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The TSHL method is an in vitro diagnostic test for the quantitative measurement of Thyroid Stimulating Hormone (TSH, thyrotropin) in human serum and plasma on the Dimension® EXL™ integrated chemistry system with LOCI® Module. Measurements of TSH are used in the diagnosis and monitoring of thyroid disease.

The FT4L method is an in vitro diagnostic test for the quantitative measurement of Free Thyroxine in human serum and plasma on the Dimension® EXL™ integrated chemistry system with LOCI® Module. Measurements of free thyroxine are used in the diagnosis and monitoring of thyroid disease.

The Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL) and Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L) assays were cleared under K081074 and K073604, respectively. The components of the cleared assays were modified to reduce biotin interference.

The modified Assays are comprised of the following components:

Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL): prepackaged liquid reagents in a plastic eight-well cartridge. Wells 1-2 contain Biotinylated TSH antibody (7.5 µg/mL mouse monoclonal), wells 3-4 contain TSH antibody coated Chemibeads (200 µg/mL mouse monoclonal), and wells 5-6 contain Streptavidin Sensibeads (1400 µg/mL recombinant E. coli). Wells 1-6 contain buffers, stabilizers and preservatives. Wells 7-8 are empty.

Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L): prepackaged liquid reagents in a plastic eight-well cartridge. Wells 1-2 contain Streptavidin Sensibeads (225 µg/mL recombinant E. coli), wells 3-4 contain T3 Chemibeads (200 µg/mL), and wells 5-6 contain FT4 Biotinylated antibody (50 ng/mL mouse monoclonal). Wells 1-6 contain buffers, stabilizers and preservatives. Wells 7-8 are empty.

Test Principle: Both devices use a homogeneous chemiluminescent immunoassay based on LOCI® technology.
For TSHL, it's a sandwich immunoassay where sample is incubated with biotinylated antibody and Chemibeads to form bead-TSH-biotinylated antibody sandwiches. Sensibeads are added and bind to the biotin to form bead-pair immunocomplexes. Illumination at 680 nm generates singlet oxygen from Sensibeads which diffuses into Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direct function of TSH concentration.
For FT4L, it's a sequential immunoassay where sample is incubated with biotinylated antibody. T3 Chemibeads are added and form bead/biotinylated antibody immunocomplexes with the non-saturated fraction of the biotinylated antibody. Sensibeads are then added and bind to the biotin to form bead pair immunocomplexes. Illumination at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is an inverse function of FT4 concentration.

The document provided is a 510(k) clearance letter from the FDA for two in-vitro diagnostic (IVD) devices: Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL) and Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L). It describes the devices, their intended use, and the performance characteristics tested to demonstrate substantial equivalence to previously cleared predicate devices.

However, it's crucial to understand that this document describes a reagent cartridge, which is a laboratory assay, not an AI/ML-driven device or an imaging device. Therefore, many of the requested criteria (e.g., sample size for training/test sets for AI, data provenance like country of origin for AI, ground truth establishment by experts, adjudication methods, MRMC studies, standalone AI performance) are not applicable to this type of device. The document details the performance of the assay itself in measuring biomarker concentrations, not an AI's ability to interpret images or assist human readers.

I will interpret the request based on the information provided for this specific IVD device, noting where certain requested details are not relevant to the nature of the device.

Acceptance Criteria and Study to Prove Device Meets Criteria (for an IVD Reagent Cartridge)

The device in question, a reagent cartridge for quantitative measurement of TSH and FT4, is a laboratory assay, not an AI/ML or imaging interpretation device. Therefore, the "acceptance criteria" and "study" are focused on analytical performance characteristics (accuracy, precision, linearity, interference, detection limits, etc.) compared to a predicate device, rather than diagnostic accuracy metrics of an AI.

1. Table of Acceptance Criteria and Reported Device Performance

For an IVD reagent cartridge, "acceptance criteria" are typically defined by ranges, limits, or statistical agreementsdemonstrating analytical performance comparable or superior to the predicate device and meeting relevant clinical or analytical standards (e.g., CLSI guidelines). The reported performance demonstrates that the modified devices meet these standards.

2. Sample Sizes and Data Provenance for the Test Set

The concept of a "test set" in the context of an IVD reagent cartridge refers to the set of samples used for various analytical performance studies. These are not typically split into "training" and "test" sets as in AI/ML.

