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The Atellica® CH Diazo Direct Bilirubin (D DBil) assay is for in vitro diagnostic use in the quantitative determination of direct bilirubin in human serum and plasma using the Atellica® CH Analyzer. Measurement of direct 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.

Atellica® CH Diazo Direct Bilirubin is a Photometric test using 2,4-dichloroaniline (DCA). Direct bilirubin in presence of diazotized 2,4-dichloroaniline forms a red colored azocompound in acidic solution. Absorbance is measured at 545/658 nm.

The provided text describes the performance characteristics and acceptance criteria for the Atellica® CH Diazo Direct Bilirubin (D DBil) assay. Here's a breakdown of the requested information:

Acceptance Criteria and Device Performance

1. Table of Acceptance Criteria and Reported Device Performance:

Note: Specific acceptance criteria for precision and reproducibility are not explicitly listed as single values but are implied by the comprehensive presentation of the data, demonstrating acceptable variability for a diagnostic assay. The document states that the results "support that the Candidate Device... is substantially equivalent."

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

• Assay Comparison: N = 100 samples
• Specimen Equivalency (Plasma vs. Serum): N = 53 samples for each plasma type (Lithium heparin, Sodium heparin, K2(EDTA)).
• Precision: N = 80 for each serum level (4 serum levels tested, total 320 measurements).
• Reproducibility: N = 225 for each serum level (4 serum levels tested, total 900 measurements).
• Interferences (HIL and Non-interfering Substances): The number of samples for interference testing is not explicitly stated as a single 'N' for the test set. However, the tables indicate specific analyte concentrations tested (e.g., for Hemoglobin, Lipemia, Acetaminophen, etc.), implying multiple measurements were performed for each interference level.

Data Provenance: The document does not explicitly state the country of origin or if the data was retrospective or prospective.

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

This information is not applicable as the device is an in vitro diagnostic assay for quantitative determination of direct bilirubin. The "ground truth" in this context refers to the measured concentration of direct bilirubin, which is established by established laboratory methods, standard reference materials, and comparison to a predicate device, rather than expert interpretation of images or clinical cases.

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

This information is not applicable. Adjudication methods like 2+1 or 3+1 are typically used in studies involving subjective interpretation (e.g., medical imaging interpretation) where multiple readers assess cases and discrepancies are resolved by a super-reader. For a quantitative diagnostic assay, the "ground truth" is determined by objective measurement rather than expert consensus on subjective findings.

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 information is not applicable. The device is an in vitro diagnostic assay, not an AI-assisted diagnostic tool that would involve human readers interpreting cases. Therefore, an MRMC study or evaluation of human reader improvement with AI assistance is not relevant to this submission.

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

The device is a standalone in vitro diagnostic assay. Its performance is measured independently of human interpretation in the clinical setting, although laboratory personnel operate the analyzer and interpret the numerical results in the context of a patient's overall clinical picture. The studies described (Precision, Reproducibility, Assay Comparison, Specimen Equivalency, Interferences) all reflect the standalone performance of the assay on the Atellica CH Analyzer.

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

The "ground truth" for this device's performance studies is established by:

• Reference Methods/Predicate Device: The "Assay Comparison" section uses the Wako Direct Bilirubin V assay as the comparative method.
• Internal Reference Standards: The assay's traceability is to internal reference standards manufactured by gravimetric methods.
• Control Samples/Spiking: For precision, reproducibility, and interference studies, samples are prepared with known concentrations of analyte or interferents.

8. The sample size for the training set:

This information is not provided in the document. This type of detail is typically associated with machine learning or AI algorithm development, which is not the primary focus of this in vitro diagnostic device submission. The device involves a chemical reaction and photometric measurement, not a "training set" in the machine learning sense.

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

This information is not provided and is not applicable as the device does not involve a "training set" in the context of machine learning. The assay mechanism is based on a defined chemical reaction (diazo colorimetry) rather than a trained algorithm.

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The Atellica® CH Diazo Total Bilirubin (D TBil) assay is for in vitro diagnostic use in the quantitative determination of total bilirubin in adults and children (non-neonates) in human serum and plasma using the Atellica® CH Analyzer. Measurement of total 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.

Atellica CH Diazo Total Bilirubin is a photometric test using 2,4-dichloroaniline (DCA). Direct bilirubin in presence of diazotized 2,4-dichloroaniline forms a red colored azocompound in acidic solution. A specific mixture of detergents enables the determination of the total bilirubin.

