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The ADVIA Centaur® TSH3-Ultra II (TSH3ULII) assay is for in vitro diagnostic use in the quantitative determination of thyroid-stimulating hormone (TSH, thyrotropin) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP system. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

This assay is a third-generation assay that employs anti-FITC monoclonal antibody covalently bound to paramagnetic particles, an FITC-labeled anti-TSH capture mouse monoclonal antibody, and a tracer consisting of a proprietary acridinium ester and an anti-TSH mouse monoclonal antibody conjugated to bovine serum albumin (BSA) for chemiluminescent detection.

The provided text describes the ADVIA Centaur® TSH3-Ultra II (TSH3ULII) assay, a device for in vitro diagnostic quantitative determination of thyroid-stimulating hormone (TSH). The document covers the device's indications for use, comparison with a predicate device, and performance characteristics data.

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

1. Table of Acceptance Criteria and Reported Device Performance

• Limit of Detection (LoD): 0.008 µIU/mL (mIU/L)
• Limit of Quantitation (LoQ): 0.010 µIU/mL (mIU/L) (Lower than predicate device's LoQ of 0.008 µIU/mL, but within acceptable range for the new device as specified in assay range) |
  | Precision | - Repeatability (Within-Run):
  • ≤ 12% CV for 0.020–0.299 µIU/mL (mIU/L)
  • ≤ 6% CV for ≥ 0.300–90.000 µIU/mL (mIU/L)
  • ≤ 7% CV for > 90.000 µIU/mL (mIU/L)
• Within-Laboratory (Total Precision):
  • ≤ 16% CV for 0.020–0.299 µIU/mL (mIU/L)
  • ≤ 8% CV for ≥ 0.300–90.000 µIU/mL (mIU/L)
  • ≤ 10% CV for > 90.000 µIU/mL (mIU/L) | Reported values (all calculated Repeatability CV and Within-Laboratory CV values are within the specified limits):
• Serum A (0.088 µIU/mL): Repeatability CV 2.5%, Within-Lab CV 3.6%
• Serum B (0.196 µIU/mL): Repeatability CV 1.8%, Within-Lab CV 3.1%
• Serum C (0.507 µIU/mL): Repeatability CV 1.7%, Within-Lab CV 2.6%
• Serum D (4.752 µIU/mL): Repeatability CV 2.3%, Within-Lab CV 2.7%
• Serum E (46.749 µIU/mL): Repeatability CV 2.4%, Within-Lab CV 4.0%
• Serum F (97.929 µIU/mL): Repeatability CV 2.2%, Within-Lab CV 3.5%
  Similar acceptable results for Plasma and Controls. |
  | Reproducibility | - Reproducibility (Total):
  • ≤ 18.5% CV for 0.020-0.299 µIU/mL (mIU/L)
  • ≤ 10.5% CV for ≥ 0.300-90.000 µIU/mL (mIU/L)
  • ≤ 12.5% CV for > 90.000 µIU/mL (mIU/L) | Reported values (all calculated Reproducibility CV values are within the specified limits):
• Serum A (0.090 µIU/mL): Reproducibility CV 3.11%
• Serum B (0.178 µIU/mL): Reproducibility CV 4.87%
• Serum C (0.474 µIU/mL): Reproducibility CV 2.21%
• Serum D (4.684 µIU/mL): Reproducibility CV 2.47%
• Serum E (56.562 µIU/mL): Reproducibility CV 2.33%
• Serum F (99.522 µIU/mL): Reproducibility CV 4.12%
  Similar acceptable results for Plasma and Controls. |
  | Assay Comparison | - Correlation coefficient (r) ≥ 0.95
• Slope of 1.0 ± 0.1 | - Correlation coefficient (r): 0.999
• Regression Equation (Slope): 0.97 (within 1.0 ± 0.1) |
  | Specimen Equivalency | - Correlation coefficient (r) ≥ 0.95
• Slope of 0.95-1.05 | - Plasma, EDTA vs. Serum: r = 0.999, Slope = 0.99 (within 0.95-1.05)
• Plasma, lithium heparin vs. Serum: r = 0.990, Slope = 1.01 (within 0.95-1.05) |
  | Interferences (HIL) | Bias due to hemoglobin, bilirubin (conjugated/unconjugated), and Intralipid does not exceed 10% | Hemoglobin (500mg/dL), Bilirubin (40mg/dL), Intralipid (1000mg/dL) do not exceed 10% bias at TSH concentrations of ~0.900 µIU/mL and ~8.000 µIU/mL. |
  | Interferences (Other Substances) | Bias due to various common substances does not exceed 10% | Various substances (e.g., Acetaminophen, Aspirin, Biotin, Heparin, Ibuprofen, Levothyroxine) at specified concentrations do not exceed 10% bias at TSH concentrations of ~0.900 µIU/mL and ~8.000 µIU/mL. |
  | Cross-Reactivity | Cross-reactivity of hCG, FSH, and LH does not exceed 5% | hCG (200000 mIU/mL), FSH (1500 mIU/mL), LH (600 mIU/mL) at specified concentrations do not exceed 5% cross-reactivity at TSH concentrations of ~0.400, 5.00, 17.00, and 90.00 µIU/mL. |
  | Linearity | Device is linear throughout its measuring interval (0.010–150.000 µIU/mL) | "The assay is linear for the measuring interval of 0.010–150.000 µIU/mL (mIU/L)." |
  | High-Dose Hook Effect | Results for TSH concentrations above the measuring interval and up to 3000 µIU/mL should report > 150 µIU/mL (not a paradoxical decrease) | "Patient samples with TSH concentrations above the measuring interval and as high as 3000 µIU/mL will report > 150 µIU/mL (mIU/L)." (This confirms the absence of a significant high-dose hook effect within this specified range, meaning the device displays the result as above the measurable range.) |

