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cobas e 801 immunoassay analyzer is intended for the in-vitro determination of analytes in body fluids.

Elecsys TSH immunoasay 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 or pituitary disorders. The Elecsys TSH immunoassay is an electrochemiluminescence immunoasay 'ECLIA', which is intended for use on the cobas e immunoassay analyzers.

The cobas e 801 immunoassay analyzer is a fully automated, software controlled analyzer system for in vitro determination of analytes in human body fluids. It is part of the cobas 8000 modular analyzer series cleared under K100853. It uses electrochemiluminescent technology for signal generation and measurement.

Here's a breakdown of the acceptance criteria and study information for the Elecsys TSH assay on the Cobas e 801 immunoassay Analyzer, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" for each performance characteristic as pass/fail thresholds. Instead, it presents the results of various validation studies. I will present the reported performance, and where applicable, infer the implied acceptance based on the presentation of the results as successful.

2. Sample Size and Data Provenance for Test Set

• Repeatability and Intermediate Precision:
  • Sample Size:
    • 7 human serum samples (5 pooled, 5 pooled spiked) and 2 control samples (PC Universal, PreciControl TS).
    • Each sample tested in 2 replicates per run, 2 runs per day for 21 days (total of 84 replicate measurements per sample type).
• Linearity:
  • Sample Size: 3 high analyte serum samples diluted to 12 concentrations. Each concentration assayed in 3-fold determination within a single run.
• Analytical Sensitivity (LoB, LoD, LoQ):
  • LoB: Blank sample tested with 60 replicates (10 replicates per run, 6 days).
  • LoD: 5 low-level human serum samples tested with 60 replicates (2 replicates per sample per run, 6 days).
  • LoQ: 10 low-level TSH samples tested over 5 days, 5 replicates per sample per day.
• Endogenous Interferences:
  • Human serum samples. Specific number not provided, but the outcome is qualitative ("No interference observed").
• Exogenous Interferences (Anticoagulants):
  • A minimum of 40 serum/plasma pairs per sample material (presumably 40 serum, 40 Li-Heparin plasma, 40 K2-EDTA plasma, 40 K3-EDTA plasma). Tested in singleton for each type.
• Exogenous Interferences (Drugs):
  • 16 commonly used drugs and 13 special drugs. Specific number of samples not provided, but the outcome is qualitative ("No interference").
• Method Comparison:
  • Sample Size: 130 human serum samples (single donors and serum pools; native, spiked as well as diluted).
• Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective). However, the use of "human serum samples" and "human serum/plasma pairs" indicates biological samples. The studies are prospective in nature, conducted specifically to validate the device.

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

This device is an immunoassay for quantitative determination of TSH. The "ground truth" for the test set is established by the reference measurement method or the quantitative value itself. No human experts are used to establish ground truth in the same way they would be for image interpretation. The accuracy of the quantitative measurements is assessed against known concentrations (e.g., in linearity, LoB/LoD studies) or against a predicate device (method comparison).

4. Adjudication Method

Not applicable for an immunoassay. Adjudication is typically used when human interpretation of results contributes to the ground truth, which is not the case here.

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

No. This type of study is relevant for diagnostic imaging or other interpretations where human readers are involved. This document describes the performance of an in-vitro diagnostic device (IVD) for quantitative measurement, which operates without direct human interpretive input being part of the core measurement.

6. Standalone Performance

Yes, these studies describe the standalone (algorithm only, in this context meaning the device's automated performance without human intervention after sample loading) performance of the Elecsys TSH assay on the cobas e 801 immunoassay analyzer. The results presented are directly from the instrument's measurements.

7. Type of Ground Truth Used

• Reference Materials/Known Concentrations: For precision, linearity, LoB, LoD, LoQ, endogenous and exogenous interference studies, ground truth implicitly refers to the expected concentration/value based on the preparation of known samples or the absence of an analyte (for blanks).
• Predicate Device Measurements: For the method comparison study, the "ground truth" for comparison is the measurement obtained from the predicate device (Elecsys TSH on Elecsys 2010 analyzer).
• Expected Values: The "Expected Values" section establishes a reference range (0.27-4.20 µIU/mL) based on healthy test subjects. This is a clinical reference range, not a direct ground truth for individual measurements, but rather a benchmark for interpretation.

