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The Glucose2 assay is used for the quantitation of glucose in human serum, plasma, urine, or cerebrospinal fluid (CSF) on the ARCHITECT c System.

Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma.

The Glucose2 assay is an automated clinical chemistry assay.

Glucose is phosphorylated by hexokinase in the presence of adenosine triphosphate (ATP) and magnesium ions to produce glucose-6-phosphate (G-6-P) and adenosine diphosphate (ADP). Glucose-6-phosphate dehydrogenase (G-6-PDH) specifically oxidizes G-6-P to 6-phosphogluconate with the concurrent reduction of nicotinamide adenine dinucleotide phosphate (NADP) to its reduced form (NADPH). One micromole of NADPH is produced for each micromole of glucose consumed. The NADPH produced absorbs light at 340 nm and can be detected spectrophotometrically as an increased absorbance.

Methodology: Hexokinase/G6PDH

N/A

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cobas pure integrated solutions is an automated analyzer, intended for running qualitative, semiguantitative and quantitative clinical chemistry and immunochemistry assays as well as ion selective measurements.

Glucose HK Gen.3 is an in vitro test for the quantitative determination of glucose in human serum, plasma, urine and CSF on Roche/Hitachi cobas c systems. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoqlycemia, idiopathic hypoglycemia and pancreatic islet cell tumors.

The ISE analytical unit of the Roche/Hitachi cobas c systems is intended for the quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. Sodium measurements are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of large amounts of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance.

Methadone II (MDN2) is an in vitro diagnostic test for the qualitative and semiquantitative detection of methadone in human urine on Roche/Hitachi cobas c systems at a cutoff concentration of 300 ng/mL. Semiquantitative test results may be obtained that permit laboratories to assess assay performance as part of a quality control program. Semiquantitative assays are intended to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as gas chromatography/mass spectrometry (GC-MS).

Elecsys TSH is an immunoassay for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid and pituitary disorders. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The cobas pure integrated solutions is a fully automated, random-access, software controlled system intended for in vitro quantitative and qualitative analysis of analytes in body fluids. It will typically be used in low to mid throughput clinical laboratories. The system consolidates clinical chemistry, homogenous immunoassays as well as electrolyte testing within one workplace. The cobas pure integrated solutions consists of a clinical chemistry analytical unit (cobas c 303) with an integrated ISE analytical unit, an immunoassay analytical unit (cobas e 402) and a core unit.

Glucose is phosphorylated by hexokinase (HK) in the presence of adenosine triphosphate (ATP) and magnesium ions to produce glucose-6-phosphate (G-6-P) and adenosine diphosphate (ADP). Glucose-6-phosphate dehydrogenase (G-6-PDH) specifically oxidizes G-6-P to 6-phosphogluconate with the concurrent reduction of nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide reduced (NADH). One micromole of NADH is produced for each micromole of glucose consumed. The NADH produced absorbs light at 340 nm and can be detected spectrophotometrically as an increased absorbance.

The ISE analytical unit for Na+ employs ion-selective membrane to develop an electrical potential (electromotive force, EMF) for the measurements of ions in solution. Selective membrane is in contact with both the test solution and an internal filling solution. Due to the selectivity of the membrane, only the ions to be EMF. The membrane EMF is determined by the difference in concentration of the test ion in the test solution and the internal filling solution.

The ISE analytical unit of the Roche/Hitachi cobas c systems is intended for the quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. Sodium is the major extracellular cation and functions to maintain fluid distribution and osmotic pressure. Some causes of decreased levels of sodium include prolonged vomiting or diarrhed reabsorption in the kidney and excessive fluid retention. Common causes of include excessive fluid loss, high salt intake and increased kidney reabsorption.

The Methadone assay is based on the kinetic interaction of microparticles in a solution (KIMS) as measured by changes in light transmission. In the absence of sample drug conjugates bind to antibody-bound microparticles, causing the formation of particle aggregates. As the aggregation reaction proceeds in the absence of sample drug, the absorbance increases.

When a urine sample contains the drug in question, this drug derivative conjugate for microparticle-bound antibody. Antibody bound to sample drug is no longer available to promote particle aggregation, and subsequent particle lattice formation is inhibited. The presence of sample drug diminishes the increasing absorbance in proportion to the concentration of drug in the sample. Sample drug content is determined relative to the value obtained for a known cutoff concentration of drug.

The Elecsys TSH immunoassay makes use of a sandwich test principle using monoclonal antibodies specifically directed against human TSH. The antibodies labeled with ruthenium complex) construct from human and mouse specific components. Elecsys TSH immunoassay is intended for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid and pituitary disorders. It is intended for use on the cobas e immunoassay analyzers.

The provided text describes several in vitro diagnostic (IVD) devices and their performance characteristics. It outlines how Roche Diagnostics established the substantial equivalence of these devices (Glucose HK Gen.3, ISE indirect Na for Gen.2, ONLINE DAT Methadone II, Elecsys TSH, and the cobas pure integrated solutions analyzer) to their predicate devices through various non-clinical tests.

However, the document does not provide a table of acceptance criteria and reported device performance in a format that easily allows for direct comparison against specific numeric targets. Instead, it describes general study types and states that the "analytical performance data for all representative assays meet specifications and support the substantial equivalence."

Furthermore, it does not explicitly detail the following requested information:

• Sample sizes used for the test set and data provenance: The document mentions "human serum, plasma, urine and CSF" as sample types but not explicit test set sample numbers or their country of origin for most tests. It generally refers to "human samples" or "pooled human plasma and serum samples."
• Number of experts used to establish the ground truth for the test set and their qualifications: This information is not present for any of the described tests. The ground truth for these IVDs is typically established through reference methods or established control materials, not expert consensus on individual cases.
• Adjudication method: Not applicable/provided as the tests are analytical and do not involve human interpretation requiring adjudication.
• Multi Reader Multi Case (MRMC) comparative effectiveness study: Not applicable, as these are IVD assays, not AI-assisted reader studies.
• Standalone performance: The entire document describes the standalone performance of the algorithms/assays.
• Type of ground truth used: For quantitative assays (Glucose, Sodium, TSH), the ground truth is implicitly based on established reference methods or known concentrations in control materials. For qualitative/semi-quantitative assays like Methadone, it's based on known concentrations relative to a cutoff or confirmed by methods like GC-MS.
• Sample size for the training set: Not explicitly stated, as these are typically not machine learning models in the sense of needing a distinct "training set" for classification, but rather reagents and analytical systems whose performance is validated. The mentioned "study" refers to validation studies, not AI model training.
• How the ground truth for the training set was established: Not applicable, as explained above.

Given the nature of the document, which focuses on device-specific analytical performance claims rather than AI model validation, several of the requested categories are not directly addressed or are not relevant.

Below is an attempt to structure the available information, noting the limitations.

1. Table of Acceptance Criteria and Reported Device Performance

As specific numerical acceptance criteria (e.g., "sensitivity ≥ 95%") are not explicitly provided in the text, this table will summarize what types of performance were evaluated and that they met specifications as stated in the document.

Overall Conclusion for all devices: "The analytical performance data for all representative assays meet specifications and support the substantial equivalence...to the predicate devices."