The study that proves the device meets the acceptance criteria is detailed across the "Performance Characteristics Data" section (Section 8) of the 510(k) Summary.

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

• Detection Capability (LoQ): Not specified (CLSI Document EP17-A2 was followed).
• Precision: 80 measurements (replicates of 2, 2 runs/day, 20-day protocol) for each of the 6 serum samples, 5 plasma samples, and 5 control samples. Total N for Precision study is 80 x (6+5+5) = 1280 measurements.
• Reproducibility: 225 measurements (replicates of 5, 1 run/day, 5-day protocol) for each of the 6 serum samples, 5 plasma samples, and 5 control samples. Total N for Reproducibility study is 225 x (6+5+5) = 3600 measurements.
• Assay Comparison: 973 samples.
• Specimen Equivalency:
  • Plasma, EDTA vs. Serum: 52 samples.
  • Plasma, lithium heparin vs. Serum: 57 samples.
• Interferences (HIL and Other Substances): Samples at two TSH concentrations (~0.900 µIU/mL and ~8.000 µIU/mL) were tested for each interfering substance. The exact number of individual samples tested is not given, but multiple samples would be required for the two TSH levels per substance.
• Cross-Reactivity: Samples at four TSH concentrations (~0.400, 5.00, 17.00, and 90.00 µIU/mL) were spiked with hCG, FSH, or LH. The exact number of individual samples is not given.
• Linearity: Not explicitly stated, but performed in accordance with CLSI Document EP06-ed2, which involves testing multiple diluted samples.
• High-Dose Hook Effect: Samples with TSH concentrations up to 3000 µIU/mL were evaluated. The number of samples tested is not explicitly stated.

Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given it's an in vitro diagnostic device, the samples would generally be human biological specimens, likely collected from a clinical laboratory setting. The use of CLSI documents (Clinical and Laboratory Standards Institute) suggests standard laboratory practices.

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

This information is not provided in the document. For an in vitro diagnostic assay like TSH, "ground truth" is typically established by:

• The reference method against which the new assay is compared (for accuracy/assay comparison). In this case, "ADVIA Centaur TSH3-UL assay" is used as the comparative assay (the predicate device).
• Traceability to an international standard (WHO 3rd International Reference Preparation for human TSH (IRP 81/565)), which implies that the TSH values are calibrated against a universally accepted standard, rather than expert consensus on individual patient cases.

4. Adjudication Method for the Test Set

This refers to the process of resolving discrepancies in expert opinions, which is not applicable here as it is an analytical performance study for an IVD, not an interpretative AI device requiring human expert label agreement.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is typically performed for AI-assisted diagnostic imaging devices where human readers interpret medical images with and without AI assistance. This document pertains to an in vitro diagnostic assay, which involves automated quantitative measurement of a biomarker.

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

Yes, implicitly. The entire performance characterization (Detection Capability, Precision, Reproducibility, Assay Comparison, Specimen Equivalency, Interferences, Cross-Reactivity, Linearity, High-Dose Hook Effect) is describing the standalone performance of the TSH3-Ultra II assay as an automated laboratory test. There is no mention of "human-in-the-loop" for this device's intended diagnostic function.

7. Type of Ground Truth Used

The ground truth for the performance studies is established by:

• Reference materials/standards: For accuracy, the assay is traceable to the World Health Organization (WHO) 3rd International Reference Preparation for human TSH (IRP 81/565).
• Comparative method: For assay comparison, the predicate device (ADVIA Centaur TSH3-UL assay) results serve as the comparative standard.
• Defined concentrations: For precision, linearity, interferences, and cross-reactivity, samples with known or spiked concentrations of TSH or interfering substances are used.

8. Sample Size for the Training Set

The document does not report a training set sample size. This is because the ADVIA Centaur TSH3-Ultra II is a chemical immunoassay, not a machine learning or AI-based device that would typically involve a "training set" in the computational sense. The "development" process for such an assay involves reagent formulation, assay optimization, and calibration curve development, which are distinct from training an AI model.

