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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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In vitro test for the quantitative determination of total bilirubin in human serum and plasma on the cobas c 111 system.

Measurements of the levels of bilirubin and organic compound formed during normal and abnormal destruction of red cells, is used in the diagnosis of liver, hemolytic hematological and metabolic disorders, including hepatitis and gall bladder block.

The Total Bilirubin Special reagent is intended for use on the cobas c 111 analyzer for the quantitative determination of total or direct bilirubin in serum and plasma.

The cobas c 111 analyzer is a partially automated, in-vitro diagnostic analyzer capable of performing clinical chemistry, specific protein and electrolyte tests. Analytes are measured photometrically or turbidimetrically; the analyzer also has an optional ISE module for measuring sodium, potassium and chloride.

The cobas c 111 instrument is a random access analyzer designed to be operated on a bench top in the professional environment using a combination of a photometric analysis unit and an optional ion selective electrodes (ISE).

Here's a breakdown of the acceptance criteria and study information for the Total Bilirubin Special reagent application to the cobas c 111 analyzer, based on the provided text:

Context: This submission is a Special 510(k) for a modification to an existing device. The modification involves applying the already cleared Total Bilirubin Special reagent to a new analyzer, the cobas c 111, which is itself a modification of the COBAS INTEGRA 400 plus. Therefore, the primary focus of the performance data is to demonstrate equivalence of the reagent's performance on the new analyzer compared to its performance on the predicate analyzer.

Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by demonstrating equivalence to the predicate device. The performance characteristics of the modified device (on cobas c 111) are compared to the predicate device (on COBAS INTEGRA Total Bilirubin Special, K063543).

Note on Acceptance Criteria: For a Special 510(k) like this, the implicit acceptance criterion is that the performance of the modified device is substantially equivalent to the predicate device, meaning it performs as well or better for the critical parameters. The table demonstrates this comparable performance.

Study Information

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

   • Test Set Sample Size: The document does not explicitly state the sample size used for the performance evaluation (precision, measuring range, detection limit, interference studies).
   • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective). This is a manufacturer's internal validation, likely conducted in a controlled lab environment.

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

   • This being an in-vitro diagnostic (IVD) chemistry analyzer, the "ground truth" for the test set is established by the reference method for total bilirubin (Doumas reference method, as mentioned in the traceability section) and highly controlled laboratory samples (e.g., control materials, spiked samples). There's no mention of human experts interpreting results in the way a radiologist interprets an image.

3. Adjudication method for the test set:

   • Not applicable in the context of an IVD chemistry analyzer. Results are quantitative outputs from the instrument.

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

   • No. This is a quantitative in-vitro diagnostic device, not an imaging device that requires human interpretation.

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

   • Yes, this is an algorithm-only (analyzer-only) performance study. The analyzer performs the test and provides a quantitative result. There is no human interpretation component in the direct measurement of bilirubin by this device.

6. The type of ground truth used:

   • Reference Method: The device is standardized against the Doumas reference method for total bilirubin. This is the primary established ground truth for bilirubin measurement.
   • Control Materials: Performance is likely evaluated using assayed control materials (e.g., Precinorm U, Precipath U mentioned as quality controls) with known concentration values.

7. The sample size for the training set:

   • Not applicable as this is not a machine learning/AI algorithm that requires a "training set" in the conventional sense. This is an analytical chemistry device where the "training" would be the initial development and calibration of the reagent and instrument platform.

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

   • Not applicable. The "ground truth" for the development of such an IVD device is based on established clinical chemistry principles and standardization against internationally recognized reference methods (like Doumas). Calibrators are used to establish the measurement curve, and these calibrators are themselves traceable to a reference method.

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The Roche Diagnostics OMNI S Analyzer is a fully automated critical care analyzer intended to be used for the measurement of pH, PO2, PCO2, sodium, potassium, ionized calcium, chloride, hematocrit, glucose, lactate, urca/BUN, bilirubin, total hemoglobin, oxygen saturation, oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin and methemoglobin in samples of whole blood, serum, plasma and aqueous solutions as appropriate.

The Roche Diagnostics OMNI S Analyzer is a fully automated critical care analyzer intended to be used for the measurement of pH, PO2, PCO2, sodium, potassium, ionized calcium, chloride, hematocrit, glucose, lactate, urea/BUN, bilirubin. hemoglobin, oxygen saturation, oxyhemoglobin, total deoxyhemoglobin, carboxyhemoglobin and methemoglobin in samples of whole blood, serum, plasma and aqueous solutions as appropriate.

The provided text describes a 510(k) submission for a bilirubin assay rather than a medical device or AI algorithm with performance metrics like sensitivity, specificity, or AUC. The document focuses on establishing substantial equivalence to predicate devices for regulatory clearance, not on demonstrating performance against clinical acceptance criteria in the way an AI diagnostic would.

Therefore, many of the requested categories for AI device studies (e.g., sample size of test set, number of experts, adjudication method, MRMC studies, standalone performance, training set details) are not applicable or cannot be extracted from this type of regulatory submission. The document primarily discusses method comparison studies with existing commercial assays.

Here's an attempt to answer the questions based only on the provided text, highlighting the limitations:

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

The document does not explicitly state quantitative "acceptance criteria" for the bilirubin assay in terms of diagnostic performance (e.g., sensitivity, specificity, or accuracy targets). Instead, it discusses "acceptable performance" through method comparison studies with predicate devices.

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 states, "The bilirubin parameter for use on the OMNI S Analyzer was compared to several legally marketed analyzers in the method comparison studies." However, it does not specify the sample size for these method comparison studies or the data provenance (country of origin, retrospective/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)

Not applicable. For laboratory assays like this, "ground truth" is typically established by reference methods or validated predicate devices, not by expert interpretation in the same way as imaging diagnostics. The text does not mention any human experts establishing ground truth for the test set.

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

Not applicable. Adjudication methods are typically used in imaging or clinical studies where subjective human interpretation needs to be reconciled. For a bilirubin assay, results are quantitative measurements, and reconciliation would involve comparing numerical values, not subjective interpretations. The text does not mention any adjudication method.

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 a laboratory assay for measuring a biomarker, not an AI-assisted diagnostic device that would involve human readers or image interpretation.

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

This refers to a standalone device, which is what the OMNI S Analyzer with the bilirubin assay is. It operates without human interpretation of results in the diagnostic pipeline beyond reading the numerical output. The entire development process would inherently evaluate its standalone performance by comparing its results to predicate devices.

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

The "ground truth" for this bilirubin assay is established by comparison to results obtained from legally marketed predicate bilirubin assays on other analyzers (Roche Hitachi Analyzers, Radiometer ABL735, Beckman LX®20 System, Kodak Vitros System). These predicate devices are considered the "truth" for establishing equivalence.

8. The sample size for the training set

Not applicable. This is a chemical assay, not an AI algorithm. There is no concept of a "training set" in the context of developing this type of device.

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

Not applicable, as there is no training set for this type of device.

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