• Method Comparison:
  • TSHL: 145 patient samples (serum)
  • FT4L: 146 patient samples (serum)
• Precision (Repeatability): 5 serum samples (TSHL), 3 serum samples (FT4L)
• Precision (Reproducibility): 5 serum samples (TSHL), 3 serum samples (FT4L)
• Linearity: Low and high human serum pools used to create dilution series (TSHL: 12 levels, FT4L: 10 levels)
• Interference (Biotin and HIL): Samples spiked with interferents, specific TSH/FT4 levels tested.
• Dilution Recovery: 7 samples (TSHL)
• Reference Range Verification: "Apparently healthy samples" (specific N not provided, but typically a statistically significant number for verification per CLSI EP28-A3C).
• Matrix Comparison: Samples of various tube types (Serum, lithium heparin, sodium heparin, K2-EDTA plasma)

Data Provenance: The document does not specify the country of origin of the patient samples. The studies are explicitly described as analytical performance studies rather than clinical outcome studies, and they are retrospective (samples tested in the lab, not followed prospectively).

3. Number of Experts and Qualifications for Ground Truth

This is not applicable as the device is a quantitative IVD assay (reagent cartridge), not an AI/ML device requiring expert interpretation of complex clinical data or images. The "ground truth" for this device is the actual concentration of TSH or FT4 in the sample, typically established either by:

• Reference methods (e.g., mass spectrometry, although not explicitly stated as the ground truth method here).
• The predicate device itself (as used in method comparison studies, where the predicate is the "comparison assay").
• Spiking known concentrations into matrices.

4. Adjudication Method for the Test Set

This is not applicable for a quantitative IVD reagent. Adjudication methods (e.g., 2+1, 3+1) are typically used in scenarios where human experts interpret data (like medical images), and their disagreements need to be resolved to establish a definitive ground truth for AI model evaluation.

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

This is not applicable. An MRMC study is designed to evaluate the diagnostic performance of human readers, often with and without AI assistance, on a set of cases. This device is a reagent cartridge that provides a quantitative measurement, not an AI that assists human interpretation.

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

This is not applicable. This device is a reagent cartridge that runs on an automated system, providing a quantitative result. It's inherently "standalone" in providing the measurement, but it's not an "algorithm only" in the sense of an AI interpreting complex data. The performance metrics listed (precision, accuracy relative to predicate, linearity, etc.) are its "standalone" performance.

7. Type of Ground Truth Used

The "ground truth" for this type of quantitative diagnostic test is based on:

• Comparison to a legally marketed predicate device: The current, FDA-cleared versions of the TSHL and FT4L assays (K081074 and K073604) acted as the "gold standard" or comparison method for the method comparison studies.
• Known concentrations: For linearity, recovery, and interference studies, samples were prepared with known concentrations or spiked with known amounts of analytes or interferents.
• Analytically verified samples: Samples used for precision studies have mean values derived from repeated measurements.

8. Sample Size for the Training Set

This is not applicable as the device is a non-AI/ML IVD reagent cartridge. There is no concept of a "training set" for this type of product. The development and optimization of the reagent formulation are internal processes, but they don't involve "training" a model on a dataset in the AI sense.

9. How Ground Truth for the Training Set Was Established

This is not applicable for the same reason as point 8.

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The Maverick Test Panel A0.B0 is an immunoassay for the quantitative determination of human thyroid stimulating hormone (thyrotropin, TSH) in human serum and K2EDTA plasma on the Maverick Diagnostic System TC1000. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

The Maverick Diagnostic System TC1000 is an automated immunoassay analyzer intended for in vitro diagnostic use to determine analytes in a clinical laboratory. The system's assay applications utilize silicon photonics technology.

The Maverick Diagnostic System TC1000 is an automated immunoassay analyzer intended for in vitro diagnostic use to determine analytes in a clinical laboratory. The system's assay applications utilize silicon photonics technology. The Maverick Test Panel A0.B0 is an immunoassay for the quantitative determination of human thyroid stimulating hormone (thyrotropin, TSH) in human serum and K2EDTA plasma on the Maverick Diagnostic System TC1000.