The provided document describes the Siemens Atellica® CH Diazo Total Bilirubin (D_TBil) assay, an in vitro diagnostic device, and its performance characteristics to demonstrate substantial equivalence to a predicate device (Dimension TBI Flex reagent cartridge).

Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for this in-vitro diagnostic device are generally defined by demonstrating performance within established statistical limits or comparison to a predicate device, as per CLSI (Clinical and Laboratory Standards Institute) guidelines. The "acceptance criteria" themselves are not always explicitly stated as pass/fail thresholds for each performance characteristic in a simple numerical format, but rather as meeting the objectives of the study design (e.g., correlation coefficient of ≥ 0.950).

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The Total Bilirubin2 assay is used for the quantitation of total bilirubin in human serum or plasma, of adults and neonates, on the ARCHITECT c System.

Measurement of total bilirubin, an organic compound formed during the normal destruction of red blood cells, is used in the diagnosis and treatment of liver, hematological, and metabolic disorders, including hepatitis and disorders of the biliary tract. In newborn infants, the Total Bilirubin2 assay is intended to measure the levels of total bilirubin (conjugated and unconjugated) in serum or plasma to aid in the diagnosis and management of neonatal jaundice and hemolytic disease of the newborn.

The Total Bilirubin2 assay (subject device) is an automated clinical chemistry assay for the quantitation of total bilirubin in human serum or plasma, of adults and neonates, on the ARCHITECT c System. Total (conjugated and unconjugated) bilirubin couples with a diazo reagent in the presence of a surfactant to form azobilirubin. The diazo reaction is accelerated by the addition of surfactant as a solubilizing agent. The increase in absorbance at 548 nm due to azobilirubin is directly proportional to the total bilirubin concentration. The methodology is Diazonium salt.

The provided text describes a 510(k) premarket notification for a medical device called "Total Bilirubin2", an in vitro diagnostic assay. This type of submission focuses on demonstrating substantial equivalence to a legally marketed predicate device, rather than proving clinical effectiveness through the extensive studies typically associated with AI/ML diagnostic tools. Therefore, the questions related to AI/ML specific criteria (like MRMC studies, number of experts for ground truth, sample size for training sets, etc.) are not applicable in this context.

The document primarily details the analytical performance of the Total Bilirubin2 assay.

Here's an analysis based on the information provided, adhering to the request:

Acceptance Criteria and Reported Device Performance

The acceptance criteria for this in vitro diagnostic device are typically defined by ranges of acceptable analytical performance, following established CLSI (Clinical and Laboratory Standards Institute) guidelines. The reported device performance is compared against these internal acceptance criteria.

Study Details:

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

   • Precision (Within-Laboratory): 80 replicates for each control/panel (on a representative combination out of 3 multi-lot/instrument combinations).
   • Reproducibility (System): 84 replicates for each control/panel.
   • Lower Limits of Measurement: ≥ 60 replicates for LoB and LoD for each of 3 lots on 2 instruments.
   • Interfering Substances: Not explicitly stated, but "Each substance was tested at 2 levels of the analyte."
   • Method Comparison:
     • Serum: 167 samples
     • Neonatal serum: 163 samples
   • Tube Type: Samples collected from a minimum of 40 donors.
   • Dilution Verification: 5 samples prepared with varying concentrations.
   • Data Provenance: Not explicitly stated regarding country of origin or whether retrospective/prospective. However, given the nature of in vitro diagnostic analytical studies, samples are typically acquired prospectively or from biobanks for specific analytical testing purposes.

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

   • For in vitro diagnostic devices like this bilirubin assay, "ground truth" is established by reference methods or highly characterized calibrators/control materials, not by expert human readers. The accuracy study, for example, compares results to material standardized to the Doumas Total Bilirubin reference method, which represents the "ground truth" for bilirubin measurement. Therefore, expert readers/adjudicators as typically seen in imaging AI studies are not applicable here.

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

   • Not applicable. This is an in vitro diagnostic assay, and its performance is evaluated against analytical measurements, not human interpretations requiring adjudication.

4. 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 device is an in vitro diagnostic test, not an AI/ML-driven imaging or diagnostic algorithm designed to assist human readers.

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

   • Not applicable. This is an assay performed on an automated system, providing a quantitative result. Its "performance" is inherently "standalone" in generating the numerical value, but it's not an AI algorithm in the sense of image interpretation or complex diagnostic inference.

