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The cobas 8000 ISE module is a fully automated ion-specific analyzer intended for the in vitro potentionetric determination of chloride, potassium, and sodium in serum, plasma, and urine ion-selective electrodes. Measurements obtained by this device are used in the diagnosis and treatment of diseases or conditions involving electrolyte imbalance.

The cobas 8000 ISE module is an Ion-Selective Electrode (ISE) system for the determination of sodium, potassium, and chloride in serum, plasma, and urine. The cobas 8000 ISE module and the ISE Gen 2 reagents were previously cleared for serum and plasma sample types under K100853 and urine sample type on K123726. This premarket notification seeks to obtain FDA review and clearance for the urine sample type for the ISE Gen 2 reagents on the cobas 8000 ISE module using an expanded measuring range for sodium and chloride analytes at the low end of the measuring range and the new calibration method cleared in K132418. An ISE makes use of the unique properties of certain membrane materials to develop an electrical potential (electromotive force, EMF) for the measurements of ions in solution. The electrode has a selective membrane in contact with both the test solution and an internal filling solution. The internal filling solution contains the test ion at a fixed concentration. Because of the particular nature of the membrane, the test jons will closely associate with the membrane on each side. The membrane EMF is determined by the difference in concentration of the test ion in the test solution and the internal filling solution. The EMF develops according to the Nernst equation for a specific ion in solution (see package insert for further explanation). Please refer to K 100853 for detailed hardware and software information relating to the cobas 8000 modular analyzer series.

This document describes the performance of the cobas 8000 ISE Indirect Na, K, Cl for Gen. 2 device, specifically focusing on its use for urine samples with an expanded measuring range for sodium and chloride.

1. Acceptance Criteria and Reported Device Performance

The device performance is compared to a predicate device (cobas 8000 ISE Module using Low/High/Serum Compensator calibration cleared under K123726) and a reference method (flame photometry for Na and K, coulometry for Cl). The acceptance criteria are implicitly demonstrated by showing substantial equivalence to the predicate device and by meeting established performance metrics for analytical devices (repeatability, intermediate precision, linearity, detection limits).

Notes on Acceptance Criteria:

• The document implies that the device meets acceptance criteria if its performance is substantially equivalent to the predicate device and the reference methods, and if the within-run precision (repeatability), total precision (intermediate precision), and detection limits are within acceptable analytical limits for clinical chemistry devices.
• For the expanded measuring range for Sodium and Chloride (20-59.9 mmol/L), the acceptance criteria are demonstrated by the stated precision (repeatability and intermediate precision) within that new range.
• The high correlation coefficients (e.g., 0.9995 for Sodium to reference method) and slopes close to 1 with small intercepts indicate good agreement with the reference methods and predicate.

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

• Test Set Sample Sizes for Method Comparison Studies:
  • Sodium:
    • Method Comparison to Reference (flame photometer): N = 106
    • Method Comparison to Predicate: N = 92
  • Potassium:
    • Method Comparison to Reference (flame photometry): N = 99
    • Method Comparison to Predicate: N = 92
  • Chloride:
    • Method Comparison to Reference (coulometry): N = 100
    • Method Comparison to Predicate: N = 92
• Data Provenance: The document does not explicitly state the country of origin of the data. The "Date Prepared: May 8, 2014" and the submitter being Roche Diagnostics (Indianapolis, IN, USA) with manufacturing in Mannheim, Germany (K100853 reference), suggests an international context, but the specific location of sample collection for the studies is not specified. The studies appear to be prospective as they are conducted to demonstrate the performance of the candidate device for a 510(k) submission.

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

This type of analytical device (Ion-Selective Electrode system for chemical determination) relies on established reference methods (e.g., flame photometry, coulometry) rather than expert interpretation of images or clinical cases. Therefore, the concept of "experts establishing ground truth" in the way it applies to diagnostic imaging or clinical decision support systems is not directly applicable here. The "ground truth" is typically defined by the accurate results obtained from the reference methods, which are performed by trained laboratory personnel following standardized protocols. No specific number or qualification of "experts" for ground truth establishment is mentioned, as it's an analytical performance study.