The provided text is an FDA 510(k) clearance letter for an in vitro diagnostic (IVD) device, specifically the Maverick Diagnostic System TC1000 and Maverick Test Panel A0.B0, which is an immunoassay for quantitative determination of human thyroid stimulating hormone (TSH).

Therefore, the concepts of "AI models," "human readers," "radiologists," "MRMC studies," "effect size," and establishing "ground truth for test/training sets by expert consensus/pathology/outcomes data" are not applicable to this type of device and its clearance process.

The FDA clearance for this IVD device is based on demonstrating substantial equivalence to a legally marketed predicate device. This typically involves performance studies (e.g., analytical performance, clinical performance) to show the new device performs as intended and is as safe and effective as the predicate. The "acceptance criteria" and "study that proves the device meets the acceptance criteria" for an IVD device like this would revolve around its analytical and clinical performance characteristics, not AI model metrics or reader studies.

Since the prompt's requested information format is tailored for an AI/CADe (Computer-Assisted Detection/Diagnosis) device, and the provided document describes an IVD device, directly answering the prompt's specific points (1-9) is not possible based on the text. The text does not contain information about AI model performance, human reader studies, or how a "ground truth" for an image-based AI would be established.

To address the spirit of the prompt, had this been an AI/CADe device, and assuming the information was present, here's how a response might look. However, it's crucial to reiterate that this specific document is not for such a device.

(Hypothetical response if the document were about an AI/CADe device, assuming the information was present within the document)

Disclaimer: The provided document is an FDA 510(k) clearance for an In Vitro Diagnostic (IVD) device (Maverick Diagnostic System TC1000 for TSH immunoassay), not an AI/CADe medical device. Therefore, the specific details requested in the prompt, such as AI model performance, expert interpretation of images, MRMC studies, or training/test set ground truth establishment for an AI, are not applicable to the content of this document. The following sections are provided as an example of how the prompt would be answered if the document were for an AI/CADe device and contained the relevant information, but the information below is NOT derived from the provided text.

(Hypothetical/Illustrative Answer - NOT based on the provided document)

(1) A table of acceptance criteria and the reported device performance

(2) Sample size used for the test set and the data provenance

• Test Set Sample Size: 500 cases (e.g., 250 positive for Condition A, 250 negative).
• Data Provenance: Retrospectively collected data from multiple institutions across the United States, Germany, and Japan.

(3) Number of experts used to establish the ground truth for the test set and the qualifications of those experts

• Number of Experts: 3 independent expert readers.
• Qualifications of Experts: Each expert was a board-certified Radiologist with at least 10 years of experience specializing in the relevant imaging modality (e.g., thoracic imaging for lung nodules, breast imaging for mammography).

(4) Adjudication method for the test set

• Adjudication Method: 2+1 adjudication. If at least 2 of the 3 initial expert readers agreed on the ground truth, that was considered the consensus. If there was a disagreement (e.g., 1 agreed, 2 disagreed; or all 3 disagreed), a fourth, highly experienced senior expert (or an expert panel) performed a final review and adjudication.

(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

• MRMC Study Status: Yes, an MRMC comparative effectiveness study was conducted.
• Effect Size of Improvement: The study demonstrated a statistically significant improvement in reader performance (e.g., AUC). Human readers assisted by the AI model showed a mean increase of 0.05 in AUC (from 0.85 without AI to 0.90 with AI assistance) when interpreting cases for Condition A, compared to their performance without AI assistance. This corresponded to a reduction in diagnostic error rate of 15%.

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

• Standalone Performance: Yes, standalone performance was evaluated. The algorithm's standalone AUC for Condition A was 0.915.

(7) The type of ground truth used

• Type of Ground Truth: Expert consensus with confirmation by pathology for positive cases of Condition A. Negative cases were confirmed through follow-up imaging and clinical outcomes over a specified period.

(8) The sample size for the training set

• Training Set Sample Size: 10,000 cases.

(9) How the ground truth for the training set was established

• Training Ground Truth Establishment: The ground truth for the training set was primarily established by a single expert radiologist's initial review, followed by confirmation from a second expert. Cases with disagreement were reviewed by a third, senior expert to reach consensus. A subset of cases (e.g., 20%) had pathology confirmation available. Automated labeling techniques, where feasible and validated, were also used to augment the manually reviewed data.

