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The Optilite Hevylite IgM Kappa Kit is intended for the quantitative in vitro measurement of IgM kappa (combined mu heavy and k light chain) in serum using the Binding Site Optilite analyser. The test result is to be used with previously diagnosed Waldenström's macroglobulinaemia. The test result should be used in conjunction with other laboratory and clinical findings. This assay has not been established for the diagnosis, monitoring and prognosis of Waldenström's macroglobulinaemia.

The Optilite Hevylite IgM Lambda Kit is intended for the quantitative in vitro measurement of IgM lambda (combined u heavy and a light chain) in serum using the Binding Site Optilite analyser. The test result is to be used with previously diagnosed Waldenström's macroglobulinaemia. The test result should be used in conjunction with other laboratory and clinical findings. This assay has not been established for the diagnosis, monitoring and prognosis of Waldenström's macroglobulinaemia.

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I apologize, but the provided text content does not contain information about the acceptance criteria or a study that proves a device meets those criteria. The document is an FDA 510(k) clearance letter for two in vitro diagnostic kits (Optilite Hevylite IgM Kappa Kit and Optilite Hevylite IgM Lambda Kit) and describes their intended use.

Specifically, the document states:

• Trade/Device Name: Optilite® Hevylite® IgM Kappa Kit, Optilite® Hevylite® IgM Lambda Kit
• Regulation Number: 21 CFR § 866.5510
• Regulation Name: Immunoglobulins A, G, M, D, and E immunological test system
• Regulatory Class: II
• Product Code: PDE, PDF
• Indications for Use: Quantitative in vitro measurement of IgM kappa or IgM lambda in serum using the Binding Site Optilite analyser, to be used with previously diagnosed Waldenström's macroglobulinaemia, and in conjunction with other laboratory and clinical findings.
• Limitation: "This assay has not been established for the diagnosis, monitoring and prognosis of Waldenström's macroglobulinaemia."

The letter confirms that the FDA has reviewed the premarket notification and determined the device is substantially equivalent to legally marketed predicate devices. However, it does not provide details about the specific studies conducted, acceptance criteria, performance data, sample sizes, ground truth establishment, or expert qualifications that would be required to answer your detailed questions.

To get this information, you would typically need to refer to the full 510(k) submission summary or other supporting documentation for these devices, which is not provided in the given text.

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Hevylite Human IgM Kappa kit for use on SPAPLUS is intended for the in-vitro quantification of IgM kappa (combined u heavy and k light chain) concentration in human serum on the Binding Site SPAPLUS. The test result is to be used with previously diagnosed Waldenström's macroglobulinaemia in conjunction with other clinical findings. This assay has not been established for the diagnosis of Waldenstrom's macroglobulinaemia.

Hevylite Human IgM Lambda kit for use on SPAPLUS is intended for the in-vitro quantification of IgM lambda (combined u heavy and A light chain) in human serum on the Binding Site SPAPLUS. The test result is to be used with previously diagnosed Waldenstrom's macroglobulinaemia. The test result is to be used in conjunction with other clinical findings.

This assay has not been established for the diagnosis, monitoring and prognosis of Waldenström's macroglobulinaemia.

Evaluating the concentration of a soluble antigen (e.g. IgM Kappa and IgM Lambda) by turbidimetry involves the addition of the test sample to a solution containing the appropriate antibody (anti-IgM kappa and anti-IgM lambda) in a reaction vessel or cuvette. A beam of light id passed through the cuvette and, as the antigen-antibody reaction proceeds, the light passing through the cuvette is scattered increasingly as insoluble immune complexes are formed. Light scatter is monitored by measuring the decrease in intensity of the incident beam of light. The antibody in the cuvette is in excess so the amount of immune complex formed is proportional to the antigen concentration. A series of calibrators of known antigen concentration are assayed initially to produce a calibration curve of measured light scatter versus antigen concentration. Samples of unknown antigen concentration can then be assayed and the results read from the calibration curve.