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

• Glucose HK Gen.3:
  • Precision studies: "Two aliquots per run, two runs per day for ≥ 21 days". Types of samples (e.g., patient, control) not specified, but typically human-derived.
  • Linearity, LoB, LoD, LoQ, Interference, Matrix Comparison, Post Dilution Check, Recovery in Controls: Sample numbers or types of samples for these specific studies are not detailed.
  • Method Comparison: "all sample types" (e.g., human serum, plasma, urine, CSF) tested between cobas c 303 and cobas c 503.
  • Data Provenance: Not specified (e.g., country of origin, retrospective/prospective).
• ISE indirect Na for Gen.2:
  • Precision studies: "One run per day for ≥ 21 days with two parts, two aliquots per part". Typically human-derived samples.
  • Endogenous Interference: "pooled human plasma and serum samples spiked with varying levels of interferent."
  • Linearity, LoB, LoD, LoQ, Drug Interference, Calibration Frequency, Post Dilution Check, Recovery in Controls: Sample numbers or specific types of samples not detailed.
  • Method Comparison: "all sample types" (e.g., human serum, plasma, urine) tested.
  • Data Provenance: Not specified.
• ONLINE DAT Methadone II:
  • Precision: "human samples and controls" (n=84 for repeatability, with 2 aliquots per run, 2 runs per day, 21 days for intermediate precision).
  • Endogenous Interference: "urine containing methadone" and "pooled human urine".
  • Drug Interference: "human urine containing methadone".
  • Cross Reactivity: Details not given, but likely spiked drug solutions into human urine.
  • Method Comparison: Urine samples compared against GC-MS and cobas c 503.
  • Data Provenance: Not specified.
• Elecsys TSH:
  • Precision: Likely control materials and potentially patient samples.
  • Endogenous Interfering Substances: "human serum samples (native serum pools)".
  • Cross-reacting Compounds: "native human serum sample pool".
  • Anticoagulants Effect: "native human serum samples, single donors as well as pools" drawn into various tubes.
  • Linearity, LoB, LoD, LoQ, Drug Interference, On-board Reagent Stability, High-dose Hook Effect: Sample numbers or types not specified.
  • Method Comparison: Human serum and plasma samples compared between cobas e 402 and cobas e 801.
  • Data Provenance: Not specified.

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

Not applicable. For in vitro diagnostic assays, "ground truth" is established through analytical reference methods, defined concentrations of calibrators/standards, or confirmed by other laboratory methods (e.g., GC-MS for Methadone) rather than expert human interpretation of results.

4. Adjudication method

Not applicable. These are analytical tests performed by automated systems; there is no human interpretation or adjudication involved in generating the primary test result.

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 for in vitro diagnostic assays on automated analyzers, not AI-assisted human reader studies. The "AI" would refer to the algorithms within the analytical unit, not a system designed to assist human readers.

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

Yes, the entire document focuses on the standalone performance of the analytical systems and assays. The results are generated directly by the device/analyzer without human intervention for interpretation beyond loading samples and performing quality control.

7. The type of ground truth used

• For Glucose, Sodium, TSH (Quantitative assays): The ground truth for these quantitative measurements is based on reference methods, known concentrations in calibrators and controls, or comparative methods (e.g., flame photometry for sodium, or existing cleared assays on predicate devices).
• For Methadone (Qualitative/Semi-quantitative assay): Ground truth is established by known concentrations relative to a cutoff (e.g., 225 ng/mL for negative control, 375 ng/mL for positive control) and confirmed by a "confirmatory method such as gas chromatography/mass spectrometry (GC-MS)".

8. The sample size for the training set

Not explicitly specified. These are not AI/ML models in the typical sense that require a distinct "training set." The development of reagents and analytical platforms involves extensive R&D and optimization, but the validation studies described here are for demonstrating performance and equivalence, not for "training" an algorithm in a machine learning context.

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

Not applicable, as a distinct "training set" with established ground truth in the context of machine learning model development is not typically associated with the development and validation of these types of in vitro diagnostic reagents and analyzers. The principles are generally based on established biochemical reactions, electrochemical measurements, or immunoassays.

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The cobas pro integrated solutions is an IVD device used for the quantitation of clinical chemistry and Ion Selective Electrolyte parameters from various biological fluids.

Glucose HK Gen.3 is an in vitro test for the quantitative determination of glucose in human serum, plasma, urine and CSF on Roche/Hitachi cobas c systems. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia and pancreatic islet cell tumors.

The ISE indirect Na for Gen. 2 is intended for the quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. Sodium measurements are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance.

Elecsys TSH immunoassay is intended for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid and pituitary disorders. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The cobas pro integrated solutions (cobas pro) is a fully automated, random-access, software controlled system intended for in vitro quantitative analysis of analytes in body fluids. It will typically be used in clinical laboratories with large workload. The system consolidates clinical chemistry, homogenous and heterogeneous immunoassays as well as electrolyte testing within one workplace. It consists of a high throughput sample distribution unit (core unit) and different analytical units for ISE (cobas pro ISE analytical unit), clinical chemistry (c 503 analytical unit) and immunoassay (e 801 analytical) testing. The system hardware is comprised of new or previously cleared members of the Roche/Hitachi cobas c or Elecsys families of analyzers. The instrument software is unique to the cobas pro and was developed from previous generations of Roche/Hitachi instrument systems.

Here's a breakdown of the acceptance criteria and study information for the cobas pro integrated solutions device, specifically focusing on the Glucose HK Gen.3, ISE indirect Na for Gen.2, and Elecsys TSH assays.

Preamble: This document describes a Traditional 510(k) Premarket Notification for the cobas pro integrated solutions. The core purpose is to show that previously cleared Glucose, Sodium, and TSH assays, when run on the new cobas pro integrated solutions system, are substantially equivalent to their predicate devices. Therefore, the acceptance criteria and studies presented are largely comparative or validation studies demonstrating consistent performance with previously cleared devices and established analytical standards.

1. Table of Acceptance Criteria and Reported Device Performance

Given that this is a 510(k) submission demonstrating substantial equivalence to pre-existing predicate devices for assays and a new integrated system, the acceptance criteria are generally focused on meeting established performance claims or showing equivalence within acceptable statistical limits. The summary provided focuses on the reported device performance which is then implicitly compared to internal acceptance criteria (often relative to the predicate device or CLSI guidelines).

Note on Acceptance Criteria: The document explicitly states "All samples met the predetermined acceptance criterion" for precision studies. For LoQ, it states "LoQ determined at maximum allowable %TE (total error) of no more than 20% (Glucose and TSH) and 30% (Sodium)." For endogenous interference, it was "recovery of 100±10%". For exogenous interference (common drugs for Elecsys TSH), it was "± 10% of the reference value". For method comparisons, the slope, intercept, and correlation coefficients approaching 1 or 0 respectively, indicate strong agreement, satisfying the intent of substantial equivalence. Specific numerical acceptance criteria are not always stated outright but are implied by the study design and conclusion of meeting criteria.