4. Adjudication Method for the Test Set

Not applicable. As noted above, this is an analytical performance study of a laboratory device measuring chemical analytes, not a diagnostic interpretation task requiring adjudication of results from multiple observers.

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

No. An MRMC study is relevant for diagnostic devices that involve human interpretation (e.g., radiologists reading images). This device is an automated in vitro diagnostic instrument; its performance is evaluated through analytical studies, not human reader performance.

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

Yes, the studies presented are standalone performance evaluations. The data provided (repeatability, intermediate precision, method comparison, detection limits) are direct measurements of the instrument's analytical capabilities without human intervention in the measurement process itself, beyond standard laboratory operation and quality control.

7. The Type of Ground Truth Used

The ground truth for the method comparison studies was established using reference methods:

• Sodium: Flame photometer
• Potassium: Flame photometry
• Chloride: Coulometry

For repeatability, intermediate precision, and detection limit studies, the "ground truth" is intrinsic to the statistical analysis of the measurements themselves, often against a known concentration of controls or calibrators.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning. This device is an automated analytical instrument based on established electrochemical principles (Ion-Selective Electrodes) and conventional calibration methods, not an AI/ML-based device that learns from a training dataset in the same way. The instrument is "trained" or calibrated using "ISE Standard Low, High, High" (LHH) calibrators, which are commercially available standards with known concentrations. The exact number of calibrator measurements for system calibration or "training" (in the sense of instrument calibration) is not provided but is typically specified by the manufacturer's protocol.

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

Not applicable as an AI/ML training set. The "ground truth" for the device's calibration refers to the assigned values of the calibrator materials (ISE Standard Low, High, High). These values are established by the manufacturer, typically through highly accurate and traceable reference methods, and are verified for consistency and accuracy. The document mentions that "Aqueous ISE standards Low and High were cleared under K053165. The LHH calibration scheme was cleared under K132418," indicating that the standards themselves and the calibration methodology have been previously reviewed and deemed acceptable.

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The ISE module of the Roche / Hitachi systems is intended for the quantitative determination of sodium, potassium, and chloride 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.

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.

The cobas 6000 analyzer series with an ISE module is an Ion-Selective Electrode (ISE) system for the determination of sodium, potassium, and chloride in serum, plasma, and urine. The cobas 6000 analyzer series, including the cobas c 501 with ISE for Serum, Plasma and Urine sample types was previously cleared in K060373. This premarket notification seeks to obtain FDA review and clearance for the cobas c 501 ISE, Modified Calibration for Serum, Plasma and Urine sample types.

An ISE makes use of the unique properties of certain membrane materials to develop an electrical potential (electromotive force, EMF) for the measurements of ions in solution. The electrode has a selective membrane in contact with both the test solution and an internal filling solution. The internal filling solution contains the test ion at a fixed concentration. Because of the particular nature of the membrane; the test ions will closely associate with the membrane on each side. The membrane EMF is determined by the difference in concentration of the test ion in the test solution and the internal filling solution. The EMF develops according to the Nernst equation for a specific ion in solution (see package insert for further explanation).

Aqueous ISE Standards Low and High were cleared in K053165. The modified calibration in this submission included the use of ISE Standards Low (S1) and High (S2) for 2-point calibration and the Standard High for compensation (S3). Previously, a serum-based ISE compensator was used for S3 compensation. The modification is switching from serum-based ISE compensator for S3 to ISE Standard High. In the new calibration scheme, the ISE Standard High will be used for both S2 and S3.

The provided text describes a 510(k) summary for the cobas c 501 ISE, Modified Calibration for Sodium, Potassium, and Chloride assays. It focuses on demonstrating substantial equivalence to a predicate device rather than presenting a study for meeting acceptance criteria in the typical AI/ML context. However, I can extract and structure the information into the requested format by interpreting "acceptance criteria" as the performance parameters considered for substantial equivalence and "reported device performance" as the data provided for the modified device.

Here's the breakdown:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly derived from the performance of the predicate device and the new device showing comparable or improved performance for various metrics. The study aims to demonstrate that the modified calibration maintains or improves performance.

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

The "test set" here refers to the samples used for method comparison studies.

