass determination for the calibrator.
• For the overall performance, comparison to legally marketed predicate devices (Dade Behring N Latex Cystatin C Test Kit, Roche Diagnostics Corp. Creatinine Plus assay) served as a comparative "ground truth" in demonstrating substantial equivalence.

8. The sample size for the training set

The document does not describe a "training set" in the context of machine learning or AI. This device is an immunoassay, not an AI/ML product. The term "training set" is not applicable here. The development of the immunoparticles would involve reagent optimization and validation, but this is not typically referred to as a "training set" in this context.

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

As there is no "training set" in the AI/ML sense, this question is not applicable. The development of the assay components would involve internal validation and standardization processes. For the purpose of regulatory substantial equivalence, the "ground truth" for comparison for the overall device performance was established by demonstrating comparable performance to the established predicate devices, which are legally marketed and are considered "safe and effective."

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