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

• Glucose HK Gen.3 (Precision):
  • Sample Size: 84 measurements for each control level (PreciControl ClinChem Multi 1 and 2) and 5 human serum samples per application (serum, urine, CSF). So, for repeatability and intermediate precision, 84 measurements for 2 controls + 5 samples, across serum, urine, and CSF applications.
  • Data Provenance: Human serum, plasma, urine, and CSF samples. These were "native, single donors as well as pools." The study was conducted in-house by Roche Diagnostics (implied by the submission).
• ISE indirect Na (Precision):
  • Sample Size: 84 measurements for each control level (PreciControl ClinChem Multi 1 and 2, Liquichek 1 and 2) and 5 human plasma, serum, and urine samples per application. So, for repeatability and intermediate precision, 84 measurements for controls + 5 samples, across Li-Heparin Plasma, Serum, and Urine.
  • Data Provenance: Human Li-Heparin plasma, serum, and urine samples. These were "native, single donors as well as pools." Conducted in-house by Roche Diagnostics.
• Elecsys TSH (Precision):
  • Sample Size: 84 measurements for each control level (PreciControl Universal, PC Thyro Sensitive) and 5 human serum samples.
  • Data Provenance: Human serum samples. These were "native, single donors as well as pools." Conducted in-house by Roche Diagnostics.
• Analytical Sensitivity (LoB, LoD, LoQ) for all assays:
  • Sample Size:
    • LoB: ≥ 60 measurements of analyte-free samples.
    • LoD: 60 measurements (5 low-analyte concentration samples, measured in duplicate over 6 runs, 3 days).
    • LoQ: ≥ 60 measurements per sample type (samples with low analyte concentration measured over 3 to 5 days).
  • Data Provenance: Not explicitly stated for specific blanks or low-concentration samples beyond "analyte-free" or "low-analyte concentration". Conducted in-house by Roche Diagnostics.
• Linearity/Assay Reportable Range:
  • Glucose HK Gen.3: Three high analyte human serum, urine, and CSF samples diluted to 12 levels.
  • ISE indirect Na: Three high analyte human serum, urine, and CSF samples diluted to multiple aliquot concentrations.
  • Elecsys TSH: Three high analyte human serum samples diluted to concentrations covering the measuring range.
  • Data Provenance: Human serum, urine, CSF samples. Conducted in-house by Roche Diagnostics.
• Endogenous Interference:
  • Glucose HK Gen.3: Plasma and urine samples, glucose levels ~79.5 mg/dL and ~116.3 mg/dL.
  • ISE indirect Na: Human plasma, serum, and urine samples. Low (~124 mmol/L) and high (~151 mmol/L) for S/P; low (26.3 mmol/L) and high (188 mmol/L) for urine.
  • Elecsys TSH: Human serum samples with TSH concentrations ~0.462 uIU/mL, ~3.95 µIU/mL, and ~7.54 µIU/mL.
  • Data Provenance: Human samples. Conducted in-house by Roche Diagnostics.
• Exogenous Interference (Drugs):
  • ISE indirect Na: Two sample pools (low and high concentration ISE indirect Na).
  • Elecsys TSH: Two human serum samples (~0.5 uIU/mL and ~8 uIU/mL TSH).
  • Data Provenance: Human samples. Conducted in-house by Roche Diagnostics.
• Analytical Specificity/Cross-Reactivity (Elecsys TSH):
  • Sample Size: Native human serum sample pool.
  • Data Provenance: Human serum samples. Conducted in-house by Roche Diagnostics.
• Method Comparison to Predicate:
  • Glucose HK Gen.3: 74 native human serum samples, 67 native human urine samples, 75 native CSF samples.
  • ISE indirect Na: 120 human Lithium heparin plasma samples (vs cobas c 501 ISE), 118 human Lithium heparin plasma (vs Flame Photometer), 120 human serum (vs cobas c 501 ISE), 120 human serum (vs Flame Photometer), 120 human urine (vs cobas c 501 ISE/Flame Photometer).
  • Elecsys TSH: 138 samples (129 native human serum, 9 diluted human serum samples; single donors and pools).
  • Data Provenance: Native human samples (serum, plasma, urine, CSF), some diluted. Conducted in-house by Roche Diagnostics.
• Sample Matrix Comparison:
  • Glucose HK Gen.3: At least 39 serum/plasma pairs for each anticoagulant type (K2-EDTA, Li-Heparin, NaF/K-Oxalate, NaF/Na2-EDTA, NaF/Citrate/Na2-EDTA, KF/Na2-EDTA plasma tubes) + serum vs. serum tube with separation gel.
  • ISE indirect Na: 50 serum/Li-Heparin plasma pairs.
  • Elecsys TSH: Minimum of 56 serum/plasma pairs for Li-Heparin, K2-EDTA, K3-EDTA plasma tubes. Serum separation tubes from 3 manufacturers, blood from five donors were used.
  • Data Provenance: Native human samples. Conducted in-house by Roche Diagnostics.

3. Number of Experts and Qualifications for Ground Truth

This submission concerns in vitro diagnostic (IVD) devices for quantitative measurements of analytes. For such devices, "ground truth" is typically established by:

• Reference methods (e.g., flame photometry for Sodium reference),

• Previously cleared and validated predicate devices,

• Known concentrations in control materials or spiked samples, or

• The inherent chemical/physical measurement by the device itself (for analytical performance criteria like precision, linearity).

• No human "experts" (like radiologists interpreting images) were used to establish ground truth in the context of these analytical performance studies. The "ground truth" is analytical, derived from established chemical/instrumental methods and reference standards.

4. Adjudication Method for the Test Set

Since this is an IVD device for quantitative measurements and the studies are analytical performance evaluations based on instrumental precision, accuracy, and comparison to established methods or predicate devices, there is no adjudication method (e.g., 2+1, 3+1) involving human experts as would be seen in diagnostic imaging studies. The data points are quantitative measurements from the instruments themselves or reference methods. Statistical analysis (e.g., regression, CVs, SDs) is used to assess performance against pre-defined criteria.

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

No MRMC comparative effectiveness study was done. This type of study, involving multiple human readers interpreting cases with and without AI assistance, is relevant for diagnostic imaging AI algorithms where human interpretation is part of the clinical pathway. This submission is for an in vitro diagnostic (IVD) measurement system, not an AI-powered diagnostic imaging tool that assists human readers. The comparative studies involved comparing the new system's analytical performance against predicate IVD systems or reference methods, not human readers.

6. Standalone Performance Study (Algorithm Only)

The entire non-clinical performance evaluation could be considered analogous to a "standalone" performance study, as it describes the analytical performance of the device itself (the integrated system with its assays) without human intervention in the measurement process. The device provides quantitative results, and these results are directly evaluated for precision, linearity, sensitivity, interference, and agreement with predicate devices or reference methods. There is no "human-in-the-loop" aspect to the core measurement and output of these IVD assays.

7. Type of Ground Truth Used

The ground truth used for these analytical studies consists of:

• Known concentrations: For studies like linearity, analytical sensitivity (LoB, LoD, LoQ), and interference, samples prepared with known concentrations of analytes or interferents serve as the ground truth.
• Reference methods: For method comparison studies, well-established and often independently validated reference methods (e.g., flame photometry for sodium measurement) serve as the ground truth or gold standard for comparison.
• Predicate device results: For demonstrating substantial equivalence, the results obtained from a legally marketed predicate device (which itself has established ground truth capabilities) serve as the comparative ground truth.
• Internal statistical controls: For precision studies, consistent and stable control materials are used, where the expected range or value is the "ground truth" against which repeatability and intermediate precision are measured.

8. Sample Size for the Training Set

This document describes the non-clinical performance evaluation for a 510(k) submission, primarily for demonstrating analytical performance and substantial equivalence. It does not describe the development or training of an AI algorithm based on machine learning, so there is no specific "training set" in the context of AI/ML models. The data presented here are validation data for the analytical performance of the assay and integrated system.

For a traditional IVD device, method development involves internal studies and optimization, but this is distinct from "training data" for a machine learning model. The various studies (precision, linearity, etc.) use samples/replicates as described in point 2.

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

As noted in point 8, there isn't a "training set" in the machine learning sense described in this document. If this were to refer to the developmental studies for the underlying assays (Glucose HK Gen.3, ISE indirect Na, Elecsys TSH, which are previously cleared), their ground truth would have been established during their initial development and validation process using:

• Reference materials: Certified reference materials (CRMs) with known analyte concentrations.
• Clinical samples: Patients samples characterized by confirmed diagnoses or clinical outcomes for intended use populations.
• Comparison to established methods: Correlation with existing, approved methods, often considered the "gold standard."
• Spiking and dilution experiments: Preparing samples with known added amounts of analyte.

These are standard practices in IVD assay development, ensuring the analytical and clinical performance of the individual assays before they are integrated into a new system like the cobas pro integrated solutions.

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The Alinity c Glucose Reagent Kit is used for the quantitation of glucose in human serum, plasma, urine, or cerebrospinal fluid (CSF) on the Alinity c analyzer. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma.

The Alinity c System is a fully automated, random/continuous access, clinical chemistry analyzer intended for the in vitro determination of analytes in body fluids.

The Alinity c Glucose Reagent Kit contains Reagent 1 with ATP •2Na, NAD, G-6-PDH, and Hexokinase as reactive ingredients, and sodium azide as a preservative. The kit is available in two sizes: 400 tests per cartridge (10 cartridges per kit, 4000 tests per kit) and 1100 tests per cartridge (10 cartridges per kit, 11,000 tests per kit). The reagent container is made of black polypropylene with a black high density polyethylene closure.

The Alinity c Multiconstituent Calibrator Kit contains Cal 1 and Cal 2, prepared from a human-based matrix containing multiple analytes, including glucose, with sodium azide as a preservative. The calibrators are standardized for glucose using NIST SRM 965 and the ID-GC/MS reference method.

The Alinity c System is a fully automated chemistry analyzer allowing random and continuous access, as well as priority and automated retest processing using photometric and potentiometric detection technology. It uses photometric detection technology to measure sample absorbance for the quantification of analyte concentration. The system features robotic sample handling, continuous reagent access, continuous bulk solution access, and priority sample loading on all carrier positions.

This document describes the analytical performance of the Alinity c Glucose Reagent Kit and the Alinity c System for measuring glucose in human serum, plasma, urine, or cerebrospinal fluid (CSF). The studies evaluate various performance characteristics against predefined acceptance criteria to demonstrate substantial equivalence to predicate devices.