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

   • For analytical performance studies, the "ground truth" for bilirubin concentration is established by reference methods (e.g., the Doumas method for accuracy) or by using certified reference materials and calibrators with known concentrations. This is the gold standard for quantitative in vitro diagnostic measurements.

7. The sample size for the training set:

   • Not applicable. This is not an AI/ML device that requires a "training set" in the computational sense. The device's performance is a function of its reagents, instrument, and established methodology, not a learned algorithm.

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

   • Not applicable. See above.

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Rx Only For in vitro diagnostic use only

The TBIL test within the VITROS XT Chemistry Products TBIL-ALKP Slides quantitatively measure total bilirubin (TBIL) concentration in serum and plasma using VITROS XT 7600 Integrated Systems. Measurements of the levels of bilirubin, an organic compound formed during the normal destruction of red blood cells, are used in the diagnosis and treatment of liver, hematological and metabolic disorders, including hepatitis and gall bladder block.

The ALKP test within the VITROS XT Chemistry Products TBIL-ALKP Slides quantitatively measure alkaline phosphatase (ALKP) activity in serum and plasma using VITROS XT 7600 Integrated Systems. Measurements of alkaline phosphatase or its isoenzymes are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases.

Not Found

This is an FDA 510(k) clearance letter for an in vitro diagnostic (IVD) device, specifically for VITROS XT Chemistry Products TBIL-ALKP Slides. The provided text is a regulatory communication and does not contain the acceptance criteria or study details for the device's performance.

To answer your request, I would need access to the actual 510(k) summary, often referred to as a "510(k) Premarket Notification." This document typically includes the performance data, acceptance criteria, and study designs to demonstrate substantial equivalence to a predicate device.

The information you've provided only states:

• Device Name: VITROS XT Chemistry Products TBIL-ALKP Slides
• Intended Use: Quantitative measurement of total bilirubin (TBIL) and alkaline phosphatase (ALKP) in serum and plasma using VITROS XT 7600 Integrated Systems.
• Regulatory Class: Class II
• Product Code: CIG (Bilirubin (total or direct) test system), CJE (Alkaline phosphatase test system)
• Date of Clearance: April 26, 2019

Without the 510(k) summary or a similar technical document, I cannot extract the specific acceptance criteria, study details, sample sizes, or ground truth information you've requested.

Therefore, I cannot provide the requested table and study details based solely on the provided text.

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ELITech Clinical Systems BILIRUBIN TOTAL 4+1 is intended for the quantitative in vitro diagnostic determination of total bilirubin in human serum and plasma on ELITech Clinical Systems Selectra Pro Series Analyzers.

ELITech Clinical Systems BILIRUBIN DIRECT 4+1 is intended for the quantitative in vitro diagnostic determination of direct bilirubin in human serum and plasma on ELITech Clinical Systems Selectra Pro Series Analyzers.

It is not intended for use in Point of Care settings.

Measurements of the levels of bilirubin (direct or total), an organic compound formed during the normal and abnormal distruction of red blood cells, are used in the diagnosis and treatment of liver, hematological, and metabolic disorders, including hepatitis and gall bladder block.

ELITech Clinical Systems BILIRUBIN TOTAL 4+1 and ELITech Clinical Systems BILIRUBIN DIRECT 4+1 are available as a kit only. Each kit consists of a bi-reagent R1 & R2.

ELITech Clinical Systems BILIRUBIN TOTAL 4+1:
Reagent 1: R1 Sulphanilic acid 29 mmol/L, Cetrimide 29 mmol/L.
Reagent 2: R2 Sodium nitrite 11 mmol/L.

ELITech Clinical Systems BILIRUBIN DIRECT 4+1:
Reagent 1: R1 Sulphanilic acid 29 mmol/L,
Reagent 2: R2 Sodium nitrite 11 mmol/L.

The document describes the analytical performance and comparison studies for the ELITech Clinical Systems BILIRUBIN TOTAL 4+1 and ELITech Clinical Systems BILIRUBIN DIRECT 4+1 devices. These devices are intended for the quantitative in vitro diagnostic determination of total and direct bilirubin, respectively, in human serum and plasma. The studies aim to demonstrate substantial equivalence to predicate devices (ABX Pentra Bilirubin, Total CP & ABX Pentra Bilirubin, Direct CP).