This document describes the Hevylite Human IgM Kappa Kit for use on SPAPLUS and the Hevylite Human IgM Lambda Kit for use on SPAPLUS, which are in-vitro quantification assays for IgM kappa and IgM lambda concentrations in human serum. The primary study presented is a substantial equivalence comparison to a predicate device.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for this device are primarily linked to its analytical performance, specifically precision, linearity, and agreement with the predicate device. The document explicitly states acceptance criteria for repeatability, reproducibility, linearity (recovery and CV), and agreement with the predicate.

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

• Precision/Reproducibility:

  • Initial Study: Three samples of processed sera (pooled with fully preserved citrate beta alanine) at high, mid, and low analyte levels. Each sample was run in duplicate, two runs/day over 21 days (resulting in 84 measurements per sample for repeatability). For reproducibility, it involved three reagent lots and four instruments.
  • Bridging Study: Five samples of pooled native sera at various analyte levels covering the measuring range. Each sample was run in duplicate, two runs/day over 21 days (84 measurements per sample for repeatability). For reproducibility, it involved one reagent lot and three instruments.
  • Data Provenance: Not explicitly stated, but given The Binding Site is a UK company, and the reference range study used 147 UK adult blood donors, it is highly likely these analytical studies used data from the United Kingdom. The studies appear to be prospective as they involved specific testing protocols over a defined period (21 days).

• Linearity/Assay Reportable Range:

  • One lot of reagent on one analyzer.
  • High and low pools prepared from serum samples (naturally high concentration or IgM depleted).
  • Dilution series provided 12 concentrations for each assay (IgM Kappa/Lambda). Three replicates of each level were run.
  • An additional study for IgM Kappa bottom range used serum samples diluted to provide 0.086 - 0.405 g/L.
  • Data Provenance: Not specified, but likely from within the company's testing facilities (e.g., UK). This is a prospective analytical study.

• Linecision (Instrument Dilution):

  • Two serum samples for instrument dilution function (run 20 aspirations each).
  • A third sample for manual pre-dilution (run 20 aspirations by 3 separate users against 1/90 instrument dilution, and 20 aspirations by 3 operators after manual dilution for 1/250 instrument dilution).
  • Data Provenance: Not specified, likely within company testing facilities. Prospective analytical study.

• Detection Limit (LoB, LoD, LoQ):

  • LoB: IgM depleted sample tested 60 times.
  • LoQ: Five serum samples tested 12 times each over 5 days.
  • Data Provenance: Not specified, likely within company testing facilities. Prospective analytical study.

• Interfering Substances:

  • Test serum samples (concentrations representing normal range, medical decision points, pathological) with added haemoglobin, bilirubin, Intralipid, and triglycerides. Samples tested three times each.
  • Data Provenance: Not specified, likely within company testing facilities. Prospective analytical study.

• Cross-reactivity:

  • Samples from multiple myeloma patients (IgA1K, IgA2K, IgA2A, IgG1K, IgG1A, IgG2K, IgG3K, IgG3A, IgG4A, K free light chain and λ free light chain).
  • IgMx patient samples tested on IgM Lambda kits, and IgMA patient samples tested on IgM Kappa kits.
  • Data Provenance: Not specified, likely patient samples gathered from a clinical setting, potentially retrospective in terms of sample collection, but prospective for the testing.

• Method Comparison with Predicate Device:

  • 227 sera samples for IgM Kappa.
  • 269 sera samples for IgM Lambda.
  • These samples included: 41 Waldenström's Macroglobulinaemia patients, 23 normal donors, and samples with elevated IgM Kappa and IgM Lambda levels.
  • Data Provenance: Not explicitly stated, but likely from a clinical cohort/laboratory setting. Given "normal donors" and patient samples, this is likely a mix of retrospective and prospective sample collection with prospective testing. The country of origin for these samples is not explicitly mentioned but could be assumed to be from the UK based on the company's location and other studies.

• Expected Values/Reference Range:

  • 147 UK adult blood donors.
  • Data Provenance: United Kingdom, collected prospectively for the study.