1. Table of Acceptance Criteria and Reported Device Performance

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

• Precision (20-Day Within-Laboratory):
  • Serum Samples: 260-264 replicates for control levels, 523-528 replicates for panel samples (across reagent lots and instrument combinations).
  • Urine Samples: 260-264 replicates for control levels, 525-528 replicates for panel samples (across reagent lots and instrument combinations).
  • CSF Samples: 263-264 replicates for control levels, 526-528 replicates for panel samples (across reagent lots and instrument combinations).
  • Data Provenance: Not explicitly stated, but typically these are prospective studies conducted in a controlled laboratory setting (likely within the manufacturer's R&D facilities or a collaborating lab).
• Accuracy (NIST Standards):
  • 22 replicates for each of the 4 NIST levels.
  • Data Provenance: Conducted in a controlled laboratory setting.
• Limit of Blank (LoB), Limit of Detection (LoD), Limit of Quantitation (LoQ):
  • LoB: n ≥ 60 replicates of zero-analyte samples.
  • LoD & LoQ: n ≥ 60 replicates of low-analyte level samples.
  • Data Provenance: Conducted in a controlled laboratory setting.
• Linearity:
  • Sample sets used to cover the linear range. Specific 'n' for each sample type not individually quantified beyond "sample set."
  • Data Provenance: Conducted in a controlled laboratory setting.
• Interference:
  • Specific numbers of samples or replicates for interference studies are not provided, but the evaluation was conducted based on CLSI document EP07-A2.
  • Data Provenance: Conducted in a controlled laboratory setting.
• Method Comparison:
  • Serum: 98 samples.
  • Urine: 118 samples.
  • CSF: 90 samples.
  • Data Provenance: Human serum, urine, and CSF specimens. Not explicitly stated if retrospective or prospective, or country of origin, but generally for device clearance, these are often prospective collections or carefully selected archived samples from diverse populations to ensure representativeness.
• Auto Dilution:
  • Glucose serum specimens. Specific 'n' not provided beyond being a set of specimens.
  • Data Provenance: Not explicitly stated, likely laboratory-prepared or clinical samples.
• Tube Type Equivalency:
  • Minimum of 40 donors.
  • Data Provenance: Samples collected from human donors.

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

This document describes the analytical performance of an in vitro diagnostic (IVD) device for measuring glucose. For such devices, "ground truth" is typically established by:

• Reference Methods: Such as NIST (National Institute of Standards and Technology) certified reference materials (e.g., SRM 965 Glucose in Human Serum) and reference methods (e.g., ID-GC/MS - Isotope Dilution-Gas Chromatography Mass Spectrophotometry). These are highly accurate, traceable methods, and do not involve human "experts" in the diagnostic interpretation sense.
• Predicate Devices: The ARCHITECT c System and its associated Glucose assay (K060383) serve as the comparator (or "ground truth" surrogate) for method comparison studies.
• Clinical Laboratory Standards: The performance is evaluated against established clinical laboratory standards and guidelines (e.g., CLSI documents EP05-A2, EP17-A2, EP06-A, EP07-A2, EP09-A3). These standards define acceptable performance metrics.

Therefore, for this type of IVD device, there isn't a team of experts (like radiologists or pathologists) establishing a visual interpretation ground truth. The 'ground truth' is analytical, based on certified reference materials and established reference methods.

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

Not applicable. Adjudication methods like 2+1 or 3+1 are typically used in studies involving subjective interpretation of medical images or clinical cases by multiple human readers (e.g., radiologists, pathologists) to establish a consensus ground truth. For an automated quantitative assay like a glucose test, the "ground truth" is objective and measured via reference methods or predicate devices, as described above.

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. An MRMC study is relevant for AI-powered diagnostic imaging or interpretation tools where human readers' performance is compared with and without AI assistance across multiple cases. This document is for a fully automated in vitro diagnostic (IVD) chemistry analyzer and reagent kit, which does not involve human "readers" interpreting results in the same way.

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

Yes, the studies presented here are for the standalone performance of the Alinity c Glucose Reagent Kit and the Alinity c System. The device measures glucose levels automatically, and the performance characteristics (precision, accuracy, linearity, interference, method comparison) are evaluated for the device itself. There is no "human-in-the-loop" aspect to the actual measurement process of the device as an IVD analyzer.

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

The ground truth used is primarily reference measurements derived from:

• Certified Reference Materials: Specifically, NIST SRM 965 (Glucose in Human Serum), analyzed by a reference method (ID-GC/MS - Isotope Dilution-Gas Chromatography Mass Spectrophotometry) for accuracy studies.
• Comparator (Predicate) Device: The predicate Glucose assay (K060383) run on the ARCHITECT c System for method comparison studies. This serves as the comparative standard of care.
• Clinical Laboratory Standards (CLSI guidelines): These provide the framework and accepted ranges for evaluating various analytical performance characteristics (e.g., precision, linearity, LoQ).

8. The sample size for the training set:

The document does not explicitly mention a "training set" in the context of machine learning. This is an IVD device, and its analytical performance is validated against established laboratory standards and predicate devices. The development of such a device involves extensive R&D, calibration, and optimization using various samples, but these are not typically referred to as "training sets" in the same way as for AI/ML algorithms. The reported studies are for performance validation (test set).

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

Not applicable, as a "training set" as defined for AI/ML models is not directly addressed or implied for this type of IVD device. The development process would rely on precise chemical and enzymatic reactions, spectrophotometric detection principles, and calibration against reference materials to ensure accurate measurements across the analytical range.

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ELITech Clinical Systems GLUCOSE HK SL is intended for the quantitative in vitro diagnostic determination of glucose in human serum, plasma and urine using ELITech Clinical Systems Selectra Pro Series Analyzers.

Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus and idiopathic hypoglycemia, and of pancreatic diseases.

ELITech Clinical Systems ELICAL 2 is a multi-parametric calibrator for in vitro diagnostic use in the calibration of quantitative ELITech Clinical Systems methods on ELITech Clinical Systems Analyzers.

ELITech Clinical Systems ELITROL II are multiparametric control sera for in vitro diagnostic use in quality control of quantitative ELITech Clinical Systems methods on ELITech Clinical Systems Analyzers.

ELITech Clinical Systems GLUCOSE HK SL is available as a kit only. It consists of a Bi-reagent R1 & R2 whose composition is: R1: Pipes buffer, pH 7.60 80 mmol/L, NAD 4.1 mmol/L, ATP 2.2 mmol/L, Sodium azide < 0.1 % R2: Hexokinase ≥ 8 500 U/L, G-6-PDH ≥ 8 500 U/L, Magnesium salt 20 mmol/L, Sodium azide < 0.1 % mmol/L.

ELITech Clinical Systems ELICAL2 is a lyophilized calibrator based on human serum containing constituents to ensure optimal calibration. ELICAL 2 is prepared exclusively from the blood of donors tested individually and found to be neqative for HbsAg and to the antibodies to HCV and HIV according to FDA-approved methods.

ELITech Clinical Systems ELITROL I and ELITROL II are two level quality control products consisting of a lyophilized human serum containing constituents at desired levels. ELITROL I and ELITROL II are prepared exclusively from the blood of donors tested individually and found to be negative for HbsAg and to antibodies to HCV and HIV according to FDA-approved methods.

The provided document describes the analytical performance of the ELITech Clinical Systems GLUCOSE HK SL reagent, ELICAL 2 calibrator, and ELITROL I/II controls. It does not describe an AI/ML powered device, therefore no information is available regarding expert consensus, MRMC studies, or multi-reader performance. The study described focuses on demonstrating substantial equivalence to predicate devices for in vitro diagnostic use.

Here's the breakdown of the available information:

1. Table of Acceptance Criteria and Reported Device Performance:

The document outlines acceptance criteria implicitly through the study design (e.g., acceptance bias for interference studies) and generally through comparison to a predicate device. Performance is reported through various analytical studies.

ELITech Clinical Systems GLUCOSE HK SL Reagent Performance Summary:

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

• Precision Studies:

  • Serum: 80 measurements for each of 4 levels (total of 320 measurements). Samples were human sera and control sera.
  • Urine: 80 measurements for each of 3 levels (total of 240 measurements). Samples were urine pools.
  • Provenance: Not specified, but likely from laboratory samples as part of a method validation. Neither retrospective nor prospective status is explicitly stated, but analytical performance studies are generally conducted prospectively on prepared samples or collected patient samples.