• Sodium (Serum/Plasma): N = 52 (Plasma, Modified), N = 51 (Serum, Modified). N = 51 (Plasma, Predicate).
• Sodium (Urine): N = 100 (Modified). N = 51 (Predicate).
• Potassium (Serum/Plasma): N = 52 (Plasma, Modified), N = 54 (Serum, Modified). N = 51 (Plasma, Predicate).
• Potassium (Urine): N = 105 (Modified). N = 51 (Predicate).
• Chloride (Serum/Plasma): N = 52 (Plasma, Modified), N = 53 (Serum, Modified). N = 51 (Plasma, Predicate).
• Chloride (Urine): N = 105 (Modified). N = 51 (Predicate).

Data Provenance: The document does not specify the country of origin of the data. The studies appear to be prospective, laboratory-based analytical studies designed to test the performance of the modified device against a reference method and the predicate device. They are not clinical studies necessarily involving patient outcomes.

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

This type of information is not applicable to this submission. This is a submission for an in vitro diagnostic (IVD) device (a measurement instrument and reagents) used to quantify specific analytes (sodium, potassium, chloride) in biological samples. The "ground truth" for the test set is established by recognized reference methods (e.g., Flame Photometry, Coulometry) which are laboratory instruments, not human experts making diagnostic decisions. There were no experts involved in establishing ground truth for these analytical performance studies.

4. Adjudication Method for the Test Set

This is not applicable. As stated above, this is an analytical performance study using objective reference standard measurements, not human interpretation requiring adjudication.

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

This is not applicable. MRMC studies are typically performed for AI/ML diagnostic interpretation algorithms where human readers' performance is evaluated and compared with and without AI assistance. This submission is for an IVD device where measurements are performed by an automated analyzer, not human "readers" interpreting cases.

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

The study described is inherently a "standalone" or "algorithm only" performance evaluation relative to the context of AI/ML. The device (cobas c 501 ISE with modified calibration) performs the measurement and produces results without human interpretation of raw data in the same way an AI algorithm would. The study directly evaluates the analytical performance of this automated system.

7. The Type of Ground Truth Used

The ground truth for the analytical performance studies was established using:

• Reference Methods:
  • Flame Photometry for Sodium (Plasma, Urine) and Potassium (Plasma, Urine).
  • Coulometry for Chloride (Plasma, Urine).
• Predicate Device Performance: The original cobas c 501 ISE Gen. 2 with serum-based ISE Compensator (K053165) served as a benchmark for comparison to demonstrate substantial equivalence, rather than a "ground truth" per se.

8. The Sample Size for the Training Set

This is not applicable in the context of AI/ML. This device is a chemistry analyzer with a modified calibration process, not a machine learning algorithm that requires a "training set" in the conventional sense. The "training" of the device involves the 2-point calibration and compensation using ISE Standards Low (S1) and High (S2, S3), as described in the submission.

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

This is not applicable in the context of AI/ML. The "ground truth" for the calibration process is established by the known concentrations of the ISE Standards Low (S1) and High (S2, S3). These are manufactured with highly controlled, known concentrations, serving as the basis for the instrument's calibration.

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The ISE module of the Roche/Hitachi cobas c system is intended for the quantitative determination of sodium, potassium and chloride in serum, plasma or urine using ion-selective electrodes.

The cobas 8000 ISE module is a fully automated ion-specific analyzer intended for the in vitro potentiometric determination of chloride, potassium, and sodium in serum, plasma, and urine using ion-selective electrodes. Measurements obtained by this device are used in the diagnosis and treatment of diseases or conditions involving electrolyte imbalance.

The cobas 8000 ISE module is an Ion-Selective Electrode (ISE) system for the determination of sodium, potassium, and chloride in serum, plasma, and urine. The cobas 8000 ISE module and the ISE Gen 2 reagents were previously cleared for serum and plasma sample types under K100853. This premarket notification seeks to obtain FDA review and clearance for the urine sample type for the ISE Gen 2 reagents on the cobas 8000 ISE module.