8. Sample Size for the Training Set

The document describes validation studies for an in vitro diagnostic device (IVD), specifically an immunoassay analyzer and assay. IVDs like this do not typically have a "training set" in the machine learning sense. The device's operational parameters, calibration curves, and algorithms are developed during the product development phase by the manufacturer, which might involve internal data, but generally, the submission focuses on external validation. The document does not provide details on the development data used.

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

As there is no "training set" described in the context of machine learning, this question about establishing ground truth for it is not applicable here. The device output is a quantitative value based on chemical reactions and detection, not a learned prediction from a ground-truthed dataset in the AI sense.

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Immunoassay for the in vitro quantitative determination of Thyroid Stimulating Hormone in human serum and plasma.

Sandwich principle: Total duration of assay: 18 minutes (37°C).
• 1st Incubation (9 minutes): Sample (50µL), a biotinylated monoclonal TSH-specific antibody (60 µL), and a monoclonal TSH-specific antibody labeled with a ruthenium complex (50 µL) react to form a sandwich complex.
• 2nd Incubation (9 minutes): After addition of streptavidin-coated microparticles (40 µL) the complex becomes bound to the solid phase via interaction of biotin and streptavidin.
• The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell.
• Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier (0.4 second read frame).
• Results are determined via a calibration curve which is instrument-specifically generated by a 2-point calibration curve and a master curve provided via the reagent bar code.

This document describes the Elecsys® TSH Assay, an electrochemiluminescence assay for the quantitative determination of Thyroid Stimulating Hormone (TSH) in human serum and plasma. The K961491 submission claims substantial equivalence to the Enzymun-Test® TSH (K915195).

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the comparison to the predicate device, Enzymun-Test® TSH, and general scientific principles for immunoassay performance. The document presents performance characteristics for both the Elecsys® TSH and the predicate device, demonstrating that the new device meets or exceeds the predicate's performance in key areas.

• Sample Control 1 (0.914 µU/ml): 2.08%
• Control 2 (2.451 µU/ml): 1.88%
• Control 3 (10.670 µU/ml): 1.47%
  Total %CV:
• Sample Control 1 (0.914 µU/ml): 3.28%
• Control 2 (2.451 µU/ml): 2.20%
• Control 3 (10.670 µU/ml): 1.76% |
  | Sensitivity | Should have a lower detection limit and functional sensitivity suitable for clinical applications, ideally comparable to or better than the predicate's 0.03 µU/ml. | Functional Sensitivity: 0.01 µU/ml
  Lower Detection Limit: 0.005 µU/mL |
  | Assay Range / Linearity | Reportable range should cover clinically relevant TSH levels, and values within this range should be linear (e.g., within ±10% deviation from the linear line). Predicate range: 0.03 µU/ml - 40.00 µU/ml. | Reportable Range: 0.01 µU/ml - 100 µU/ml
  (within ±10% deviation from the linear line) |
  | Method Comparison (Correlation with Predicate) | Should demonstrate good correlation with the predicate device (e.g., r > 0.95, slope near 1, intercept near 0). | Vs Enzymun-Test® TSH:
• Least Squares: y = 1.09x + 0.14, r = 0.991, SEE = 0.798 (N=132)
• Passing/Bablok: y = 1.12X - 0.05, r = 0.991, SEE = 0.798 (N=132)
  Vs Nichols 3rd Generation:
• Least Squares: y = 1.02x - 0.24, r = 0.985, SEE = 1.12 (N=142) |
  | Interfering Substances | Should show no significant interference from common biological substances at clinically relevant concentrations. | No interference at:
• Bilirubin 25 mg/dL
• Hemoglobin 1 g/dL
• Lipemia 1500 mg/dL
• Biotin 30 ng/mL
• RF 339 IU/mL |
  | Specificity (Cross-Reactivity) | Should demonstrate minimal or no cross-reactivity with other related hormones to avoid false positives/negatives. | Conc % Cross-Reactivity:
• HCG 200: 0
• LH 400: 0.038
• FSH 400: 0.008
• HGH 400: 0.00004 |