• Linearity Studies:

  • Serum: 11 levels of mixed samples.
  • Urine: 11 levels of mixed samples.
  • Provenance: Not specified, but likely prepared in a laboratory.

• Interference Studies:

  • Serum: Two serum sample pools (low and high glucose activity), spiked with increasing interferent concentrations. Each interferent tested across multiple concentrations (e.g., 9 for triglycerides, 7 for bilirubin). Each point measured in triplicate per run. Two levels of control materials also tested.
  • Urine: Two urine sample pools (low and high glucose activity), spiked with increasing interferent concentrations. Each interferent tested across multiple concentrations. Each point measured in triplicate per run. Two levels of control materials also tested.
  • Provenance: Not specified, but laboratory prepared spiked samples.

• Method Comparison Studies (Test Set):

  • Serum: 100 serum patient samples (ranging from 20.5 to 707.5 mg/dL).
  • Urine: 40 urine patient samples (with glacial acetic acid as preservative, ranging from 10.1 to 703.9 mg/dL).
  • Plasma (Lithium Heparin): 40 plasma patient samples (ranging from 24.3 to 710.1 mg/dL).
  • Plasma (Sodium Fluoride/Oxalate): 40 plasma patient samples (ranging from 21.2 to 701.4 mg/dL).
  • Provenance: "patient samples" implies retrospective or prospectively collected clinical samples. The country of origin is not specified but given the submitter's address (France and USA), it could be either.

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

Not applicable, as this is an in-vitro diagnostic test measuring a quantitative analyte (glucose). The "ground truth" for the test set is established by the reference method (Roche Diagnostics Cobas C111 Glucose HK) or known values/concentrations for engineered samples in analytical studies.

4. Adjudication Method for the Test Set:

Not applicable, as this is an in-vitro diagnostic test. Results are quantitative measurements compared against a reference method or known values, not subjective interpretations requiring adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, Effect Size:

Not applicable, as this is an in-vitro diagnostic test. There is no human reader involvement in interpreting the device's quantitative output.

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

Yes, the studies described are all "standalone" in the sense that they evaluate the analytical performance of the device (reagent, calibrator, controls) on an automated analyzer (ELITech Clinical Systems Selectra ProM Analyzer) without human intervention in the result determination process.

7. The Type of Ground Truth Used:

• Known concentrations: For linearity, LoD/LoQ, and interference studies, samples were prepared to have known or target concentrations of glucose and interferents.
• Reference method/device: For method comparison studies, the predicate device (Roche Diagnostics Cobas C111 Glucose HK) was used as the comparative "ground truth" for patient samples.
• NIST Traceability: For calibration, the glucose value assigned to the calibrator (ELICAL 2) is traceable to Isotope-dilution/Mass spectrometry, validated through the testing of SRM 965b of National Institute of Standards and Technology (NIST).

8. The Sample Size for the Training Set:

Not applicable. This is not an AI/ML powered device, so there is no "training set." The device performance is based on the chemical reagent's properties and the analyzer's measurement capabilities.

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

Not applicable (no training set).

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Diatron Glucose Hexokinase Method is for the in vitro quantitative determination of Glucose in serum for use with Diatron Pictus 700 Chemistry Analyzer. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes.

Diatron ISE is for the in vitro quantitative determination of Sodium (Na+), Potassium (K+), and Chloride (Cl-) concentrations in serum on the Diatron Pictus 700 Chemistry Analyzer. Sodium measurements are used in the diagnosis and treatment of diseases involving electrolyte imbalance. Potassium measurements are used in monitoring electrolyte balance and in the diagnosis and treatment of diseases/conditions characterized by low or high blood potassium levels. Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders.

The Diatron Pictus 700 Clinical Chemistry Analyzer is a wet-chemistry analyzer for the direct determination of sodium, potassium, chloride and glucose concentrations in serum, and to measure a variety of analytes that may be adaptable to the analyzer depending on the reagent used. It is for in vitro diagnostic use.

The Pictus 700 Clinical Chemistry Analyzer is an automatic, floor-standing, wet chemistry system, designed for the qualitative and quantitative analyses of various diagnostic test systems. This premarket notification is for the direct quantitative measurements of Na (sodium), K (potassium), CI (chloride) and glucose in serum samples. Additionally, other types of chemistry assays may be performed on the analyzer, provided that suitable colorgenerating reactions or reactions with variation of color are used. The system is intended for use in clinical laboratories.

The instrument consists of an analyzer unit and an operations computer with a screen that allows the user to input commands for system operation and data display. The analyzer unit includes two temperature-controlled incubation rotors and a multi-wavelength photometer, a cooled carousel for loading barcoded sample tubes or micro cups and reagent cartridges, and two probes that deliver reagents and samples to the incubation rotors and the ISE measurement flow cell. The analyzer unit also houses containers for wash solution and waste. An ISE module, installed on the analyzer unit, is used to measure sodium, potassium and chloride ionic activity in serum.

The provided text describes the acceptance criteria and the study performance for the Diatron ISE, Diatron Glucose Hexokinase Method, and Diatron Pictus 700 Clinical Chemistry Analyzer. This is a submission for a 510(k) premarket notification for an in vitro diagnostic device, specifically a clinical chemistry analyzer and associated assay methods. The studies presented are nonclinical performance studies to demonstrate substantial equivalence to a predicate device, not clinical effectiveness studies involving human subjects in an MRMC setting.

Here's a breakdown of the requested information based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the claim of substantial equivalence to the predicate device and the successful demonstration of various analytical performance characteristics. The document explicitly states acceptance criteria for linearity.

2. Sample Sizes and Data Provenance for Test Sets

• Glucose Functional Sensitivity/LoQ: Glucose depleted samples, tested in 5 replicates per dilution for functional sensitivity. LoQ testing was performed according to CLSI EP17-A2. The document mentions "Testing the neat sample, depleted of Glucose y standing > 24 hrs exposed to red cells in the sample draw."
• Linearity: Eleven levels of each analyte were tested, in duplicate.
• Precision: Control samples (low, middle, and high levels) were tested in duplicate, twice a day, for 20 days, for a total of 80 results per level.
• Interferences: A two-level control set (low and high analyte levels) was spiked to seven or eight levels of interferent. Spiked samples plus neat samples were tested in duplicates.
• Method Comparison:
  • Sodium: N=69 clinical specimens
  • Potassium: N=69 clinical specimens (listed under Sodium, but context implies N=69 for K as well given the table structure)
  • Chloride: N=69 clinical specimens
  • Glucose: N=136 clinical specimens
  • Data Provenance: Clinical specimens were "previously-collected serum samples that had been stored frozen and then thawed prior to analysis." The country of origin is not specified but typically for a US FDA submission, these would be collected in the US or under similar regulatory standards. The data is retrospective in that it uses "previously-collected" and "stored frozen" samples.

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

Not applicable. This is an analytical performance study for an in vitro diagnostic device, not an AI/imaging device requiring expert interpretation for ground truth. The "ground truth" for the test samples in this context relates to their known concentrations as determined by a reference method or the predicate device.

4. Adjudication Method for the Test Set

Not applicable. This is an analytical performance study for an in vitro diagnostic device, where quantitative results are compared to reference methods/predicate, not subjective interpretations requiring adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size on Human Readers

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed. This type of study is typically done for AI-driven diagnostic imaging devices where human readers' performance (with or without AI assistance) is evaluated. This submission is for an automated clinical chemistry analyzer.

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

Yes, the studies presented are essentially "standalone" performance evaluations of the Diatron Pictus 700 Clinical Chemistry Analyzer and its associated methods (Diatron Glucose Hexokinase Method and Diatron ISE). The performance measured is that of the automated instrument itself, without direct human intervention in the analytical process being tested for. The output is a quantitative measurement of analytes.

7. The Type of Ground Truth Used

The ground truth for the analytical studies are based on:

• Reference methods/assigned values: For linearity, samples were assigned their reference values arithmetically from labeled values. For method comparison, the predicate system served as the comparative method against which the new device's performance was evaluated.
• Known concentrations: For precision, control samples with known low, medium, and high concentrations were used.
• Spiked samples: For interference studies, samples were spiked with known concentrations of interferents to assess their impact.