Here's the breakdown of the information based on your request:

1. Table of Acceptance Criteria and Reported Device Performance

For ELITech Clinical Systems BILIRUBIN TOTAL 4+1:

For ELITech Clinical Systems BILIRUBIN DIRECT 4+1:

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

• Precision (Test Set):

  • Sample Size: 80 measurements for each of 3 levels of samples (total 240 measurements per device) per instrument (2 instruments used).
  • Data Provenance: Not explicitly stated (e.g., country of origin). The samples are referred to as "samples" or "patient samples." The study was prospective in the sense that controlled experiments were performed to gather data for precision.

• Linearity (Test Set):

  • ELITech Clinical Systems BILIRUBIN TOTAL 4+1: 11 levels of mixed samples.
  • ELITech Clinical Systems BILIRUBIN DIRECT 4+1: 11 levels of mixed samples.
  • Data Provenance: Not explicitly stated. Likely prepared in a laboratory setting.

• Detection Limit (Test Set):

  • Sample Size: 15 measurements of 4 samples for each device.
  • Data Provenance: Prepared from patient samples and diluted with Albumin 6 g/dL - NaCl 0.9 %.

• Interference (Test Set):

  • Sample Size: For each potential interferent, 2 serum sample pools (low and high concentration), with aliquots spiked at various interferent concentrations (9 or 7 or 8 different concentrations). Each point was measured in triplicate per run. Two levels of control were also tested. A control sample was prepared from the sample pool diluted in appropriate diluent.
  • Data Provenance: "Serum sample pools." Not explicitly stated.

• Method Comparison (Test Set):

  • Sample Size: 100 serum patient samples for each device.
  • Data Provenance: "Serum patient samples." Not explicitly stated, but likely from a clinical laboratory or hospital in the country where the studies were conducted (France or USA, as these are locations given for the submitter and contact person). The study was likely prospective in nature for collecting these samples for comparison against the predicate.

• Matrix Comparison (Test Set):

  • Sample Size: 40 plasma patients (lithium heparin samples) for each device.
  • Data Provenance: "Plasma patients." Not explicitly stated. Likely from a clinical laboratory or hospital.

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

For this type of in vitro diagnostic device (quantitative measurement of bilirubin), the "ground truth" is typically established by reference methods or comparison to legally marketed predicate devices, not by expert interpretation. The predicate devices are considered the "ground truth" for the method comparison studies. The document implicitly uses the performance of the legally marketed predicate device (ABX Pentra Bilirubin, Total CP & ABX Pentra Bilirubin, Direct CP) as the standard against which the new device's performance is compared for substantial equivalence.

There is no mention of experts establishing ground truth in the traditional sense of medical imaging or clinical diagnosis.

4. Adjudication Method for the Test Set

Not applicable. This is an in vitro diagnostic device performing quantitative measurements, not an AI or imaging device requiring human adjudication of results. The performance is assessed by comparing quantitative results against reference or predicate methods.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not done. This type of study is typically for imaging devices where human readers interpret medical images with and without AI assistance. The described device is an in vitro diagnostic assay.

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

Yes, the studies described are standalone performance evaluations of the device (reagents on an analyzer). The device itself (the reagent system) functions as an "algorithm only" in the sense that it performs the chemical reaction and measurement without human interpretive input for each test result. Clinical laboratory technologists would operate the analyzer and interpret the numerical results, but the analytical performance described is the device's intrinsic capability.

7. The Type of Ground Truth Used

The primary ground truth for demonstrating substantial equivalence is the performance of the legally marketed predicate devices (ABX Pentra Bilirubin, Total CP & ABX Pentra Bilirubin, Direct CP). In the method comparison studies, the results from the new devices are compared against the results from the predicate devices using patient samples.

Additionally, for analytical performance like linearity, detection limit, and interference, the "ground truth" for evaluating the performance of the device is based on prepared samples with known concentrations or expected behaviors (e.g., spiked samples with interferents, serially diluted samples).

8. The Sample Size for the Training Set

Not applicable. This device is an in vitro diagnostic reagent system, not an AI/ML-based device that requires a "training set" in the computational sense. Its performance is based on chemical reactions and instrumental measurements, which are validated through analytical studies.

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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The Total Bilirubin assay is used for the quantitation of total bilirubin in human serum or plasma of adults and neonates on the ARCHITECT c8000 System.

Measurement of total bilirubin, an organic compound formed during the normal destruction of red blood cells, is used in the diagnosis and treatment of liver, hematological and metabolic disorders, including hepatitis and gall bladder block. A bilirubin (total and unbound) in the neonate test system is a device intended to measure the levels of bilirubin (total and unbound) in the blood (serum) of newborn infants to aid in indicating the risk of bilirubin encephalopathy (kernicterus).