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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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The Atellica® CI Analyzer is an automated, integrated system in vitro diagnostic tests on clinical specimens. The system is intended for the qualitative analysis of various body fluids, using photometry, turbidimetric, chemiluminescent, and integrated ionselective electrode technology for clinical use.

The Atellica® IM Thyroid Stimulating Hormone 3-Ultra (TSH3-UL) 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 Atellica® CI Analyzer. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

The Atellica® CH Albumin BCP (AlbP) assay is for in vitro diagnostic use in the quantitative measurement of albumin in human serum and plasma (lithium heparin, potassum EDTA) using the Atellica® CI Analyzer. Albumin measurements are used in the diagnosis and treatment of numerous diseases primarily involving the liver or kidneys.

The Atellica® CI Analyzer is an automated, integrated system designed to perform in vitro diagnostic tests on clinical specimens. The system is intended for the qualitative and quantitative analysis of various body fluids, using photometric, turbidimetric, chemiluminescent, and integrated ionselective electrode technology for clinical use.

The Atellica CI Analyzer with Atellica® Rack Handler supports both clinical chemistry (CH) and Immunoassay (IM) features and contains all the necessary hardware, electronics, and software to automatically process samples and generate results, including sample and reagent dispensing, mixing, and incubating.

The Atellica IM TSH3-UL 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 Atellica CH Albumin BCP (AlbP) assay is an adaptation of the bromocresol purple dy-e binding method reported by Carter and Louderback et al. In the Atellica CH AlbP assay, serum or plasma albumin quantitatively binds to BCP to form an albumin-BCP complex that is measured as an endpoint reaction at 596/694 nm coenzyme NAD+ functions only with the bacterial (Leuconostoc mesenteroides) enzyme employed in the assay.

The document provided is a 510(k) summary for in vitro diagnostic devices (IVDs), specifically the Atellica® CI Analyzer and its associated assays for Thyroid Stimulating Hormone (TSH3-UL) and Albumin (AlbP). IVDs, by their nature, measure specific analytes in biological samples and are evaluated against performance criteria such as precision, accuracy, linearity, and interference, rather than diagnostic accuracy metrics like sensitivity and specificity that would typically apply to AI/ML software. Therefore, many of the requested elements pertaining to AI/ML acceptance criteria and human-in-the-loop studies are not applicable to this type of device.

Here's a breakdown of the relevant information provided:

1. A table of acceptance criteria and the reported device performance:

The document describes the performance characteristics for the Atellica IM Thyroid Stimulating Hormone 3-Ultra (TSH3-UL) assay and the Atellica CH Albumin BCP (AlbP) assay. These are performance criteria, which serve as the acceptance criteria for the device's analytical performance.

Atellica IM Thyroid Stimulating Hormone 3-Ultra (TSH3-UL) Assay:

Atellica CH Albumin BCP (AlbP) Assay:

2. Sample sizes used for the test set and the data provenance:

• TSH3-UL Assay:
  • Precision: 80 samples for each type (Serum A-F, EDTA Plasma A-C, Heparin Plasma A-C, Control 1-3).
  • Assay Comparison (Serum): 112 samples.
  • Interferences (Specific substances): Not explicitly stated how many samples per substance, but concentrations tested at two analyte levels.
  • Specimen Equivalency: 64 samples for Plasma (Lithium heparin) and 64 for Plasma (EDTA).
  • Onboard Dilution Recovery: 3 samples (Serum and Plasma) tested at two dilution levels.
  • Linearity: Not explicitly stated, but "at least 14 levels created by mixing high and low serum samples" with N=5 replicates per level.
• AlbP Assay:
  • LoD: 486 determinations (270 blank, 216 low level replicates).
  • LoQ: n=5 replicates using 3 reagent lots over 5 days.
  • Precision: N ≥ 80 for each sample (Serum 1-3, Serum QC 1).
  • Reproducibility: 225 samples for each serum level (assayed n=5 in 1 run for 5 days using 3 instruments and 3 reagent lots).
  • Assay Comparison (Serum): 106 samples.
  • Specimen Equivalency: 76 samples for Plasma (Lithium heparin) and 55 for Plasma (Potassium EDTA).
  • HIL: Not explicitly stated how many samples per interferent, but concentrations tested at two analyte levels.
  • Non-Interfering Substances: Not explicitly stated how many samples per substance, but tested at two analyte concentrations.
  • Linearity: "at least nine levels created by mixing the high and low pools of serum" with N=5 replicates per level.

Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given it's a 510(k) submission for a medical device intended for broad use, it's highly likely the studies were prospective analytical validation studies conducted under controlled laboratory conditions, typically in multiple sites to ensure robustness.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience):

This information is not applicable to this type of device. The "ground truth" for clinical laboratory assays like TSH and Albumin comes from established analytical methods, reference materials, and accepted scientific principles of chemistry and immunology. It's about measuring the concentration of an analyte, not interpreting an image or diagnosing a condition based on expert consensus. The "experts" involved would be clinical chemists, laboratory scientists, and engineers responsible for assay development and validation, following established guidelines like those from CLSI (Clinical and Laboratory Standards Institute).

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

This is not applicable for this type of device. Adjudication methods are used in studies involving subjective interpretations (e.g., image reading) where multiple readers provide opinions that need to be reconciled to establish ground truth. For quantitative chemical assays, the "truth" is determined by reference methods and the intrinsic properties of the analyte, not by human consensus or adjudication.

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:

This is not applicable. An MRMC study is designed for evaluating the impact of a system on human readers' diagnostic performance, typically in the context of imaging. This document describes an automated in vitro diagnostic analyzer and its assays, which do not involve human "readers" in the sense of interpreting outputs like medical images.

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

The performance characteristics presented (precision, linearity, assay comparison, interference, etc.) represent the standalone performance of the device and its assays. The Atellica® CI Analyzer and its assays are automated systems designed to perform measurements without human interpretative input beyond setting up the instrument and following standard laboratory procedures for running samples and quality control.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

The ground truth for these quantitative assays is established through:

• Reference Methods / Comparability: The performance is evaluated by comparing the new device's results to a legally marketed predicate device (Siemens Trinidad systems) which serve as the reference. This establishes the equivalence of the new device to already accepted technology.
• Traceability to International Standards: For TSH3-UL, traceability is to the World Health Organization (WHO) 3rd International Standard for human TSH (IRP 81/565). For AlbP, traceability is to ERM-DA470k Reference Material. These international standards or reference materials provide the "true" or accepted values against which the device's measurements are calibrated and verified.
• Analytical Procedures: The "ground truth" for characteristics like limit of detection, precision, and linearity are determined by rigorous statistical methods and established protocols (e.g., CLSI guidelines EP05-A3, EP07-ed3, EP09c-ed3, EP17-A2, EP06-ED2) during analytical validation.

8. The sample size for the training set:

This information is not applicable in the context of an IVD where "training set" implies machine learning or AI model development. For an IVD, there is a development and validation process. The number of samples for analytical validation studies (which is what is presented) is given under point 2.

9. How the ground truth for the training set was established:

As this is not an AI/ML device, the concept of a "training set" for an algorithm and its associated ground truth establishment methods (e.g., expert annotations) are not applicable. The "ground truth" or reference for the development and validation of these IVD assays is based on established laboratory practices, chemical principles, certified reference materials, and comparison to predicate devices, as described in point 7.

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The Access TSH (3rd IS) assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of human thyroid-stimulating hormone (thyrotropin, TSH, hTSH) levels in human serum and plasma using the Access Immunoassay Systems. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders. This assay is capable of providing 3rd generation TSH results.

The DxI 9000 Access Immunoassay Analyzer is an in vitro diagnostic device used for the quantitative, semiquantitative, or qualitative determination of various analyte concentrations found in human body fluids.

Access TSH (3rd IS) assay is a two-site immunoenzymatic ("sandwich") assay. The Access TSH (3rd IS) reagent kit is in a liquid ready-to-use format designed for optimal performance on Beckman Coulter's immunoassay analyzers. Each reagent kit contains two reagent packs. Other items needed to run the assay include substrate, calibrators and wash buffer.

The Dxl 9000 Access Immunoassay Analyzer is a fully automated, continuous, random-access sample processing and analysis instrument. The Dxl 9000 Access Immunoassay Analyzer uses enzyme immunoassays (utilizing paramagnetic particle solid phase and chemiluminescent detection) for the quantitative, semi-quantitative or qualitative determination of various analyte concentrations found in human body fluids.

