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Creatine Kinase is an in vitro test for the quantitative determination of creatine kinase (CK) in human serum and plasma on Roche/Hitachi cobas c systems. The determination of CK and CK isoenzyme activities is utilized in the diagnosis and monitoring of myocardial infarction and myopathies such as the progressive Duchenne muscular dystrophy.

Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.

The Creatine Kinase assay is a two reagent assay for the quantitative determination of creatine kinase (CK) in human serum and plasma on automated clinical chemistry analyzers. Photometrically measured NAPDP formation is directly proportional to CK activity in a human sample.

Here's a breakdown of the acceptance criteria and study information based on the provided document:

Creatine Kinase Device Performance Study Summary

1. Acceptance Criteria and Reported Device Performance

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

• Detection Limits (LoB, LoD):
  • LoB: One analyte-free sample, measured with three lots, 10-fold determination in 6 runs (total 60 measurements per lot).
  • LoD: Five low-analyte concentration samples, measured with three lots, two-fold determination in 6 runs (total 60 measurements per lot).
• Limit of Quantitation (LoQ):
  • Five human serum samples, tested in 5 replicates per sample on 5 days.
• Precision (Repeatability & Intermediate):
  • Not explicitly stated as a single number, but experiments conducted with multiple human serum samples (5) and control materials (2), with two aliquots per run, two runs per day for ≥ 21 days on the same analyzer using 3 lots of reagent.
• Linearity (Serum & Plasma):
  • Two separate dilution series (serum and plasma), each with 14 concentrations, measured in triplicate.
• Matrix Comparison - Anticoagulants:
  • For each of the four tube types (Serum Gel Separation, Li-heparin, K2-EDTA, K3-EDTA), 30 tubes were filled completely. This implies 30 samples for each comparison.
• Interferences - H, L, I Indices:
  • Pooled human serum samples spiked with varying levels of interferent. The resulting sample series (10 dilution steps per sample) were tested in triplicate.
• Interferences - Drugs:
  • Two sample pools (low and high CK concentrations), divided into aliquots. Each spiked aliquot measured in triplicate.
• Method Comparison to Predicate:
  • 132 human serum samples (9 of which were spiked with human recombinant CK MB). Samples tested in singlicate.

Data Provenance: The document explicitly mentions "human serum samples" and "pooled human serum samples." The manufacturer is Roche Diagnostics Operations, located in Indianapolis, IN, USA. Based on the context of FDA submission for a device to be marketed in the USA, it is highly probable the data is retrospective and likely collected in a clinical laboratory setting (possibly in the USA or aligned with international standards like CLSI), but the specific country of origin for the patient samples is not stated.

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

N/A. This is a submission for an in vitro diagnostic device that quantitatively measures a biomarker (Creatine Kinase). The "ground truth" for the test set is established by the reference measurement procedure or the known concentration of the analyte in calibrators/controls, not by expert interpretation of images or clinical data. Therefore, human experts for ground truth adjudication are not applicable in this context.

4. Adjudication Method for the Test Set

N/A. See explanation above. The measurements are quantitative chemical analyses against instrument-derived values and established reference methods/materials, not subjective interpretations.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No. This is an in vitro diagnostic device for quantitative measurement of a biomarker in biological samples. MRMC studies are typically performed for imaging devices or other diagnostic tools where human interpretation plays a significant role, to evaluate how AI assistance impacts human reader performance. This is not applicable here.

6. Standalone (Algorithm Only) Performance Study

Yes, the entire submission is a standalone performance study of the Creatine Kinase assay on the Roche/Hitachi cobas c systems. The device itself is an "algorithm only" in the sense that it is an automated analytical system (reagent + instrument) that produces quantitative results without human intervention in the measurement process itself, beyond sample loading and system maintenance. The studies described (Detection Limits, Precision, Linearity, Interference, Method Comparison) directly assess the performance of this standalone analytical system.

7. Type of Ground Truth Used

The ground truth for the performance studies relies on:

• Reference Materials/Methods: For calibration and verification of accuracy, the method is stated to be traceable to IFCC (International Federation of Clinical Chemistry and Laboratory Medicine) Method for Creatine Kinase.
• Known Concentrations: For studies like LoB, LoD, LoQ, linearity, and interference, samples are either analyte-free, spiked with known concentrations of analyte or interferents, or diluted from samples with established reference values. This essentially uses calibrated reference standards and materials as the ground truth.
• Predicate Device Measurements: For method comparison, the predicate device's results (COBAS INTEGRA Creatine Kinase cleared in K951595 on the COBAS INTEGRA analyzer) serve as a comparative ground truth to establish substantial equivalence.

8. Sample Size for the Training Set

N/A. This is not a machine learning or AI-based diagnostic device in the modern sense that requires a "training set" of data to learn from. It is a traditional in vitro diagnostic assay based on a defined enzymatic chemical reaction and photometric measurement. The development of such assays involves extensive research and development to optimize reagents and instrument parameters, but not in the framework of a "training set" as understood in AI/ML.

