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System reagent for the quantitative determination of IgG immunoglobulins in human serum, plasma and cerebrospinal fluid on Beckman Coulter AU/DxC AU analyzers. The measurement of IgG aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents.

The device consists of two reagents: R1 buffer (Tris buffer pH 7.2, polyethylene glycol 6000) and R2 (goat anti-IgG antiserum). The reagents contain sodium azide as preservative.

When a sample is mixed with R1 buffer and R2 antiserum solution, human IqG reacts specifically with anti-human IgG antibodies to yield insoluble aggregates. Immune complexes formed in solution scatter light in proportion to their size, shape, and concentration. Turbidimeters then measure the reduction of incidence light due to reflection, absorption, or scatter. The decrease in intensity of light transmitted (increase in absorbance) through particles suspended in solution is a result of complexes formed during the antigen-antibody reaction.

The Beckman Coulter Immunoglobulin G (IgG) reagent for quantitative determination of IgG immunoglobulins in human serum, plasma, and cerebrospinal fluid on Beckman Coulter AU/DxC AU analyzers, device K221114, underwent various non-clinical (bench) studies to demonstrate substantial equivalence to its predicate device (K162208).

Here is a summary of the acceptance criteria and reported device performance based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Method Comparison:
  • Serum: 147 samples
  • CSF: 114 samples
  • Data Provenance: Not explicitly stated regarding country of origin or whether retrospective/prospective. The studies were conducted "using patient correlation studies", suggesting human patient samples were used.
• Linearity/Reportable Range: Each dilution was assayed in quadruplicate on a DxC 500 AU analyzer. High and low pools were prepared and inter-diluted. Number of distinct patient samples used for pooling is not specified.
• Sensitivity (LOB, LOD, LOQ):
  • LOB: 72 blank replicates per reagent lot (4 blank native serum samples 'analyte-depleted' run n=6 for 3 days).
  • LOD and LOQ: 500 replicates per reagent lot for each application (10 low-level samples for IgG run 10-fold for 5 days).
• Precision:
  • 20-day study: Not explicitly stated as a number of distinct samples, but samples were tested over 20 days.
  • 5-day study: Not explicitly stated as a number of distinct samples, but samples were tested over 5 days.
• Interference: All test samples were assayed n=5 at two analyte levels. The number of distinct samples for each interferent type is not specified.
• Reference Interval: "Transference approach" used to validate the original IgG serum reference interval. The specific number of samples for the transference study is not detailed.

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

This device is an in vitro diagnostic (IVD) test for quantitative measurement of immunoglobulins. The "ground truth" in this context is the analytically measured concentration of IgG in samples, determined by laboratory methods. Therefore, expert interpretation or consensus as seen in imaging or clinical diagnosis is not directly applicable. The "ground truth" is established by the analytical method itself, calibrated against known standards, and verified through method comparison with predicate devices and established guidelines.

4. Adjudication method for the test set:

Not applicable in the context of quantitative IVD testing. Analytical results are directly compared to predefined acceptance criteria based on industry guidelines (e.g., CLSI).

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, not an AI-assisted diagnostic imaging or clinical decision support tool that involves human readers.

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

The device is an analytical reagent system used on automated analyzers. Its performance is inherently "standalone" in the sense that the instrument and reagent determine the quantitative result without human subjective interpretation of the primary measurement. Human involvement lies in sample preparation, loading, and result interpretation, but not in the analytical measurement itself. The studies described are assessing the performance of this standalone analytical system.

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

The ground truth used for performance evaluation is based on analytical measurements against established standards and comparison to a legally marketed predicate device. For example:

• Method Comparison: Comparison against the predicate device (Beckman Coulter IgG Reagent on DxC 700 AU analyzer) to demonstrate similar quantitative results.
• Linearity/Sensitivity/Precision: Determined by assessing the device's ability to accurately and reproducibly measure known concentrations or concentrations derived from highly characterized samples.
• Reference Interval: Validation of an existing reference interval for the predicate device, implying that the ground truth for this is derived from previously established clinical studies.

8. The sample size for the training set:

Not applicable. This device is a diagnostic reagent, not a machine learning or AI algorithm that requires a "training set" in the conventional sense. The development of the reagent and its methods would involve extensive research and development, but this is distinct from "training data" for an AI model.

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

Not applicable, as there is no "training set" in the context of this IVD device.