The provided text describes the performance of the Access TSH (3rd IS) Assay on the DxI 9000 Access Immunoassay Analyzer. This is an in vitro diagnostic device, and the detailed information typically provided for AI/ML devices regarding ground truth establishment, expert qualifications, and MRMC studies is not directly applicable to this type of device.

Here's a breakdown based on the information available:

1. A table of acceptance criteria and the reported device performance

• %CV ranged from 2.5% to 4.5%.
  For TSH concentrations ≤ 0.02 µlU/mL:
• SD ranged from 0.0007 to 0.0014.
  (Detailed table with specific sample means and SD/CV values provided in the text) |
  | Reproducibility | SD ≤ 0.0038 for values ≤ 0.02 ulU/mL
  CV 0.02 ulU/mL | For values ≤ 0.02 ulU/mL (Sample 1, mean 0.024): Overall Reproducibility SD = 0.0010 (meets criteria)
  For values > 0.02 ulU/mL:
• Sample 2 (mean 0.37): Reproducibility CV = 4.3% (meets criteria)
• Sample 3 (mean 4.8): Reproducibility CV = 3.7% (meets criteria)
• Sample 5 (mean 12): Reproducibility CV = 3.8% (meets criteria)
• Sample 4 (mean 46): Reproducibility CV = 3.4% (meets criteria) |
  | Linearity | Not explicitly stated as a numerical criterion, but implies demonstration of accuracy across the measuring range. | Linear throughout the analytical measuring interval of approximately 0.01 - 50.0 µIU/mL (mIU/L). |
  | Limit of Blank (LoB)| Not explicitly stated as a numerical criterion, but implies a low detection threshold. | 0.002 µIU/mL |
  | Limit of Detection (LoD)| Not explicitly stated as a numerical criterion, but implies a low detection threshold. | 0.003 µIU/mL |
  | Limit of Quantitation (LoQ)| LoQ must be greater than or equal to LoD. | Maximum LoQ determined was 0.001 µlU/mL, but reported as 0.003 µIU/mL to align with LoD, following CLSI EP17-A2 recommendation. |

2. Sample size used for the test set and the data provenance

• Method Comparison Test Set: 111 serum samples.
• Imprecision Test Set: 80 replicates per sample level across multiple runs/days.
• Reproducibility Test Set: 75 replicates per sample level.
• Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective). Given it's an in vitro diagnostic device, these samples are typically laboratory-generated or clinical samples collected for analytical validation.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

This information is not applicable to the analytical performance studies conducted for this in vitro diagnostic device. The "ground truth" for these studies is established by the reference method (the predicate device for method comparison) or by known concentrations/spikes for other performance characteristics like linearity, LoB, LoD, LoQ, and imprecision.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

Not applicable. Adjudication methods are typically used in clinical studies or for subjective interpretations of results, not for the analytical performance of an immunoassay system where quantitative measurements are directly compared.

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 device is an automated immunoassay analyzer, not an AI-assisted diagnostic tool that requires human interpretation or aids human readers.

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

Yes, the studies presented as "Summary of studies" directly represent the standalone performance of the Access TSH (3rd IS) Assay on the DxI 9000 Access Immunoassay Analyzer. The device is an automated system, and its performance is evaluated directly without human interpretation in the analytical process.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

• Method Comparison: The predicate device, Access TSH (3rd IS) Assay on UniCel DxI 800 Immunoassay System (K153651), served as the reference or "ground truth" for comparative performance.
• Imprecision, Reproducibility, Linearity, LoB, LoD, LoQ: "Ground truth" is established by the study design, using known concentrations, spiked samples, or statistical methods (e.g., CLSI guidelines) to define true values and assess the device's ability to measure them accurately and precisely.

8. The sample size for the training set

Not applicable. This is not an AI/ML device that requires a training set in the typical sense. Its performance is based on the inherent analytical characteristics of the reagents and instrumentation.

9. How the ground truth for the training set was established

Not applicable, as there is no "training set" in the context of an AI/ML algorithm.

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cobas pure integrated solutions is an automated analyzer, intended for running qualitative, semiguantitative and quantitative clinical chemistry and immunochemistry assays as well as ion selective measurements.

Glucose HK Gen.3 is an in vitro test for the quantitative determination of glucose in human serum, plasma, urine and CSF on Roche/Hitachi cobas c systems. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoqlycemia, idiopathic hypoglycemia and pancreatic islet cell tumors.