The Total Bilirubin reagent kit contains Reagent 1 and Reagent 2. Reagent 1 contains Surfactants and HCl. Reagent 2 contains 2, 4-dichloroaniline, HCl, Sodium nitrite, and Surfactant. The principles of the procedure involve total (conjugated and unconjugated) bilirubin coupling with a diazo reagent in the presence of a surfactant to form azobilirubin. The increase in absorbance at 548 nm due to azobilirubin is directly proportional to the total bilirubin concentration. The detection of the analyte is end-point colorimetric.

Here's an analysis of the provided text regarding the acceptance criteria and study for the Total Bilirubin device:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" for each test in a formal table, but rather describes the methodology and then reports the results. I will infer the acceptance criteria from the statements provided about what is considered acceptable or how performance supports the claims.

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

• Limit of Quantitation (LOQ), Limit of Detection (LOD), Limit of Blank (LOB):
  • Zero-analyte samples: 4 samples. Tested in a minimum of 5 replicates on 5 separate runs.
  • Low-analyte samples: Minimum of 2 samples gravimetrically prepared at 8 target concentrations. Tested in a minimum of 10 replicates on 5 separate runs.
  • Data Provenance: Not explicitly stated (e.g., country of origin) but "human serum albumin" and "unconjugated bilirubin" are used. The study is prospective in nature, as samples are prepared for the purpose of the test.
• Linearity: 12 levels per pool in each of three combined bilirubin pools. Tested in a minimum of 4 replicates.
  • Data Provenance: "combined bilirubin pools" from "conjugated bilirubin stock" and "unconjugated bilirubin stock", "serum". Prospective.
• Within-Laboratory Precision: 4 control materials (Bio-Rad serum based). Tested in a minimum of 2 replicates, 2 times per day for 20 days.
  • Data Provenance: Commercial control materials (Bio-Rad Lyphochek Unassayed Chemistry Control, Bio-Rad Liquichek Pediatric Control). Prospective.
• Interference: Not specified.
  • Data Provenance: Not specified, but uses "bilirubin concnetrations". Prospective.
• Method Comparison:
  • Adult patient specimens: 124. 4 spiked.
  • Neonatal patient specimens: 64. 4 spiked.
  • Data Provenance: Patient specimens. Not specified if retrospective or prospective or country of origin, but generally method comparison studies use collected patient samples.
• Reference Range: 40 adult patient serum samples.
  • Data Provenance: Fresh, adult patient serum samples from a clinically healthy population. Stored at 2-8°C, protected from light. Assumed to be prospective as samples were collected for the study.
• Automated Dilution Protocol versus Manual Dilution Procedure: Not specified (samples were pooled to create desired concentrations).
  • Data Provenance: "Fresh serum specimens" obtained and pooled. Prospective.
• Specimen Tube Type (Matrix Equivalence): Minimum of 40 samples from adult subjects for each tube type. (Serum glass N=41, SST N=40, EDTA N=39, Lithium Heparin N=40, PST N=40, Sodium Heparin N=39).
  • Data Provenance: "Fresh or frozen sample sets" from subjects. Assumed to be prospective as these are explicitly collected to test tube types.

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

• This device is an in vitro diagnostic (IVD) for quantitative measurement. The "ground truth" for such devices is typically established through analytical methods, reference materials, gravimetric preparation, or comparison to a gold standard reference method/device, rather than expert human interpretation.
• Therefore, the concept of "experts used to establish the ground truth" as it applies to image-based AI or clinical diagnostic interpretation by physicians is not applicable here. The ground truth is the chemical concentration of bilirubin.

4. Adjudication Method for the Test Set:

• Again, as this is a quantitative chemical measurement, adjudication methods for expert interpretation (like 2+1, 3+1) are not applicable. The "adjudication" is inherent in the analytical process (e.g., repeating measurements, using certified reference materials, performing statistical analysis of replicates).

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 an in vitro diagnostic (IVD) device. MRMC studies, which assess human reader performance with and without AI assistance, are typically conducted for AI-powered medical image analysis or clinical decision support systems.
• Therefore, an MRMC comparative effectiveness study is not applicable to this type of device. There are no "human readers" interpreting an output in the same way a radiologist reads an image.

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

• Yes, this entire submission is a standalone performance evaluation of the assay (the "algorithm only" in a broader sense of the measurement procedure). The device is designed to quantitatively measure bilirubin, and the tests (LOQ, linearity, precision, interference, method comparison) evaluate its analytical performance without direct human interpretive intervention beyond running the instrument and analyzing the data.

