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510(k) Data Aggregation
(192 days)
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
| Performance Characteristic | Acceptance Criteria (Design Goal) | Reported Device Performance |
|---|---|---|
| Detection Capability | N/A (LoB, LoD, LoQ are reported values, not acceptance criteria for determination) | - Limit of Blank (LoB): 0.005 µIU/mL (mIU/L) - 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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(142 days)
The Trinidad Immunoassay (IM) system is an automated, immunoassay analyzer designed to perform in vitro diagnostic tests on clinical specimens. The Trinidad IM system's assay applications utilize chemiluminescent technology for clinical use.
The Trinidad IM Thyroid Stimulating Hormone (TSH) 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 Trinidad IM system. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.
The Trinidad IM TSH Calibrators are for in vitro diagnostic use in calibrating the Trinidad IM system TSH assay.
The Siemens Healthcare Diagnostics Trinidad Immunoassay (IM) system is a floor model, fully automated, microprocessor-controlled, integrated instrument system that utilizes chemiluminescent technology and uses pre-packaged reagent packs to measure a variety of analytes in human body fluids. It is controlled through a combination of custom and off-the-shelf software.
The Trinidad IM TSH assay reagent kit comes in two configurations (100 or 500 test kit) and each kit contains the following:
500 Test Kit:
- 5 ReadyPack primary reagent packs containing Trinidad IM TSH Lite Reagent, Solid Phase, and Ancillary Reagent
- 2 vials of lyophilized Trinidad IM TSH low calibrator
- 2 vials of lyophilized Trinidad IM TSH high calibrator
100 Test Kit:
- 1 ReadyPack primary reagent packs containing Trinidad IM TSH Lite Reagent, Solid Phase, and Ancillary Reagent
- 1 vial of lyophilized Trinidad IM TSH low calibrator
- 1 vial of lyophilized Trinidad IM TSH high calibrator
The ReadyPack consists of the following:
- Lite Reagent 6.0 mL/ reagent pack: The Lite Reagent contains bovine serum albumin (BSA) conjugated to murine monoclonal anti-TSH (~0.3 µg/mL) antibody labeled with acridinium ester, buffer, stabilizers (murine, bovine, caprine proteins), surfactant, and preservatives.
- Solid Phase Reagent 21.0 mL/ reagent pack: The Solid Phase reagent contains anti-fluorescein murine monoclonal antibody covalently linked to paramagnetic particles (~85 µg/mL), buffer, stabilizers (bovine, caprine proteins), surfactant, and preservatives.
- Ancillary Reagent 6.0 mL/ reagent pack: The Ancillary reagent contains FITC conjugated to murine monoclonal anti-TSH antibody (~3 µg/mL), buffer, stabilizers (murine, bovine, caprine proteins), surfactant, and preservatives.
The TSH Calibrator consists of the following:
- After reconstitution, low and high levels of thyroid stimulating hormone (TSH) in HEPES buffered equine serum with sodium azide (< 0.1%) and preservatives. The low and high calibrators are targeted at ~ 0.032 and 97.5 µIU/mL, respectively.
Here's a breakdown of the acceptance criteria and the study details for the Trinidad IM Thyroid Stimulating Hormone (TSH) assay, Trinidad Immunoassay (IM) system, and Trinidad IM TSH Calibrators, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance:
| Performance Characteristic | Acceptance Criteria (Implicit) | Reported Device Performance (Trinidad IM TSH Assay) |
|---|---|---|
| Detection Limits | ||
| Limit of Blank (LoB) | Per CLSI Document EP17-A2 | 0.001 µIU/mL |
| Limit of Detection (LoD) | Per CLSI Document EP17-A2 | 0.005 µIU/mL |
| Limit of Quantitation (LoQ) | Total imprecision ≤ 20% | 0.008 µIU/mL |
| Linearity | Good correlation (R value) | Linear from 0.0001 to 150 µIU/mL (R = 1.000) |
| Precision | Per CLSI Document EP05-A2 | |
| Repeatability (CV%) | Low %CV | 1.45% - 3.68% (across various specimens) |
| Within-Lab (CV%) | Low %CV | 3.59% - 5.95% (across various specimens) |
| Interfering Substances | < 10% effect | < 5% change at tested interferent levels |
| Hemolyzed | 500 mg/dL of hemoglobin | |
| Lipemic | 1000 mg/dL of triglycerides | |
| Icteric (conjugated) | 40 mg/dL of conjugated bilirubin | |
| Icteric (unconjugated) | 40 mg/dL of unconjugated bilirubin | |
| Heterophile Interference | No interference observed | No interference observed |
| Cross-reactivity | Non-detectable | Non-detectable for hCG, FSH, LH at tested levels |
| High Dose Hook Effect | No hook effect | No high dose hook effect up to 3,000 µIU/mL |
| Method Comparison (vs. Predicate) | Good correlation (R value) | R = 0.994, Slope = 1.07, Intercept = -0.003 |
| Serum Plasma Matrix Equivalency | Equivalent with good correlation | R = 1.00 (Lithium Heparin), R = 1.00 (EDTA Plasma) |
| Expected Values | Verified | Verified across infant, children, adolescent, adult populations |
| Stability | Verified shelf-life | 12 months at 2 – 8°C |
2. Sample Sizes Used for the Test Set and Data Provenance:
- Detection Limits:
- LoB: 10 times in each of at least 10 runs using 1 lot of reagent on 2 systems over a period of at least 5 days (n = 200).