The ISE analytical unit of the Roche/Hitachi cobas c systems is intended for the quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. Sodium measurements are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of large amounts of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance.

Methadone II (MDN2) is an in vitro diagnostic test for the qualitative and semiquantitative detection of methadone in human urine on Roche/Hitachi cobas c systems at a cutoff concentration of 300 ng/mL. Semiquantitative test results may be obtained that permit laboratories to assess assay performance as part of a quality control program. Semiquantitative assays are intended to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as gas chromatography/mass spectrometry (GC-MS).

Elecsys TSH is an immunoassay for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid and pituitary disorders. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The cobas pure integrated solutions is a fully automated, random-access, software controlled system intended for in vitro quantitative and qualitative analysis of analytes in body fluids. It will typically be used in low to mid throughput clinical laboratories. The system consolidates clinical chemistry, homogenous immunoassays as well as electrolyte testing within one workplace. The cobas pure integrated solutions consists of a clinical chemistry analytical unit (cobas c 303) with an integrated ISE analytical unit, an immunoassay analytical unit (cobas e 402) and a core unit.

Glucose is phosphorylated by hexokinase (HK) in the presence of adenosine triphosphate (ATP) and magnesium ions to produce glucose-6-phosphate (G-6-P) and adenosine diphosphate (ADP). Glucose-6-phosphate dehydrogenase (G-6-PDH) specifically oxidizes G-6-P to 6-phosphogluconate with the concurrent reduction of nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide reduced (NADH). One micromole of NADH is produced for each micromole of glucose consumed. The NADH produced absorbs light at 340 nm and can be detected spectrophotometrically as an increased absorbance.

The ISE analytical unit for Na+ employs ion-selective membrane to develop an electrical potential (electromotive force, EMF) for the measurements of ions in solution. Selective membrane is in contact with both the test solution and an internal filling solution. Due to the selectivity of the membrane, only the ions to be EMF. The membrane EMF is determined by the difference in concentration of the test ion in the test solution and the internal filling solution.

The ISE analytical unit of the Roche/Hitachi cobas c systems is intended for the quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. Sodium is the major extracellular cation and functions to maintain fluid distribution and osmotic pressure. Some causes of decreased levels of sodium include prolonged vomiting or diarrhed reabsorption in the kidney and excessive fluid retention. Common causes of include excessive fluid loss, high salt intake and increased kidney reabsorption.

The Methadone assay is based on the kinetic interaction of microparticles in a solution (KIMS) as measured by changes in light transmission. In the absence of sample drug conjugates bind to antibody-bound microparticles, causing the formation of particle aggregates. As the aggregation reaction proceeds in the absence of sample drug, the absorbance increases.

When a urine sample contains the drug in question, this drug derivative conjugate for microparticle-bound antibody. Antibody bound to sample drug is no longer available to promote particle aggregation, and subsequent particle lattice formation is inhibited. The presence of sample drug diminishes the increasing absorbance in proportion to the concentration of drug in the sample. Sample drug content is determined relative to the value obtained for a known cutoff concentration of drug.

The Elecsys TSH immunoassay makes use of a sandwich test principle using monoclonal antibodies specifically directed against human TSH. The antibodies labeled with ruthenium complex) construct from human and mouse specific components. Elecsys TSH immunoassay 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 and pituitary disorders. It is intended for use on the cobas e immunoassay analyzers.

The provided text describes several in vitro diagnostic (IVD) devices and their performance characteristics. It outlines how Roche Diagnostics established the substantial equivalence of these devices (Glucose HK Gen.3, ISE indirect Na for Gen.2, ONLINE DAT Methadone II, Elecsys TSH, and the cobas pure integrated solutions analyzer) to their predicate devices through various non-clinical tests.

However, the document does not provide a table of acceptance criteria and reported device performance in a format that easily allows for direct comparison against specific numeric targets. Instead, it describes general study types and states that the "analytical performance data for all representative assays meet specifications and support the substantial equivalence."