7. The Type of Ground Truth Used:

• For LOQ, LOD, LOB: Gravimetrically prepared samples (human serum albumin and unconjugated bilirubin) provide the known "ground truth" concentrations.
• For Linearity: Combined bilirubin pools with known proportional compositions.
• For Precision: Commercial control materials with established (though perhaps unassayed) target ranges, tested repeatedly.
• For Method Comparison: The predicate device's measurements are used as the comparative "ground truth" or reference, as the goal is to show substantial equivalence.
• For Reference Range: Clinical health status of the adult population samples.
• For Automated Dilution: Known target concentrations and manual dilution results.
• For Specimen Tube Type: The control tube type (serum plastic tube) serves as the reference for comparison.

8. The Sample Size for the Training Set:

• This document describes the analytical validation of a re-agent kit for an existing instrument (ARCHITECT c8000 System). It's not an AI model that undergoes "training" in the conventional sense.
• Therefore, the concept of a "training set" for an AI algorithm is not applicable. The development of the reagent and its underlying chemical principles involved R&D and optimization, but not machine learning training on a dataset.

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

• As explained above, there is no "training set" in the context of an AI algorithm described here. The "ground truth" used during the development of the assay would have been based on established clinical chemistry principles, reference methods, and gravimetric preparations to ensure accurate concentration measurements during formulation and optimization.

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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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The S TEST Reagent Cartridge Total Bilirubin (T-BIL) is intended for the quantitative determination of total bilirubin in serum, lithium heparin plasma, K3 EDTA plasma, and sodium citrate plasma using the Hitachi Clinical Analyzer E40. The S TEST Reagent Cartridge Total Bilirubin is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

Total Billirubin measurements are used in the diagnosis and treatment of disorders of the liver.

The Hitachi Clinical Analyzer is an automatic, bench-top, wet chemistry system intended for use in clinical laboratories or physician office laboratories. The instrument consists of a desktop analyzer unit, an operations screen that prompts the user for operation input and displays data, a printer, and a unit cover. The analyzer unit includes a single probe, an incubation rotor, carousels for sample cups and reagent cartridges, and a multi-wavelength photometer. The single-use reagent cartridges may be placed in any configuration on the carousel, allowing the user to develop any test panel where the reagent cartridges are available.

The S TEST reagent cartridges are made of plastic and include two small reservoirs capable of holding two separate reagents (R1 and R2), separated by a reaction cell/photometric cuvette. The cartridges also include a dot code label that contains all chemistry parameters, calibration factors, and other production-related information, e.g., expiration dating. The dimensions of the reagent cartridges are: 13.5 mm (W) × 28 mm (D) × 20.2 mm (H).

System operation: After the sample cup is placed into the carousel, the analyzer pipettes the sample, pipettes the reagent, and mixes (stirs) the sample and reagent together. After the sample and reagent react in the incubator bath, the analyzer measures the absorbance of the sample, and based on the absorbance of the reactions, it calculates the concentration of analyte in the sample. The test system can measure analytes in serum or plasma and results are available in approximately 15 minutes per test. This submission is for Reagent Cartridge Total Bilirubin.

Chemistry reaction: Nitrous acid method: Total bilirubin in samples is oxidized to biliverdin by the action of nitrous acid at pH 3.7. The concentration of total bilirubin can be determined by measuring the decrease of absorbance at a wavelength of 450nm .

Here's a breakdown of the acceptance criteria and the study details for the Hitachi S TEST Reagent Cartridge Total Bilirubin (T-BIL), based on the provided document:

1. Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for all performance characteristics in a single table. Instead, it presents various test results and implicitly suggests that these results are considered acceptable for demonstrating substantial equivalence to the predicate device.

