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CardioPhase hsCRP is an in-vitro diagnostic reagent for the quantitative determination of C-reactive protein (CRP) in human serum, and heparin and EDTA plasma by means of particle enhanced immunonephelometry using the BN II and BN ProSpec® System. In acute phase response, increased levels of a number of plasma proteins, including C-reactive protein, is observed. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. High sensitivity CRP (hsCRP) measurements may be used as an independent risk marker for the identification of individuals at risk for future cardiovascular disease. Measurements of hsCRP, 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.

The CardioPhase hsCRP assay is an in-vitro diagnostic reagent for the quantitative determination of Creactive protein (CRP) in human serum, and heparinized and EDTA plasma by means of particleenhanced immunoassay determination. The assay is traceable to the international standard ERM-DA474/IFCC. N Rheumatology Standard SL (cleared under K964527) is used for the establishment of reference curves for the immunonephelometric determination of C-reactive protein on the BN II and BN ProSpec® Systems. This calibrator consists of a mixture of human sera and elevated concentrations of CRP. The CardioPhase hsCRP reagent is a suspension of polystyrene (Latex) particles to which mouse monoclonal anti-human CRP antibodies (< 0.016 g/L) have been attached by covalent bonding. The reagent is a ready-to-use liquid containing preservatives. There are two product variants available. One variant (REF OQIY13) contains 3 x 2 mL vials / box, and the other variant (REF OQIY21) contains 5 x 5 mL vials / box. The assay's polystyrene particles coated with monoclonal antibodies specific to human CRP are aggregated when mixed with samples containing CRP. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the relevant protein in the sample. The result is evaluated by comparison with a standard of known concentration.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the method comparison study were that "Results from each lot of CardioPhase hsCRP met the predefined acceptance criteria." While the specific numerical acceptance criteria (e.g., maximum allowable bias) are not explicitly detailed in a table format within the provided text, the successful outcome is stated, and the resulting performance is presented as follows:

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

• Sample Size:
  • Lot 1: N = 119
  • Lot 2: N = 116
  • Lot 3: N = 113
  • The total number of samples used in the method comparison study is the sum of these, which is 348.
• Data Provenance: The study was conducted at the "company site in Marburg, Germany." The samples used were "Native serum samples." The text does not explicitly state whether the samples were retrospective or prospective, but the phrasing "Native serum samples were measured" suggests they were existing samples at the time of the study rather than collected specifically for this study.

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

This information is not provided in the text. The study describes a method comparison between two quantitative laboratory assays (CardioPhase hsCRP and RCRP Flex reagent cartridge). For this type of in-vitro diagnostic device, the "ground truth" is typically defined by the reference method or the predicate device's measurement, not by human expert consensus or adjudication in the way it might be for image-based diagnostic AI.

4. Adjudication Method for the Test Set

Not applicable for this type of in-vitro diagnostic device and study design. The comparison is quantitative between two analytical methods, not involving human interpretation requiring adjudication.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is typically performed for image analysis or other diagnostic tools where human interpretation is a key component. The CardioPhase hsCRP is an in-vitro diagnostic reagent for quantitative measurement, which does not involve human readers in the same way.

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

Yes, the study described is a standalone performance study of the CardioPhase hsCRP assay compared to a predicate device. It evaluates the device's ability to quantitatively determine C-reactive protein concentrations independently. No human-in-the-loop component is mentioned for the performance evaluation itself.

7. The Type of Ground Truth Used

The "ground truth" for this method comparison study was established by the predicate device, RCRP Flex® reagent cartridge, which runs on the Dimension clinical chemistry system. Both the proposed device (CardioPhase hsCRP) and the predicate device are traceable to the international standard ERM-DA474/IFCC for C-reactive protein measurements. Therefore, the predicate device's measurements serve as the reference for comparison, and that reference itself is traceable to an international standard.

8. The Sample Size for the Training Set

The text does not specify a separate training set or its sample size. The described "method comparison study" is focused on verifying the performance of the device for regulatory submission, using a test set of samples. For in-vitro diagnostic devices, "training sets" are usually relevant for developing the assay itself (e.g., optimizing reagent concentrations, reaction conditions), but this information is not typically detailed in a 510(k) summary with respect to a "training set" of patient data for algorithm development.

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

As no specific "training set" of patient samples is described in the provided text in the context of algorithm development, this information is not applicable. The assay itself relies on a biochemical principle and calibration traceable to an international standard (ERM-DA474/IFCC), and the calibration is established using N Rheumatology Standard SL, which is traceable to Siemens internal Master Calibrator, which is in turn directly traceable to ERM-DA474/IFCC.