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

• Precision: For "Within-Run" and "Total" precision, N = 60 was used for each of the three control levels for the Elecsys® TSH. (The predicate used N=120 for each of its three levels.)
• Method Comparison:
  • N = 132 samples were used for comparison between Elecsys® TSH and Enzymun-Test® TSH.
  • N = 142 samples were used for comparison between Elecsys® TSH and Nichols 3rd Generation.
• Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given the context of a 510(k) summary for a diagnostic assay, it is highly probable that these studies involved prospective collection of human serum and plasma samples according to standard clinical laboratory practices.

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

For an in vitro diagnostic (IVD) immunoassay like the Elecsys® TSH, the "ground truth" is typically established by the reference method (the predicate device, in this case, Enzymun-Test® TSH, and an additional comparator, Nichols 3rd Generation TSH assay) or by expert consensus on the clinical state of the patient using standard clinical diagnostic criteria for thyroid function, rather than by human interpretation of images by experts. Therefore, the concept of "experts" as in radiologists, for example, is not applicable in this context. The "ground truth" values for TSH concentration are derived directly from the laboratory measurements by the reference assays.

4. Adjudication Method for the Test Set

Not applicable for this type of IVD device. The "ground truth" is the quantitative measurement from the reference methods, not subjective interpretation requiring adjudication among human experts.

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 immunoassay for TSH, not an imaging device requiring human readers or AI assistance.

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

This device is a standalone algorithm/instrument system. The Elecsys® TSH Assay on the Elecsys® 2010 instrument performs the measurement and provides a quantitative TSH value without human interpretation in the loop impacting the result generation directly. The reported "Performance Characteristics" (precision, sensitivity, linearity, method comparison, interference, specificity) represent the standalone performance of the assay and instrument system.

7. The Type of Ground Truth Used

The ground truth used for establishing the performance of the Elecsys® TSH Assay was:

• Reference Method Comparison: TSH values obtained from samples analyzed by the predicate device (Enzymun-Test® TSH) and another established method (Nichols 3rd Generation TSH). These assays provide quantitative measurements that serve as the "true" or reference values for TSH concentration.
• Known Concentrations/Spiked Samples: For studies like linearity, sensitivity, and interfering substances, samples with known TSH concentrations or spiked with interfering substances would be used as the ground truth.
• Clinical Samples: Samples from patients with various TSH levels (e.g., hyperthyroid, euthyroid, hypothyroid) would be used for method comparison studies to ensure broad clinical utility.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning. For an immunoassay, the "training" analogous to adjusting an algorithm would be the development and optimization of the assay reagents, protocols, and calibration procedures. The calibration curve for the Elecsys® TSH is generated by a 2-point calibration curve and a master curve provided via the reagent bar code. This essentially "calibrates" the system, allowing it to accurately quantitate unknown samples. The details of the samples used to establish the master curve are not provided but would typically involve highly characterized standard materials.

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

As discussed above, the concept of a training set as understood in AI/ML is not directly applicable. However, the "ground truth" for the development and calibration of the assay would be established through:

• WHO Standardization: The assay standardization is stated to be via the World Health Organization (WHO), indicating that the assay's measurements are traceable to international reference standards for TSH. These standards are rigorously characterized and assigned specific TSH values by expert international committees.
• Internal Validation and Reference Materials: Boehringer Mannheim would have used a series of internal reference materials and standards, carefully characterized for their TSH concentrations, during the assay development and for establishing the master curve. These internal standards would be assigned values based on comparisons to WHO international standards and/or highly accurate internal reference methods.

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