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

As there is no "training set" in the context of an AI/ML model, this question is not applicable. The assay's analytical characteristics are established through various studies (precision, accuracy, linearity, etc.) using calibrated materials and established reference methods, as detailed in the performance characteristics.

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For in vitro diagnostic use in the quantitative determination of thyroid-stimulating hormone (TSH, thyrotropin) in serum, heparinized plasma, and EDTA plasma using the ADVIA Centaur XP systems. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

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The provided text describes an update to a previously approved device, the ADVIA Centaur® TSH3-Ultra assay, to include updated pediatric reference intervals. Crucially, the 510(k) submission (K150403) explicitly states that no additional analytical performance data was collected for this update. Instead, it cross-references all performance data to the original 510(k) submission (K083844) for the device.

Therefore, the acceptance criteria and the study that "proves the device meets the acceptance criteria" in this context primarily pertain to the establishment of the pediatric reference intervals, and not to the broader analytical performance of the device (such as precision, linearity, sensitivity, etc.), which was evaluated in the original submission.

Here's the breakdown based on the information provided for the pediatric reference interval update:

1. Table of Acceptance Criteria and Reported Device Performance

The concept of "acceptance criteria" for the device performance itself (e.g., accuracy, precision) is not explicitly detailed in this document for the current submission (K150403), as that data was accepted in the original 510(k). The focus of this submission is on the establishment of new reference intervals. For the purpose of these new intervals, the acceptance criteria would be that the established intervals are representative of the studied pediatric population and align with recognized medical practice for TSH interpretation in these age groups.

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

• Sample Size: A total of 442 patients were analyzed.
  • 94 infants
  • 198 children
  • 150 adolescents
• Data Provenance: Not explicitly stated (e.g., country of origin, specific sites). The document is a 510(k) submission to the FDA for a device manufactured by Siemens Healthcare Diagnostics, Inc. (Tarrytown, NY), but this does not specify the origin of the clinical samples.
• Retrospective or Prospective: Not explicitly stated. The phrasing "Data from a total of 442 patients... were analyzed to establish..." suggests this could be retrospective analysis of existing samples or prospectively collected samples for this study. The document focuses on the analysis of these patients' data.

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

• Number of Experts: Not mentioned in this document. The establishment of reference intervals typically involves statistical analysis of a healthy population, with clinical review of the resulting intervals by medical professionals. However, specific details on expert involvement for this particular data are absent.
• Qualifications of Experts: Not mentioned.

4. Adjudication Method for the Test Set

• Not applicable/Not mentioned. The study involved establishing reference intervals, which is a statistical process based on a healthy population, rather than assessing diagnostic accuracy against "ground truth" labels that would require adjudication.

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 assay (a laboratory test), not an imaging or diagnostic device that typically involves human readers interpreting results. Therefore, the concept of human readers improving with or without AI assistance is not relevant to this type of device.

6. Standalone Performance Study (Algorithm Only)

• Yes, in a sense, a standalone study was presented for the establishment of the reference intervals. The output (the reference interval values) is directly derived from the measurements from the device (ADVIA Centaur TSH3-Ultra) on the patient samples. The device itself performs the quantitative determination of TSH. The performance characteristics of the assay (precision, linearity, etc.) were established in the original 510(k) (K083844) as a standalone algorithm/device. This current submission focuses on applying that standalone performance to interpret results within newly defined pediatric reference ranges.

7. Type of Ground Truth Used (for pediatric reference intervals)

• The "ground truth" for establishing reference intervals is typically based on measurements from a statistically representative population of healthy individuals (euthyroid individuals in this case). The objective is to define the range of normal values within specific demographics (age groups) for a given analyte. The document specifies that these are for "ADVIA Centaur thyroid assay reference intervals for the studied pediatric population," implying these individuals were considered clinically "normal" or "euthyroid" for TSH levels.

8. Sample Size for the Training Set

• The 442 patients (94 infants, 198 children, 150 adolescents) mentioned for establishing the pediatric reference intervals essentially serve as the "training set" (or more accurately, the reference population set) for these intervals. There's no separate mention of a distinct training set vs. test set for the reference interval establishment itself, as the goal is to define the range from this population.
• For the analytical performance of the assay (linearity, precision, etc.), the training sets would have been part of the original K083844 submission and are not detailed here.

9. How the Ground Truth for the Training Set (Reference Population) Was Established

• The ground truth for the pediatric reference population (i.e., defining "healthy" or "euthyroid") is implied to be through clinical assessment and exclusion criteria, although not explicitly detailed. Reference interval studies typically involve recruiting subjects who are free from conditions that might affect the analyte being measured. The standard followed, CLSI EP28-A3c ("Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory"), describes methods for selecting and characterizing a reference population to establish clinical reference intervals.

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