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N Latex FLC kappa and lambda are in-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTA-plasma. N Latex FLC kappa and lambda assays are used:
• as an aid in the diagnosis and monitoring of multiple myeloma (MM) on the BN Systems and Atellica® CH Analyzer,
• as an aid in the diagnosis of amyloidosis (AL) on the BN Systems and Atellica® CH Analyzer,
• as an aid in the evaluation of Monoclonal Gammopathy of Undetermined Significance (MGUS) on the BN Systems.
Results of FLC measurements should always be interpreted in conjunction with other laboratory and clinical findings.

The N Latex FLC (free light chain) assays are in vitro diagnostic reagents for the quantitative determination of free light chains, type kappa or type lambda, in human serum and EDTA plasma by means of particle-enhanced immunoassay determination. Used in conjunction with other clinical and laboratory findings, FLC measurements are used as an aid in the diagnosis and monitoring of multiple myeloma (MM), as an aid in the diagnosis of amyloidosis (AL) and on the BN Systems, as an aid in the evaluation of MGUS.
Polystyrene particles coated with antibodies to human free light chains, type kappa or lambda, are agglutinated when mixed with samples containing FLC. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the concordance percentages achieved in various patient cohorts. The document does not explicitly state numerical thresholds as "acceptance criteria" but rather presents the performance results.

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

• MGUS Concordance:
  • Test Set Sample Size: 121 MGUS samples (89 Non-IgM, 21 IgM, 11 LC MGUS)
  • Data Provenance: Not explicitly stated, but the study was described as a "multi-center study," suggesting samples were collected from various clinical sites. It is implied to be retrospective as they are described as "clinically defined samples" and patients with "diagnosed" MGUS or polyclonal immunostimulation.
• LC MGUS Concordance:
  • Test Set Sample Size: 11 LC MGUS samples (subset of the 121 MGUS samples).
  • Data Provenance: Same as above (multi-center, implied retrospective).
• Polyclonal Immunostimulation Concordance:
  • Test Set Sample Size: 102 specimens.
  • Data Provenance: Same as above (multi-center, implied retrospective).
• Evaluation of MGUS Patients (Stable Cohort):
  • Test Set Sample Size: 61 patients.
  • Data Provenance: Not explicitly stated, but patients were "initially diagnosed for MGUS" and "evaluated over different time periods" with "at least 4 sample draws at various time intervals," indicating a prospective or longitudinal study design over time.
• Evaluation of MGUS Patients (Progressive Cohort):
  • Test Set Sample Size: 4 patients.
  • Data Provenance: Same as above (prospective/longitudinal).

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

The document does not specify the number or qualifications of experts used to establish the ground truth for the test set. It refers to "clinically defined samples" and "clinical diagnosis," implying that the ground truth was based on a comprehensive clinical assessment, likely by medical professionals (e.g., oncologists, hematologists), but the details are not provided.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method for establishing the ground truth of the test set (e.g., 2+1, 3+1). The ground truth appears to be based on pre-existing "clinical diagnosis" or "clinically defined samples."

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

• No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic reagent, which provides quantitative measurements, not an imaging device that human readers interpret. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable in this context.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

• Yes, a standalone performance study was done. The studies described (concordance and evaluation of stable/progressive patients) assessed the performance of the N Latex FLC assays (the "device" or "algorithm" in this context) directly against clinical diagnoses and criteria. The results are reported as the "N Latex FLC κ/λ Ratio Concordance" and "N Latex FLC results," indicating an assessment of the device's output without direct human-in-the-loop interpretation of the assay results during the diagnostic process itself (though human interpretation of the FLC results in conjunction with other clinical findings is part of the intended use).

7. Type of Ground Truth Used

The ground truth used was expert consensus / clinical diagnosis / outcomes data.

• "Clinically defined samples" with diagnoses of MGUS or polyclonal immunostimulation.
• "Clinical diagnosis of MGUS" and "change in clinical diagnosis of MGUS to MM" for the stable and progressive cohorts, respectively. This implies that the ground truth was established by medical professionals using a combination of clinical findings, established diagnostic criteria, and other laboratory results, which could be considered a form of expert consensus or clinical outcomes.

8. Sample Size for the Training Set

The document does not report on a separate training set or its sample size. The performance data provided is for the evaluation of the device, implying the device was already developed. For an in-vitro diagnostic assay like this (which is a reagent test and analytical system), the "training" typically refers to the development and optimization of the assay's chemical and biological components, calibration, and establishment of analytical performance characteristics, rather than machine learning model training on a distinct labeled dataset. The document refers to prior submissions (K171742 and K182098) for "previously documented analytical and clinical studies," which likely covered the initial development and analytical validation.