However, based on the intended use and common analytical performance benchmarks for in vitro diagnostics, we can infer some criteria and list the reported performance:

2. Sample Sizes and Data Provenance

• Analytical Sensitivity (LoQ): Not specified for LoB and LoD. For LoQ, "three low level specimens in six runs over three [days] with three instruments."
• Linearity: 15 serial dilutions, plus the zero standard.
• 20-day In-house Precision: Four levels of samples, "each tested in two runs, twice a day, for 20 days." (Total of 80 measurements per level).
• Interference Testing:
  • Ascorbic acid and Hemoglobin: Two pools (approx. 1 and 4 mg/dL total bilirubin), spiked samples tested in triplicate.
  • Lipids: Three sets of serum samples with differing natural triglyceride levels and similar T-BIL, plus three sets of serum with low TG and similar T-BIL. Tested in triplicate.
• Method Comparison (Internal): 92 clinical specimens.
• Matrices Comparisons: 39 matched serum/plasma samples (sodium citrate, EDTA, lithium heparin).
• External Site Precision Study: Three blinded serum samples (A, B, C). Each sample assayed six times per day for five days, resulting in 30 replicates per level per site. (Total 90 replicates per sample level across 3 sites).
• External Method Comparison Studies: Approximately 50 serum specimens with total bilirubin values ranging from 0.4 to 38.1 mg/dL per site. (Total ~150 specimens across 3 sites).

Data Provenance: The document does not explicitly state the country of origin for the data. Given the address of the applicant (Mountain View, CA, USA) and the context of a 510(k) submission to the FDA, it is highly probable that the studies were conducted in the USA. All studies appear to be prospective as they were specifically designed and executed for this submission to evaluate the device's performance characteristics.

3. Number of Experts and Qualifications for Ground Truth

The document describes performance studies for an in vitro diagnostic device (reagent cartridge for total bilirubin). The "ground truth" in this context is typically established by a reference method or a standard laboratory system, not by human experts interpreting results.

Therefore, the concept of "number of experts used to establish the ground truth" and their "qualifications" as it applies to image analysis or diagnostic interpretation by humans is not applicable to this type of device and study. The comparison is against established chemical measurement techniques.

4. Adjudication Method

As the "ground truth" is established by chemical reference methods rather than human interpretation, an adjudication method (like 2+1 or 3+1 often used in imaging studies) is not applicable. The results are quantitative measurements compared against other quantitative measurements.

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

A Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed, nor would it be appropriate for this type of in vitro diagnostic device. MRMC studies are typically used to evaluate diagnostic accuracy and reader performance (e.g., radiologists, pathologists) for devices that involve human interpretation of images or other diagnostic data, often comparing AI-assisted vs. unassisted human performance.

This device, the "S TEST Reagent Cartridge Total Bilirubin (T-BIL)," is an automated chemistry assay that provides a quantitative measurement. There is no human "reader" in the loop whose performance would be improved by AI assistance.

6. Standalone (Algorithm Only) Performance Study

Yes, a standalone performance study was done. All the studies described (analytical sensitivity, linearity, precision, interference, and method comparisons) evaluate the performance of the S TEST Reagent Cartridge Total Bilirubin when used with the Hitachi Clinical Analyzer E40, without human intervention in the result generation beyond operating the analyzer and collecting the samples.

The method comparison studies specifically compare the algorithm-generated result (from the S TEST T-BIL system) against results from a "standard laboratory system" or "comparative method," demonstrating its standalone performance.

7. Type of Ground Truth Used

The ground truth used for the performance studies was comparison against a standard laboratory system (or comparative method). For example:

• Linearity, Precision, Interference: These studies used prepared samples with known concentrations or manipulated matrices where the expected result provides the ground truth benchmark.
• Method Comparison (Internal & External): The results from the S TEST T-BIL system were compared against a "standard laboratory system" or a "comparative method" (implicitly, another cleared and accepted total bilirubin assay).
• Matrices Comparisons: Comparison was made between the T-BIL results in plasma types against serum using the same or an established method.

There is no mention of pathology, outcome data, or expert consensus in the setting of diagnostic interpretation, as this is a quantitative chemical measurement.

8. Sample Size for the Training Set

The document does not provide information on a training set sample size. This is common for traditional in vitro diagnostic devices like reagent cartridges. These devices are developed based on established chemical principles (Nitrous acid method in this case) and tested for performance, rather than being "trained" using a dataset in the way an AI algorithm for image recognition would be.

Thus, the concept of a "training set" in the context of machine learning or AI is not applicable here. The development and validation process focuses on analytical performance characteristics.

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

Since there is no "training set" as understood in AI/ML, the question of how its ground truth was established is not applicable. The device's performance is validated against established laboratory standards and reference methods as detailed in section 7.

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The EasyRA TBIL reagent is intended for the quantitative measurement of Total Bilirubin in human serum and plasma of adults on the Medica EasyRA analyzer in clinical laboratories. Bilirubin measurements are used in the diagnosis and treatment of liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gall bladder block. For in vitro diagnostic use only.