- LoD: Low level TSH serum samples assayed in duplicate in each of at least 20 runs using 1 lot of reagents on 2 systems over a period of at least 10 days (n=80).
- LoQ: Multiple patient samples with low TSH values assayed in duplicate in each of 10 runs on 2 systems over a period of 10 days. (Specific n not given, but many samples implied).
- Linearity: Nine (9) equally spaced pools, ranging in TSH levels from 0.0001 to 151 ulU/mL, prepared from a high TSH serum sample mixed with an equine serum pool.
- Precision: Four commercial controls, six serum samples, and six plasma samples. Each sample was assayed in 2 replicates per run, 2 runs per day for 20 days. (Total of 80 replicates per sample tested).
- Interfering Substances: Specific number of samples not provided, but tested with various levels of hemolyzed, lipemic, and icteric specimens.
- Cross-reactivity: Human samples containing TSH, with added hCG, FSH, and LH. Specific number of samples not provided.
- High Dose Hook Effect: Serial dilutions of a very high TSH sample. Specific number of samples not provided.
- Method Comparison: Sample Range of 0.008 – 148.8 µIU/mL. (Exact number of samples not provided).
- Serum Plasma Matrix Equivalency: Sample Range of 0.014 – 134.5 µIU/mL for both lithium heparin and EDTA plasma vs. serum. (Exact number of samples not provided).
- Expected Values:
- Infants (01 - 23 months): N = 46
- Children (02 - 12 years): N = 136
- Adolescents (13 - 20 years): N = 160
- Adults (≥ 21 years): N = 155
Data Provenance: The document does not explicitly state the country of origin of the data or whether it was retrospective or prospective. It refers to "human serum and plasma" samples and "patient samples," suggesting clinical samples were used.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
This type of immunoassay device measures a quantitative biomarker. The "ground truth" for each sample is typically the concentration of TSH in that sample, as measured by a highly accurate and precise reference method or an existing, validated device. Therefore, the concept of "experts" to establish ground truth in the way it's used for AI image analysis (e.g., radiologists interpreting images) is not directly applicable here. The ground truth for method comparison studies is the measurement from the predicate device (ADVIA Centaur TSH3 Ultra assay).
4. Adjudication Method for the Test Set:
Not applicable in the context of quantitative laboratory assays. The "ground truth" values are instrumental measurements, not subjective interpretations requiring adjudication.
5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study:
No, an MRMC comparative effectiveness study was not done. This type of study is relevant for diagnostic imaging devices where human readers interpret cases, and the AI's effect on their performance is evaluated. For this TSH assay, the comparison is directly between the new device's readings and a predicate device's readings.
6. Standalone Performance:
Yes, a standalone performance was done. All the performance characteristics listed (detection limits, linearity, precision, interference, cross-reactivity, high dose hook effect, serum plasma matrix equivalency, expected values, stability) evaluate the algorithm's performance independent of human intervention once the sample is loaded into the automated system. The "method comparison" also compares the new device's standalone measurements directly against those of the predicate device.
7. Type of Ground Truth Used:
- Quantitative measurements: For most performance characteristics, the ground truth is implicitly defined by highly accurate and precise laboratory methods or reference materials.
- Predicate device measurements: For the method comparison study, the "ground truth" against which the new device's performance was compared was the measurements obtained from the legally marketed ADVIA Centaur TSH3 Ultra assay.
8. Sample Size for the Training Set:
This document does not specify a separate "training set" in the context of machine learning. For traditional immunoassay development, methods are developed and validated using various samples to establish performance characteristics. The document describes several testing phases:
- Detection Limits, Linearity, Precision, Interference, Cross-reactivity, High Dose Hook Effect: These involve testing across various samples and conditions to characterize the assay's fundamental performance.
- Expected Values: Human populations are tested (Infants N=46, Children N=136, Adolescents N=160, Adults N=155) to establish reference ranges.
- Method Comparison: Samples covering a range from 0.008 – 148.8 µIU/mL were used for comparison against the predicate.
While these tests inform the overall validation, they are not typically referred to as "training sets" in the AI sense. The assay principle is a fixed chemical reaction, not a machine learning model that "learns" from data.
9. How the Ground Truth for the Training Set Was Established:
As there isn't a traditional "training set" for a machine learning algorithm, this question isn't directly applicable. For the performance characteristics, the "ground truth" is established as follows:
- Reference Methods/Materials: For limits and linearity, the "true" concentrations are often derived from highly controlled preparations or validated reference materials.
- Predicate Device: For method comparison, the results from the previously cleared predicate device (ADVIA Centaur TSH3 Ultra assay) serve as the comparative "ground truth."
- Standardization to WHO International Standard: The TSH assay and calibrators are stated to be traceable to the World Health Organization (WHO) 3rd International standard for human TSH (IRP 81/565), which acts as a primary ground truth for TSH measurement comparability.
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