8. The Sample Size for the Training Set

Not applicable. This is not a study involving machine learning with distinct training and test sets in the typical sense of AI algorithm development. This is a traditional analytical validation for an in vitro diagnostic device.

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

Not applicable for the reason stated in point 8.

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UniCel DxC SYNCHRON Systems Glucose reagent (GLUH), when used in conjunction with UniCel® DxC 600/800 SYNCHRON System(s) and SYNCHRON Systems AQUA CAL 1 and 3, is intended for the quantitative determination of glucose concentration in human serum. plasma, urine or cerebrospinal fluid (CSF).

Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, idiopathic hypoglycemia, and pancreatic islet cell carcinoma.

GLUH reagent is used to measure the glucose concentration by a timed endpoint method. In the reaction, hexokinase (HK) catalyses the transfer of a phosphate group from adenosine triphosphate (ATP) to glucose to form adenosine diphosphate (ADP) and glucose-6phosphate. The glucose-6-phosphate is then oxidized to 6-phosphogluconate with the concomitant reduction of ß-nicotinamide adenine dinucleotide (NAD) to reduced ßnicotinamide adenine dinucleotide (NADH) by the catalytic action of glucose-6-phosphate dehydrogenase (G6PDH).

The UniCel® DxC 600/800 SYNCHRON System(s) automatically proportions the appropriate sample and reagent volumes into the cuvette. The ratio used is one part sample to 100 parts reagent. The system monitors the change in absorbance at 340 nanometers. This change in absorbance is directly proportional to the concentration of glucose in the sample and is used by the System to calculate and express glucose concentration.

Here's a summary of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Device: UniCel DxC SYNCHRON Systems Glucose (GLUH) reagent

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document describes the "claimed" limits for some performance characteristics, implying these are the acceptance criteria. For others, the criteria are implied by the study design (e.g., linearity within a range, interference values less than or equal to a certain threshold).

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

• Method Comparison:
  • Serum (DxC 600 & 800): 120 samples each (total 240)
  • CSF (DxC 600 & 800): 100 samples each (total 200)
  • Urine (DxC 600 & 800): 117 samples each (total 234)
  • Total for Method Comparison: 674 samples.
• Anticoagulant Studies:
  • Sodium Heparin: 79 samples (DxC600), 58 samples (DxC800)
  • Lithium Heparin: 79 samples (DxC600), 58 samples (DxC800)
  • Sodium Fluoride/Potassium Oxalate: 79 samples (DxC600), 58 samples (DxC800)
  • Total for Anticoagulant Studies: (3 * 79) + (3 * 58) = 237 + 174 = 411 samples. (Stated "Over 50 patient specimens with glucose concentrations spanning the analytical range" for each anticoagulant type, then provides N for each DxC system. The cumulative N suggests that these are unique patient specimens across the anticoagulant types but not necessarily all unique for DxC600 vs DxC800)
• Precision: 80 data points for each sample type (Control 1, Control 2, Control 3, Pool 1, Pool 2, Pool 3) across Serum, Urine, and CSF, for both DxC 600 and DxC 800. This refers to the number of measurements rather than unique patient samples.
• Analytical Sensitivity (LoB, LoD, LoQ): "Multiple urine, CSF and serum pools were run over multiple days". Specific number of samples not given, but refers to "pools."
• Linearity: "Multiple replicates of the pools over the range of the assay." Specific number of samples not given, but refers to "pools."
• Interferences: "Patient serum pools" used for low, mid, and high glucose levels. Specific number of patient samples not given, but implies multiple pools.
• Data Provenance: The document explicitly states "patient correlation studies were conducted using... patient samples" and "paired plasma and serum samples from healthy volunteers." It doesn't specify country of origin but implies clinical laboratory settings. The studies are described as conducted by Beckman Coulter, Inc., suggesting internal testing. The nature of these studies (evaluating device performance against a predicate and known standards) indicates these are primarily prospective data collections for device validation.

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

This type of information (number and qualifications of experts) is generally not applicable or stated for in vitro diagnostic devices like a glucose reagent. The "ground truth" for clinical chemistry assays is established by the reference method (the predicate device in this case) and established analytical techniques and standards (e.g., standard concentrations, known interference levels). Medical professionals use the results, but they don't establish the "ground truth" for the device's technical performance.

4. Adjudication Method

Not applicable for this type of in vitro diagnostic device study. Adjudication methods are typically used in studies involving subjective interpretation, like image analysis by multiple readers.

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

No, an MRMC comparative effectiveness study was not done. This type of study involves human readers interpreting cases, often with and without AI assistance, which is not relevant for an automated glucose reagent.

6. Standalone (Algorithm Only) Performance

Yes, the studies described are for the standalone performance of the UniCel DxC SYNCHRON Systems Glucose reagent (GLUH) itself, as implemented on the UniCel DxC 600/800 SYNCHRON Systems. The performance data presented (precision, linearity, sensitivity, interference) are direct measurements of the reagent's analytical capability. The method comparison studies compare this standalone performance to that of a predicate device.

7. Type of Ground Truth Used

The ground truth for the test set was established using:

• Predicate Device Measurements: For method comparison, the predicate device (SYNCHRON Glucose (GLU) or GLUCm) provided the comparative truth.
• Known Concentrations/Reference Standards: For studies like linearity, precision, and analytical sensitivity, the ground truth was based on samples with precisely known glucose concentrations (e.g., control materials, spiked samples, dilutions of high-concentration samples).
• Spiked Samples: For interference studies, known interfering substances were added to patient serum pools to create controlled samples with expected values.
• Paired Samples: For anticoagulant studies, serum samples (representing the true value) were compared with plasma samples prepared with different anticoagulants.

8. Sample Size for the Training Set

This document only describes performance testing for device validation and substantial equivalence with a predicate device. It does not refer to a "training set" in the context of machine learning. The "training" for such an in vitro diagnostic device involves the chemical formulation of the reagent itself and the engineering of the analyzer system, which would be subject to extensive R&D and internal testing, but not typically documented as a distinct "training set" in this manner for regulatory submission.

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

As mentioned above, there isn't a "training set" in the machine learning sense for this device. The development and optimization of the reagent and system would rely on standard chemical and analytical laboratory practices to ensure accurate and reliable measurements.

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The ACE Alera Clinical Chemistry System is an automated, discrete, bench-top, random access analyzer that is intended for in vitro diagnostic use in the quantitative measurement of general chemistry assays, such as glucose, sodium, potassium, and chloride, for clinical use in physician office laboratories or clinical laboratories. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma. Sodium measurements are used in the diagnosis and treatment of diseases involving electrolyte imbalance. Potassium measurements are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels. Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such as cystic fibrosis and diabetic acidosis.

ACE Glucose Reagent is intended for the quantitative determination of glucose in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE Ion Selective Electrode (ISE) module on the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems is used to measure concentrations of sodium, potassium, and chloride in undiluted serum and lithium heparin plasma. Sodium measurements are used in the diagnosis and treatment of diseases involving electrolyte imbalance. Potassium measurements are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels. Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such as cystic fibrosis and diabetic acidosis. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE Alera Clinical Chemistry System is an automated, discrete, bench-top, random access analyzer that is intended for in vitro diagnostic use in the quantitative determination of general chemistry assays for clinical use in physician office laboratories or clinical laboratories. The ACE Alera Clinical Chemistry System consists of a bench-top analyzer and an internal computer. The bench-top analyzer includes a single pipettor (syringe module/fluid arm/probe), a temperature-controlled reagent compartment, a reaction wheel and a holographic diffraction grating spectrophotometer.

In the ACE Glucose Reagent assay, glucose in serum or heparin plasma reacts with adenosine triphosphate in the presence of hexokinase and magnesium with the formation of glucose-6-phosphate and adenosine diphosphate. Glucose-6-phosphate dehydrogenase catalyzes the oxidation of glucose-6-phosphate with NAD+ to form 6-phosphogluconate and NADH. NADH absorbs strongly at 340 nm, whereas NAD+ does not. The total amount of NADH formed is proportional to the concentration of glucose in the sample. The increase in absorbance is measured bichromatically at 340 nm/378 nm.