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

N/A. As explained above, there is no "training set" in the context of an AI/ML device for this product. The development of the assay involves chemical and enzymatic principles, optimized through laboratory experimentation and knowledge of biochemistry, rather than learning from a dataset via a specified ground truth.

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cobas c Bilirubin Total Gen.3 is an in vitro test for the quantitative determination of total bilirubin in serum and plasma of adults and neonates on Roche/Hitachi cobas c systems. Measurement of the levels of bilirubin, an organic compound formed during the normal and abnormal destruction of red blood cells, is used in the diagnosis and treatment of liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gall bladder block.

cobas c Bilirubin Total Gen.3 reagent provides quantitative measurement of the total bilirubin that is present in serum and plasma of adults and neonates. Reagents are packaged in a cassette with two bottles labeled with their instrument positioning, R1 (Reagent 1) and R2 (Reagent 2). R1 contains detergent, buffer, and stabilizers at pH 1.0. R2 is a 3,5-dichlorophenyl diazonium salt: ≥ 1.35 mmol/L.

The provided text describes the 510(k) summary for the cobas c Bilirubin Total Gen.3 device, a quantitative colorimetric method for determining total bilirubin in serum and plasma. The acceptance criteria and supporting studies are detailed for various performance characteristics.

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

• PCCC1: 0.02 mg/dL (2.1% CV)
• PCCC2: 0.02 mg/dL (0.6% CV)
• Human Serum 1 (0.51 mg/dL): 0.01 mg/dL (2.9% CV)
• Human Serum 2 (17.7 mg/dL): 0.10 mg/dL (0.6% CV)
• Human Serum 3 (31.8 mg/dL): 0.14 mg/dL (0.4% CV)
  Intermediate Precision (Total Imprecision):
• PCCC1: 0.02 mg/dL (2.1% CV)
• PCCC2: 0.03 mg/dL (0.8% CV)
• Human Serum 1 (0.51 mg/dL): 0.02 mg/dL (3.3% CV)
• Human Serum 2 (17.7 mg/dL): 0.14 mg/dL (0.8% CV)
• Human Serum 3 (31.8 mg/dL): 0.18 mg/dL (0.6% CV) |
  | Linearity/Measuring Range | For both serum and plasma, the first-order (linear) regression must be significant. | Serum: Range tested and found: 0.12-38.9 mg/dL. Recommended measuring range: 0.15-35.1 mg/dL. Linear Regression: y=1.0021x-0.0317, r² = 0.999881 (Significant).
  Plasma: Range tested and found: 0.12-39.0 mg/dL. Recommended measuring range: 0.15-35.1 mg/dL. Linear Regression: y = 1.0014x - 0.0232, r² = 0.999954 (Significant). |
  | Detection Limit (LoB, LoD, LoQ) | Not explicitly stated in terms of acceptance criteria values, but the reported claims represent the specifications. The LoQ is determined based on precision at 20% CV. | LoB claim: 0.10 mg/dL
  LoD claim: 0.15 mg/dL
  LoQ claim: 0.15 mg/dL |
  | Analytical Specificity (Endogenous Substances) | Lipemia: ≤± 0.10 mg/dL for samples ≤ 1 mg/dL or ≤± 10% for samples > 1 mg/dL
  Hemolysis HbA: ≤±0.20 mg/dL for samples ≤ 2 mg/dL or ≤± 10% for samples > 2 mg/dL
  Hemolysis HbF: ≤± 0.10 mg/dL for samples ≤ 1 mg/dL or ≤ ± 10% for samples > 1 mg/dL
  Indican: ≤± 0.10 mg/dL for samples ≤ 1 mg/dL or ≤± 10% for samples > 1 mg/dL | Lipemia: No significant interference up to an L index of 1000. (Tested up to 1196-1217 L index)
  Hemolysis HbA: No significant interference up to an H index of 800. (Tested up to 946-951 H index)
  Hemolysis HbF: No significant interference up to an H index of 1000. (Tested up to 1047-1053 H index)
  Indican: No significant interference from indican up to 3 mg/dL. (Tested up to 3.75 mg/dL) |
  | Analytical Specificity (Common Drugs) | Difference in recovery to the reference sample: ≤± 10% | All tested drugs (Acetylcystein, Ampicillin - Na, Ascorbic acid, Phenylbutazone, Cyclosporine A, Cefoxitin, Levodopa, Methyldopa + 1.5, Metronidazole, Doxycyclin, Acetylsalycilic acid, Rifampicin, Acetaminophen, Ibubrofen, Theophylline) passed the acceptance criteria at their respective highest concentrations. |
  | Matrix Comparison (Anticoagulants) | For sample concentrations ≤ 0.99 mg/dL, the deviation must be ≤ ± 0.10 mg/dL. For sample concentrations > 0.99 mg/dL, the deviation must be ≤± 10%. | All data passed the criteria.
• Li-Heparin (full & half), K2-EDTA (full & half), and Gel Separation Tube showed acceptable recovery within the tested ranges (e.g., Li-Heparin full: 0.35 - 34.52 mg/dL).
• Serum vs. Li-heparin: y = 1.000x + 0.000, r = 0.9998 |
  | Adult Method Comparison with Predicate Device | Not explicitly stated with a numerical criterion, but the strong correlation (r=0.9997) and the regression equation (y = 0.959x + 0.091 mg/dL) demonstrate substantial agreement. | Equation: y = 0.959x + 0.091 mg/dL
  Correlation coefficient: r = 0.9997 |