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

As no explicit "training set" for an AI/ML model is mentioned, this question is not directly applicable. For a traditional diagnostic assay, the "ground truth" during development involves rigorous analytical validation (e.g., using reference materials, spiked samples, and comparison to established methods) and initial clinical studies to define normal ranges and characteristic responses in different disease states. These would have been established through standard laboratory and clinical practices, likely involving certified reference materials, reference methods, and clinical expert assessment of patient samples.

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N Latex FLC kappa and lambda assays: In-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda, in human serum and EDTA plasma by means of particle-enhanced immunonephelometry using the BN Systems. FLC measurements are used as an aid in the diagnosis of multiple myeloma (MM) and amyloidosis (AL).
N FLC Supplementary Reagent: Supplementary reagent for the immunonephelometric determination of free light chains (FLC), type kappa and type lambda on BN Systems. A mixture of both supplementary reagents is used to suppress interference by rheumatoid factors and human anti-mouse antibodies (HAMA).
N FLC Standard SL: Establishment of reference curves for the determination of free light chains (FLC), type kappa and type lambda on the BN Systems.
N FLC Controls SL1 and SL2: The N FLC Controls SL1 and SL2 are for use as assayed accuracy controls in the determination of free light chains (FLC), type kappa and type lambda by immunonephelometry with the BN Systems.

The N Latex FLC (free light chain) assays are in vitro diagnostic reagents for the quantitative determination of free light chains, type kappa or type lambda, in human serum and EDTA plasma by means of particle-enhanced immunonephelometry using the BN™ II and BN ProSpec® Systems. Used in conjunction with other clinical and laboratory findings, FLC measurements are used as an aid in the diagnosis of multiple myeloma (MM) and amyloidosis (AL). Used in conjunction with the assay reagents, N FLC Standard SL is for use in the establishment of reference curves for the determination of free light chains, type kappa and type lambda on the BN™ II and BN ProSpec® Systems. The N FLC Control SL 1 and 2 products are for use as assayed accuracy controls and precision controls in the determination of free light chains, type kappa and type lambda by immunonephelometry with the BN™ II and BN ProSpec® Systems. The FLC test systems are based upon the principles of particle-enhanced immunonephelometry. Polystyrene particles coated with monoclonal antibodies to human free light chains, type kappa or lambda, respectively, are agglutinated when mixed with samples containing FLC. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration.

The provided text describes the Siemens N Latex FLC kappa and N Latex FLC lambda assays, along with their associated calibrators and controls. These devices are intended for the quantitative determination of free light chains (FLC) in human serum and EDTA plasma, used as an aid in diagnosing multiple myeloma (MM) and amyloidosis (AL).

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 generally implied by the performance characteristics presented in the study. For analytical performance, typical acceptance limits for precision (CV%), linearity, and interference are industry standards for IVD devices. For clinical performance, the reported sensitivity and specificity values against clinical diagnosis are the acceptance metrics.

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

• Precision and Reproducibility:
  • Sample Size: Serum samples were obtained from commercial sources. Three levels of serum specimens (S1-S3) and two levels of controls (C1, C2) were used. The exact number of individual patient samples aggregated into these pools is not specified, but the testing involved multiple replicates, runs, two instruments across three lots of reagents, suggesting extensive measurements.
  • Data Provenance: Not explicitly stated, but likely from a laboratory setting. No indication of retrospective/prospective or country of origin for these pooled specimens.
• Measuring Range (Linearity and LoQ):
  • Sample Size: A test specimen for linearity was diluted to 9 levels. Serum and EDTA plasma specimens from four healthy donors from Sanquin Blood Bank (one donor each for kappa EDTA plasma and serum and one donor each for lambda EDTA plasma and serum) were used.
  • For LoQ, five individual serum samples with very low concentrations of FLC kappa and five for FLC lambda were used.
  • Data Provenance: Fresh human serum and EDTA plasma. Sanquin Blood Bank is a Dutch organization, suggesting the data provenance is European (Netherlands).
• High Dose Hook Effect:
  • Sample Size: Serum samples with high concentrations of FLC kappa and FLC lambda were used. The number of samples is not specified.
  • Data Provenance: Not specified.
• Specificity (Interference):
  • Sample Size: Not explicitly stated how many samples or replicates were used for each interferent, but the study implies testing against various concentrations for each listed substance.
  • Data Provenance: Not specified.
• Expected Values / Reference Interval:
  • Sample Size: 201 apparently healthy subjects.
  • Data Provenance: US-population. This was a prospective study to establish reference intervals.
• Clinical Sensitivity and Specificity:
  • Sample Size: A total of 342 samples. This included:
    • 96 samples from Multiple Myeloma patients.
    • 83 samples from AL Amyloidosis patients.
    • 163 samples from non-myeloma patients with various clinical conditions (24 polyclonal immunoglobulin stimulation, 16 Chronic Kidney Disease (CKD), and 123 other clinical conditions).
  • Data Provenance: Not explicitly stated, but these are patient samples. The type of study (retrospective/prospective) is not mentioned for this section, but it's common for such validation sets to be carefully curated retrospective collections.
• Method Comparison with Predicate Device:
  • Sample Size: 152 serum samples from patients with monoclonal gammopathy.
  • Data Provenance: Patients with monoclonal gammopathy. Not specified if retrospective or prospective or country of origin.