The EasyRA DBIL reagent is intended for the quantitative measurement of Direct Bilirubin in human serum and plasma of adults on the Medica EasyRA analyzer in clinical laboratories. Bilirubin measurements are used in the diagnosis and treatment of liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gall bladder block. For in vitro diagnostic use only.

The EasyRA CK reagent is intended for the quantitative determination of Creatine Kinase (CK) in human serum and plasma, using the MEDICA "EasyRA Chemistry analyzer" in clinical laboratories. Measurements of CK are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy. For in vitro diagnostic use only.

Not Found

This is a 510(k) premarket notification for in-vitro diagnostic reagents, not an AI/ML device. Therefore, the requested information about acceptance criteria, study design, and ground truth for an AI/ML device is not applicable here.

The document discusses the substantial equivalence of the EasyRA Total Bilirubin Reagent, EasyRA Direct Bilirubin Reagent, and EasyRA Creatinine Kinase Reagent to legally marketed predicate devices. The review is focused on the regulatory classification and general controls provisions for these diagnostic reagents.

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COBAS INTEGRA Bilirubin Direct Gen.2 is an in vitro test for the quantitative determination of direct bilirubin in human serum and plasma on COBAS INTEGRA 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 INTEGRA Bilirubin Direct Gen.2 reagent provides quantitative measurement of the direct bilirubin that is present in a human serum or human plasma sample. Reagents are packaged in a cassette with two bottles labeled with their instrument positioning, R1 and SR. R1, or Reagent 1, contains Phosphoric acid 85 mmol/L, NaCl 50 mmol/L, and HEDTA 4.0 mmol/L at pH 1.9. SR, or Start Reagent, is a 3,5-dichlorophenyl diazonium salt at 1.5 mmol/L in acid buffer, pH 1.3.

Here's a summary of the acceptance criteria and study information for the COBAS INTEGRA Bilirubin Direct Gen.2 reagent, based on the provided text:

Acceptance Criteria and Device Performance

• Human Serum 1 (0.12 mg/dL): SD 0.01 mg/dL, CV 7.4%
• Human Serum 2 (3.8 mg/dL): SD 0.01 mg/dL, CV 0.4%
• Human Serum 3 (13.2 mg/dL): SD 0.04 mg/dL, CV 0.3%
  Intermediate Precision:
• Human Serum 1 (0.12 mg/dL): SD 0.01 mg/dL, CV 7.7%
• Human Serum 2 (3.8 mg/dL): SD 0.04 mg/dL, CV 1.0%
• Human Serum 3 (13.2 mg/dL): SD 0.05 mg/dL, CV 0.4% |
  | Measuring Range (Linearity) | Based on CLSI EP6-A guidelines. | Plasma: Range tested 0.01 - 19.5 mg/dL, Range found 0.01 - 19.5 mg/dL, Recommended measuring range 0.07 - 13.8 mg/dL
  Serum: Range tested 0.02 - 19.4 mg/dL, Range found 0.02 - 17.4 mg/dL, Recommended measuring range 0.07 - 13.8 mg/dL
  Both showed a significant quadratic model, with linear regression for serum y = 1.0000x + 0.0000 (r² = 0.9944) and for plasma y = 1.0000x - 0.0000 (r² = 0.9977). |
  | Detection Limits (LoB, LoD, LoQ) | Based on CLSI EP17-A2 guidelines. | LoB claim: 0.05 mg/dL
  LoD claim: 0.07 mg/dL
  LoQ claim: 0.07 mg/dL (based on 20% CV) |
  | Analytical Specificity (Endogenous Substances) | "No significant interference" | Lipemia: No significant interference up to an L index of 750 (reported lowest L index for no interference was 1098).
  Hemolysis: No significant interference up to an H index of 25 (reported lowest H index for no interference was 25). |
  | Analytical Specificity (Common Drugs) | "No interference" from specific drugs. | Phenylbutazone causes falsely low bilirubin results (stated in labeling). The other 17 tested drugs (e.g., Acetylcystein (150 mg/L), Ampicillin - Na (1000 mg/L), Ascorbic acid (300 mg/L), Heparin - Na (5000 U)) produce no interference. |
  | Method Comparison with Predicate Device | Substantial equivalence to predicate device (COBAS INTEGRA Bilirubin Direct). | Passing/Bablok regression with predicate device showed: y = 1.0490x + 0.0699 mg/dL with R² = 0.9979. |
  | Matrix Comparison (Anticoagulants) | Median recovery: 90 to 110%
  Median absolute deviation:

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