The ACE Ion Selective Electrode (ISE) Module, as part of the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems, uses a potentiometric method via ion-specific electrodes to simultaneously measure sodium, potassium and chloride in undiluted serum. Ion-specific membranes measure the difference in ionic concentrations between an inner electrolyte solution and the sample. The connection of the amplifier and ground (reference electrode) to the ion selective electrode forms the measuring system. A two-point calibration utilizes ACE CAL A and CAL B undiluted ISE Calibration Solutions with precisely known ion concentrations. The measured voltage difference of the sample and the CAL A and CAL B solutions determines the ion concentration in the sample on the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems.

The device is the ACE Alera Clinical Chemistry System, ACE Glucose Reagent, and ACE Ion Selective Electrode (ISE) Module. The study assesses the performance of these components, focusing on the quantitative measurement of glucose, sodium, potassium, and chloride.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical targets that the device must meet in a formal, quantifiable way (e.g., "Accuracy must be > 95%"). Instead, the study aims to demonstrate substantial equivalence to predicate devices, showing that the performance of the ACE Alera system is comparable to established systems. The performance data presented focuses on precision (reproducibility) and method comparison with existing devices.

Since specific numerical acceptance criteria were not listed, one reasonable interpretation for implied acceptance criteria for laboratory diagnostic devices typically includes:

• Acceptable Precision: Coefficients of Variation (CV) or Standard Deviations (SD) for within-run and total precision across different concentration levels should be within generally accepted laboratory limits for each analyte. For clinical chemistry, these are often defined considering medical usefulness.
• Acceptable Method Agreement: Linear regression analysis (slope, intercept, correlation coefficient) and standard error between the new device and a reference method (or predicate device) should indicate good agreement. Slopes close to 1, intercepts close to 0, and high correlation coefficients (e.g., >0.975) are generally desired.
• No Significant Interference: The device should not be significantly affected by common interfering substances (icterus, hemolysis, lipemia, ascorbic acid) at clinically relevant levels.

Here's the performance data as reported, which serves as the evidence that these implicit acceptance criteria are met:

The study essentially acts as a validation against these implied criteria, demonstrating that the ACE Alera system's performance is acceptable for its intended use, comparable to the predicate devices.

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

• Precision Studies: The document does not explicitly state the number of individual sample replicates for the core (non-POL) precision studies. However, for the POL Precision studies, for each analyte (Glucose, Sodium, Potassium, Chloride), there were 3 samples tested in each of 4 labs (In-House and 3 POLs). The tables show means, within-run, and total standard deviations/CVs, which typically imply multiple replicates per sample (e.g., 20 or more replicates are common in such studies).
• Method Comparison Studies:
  • Glucose: n = 46 samples for each of the three POL comparisons.
  • Sodium: n = 42 samples for each of the three POL comparisons.
  • Potassium: n = 43 samples for each of the three POL comparisons.
  • Chloride: n = 41 samples for each of the three POL comparisons.
• Data Provenance: The method comparison data is identified as "(2012 Data)" and collected from an "In-House" lab comparing against "ACE Alera system POL" data from three different Physician Office Laboratories (POLs 1, 2, 3), suggesting multi-center evaluation within the United States. The data is retrospective in the sense that it's reported for a 510(k) submission, but the studies themselves would have been conducted prospectively as a part of the device validation. The term "POL" indicates that these are real-world, clinical laboratory settings.

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

There were no human experts establishing ground truth in the context of interpretation for these types of in vitro diagnostic devices. The "ground truth" or reference values for chemical assays like glucose, sodium, potassium, and chloride are established by:

• Reference Methods: Often, a more established or gold-standard laboratory analyzer (in this case, the predicate ACE system in the In-House lab) is used to generate the "reference" values for comparison.
• Certified Reference Materials: Calibrators and controls with precisely known concentrations are used to calibrate and verify the accuracy of the instruments.

The qualifications of personnel operating these instruments are typically trained medical technologists or clinical laboratory scientists, but they do not establish "ground truth" in the way an expert radiologist might interpret an image.

4. Adjudication Method for the Test Set

Not applicable for this type of in vitro diagnostic device study. Adjudication methods (like 2+1, 3+1 consensus) are used for subjective interpretations, such as medical image analysis, where human experts might disagree. For quantitative chemical measurements, the comparison is directly between numerical results from different instruments.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This is an in vitro diagnostic device for quantitative chemical analysis, not an AI-assisted diagnostic tool that involves human interpretation of "cases" or "reads" in the way an MRMC study would evaluate.

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

Yes, the studies presented are essentially standalone performance evaluations of the ACE Alera Clinical Chemistry System, the ACE Glucose Reagent, and the ACE Ion Selective Electrode (ISE) Module. The tables show the performance characteristics (precision, method comparison, interference) of the device itself in generating quantitative results. Human involvement is limited to operating the instrument, performing quality control, and routine maintenance, not subjective interpretation of results. The output (e.g., glucose concentration) is a direct numerical value from the instrument.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The ground truth for the test set (the samples used in the method comparison studies) was established by comparison against a legally marketed predicate device, the Alfa Wassermann ACE system (specifically the ACE plus ISE/Clinical Chemistry System, K930140, K933862), effectively treating the predicate device's measurements as the reference standard. This is a common approach for demonstrating substantial equivalence for new IVD devices.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of a machine learning algorithm. For clinical chemistry analyzers, the "training" analogous to machine learning would be:

• Instrument Calibration: The device is calibrated using commercially available calibrator solutions with known concentrations. The specific number of calibration points is not detailed but is typically specified by the manufacturer.
• Reagent Development and Optimization: The reagents themselves (like ACE Glucose Reagent) undergo extensive development and optimization, which involves testing on numerous samples to establish their performance characteristics (e.g., linearity, stability, interference). The exact sample sizes used during this development are not provided in this regulatory summary.

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

As above, for an IVD analyzer, the "ground truth" for calibration or reagent development typically relies on:

• Certified Reference Materials: These are materials with highly accurate and traceable analyte concentrations, used to set the instrument's measurement scale.
• Validated Reference Methods: Established laboratory methods, often more complex or time-consuming, that are known to be highly accurate and precise for measuring the analyte.

The document implies that the ground truth for comparison samples was the predicate ACE system, and it is reasonable to assume that the calibration and internal controls for the ACE Alera system would rely on industry-standard reference materials and methods to establish accurate known values.

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For in vitro diagnostic use in the quantitative determination of glucose in human serum, plasma, urine and CSF on the ADVIA Chemistry systems. Such measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, idiopathic hypoglycemia, and insulin overdose.

The ADVIA Chemistry Glucose Hexokinase 3 (GLUH 3) method uses a two-component reagent. Sample is added to Reagent 1, which contains the buffer, ATP, and NAD. Absorbance readings of the sample in Reagent 1 are taken and are used to correct for interfering substances in the sample. Reagent 2 is added, which initiates the conversion of glucose and the development of absorbance at 340/410 nm. The difference between the absorbance in Reagent 1 and Reagent 2 is proportional to the glucose concentration.

1. Acceptance Criteria and Device Performance

The acceptance criteria for the new device (specifically for the Na-Fluoride/K-Oxalate plasma type) are implicitly based on demonstrating substantial equivalence to the predicate device's performance with other plasma types. The reported performance for the new plasma type shows a strong correlation (r=0.999) and a regression equation very close to ideal (slope near 1, intercept near 0), indicating good agreement with the serum measurements using the existing GLUH_3 assay.

2. Sample Size and Data Provenance for Test Set

• Sample Size for Test Set: 82 data-points were included in the calculations. This was derived from 56 matched serum and plasma (Sodium Fluoride/Potassium Oxalate) samples, with some samples being spiked and/or diluted to achieve a wider range of concentrations.
• Data Provenance: Not explicitly stated, but based on the context of a 510(k) submission by Siemens Healthcare Diagnostics Inc., the data is likely from internal studies conducted in a controlled laboratory environment. It is a prospective study as it involves new testing for the expanded sample type.

3. Number of Experts and Qualifications for Ground Truth (Test Set)

• Number of Experts: Not applicable. This study is a method comparison for an in vitro diagnostic device, not an interpretation of images or clinical cases by experts.
• Qualifications of Experts: N/A

4. Adjudication Method (Test Set)

• Adjudication Method: Not applicable. Ground truth for this type of device comparison is established by reference measurement methods or the predicate device's results, not through expert adjudication of subjective interpretations.