An ISE makes use of the unique properties of certain membrane materials to develop an electrical potential (electromotive force, EMF) for the measurements of ions in solution. The electrode has a selective membrane in contact with both the test solution and an internal filling solution. The internal filling solution contains the test ion at a fixed concentration. Because of the particular nature of the membrane, the test ions will closely associate with the membrane on each side. The membrane EMF is determined by the difference in concentration of the test ion in the test solution and the internal filling solution. The EMF develops according to the Nernst equation for a specific ion in solution (see package insert for further explanation). Please refer to K100853 for detailed hardware and software information relating to the cobas 8000 modular analyzer series.

Commercially available controls are recommended for the urine sample type. Aqueous ISE standard calibrators (S1, S2, and S3) were cleared under K053165 and ISE Compensator under K052193.

The cobas 8000 ISE Indirect Na, K, Cl for Gen. 2 device is intended for the in vitro potentiometric determination of chloride, potassium, and sodium in serum, plasma, and urine using ion-selective electrodes. This summary outlines the acceptance criteria and the study results demonstrating the device's performance.

1. Acceptance Criteria and Reported Device Performance

The device's performance was evaluated against a predicate device (COBAS INTEGRA ISE cleared under K963627) and, for method comparison, against reference methods (flame photometer for Sodium and Potassium, coulometry for Chloride). While explicit acceptance criteria (e.g., target CV% or correlation coefficients) are not directly stated as numerical thresholds for substantial equivalence, the reported performance metrics are compared to the predicate device and reference methods to demonstrate analytical validity. The tables below summarize the reported performance for the cobas 8000 Urine ISE.

Sodium Performance

Potassium Performance

Chloride Performance

2. Sample Size and Data Provenance for the Test Set

• Sample Size for Test Set:
  • Method Comparison (to reference method and predicate): N = 59 unique samples were used for the method comparison studies for Sodium, Potassium, and Chloride. These samples were tested over 2 days.
  • Repeatability and Intermediate Precision: The number of unique samples for these studies is not explicitly stated as 'test set' but rather multiple levels of controls/samples were run, e.g., "Low", "Med", "High", "Liq 1", "Liq 2" for the cobas 8000 Urine ISE. The data presented are statistical summaries (mean, SD, CV%) derived from these runs.
• Data Provenance: The document does not explicitly state the country of origin for the data. However, the submitter is Roche Diagnostics (Indianapolis, IN, USA) with establishment registration in Mannheim, Germany, suggesting the studies could have been conducted in either or both locations. The studies appear to be prospective as they detail the evaluation of the new device for urine sample types.

3. Number of Experts and Qualifications for Ground Truth

Not applicable. This is a submission for an in vitro diagnostic device (analyzing electrolytes) where the 'ground truth' is established by established reference methods (e.g., flame photometry, coulometry) or by comparison to a legally marketed predicate device, not by expert human interpretation of medical images or other subjective data.

4. Adjudication Method for the Test Set

Not applicable. As described above, the ground truth is established by objective laboratory methods, not by human interpretation requiring adjudication.

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

Not applicable. This is an IVD device and does not involve human readers for interpretation, thus an MRMC study is not relevant.

6. Standalone Performance Study

Yes, a standalone performance study was done. The entire submission details the performance of the cobas 8000 ISE module as an algorithm-only (device-only) without human-in-the-loop performance measurement. The repeatability, intermediate precision, method comparison, detection limits (LOB, LOD, LOQ), and reportable range data reflect the standalone performance of the device.

7. Type of Ground Truth Used

The ground truth used for performance evaluation includes:

• Reference Methods:
  • For Sodium and Potassium: Flame Photometer
  • For Chloride: Coulometry
• Comparison to a Predicate Device: COBAS INTEGRA ISE (K963627)

8. Sample Size for the Training Set

Not applicable. This device is a diagnostic instrument using ion-selective electrodes, not a machine learning or AI algorithm that requires a "training set" in the context of supervised learning. The device's calibration and controls would be analogous to continuous internal checks, but there isn't a "training set" in the traditional AI sense.

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

Not applicable, as there is no training set in the context of an AI algorithm. The device's operational parameters and calibration are established through physical and chemical principles of ion-selective electrodes, and validated through the performance studies described.

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