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The Beckman Coulter DxC 500 AU Clinical Chemistry Analyzer is an automated chemistry analyzer that measures analytes in samples, in combination with appropriate reagents, calibrators, quality control (QC) material and other accessories. This system is for in vitro diagnostic use only.

The Glucose test system is for the quantitative measurement of glucose in human serum, plasma, urine and cerebrospinal fluid on Beckman Coulter AU/DxC AU analyzers. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and of pancreatic islet cell carcinoma.

System reagent for the quantitative determination of C-Reactive Protein in human serum and plasma on Beckman Coulter AU/DxC AU Analyzers. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. Measurements may also be useful as an aid in the identification of individuals at risk for future cardiovascular disease. High sensitivity CRP (hsCRP) measurements, when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, may be useful as an independent marker of prognosis for recurrent events, in patients with stable coronary disease or acute coronary syndromes. Reagents for the quantitative determination of Sodium, Potassium and Chloride concentrations in human serum, plasma and urine on the Beckman Coulter ISE modules.

The sodium test system is intended for the quantitative measurement of sodium in serum, plasma, and urine.

Measurements obtained by this device 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.

The potassium test system is intended for the quantitative measurement of potassium in serum, plasma, and urine. Measurements obtained by this device are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels.

The chloride test system is intended for the quantitative measurement of the level of chloride in plasma, serum, and urine. Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such as cystic fibrosis and diabetic acidosis.

The Beckman Coulter DxC 500 AU Clinical Chemistry Analyzer carries out automated analysis of serum, plasma, urine samples and other body fluids and automatically generates results. The device is an automated photometric clinical analyzer that measures analytes in samples, in combination with appropriate reagents, calibrators, quality control (QC) material and other accessories. This system is for in vitro diagnostic use only. Electrolyte measurement is performed using a single cell lon Selective Electrode (ISE) which is also common among the other members of the AU family.

The ISE module for Na+, K+, and Cl- employs crown ether membrane electrodes for sodium and potassium and a molecular oriented PVC membrane for chloride that are specific for each ion of interest in the sample. An electrical potential is developed according to the Nernst Equation for a specific ion. When compared to the Internal Reference Solution, this electrical potential is translated into voltage and then into the ion concentration of the sample.

In this Beckman Coulter procedure, 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-6phosphate dehydrogenase (G6P-DH) specifically oxidizes G-6-P to 6phosphogluconate with the concurrent reduction of nicotinamide adenine dinucleotide (NAD+) to nicotinamide adenine dinucleotide, reduced (NADH). The change in absorbance at 340/660 nm is proportional to the amount of glucose present in the sample.

The CRP Latex reagent is an in vitro diagnostic device that consists of ready to use buffer and latex particles coated with rabbit anti-CRP antibodies. In this procedure, the measurement of the rate of decrease in light intensity transmitted through particles suspended in solution is the result of complexes formed during the immunological reaction between the CRP of the patient serum and rabbit anti-CRPantibodies coated on latex particles. Two measuring range settings are available: Normal application (CRP Concentrations ranging between 5.0-480 mg/L) and Highly Sensitive (Cardiac) Application- (CRP concentrations ranging between 0.2-80mg/L).

This document describes the acceptance criteria and supporting study for the Beckman Coulter DxC 500 AU Clinical Chemistry Analyzer and its associated reagents (Glucose, CRP Latex, ISE Reagents for Sodium, Potassium, and Chloride).

1. Table of Acceptance Criteria and Reported Device Performance

The device performance was evaluated across several metrics. The table below summarizes the acceptance criteria (often implied by the "Pass" result and the specific targets within the CLSI guidelines references) and the reported performance for key tests:

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

The studies used various sample sizes for different tests, primarily patient samples and prepared sample pools. The provenance of the data is not explicitly stated in terms of country of origin, but it is implied to be clinical laboratory data. The studies are non-clinical (bench) studies following CLSI protocols, which suggests they were conducted in a controlled laboratory environment. The data is retrospective in the sense that it relies on established methods and samples to evaluate the new device against a predicate.

• Method Comparison:

  • hsCRP (Cardiac): 115 serum samples
  • CRP Normal: 120 serum samples
  • Glucose (Serum): 133 serum samples
  • Glucose (Urine): 113 urine samples
  • Glucose (CSF): 111 CSF samples
  • ISE Sodium (Serum): 120 serum samples
  • ISE Potassium (Serum): 119 serum samples
  • ISE Chloride (Serum): 120 serum samples
  • ISE Sodium (Urine): 117 urine samples
  • ISE Potassium (Urine): 120 urine samples
  • ISE Chloride (Urine): 114 urine samples

• Linearity/Reportable Range: High and low sample pools were prepared and inter-diluted. Test samples were assayed in quadruplicate. The total number of unique samples is not specified, but multiple dilutions were tested.