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

• MRMC Study: No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is typically performed for image-based diagnostic devices where human interpretation plays a significant role.
• Effect Size of AI Improvement: N/A

6. Standalone Performance Study

• Standalone Performance: Yes, a standalone performance study was done for the algorithm (the ADVIA Chemistry GLUH_3 assay) using the new Na-Fluoride/K-Oxalate plasma type. The study compared the results obtained with this new plasma type against results obtained from serum samples using the predicate device's established method. The reported regression equation and correlation coefficient demonstrate the standalone performance of the device with the new sample type.

7. Type of Ground Truth Used

• Type of Ground Truth: The ground truth for the comparison study was established by the results obtained from serum samples using the predicate ADVIA Chemistry GLUH_3 assay (K101854). This is a common approach for method comparison studies for IVD devices, treating the established method (here, using serum) as the reference or "ground truth" to determine the performance of the new application (using Na-Fluoride/K-Oxalate plasma).

8. Sample Size for Training Set

• Sample Size for Training Set: Not explicitly mentioned as a separate "training set" in the context of this 510(k) summary. For in vitro diagnostic assays, the development and initial validation (which might be analogous to "training") typically involve numerous experiments and data points to optimize the reagent formulation and assay parameters. The submitted data focuses on the verification and validation of the new sample type's performance against the established method.

9. How Ground Truth for Training Set was Established

• How Ground Truth for Training Set was Established: As noted above, a distinct "training set" with established ground truth is not typically described in this manner for IVD assay submissions. The development of the ADVIA Chemistry GLUH_3 reagen itself (prior to this modification) would have involved extensive analytical studies, including:

  • Using certified reference materials.
  • Comparing results to established reference methods (e.g., isotope dilution mass spectrometry, enzymatic reference methods).
  • Correlation with clinically validated predicate devices.

  For this particular modification, the existing, cleared GLUH_3 reagent used with serum (and other plasma types) serves as the reference, and the new plasma type's performance is evaluated against this established performance.

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The S TEST reagent cartridge for glucose is intended for the quantitative measurement of glucose in serum, lithium heparin plasma, K3 EDTA plasma, and sodium citrate plasma on the Hitachi Clinical Analyzer. The test system is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus and idiopathic hypoglycemia.

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 test systems for glucose.

Chemistry reactions: Glucose is phosphorylated to glucose-6-phosphate by hexokinase (HK) in the presence of ATP. When the glucose-6-phosphate is converted into 6-phosphogluconic acid by glucose-6phosphate dehydrogenase (G6PD), NADP is converted into NADPH with an increase in absorbance at 340 nm. The concentration of glucose can be determined by measuring the amount of change in absorbance of NADPH.

HK Glucose + ATP Glucose-6-phosphate + ADP Mg2+ GRPD

Glucose-6-phosphate + NADP 6-Phosphogluconic acid + NADPH

The provided text describes the 510(k) summary for the Hitachi Clinical Analyzer S TEST Reagent Cartridge for Glucose. It details various performance studies conducted to demonstrate its safety and effectiveness.

Here's an analysis of the acceptance criteria and study information provided:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state formal "acceptance criteria" as pass/fail thresholds for each metric. Instead, it presents the results of various performance studies and implies that these results demonstrate substantial equivalence to the predicate devices. The information available allows for a comparison of the Hitachi S TEST and the predicate device's listed performance.

2. Sample Sizes and Data Provenance

The document does not explicitly state the "test set" in the context of an AI/ML device, as this is a traditional in-vitro diagnostic device. However, studies were performed to validate its performance.

• Analytical Sensitivity (Limits of Detection):
  • One experiment: "sensitivity for glucose was calculated to be 0.3 mg/dL." (Exact sample size not specified for this calculation).
  • Second experiment: "three low-level samples assayed 6 times a day for 3 days on three separate analyzers" (54 measurements per sample, total 162 measurements).
• Linearity: "The S TEST glucose is linear between 5 and 500 mg/dL." (Exact sample size not specified, but followed CLSI EP-6A which typically uses multiple levels and replicates).
• 20-day In-house Precision: 80 measurements per level (3 levels), total 240 measurements.
• Interference Testing: "not affected by high levels of the following substances at the levels noted" (Number of samples for each interference test not explicitly stated, but followed CLSI EP7-A2).
• Method Comparison (In-house): 100 serum samples.
• Matrices Comparisons: 38 matched serum/plasma samples (sodium citrate, lithium heparin, K3 EDTA).
• External POL Precision Study: Each of the 3 sites received 3 blinded serum samples (A, B, C). Each sample was assayed 6 times per day for 5 days, resulting in 30 results per level per analyte per site (3 sites * 3 levels * 30 results = 270 measurements for precision).
• External POL Method Comparisons Study: Each of the 3 POL sites received approximately 50 blinded serum samples (Total ~150 samples).

Data Provenance: The studies were conducted "in-house" (Hitachi Chemical Diagnostics) and at "three external POL-type sites" (Physician Office Laboratories). The central laboratory for predicate comparisons was likely in the US, but specific country of origin is not mentioned. All studies appear to be prospective as they are designed to evaluate the performance of the device.

3. Number of Experts and Qualifications for Ground Truth

This is an in-vitro diagnostic device (chemistry analyzer) measuring a biological analyte (glucose). The ground truth is established by quantitative measurement methods rather than expert interpretation of images or clinical data.

• Ground Truth for Method Comparison: The "ground truth" or reference method for comparison was primarily the Roche/Hitachi cobas 6000, which is a legally marketed predicate device (K100853). The cobas 6000 itself is a chemistry analyzer, not a human expert.
• Ground Truth for Matrices Comparison: The reference for plasma samples was serum samples.

Therefore, the concept of "number of experts used to establish the ground truth" and "qualifications of those experts" as it might apply to image-based diagnostics or disease diagnosis is not directly applicable here. The ground truth accuracy is against established, validated methods.

4. Adjudication Method for the Test Set

Adjudication methods (like 2+1, 3+1) are typically used for subjective assessments or when multiple human readers interpret results. This is an automated quantitative measurement device. Therefore, no adjudication method as described would be applicable or necessary. The comparisons are statistical (linear regression, correlation) between two quantitative measurements.

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

No MRMC comparative effectiveness study was done. This type of study is relevant for AI systems that assist human readers in tasks like image interpretation to evaluate the impact of AI assistance on human performance (e.g., accuracy, efficiency). The Hitachi Clinical Analyzer is a standalone automated diagnostic device, not an AI-assisted human reading system.

6. Standalone (Algorithm Only) Performance

Yes, a standalone performance study was done. The entire performance evaluation described (analytical sensitivity, linearity, precision, interference, method comparison, matrices comparison) demonstrates the performance of the Hitachi Clinical Analyzer S TEST Reagent Cartridge for Glucose as a standalone automated system, without human-in-the-loop performance modifications or assistance once the samples are loaded and the test initiated.

7. Type of Ground Truth Used

The primary ground truth used for comparison and validation was:

• Comparison to a Legally Marketed Predicate Device: Specifically, the Roche/Hitachi cobas 6000 (a chemistry analyzer with a glucose module), which itself has established performance characteristics. This is a form of reference method comparison.
• Internal reference (e.g., serum for plasma matrices): For the matrices comparison, serum was used as the reference against different plasma types.
• Defined reference standards/controls: For precision, linearity, and sensitivity, the device was tested against samples with known or precisely characterized glucose concentrations, which serves as the "ground truth" for those specific studies.

This is not "expert consensus," "pathology," or "outcomes data" in the typical sense, but rather comparison against established analytical chemical methods and reference materials.

8. Sample Size for the Training Set

The concept of a "training set" is not applicable here. This is a traditional in-vitro diagnostic device (chemistry analyzer) and not an AI/ML algorithm that undergoes a "training" phase with data. The device's calibration, which is somewhat analogous to initial setup/tuning, would be done using calibrator materials provided or specified by the manufacturer, but this is not "data training" in the AI sense.

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

As mentioned above, there is no "training set" in the AI/ML context for this traditional IVD device.

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