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

The document does not specify the number or qualifications of experts used to establish the "ground truth" for the test set in the conventional sense of a diagnostic imaging or pathology study.

• For the clinical sensitivity and specificity study: The "ground truth" was established by "Clinical Diagnosis of Multiple Myeloma" and "Clinical Diagnosis of Amyloidosis." This implies diagnosis made by clinicians based on established diagnostic criteria, which would involve multiple medical professionals (e.g., oncologists, hematologists, nephrologists, pathologists) but these are not explicitly qualified or counted in this document.
• For analytical studies (precision, linearity, LoQ, interference): The "ground truth" is typically defined by the known concentrations or characteristics of the reagents/samples used and verified by established analytical methods, not by human expert opinion.

4. Adjudication Method for the Test Set

Not applicable for this type of in-vitro diagnostic device study. Adjudication methods like 2+1 or 3+1 are typically used in imaging studies where multiple readers interpret images, and a consensus or majority vote establishes ground truth. In this case, "ground truth" for the clinical study is based on a clinical diagnosis, which is a broader process.

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

No, an MRMC comparative effectiveness study was not done. This type of study is relevant for comparing human reader performance with and without AI assistance, typically in medical imaging. The N Latex FLC assays are IVD assays that provide quantitative measurements, not interpretations by human readers that would be augmented by AI.

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

Yes, the studies described are for the standalone performance of the N Latex FLC assays. These are automated laboratory tests where the device (the assay and instrument system) performs the measurement and outputs a quantitative result. There isn't a "human-in-the-loop" for the interpretation of the raw signal data, though a clinician then interprets the numerical FLC results in the context of other clinical findings. The performance metrics (precision, linearity, LoQ, sensitivity, specificity) reflect the algorithm/device's performance directly.

7. The Type of Ground Truth Used

• Clinical Sensitivity and Specificity: "Clinical Diagnosis of Multiple Myeloma" and "Clinical Diagnosis of Amyloidosis." This would typically be based on a combination of clinical signs, symptoms, other laboratory tests, bone marrow biopsy results, and imaging studies, as per established medical guidelines.
• Analytical Studies (Precision, Linearity, LoQ, Hook Effect, Interference): Ground truth was established by known concentrations of analytes in prepared samples or by the absence/presence of interfering substances at specified levels. For example, linearity samples were prepared by serial dilution from a high concentration, and LoQ samples were prepared to known very low concentrations. For interference, substances were added at specific concentrations.
• Reference Intervals: Based on measurements from an "apparently healthy subject" population (201 subjects from a US-population).

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of an AI/ML algorithm. This device is an immunoassay using a well-established technology (particle-enhanced immunonephelometry). Such systems are typically developed and validated using calibration and verification samples, but not "training sets" in the machine learning sense. The N FLC Standard SL is used for establishing reference curves (calibration), which is a form of "training" for quantitative measurement but not for a high-level diagnostic algorithm that learns from data.

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

As noted above, a "training set" in the AI/ML context is not directly applicable here.

• For the calibration (N FLC Standard SL): "Calibration of the assay is traceable to an internal master calibrator." This master calibrator's "ground truth" (assigned value) would have been established through a rigorous internal development and characterization process, likely involving primary reference materials or highly characterized analytical methods, though the specific details are not provided in this summary.
• For the controls (N FLC Control SL1 and SL2): "The concentration of the free light chains (FLC), type kappa and type lambda is calibrated against standard preparations and is lot-dependent." This means their "ground truth" values are assigned relative to the calibration curve established using the N FLC Standard SL, which in turn refers to the internal master calibrator.

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