• Sensitivity (Detection Limits): Replicate measurements on blank and low-level samples across multiple days using multiple reagent lots. The specific number of samples is not detailed, but the method suggests an adequate number of replicates for statistical determination.

• Precision/Reproducibility: Duplicate sample analysis, twice daily, over 20 days (n=80) for multiple sample levels (typically 3-5 levels per test).

• Interferences: 5 replicates of test samples at two analyte levels.

• Reference Interval: At least 20 reference individuals (e.g., 25 for CRP Latex Serum, 23 for Glucose Serum, 24 for Glucose Urine, 20 for ISE Serum tests).

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

This submission is for an in vitro diagnostic (IVD) device, specifically a clinical chemistry analyzer and its reagents. For such devices, "ground truth" is typically established by comparing the device's results to established, legally marketed predicate devices and reference methods, as well as adherence to recognized industry standards (CLSI guidelines).

• Experts: The document does not describe the use of human experts to establish "ground truth" in the way it might for an AI-powered image analysis device (e.g., radiologists). Instead, the "ground truth" for the test set values themselves is derived from the established analytical performance of the predicate device and the reference methods outlined in the CLSI guidelines.
• Qualifications: The "experts" in this context would be the skilled laboratory personnel performing the CLSI guideline-based studies and the manufacturers establishing the performance claims for both the candidate and predicate devices. Their qualifications align with standard laboratory practices and regulatory requirements for IVD development and validation.

4. Adjudication Method for the Test Set

No explicit adjudication method (like 2+1 or 3+1 consensus) is described, as this would typically apply to subjective interpretations (e.g., image reading by multiple human experts). For an IVD device measuring analytes, the evaluation is based on quantitative data comparison against established reference methods and performance specifications, using statistical analysis. The "pass" criteria for each test inherently serve as the "adjudication" against the set performance targets.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Reader Improvement with AI vs. Without AI Assistance

No MRMC study was done, nor is it applicable. This submission is for an automated clinical chemistry analyzer and its reagents, which quantitatively measure analytes. It is not an AI-assisted diagnostic imaging or interpretation device that clinicians would use to read cases or images. Therefore, there is no human-in-the-loop component for which an AI assistance effect size would be relevant.

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

Yes, the studies presented are essentially standalone performance evaluations of the DxC 500 AU Clinical Chemistry Analyzer and its associated reagents. The "algorithm" here refers to the instrument's automated analytical processes (photometric, ISE, etc.) and the reagent chemistries. The performance data (method comparison, linearity, precision, sensitivity, interference) directly reflects the device's analytical capability without direct human interpretation or intervention in the measurement process itself, beyond sample preparation and loading. Human oversight is involved in quality control and interpretation of results, but the core analytical performance is standalone.

7. The Type of Ground Truth Used

The ground truth for evaluating the device's performance is primarily established through:

• Comparison to Predicate Device: The DxC 700 AU Clinical Chemistry Analyzer (K161837), which is a legally marketed device with established performance.
• CLSI Guidelines: Standardized laboratory protocols (e.g., EP09C-ED3 for Method Comparison, EP06-ED2 for Linearity, EP17-A2 for Sensitivity, EP05-A3 for Precision) that define acceptable analytical performance.
• Established Reference Ranges: For reference interval studies, existing medical literature or established clinical laboratory reference intervals are used, with verification that a high percentage of samples fall within these ranges on the new device.
• Spiked Samples and Known Concentrations: For linearity, sensitivity, and interference studies, samples are engineered with known concentrations of analytes and/or interferents to challenge the device across its claimed range and conditions.

8. The Sample Size for the Training Set

This type of product (clinical chemistry analyzer and reagents) does not typically involve a "training set" in the context of machine learning or AI models. The development process for such devices relies on chemical and engineering principles, followed by rigorous analytical validation (the studies described above). Therefore, a "training set" size is not applicable.

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

As explained above, there is no "training set" for this type of medical device. The "ground truth" and performance establishment for the device's design and analytical methods would be rooted in fundamental scientific knowledge of chemistry, reagent interactions, and photometric/electrochemical detection, corroborated by extensive internal development and testing against established analytical standards and predicate devices.

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