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

There is no mention of "experts" being used to establish ground truth in the traditional sense of image analysis or diagnostic interpretation for this type of in-vitro diagnostic device.

• For analytical performance studies (precision, linearity, detection limits, interference, cross-reactivity), the "ground truth" is established by the known concentrations of calibrators, controls, or spiked samples, or by reference methods (like the predicate device for method comparison).
• For the method comparison with the predicate device, the predicate device itself (Hevylite Human IgM Kappa and IgM Lambda Kits for use on Siemens BN™II Systems) serves as the "ground truth" or reference, against which the new device's measurements are compared.
• For the determination of normal ranges, the ground truth is statistical – deriving reference intervals from a healthy reference population (147 UK adult blood donors) using non-parametric analysis.

Therefore, there were no specific experts establishing "ground truth" in terms of diagnostic interpretation; instead, the performance is validated against established laboratory standards, known concentrations, and a predicate device.

4. Adjudication Method for the Test Set

Not applicable. As this is an in-vitro diagnostic device for quantitative measurement of analytes (IgM Kappa and IgM Lambda), diagnostic "test sets" typically involve comparing device results against a gold standard, historical patient data, or a predicate device. There is no mention of an adjudication process (like 2+1 or 3+1 consensus among human readers) for the test results in this context, as would be common in diagnostic imaging studies. The comparison is statistical and performance-based against a reference.

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 (IVD) device for quantitative biochemical measurement, not an AI or imaging device that assists human readers in interpretation. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not relevant to this device.

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

This device is an in-vitro diagnostic (IVD) assay used on an automated analyzer (SPAPLUS). Its performance is inherently "standalone" in the sense that the analyzer (algorithm/system) processes the sample and generates a quantitative result without direct human interpretation of a raw signal/image (as might be the case for AI in imaging). The device's analytical performance studies (precision, linearity, detection limits, etc.) and method comparison are all evaluations of this standalone performance. No human-in-the-loop performance is described as part of the core function of the device for generating the reported values.

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

The type of "ground truth" used varies depending on the specific study:

• Analytical Performance (Precision, Linearity, Detection Limit, Interference):
  • Known concentrations of analytes in calibrators, controls, or spiked samples.
  • IgM-depleted serum for blank/detection limit studies.
• Method Comparison with Predicate Device:
  • The results obtained from the legally marketed predicate device (Hevylite Human IgM Kappa and IgM Lambda Kits for use on Siemens BN™II Systems) were used as the comparative "ground truth" for demonstrating substantial equivalence.
• Cross-reactivity:
  • Patient samples with known high concentrations of potentially cross-reacting monoclonal proteins (e.g., various IgA, IgG, free light chains) were used to test for specificity.
• Expected Values/Reference Range:
  • Measurements from a statistically appropriate population of "normal" individuals (147 UK adult blood donors) to establish a physiological reference range.

8. The Sample Size for the Training Set

No explicit "training set" is mentioned in the context of machine learning or AI models. This is a traditional IVD assay based on turbidimetry. The development of the assay and optimization would involve numerous samples, but these are not formally designated as a "training set" in the way an AI model would be.

However, if we interpret "training" more broadly as the data used to initially establish performance and parameters before final validation, this could implicitly include:

• Samples used during assay development and optimization to define reagent concentrations, reaction kinetics, and algorithm parameters for the SPAPLUS instrument.
• The calibrators themselves are used to "train" or establish the calibration curve for each run.

The document does not provide a specific sample size for such an implicit "training set."

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

Since there is no explicit "training set" in the AI sense:

• Calibrator Ground Truth: The calibrators are traceable to ERM-DA470k International Reference Material. This means their "ground truth" concentrations are established through an international standard, ensuring accuracy and comparability.
• Assay Development Ground Truth: During assay development, the ground truth for optimizing parameters would be established through a combination of reference methods, known concentrations of purified analytes, and clinical samples characterized by other established clinical methods. This iterative process is standard for IVD development but not detailed in this 510(k) summary as a discrete "ground truth establishment" step for a training set.

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