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

• Precision:
  • Human Sera Samples: 3 samples (0.51, 17.7, and 31.8 mg/dL)
  • Control Samples: 2 serum-based control samples (PCCC1, PCCC2)
  • Each sample/control run in two aliquots per run, two runs per day for 21 days.
  • Data Provenance: Not explicitly stated, but implied to be laboratory-generated (not from real patient populations with specific countries of origin). Retrospective or prospective is not specified, but the study design suggests prospective lab testing.
• Linearity/Assay Reportable Range:
  • Serum dilution series: 14 levels
  • Plasma dilution series: 13 levels
  • Data Provenance: Laboratory-generated, with human serum/plasma pool spiked with unconjugated bilirubin. Not specified for country of origin or retrospective/prospective.
• Detection Limits (LoB, LoD, LoQ):
  • LoB: One blank sample
  • LoD: Five low-analyte samples
  • LoQ: A low-level sample set of nine
  • Data Provenance: Laboratory-generated.
• Analytical Specificity (Endogenous Substances):
  • Interferents: Hemoglobin, lipids, indican.
  • Two pools of human serum used (one spiked, one unspiked) to create dilution series.
  • Interference tested at two levels of bilirubin.
  • Data Provenance: Laboratory-generated using human serum.
• Analytical Specificity (Common Drugs):
  • 15 commonly used drugs.
  • Serum sample pools at two target concentrations of total bilirubin (~1.0 mg/dL and ~14.0 mg/dL).
  • Data Provenance: Laboratory-generated using serum.
• Adult Method Comparison with Predicate Device:
  • Sample Size: n=131 human sera adult samples.
  • Data Provenance: Not explicitly stated for country of origin or retrospective/prospective, but implies de-identified human serum samples.
• Matrix Comparison (Anticoagulants):
  • Sample Size: 35 tubes collected per anticoagulant type (Li-heparin, K2-EDTA, Gel Separation Tube).
  • Data Provenance: Not explicitly stated for country of origin or retrospective/prospective, but implies human plasma/serum samples.

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

This device is an in vitro diagnostic (IVD) for quantitative measurement of total bilirubin. Expert consensus is not typically used to establish ground truth for this type of quantitative biochemical assay. The ground truth is generally established by:

• Reference Methods: For this device, the "ground truth" or reference method for traceability is explicitly stated as "Standardized against the Doumas manual reference method."
• Predicate Device: For method comparison, the predicate device (Total Bilirubin reagent on the cobas c 501) serves as the comparator.

Therefore, the concept of "experts" in the context of clinical interpretation for ground truth is not applicable here.

4. Adjudication Method for the Test Set

Adjudication methods (e.g., 2+1, 3+1) are typically used in studies where human readers provide subjective assessments (e.g., image interpretation). This is a quantitative chemical assay, where measurements are objective. Therefore, no adjudication method was used or is relevant.

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 MRMC comparative effectiveness study was done. This device is a fully automated in vitro diagnostic test for measuring bilirubin levels. It does not involve human readers for interpretation, nor does it incorporate AI (Artificial Intelligence) in a way that would assist human readers.

6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, a standalone study was done. The entire performance evaluation (precision, linearity, detection limits, interference, method comparison) described in the document is for the device operating as a standalone quantitative assay without human intervention in the measurement process. The "algorithm" here refers to the chemical reaction principles and photometric measurement methodology.

7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, Etc.)

The ground truth for the quantitative measurement of total bilirubin is generally established by:

• Reference Methods: The device is standardized against the Doumas manual reference method (as stated under "Traceability"). This is the gold standard for bilirubin measurement.
• Comparator Methods: In the adult method comparison study, the predicate device (Total Bilirubin reagent) values served as the comparator for assessing agreement.

8. The Sample Size for the Training Set

The provided document describes a 510(k) submission for a diagnostic test. Unlike AI/ML-based diagnostic devices, this type of device does not typically involve "training sets" in the machine learning sense. The "training" in developing such a device involves refining chemical reagents and optimizing instrument parameters, which is a different process than training an algorithm on a dataset. The studies described are performance validation studies.

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

As explained above, there isn't a "training set" in the context of an AI/ML algorithm for this type of IVD device. The development process would involve optimizing the reagent formulation and assay conditions against an established reference method (like the Doumas method) to ensure accurate and precise measurements.

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