Furthermore, it does not explicitly detail the following requested information:

• Sample sizes used for the test set and data provenance: The document mentions "human serum, plasma, urine and CSF" as sample types but not explicit test set sample numbers or their country of origin for most tests. It generally refers to "human samples" or "pooled human plasma and serum samples."
• Number of experts used to establish the ground truth for the test set and their qualifications: This information is not present for any of the described tests. The ground truth for these IVDs is typically established through reference methods or established control materials, not expert consensus on individual cases.
• Adjudication method: Not applicable/provided as the tests are analytical and do not involve human interpretation requiring adjudication.
• Multi Reader Multi Case (MRMC) comparative effectiveness study: Not applicable, as these are IVD assays, not AI-assisted reader studies.
• Standalone performance: The entire document describes the standalone performance of the algorithms/assays.
• Type of ground truth used: For quantitative assays (Glucose, Sodium, TSH), the ground truth is implicitly based on established reference methods or known concentrations in control materials. For qualitative/semi-quantitative assays like Methadone, it's based on known concentrations relative to a cutoff or confirmed by methods like GC-MS.
• Sample size for the training set: Not explicitly stated, as these are typically not machine learning models in the sense of needing a distinct "training set" for classification, but rather reagents and analytical systems whose performance is validated. The mentioned "study" refers to validation studies, not AI model training.
• How the ground truth for the training set was established: Not applicable, as explained above.

Given the nature of the document, which focuses on device-specific analytical performance claims rather than AI model validation, several of the requested categories are not directly addressed or are not relevant.

Below is an attempt to structure the available information, noting the limitations.

1. Table of Acceptance Criteria and Reported Device Performance

As specific numerical acceptance criteria (e.g., "sensitivity ≥ 95%") are not explicitly provided in the text, this table will summarize what types of performance were evaluated and that they met specifications as stated in the document.

Overall Conclusion for all devices: "The analytical performance data for all representative assays meet specifications and support the substantial equivalence...to the predicate devices."

2. Sample sizes used for the test set and the data provenance

• Glucose HK Gen.3:
  • Precision studies: "Two aliquots per run, two runs per day for ≥ 21 days". Types of samples (e.g., patient, control) not specified, but typically human-derived.
  • Linearity, LoB, LoD, LoQ, Interference, Matrix Comparison, Post Dilution Check, Recovery in Controls: Sample numbers or types of samples for these specific studies are not detailed.
  • Method Comparison: "all sample types" (e.g., human serum, plasma, urine, CSF) tested between cobas c 303 and cobas c 503.
  • Data Provenance: Not specified (e.g., country of origin, retrospective/prospective).
• ISE indirect Na for Gen.2:
  • Precision studies: "One run per day for ≥ 21 days with two parts, two aliquots per part". Typically human-derived samples.
  • Endogenous Interference: "pooled human plasma and serum samples spiked with varying levels of interferent."
  • Linearity, LoB, LoD, LoQ, Drug Interference, Calibration Frequency, Post Dilution Check, Recovery in Controls: Sample numbers or specific types of samples not detailed.
  • Method Comparison: "all sample types" (e.g., human serum, plasma, urine) tested.
  • Data Provenance: Not specified.
• ONLINE DAT Methadone II:
  • Precision: "human samples and controls" (n=84 for repeatability, with 2 aliquots per run, 2 runs per day, 21 days for intermediate precision).
  • Endogenous Interference: "urine containing methadone" and "pooled human urine".
  • Drug Interference: "human urine containing methadone".
  • Cross Reactivity: Details not given, but likely spiked drug solutions into human urine.
  • Method Comparison: Urine samples compared against GC-MS and cobas c 503.
  • Data Provenance: Not specified.
• Elecsys TSH:
  • Precision: Likely control materials and potentially patient samples.
  • Endogenous Interfering Substances: "human serum samples (native serum pools)".
  • Cross-reacting Compounds: "native human serum sample pool".
  • Anticoagulants Effect: "native human serum samples, single donors as well as pools" drawn into various tubes.
  • Linearity, LoB, LoD, LoQ, Drug Interference, On-board Reagent Stability, High-dose Hook Effect: Sample numbers or types not specified.
  • Method Comparison: Human serum and plasma samples compared between cobas e 402 and cobas e 801.
  • Data Provenance: Not specified.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

Not applicable. For in vitro diagnostic assays, "ground truth" is established through analytical reference methods, defined concentrations of calibrators/standards, or confirmed by other laboratory methods (e.g., GC-MS for Methadone) rather than expert human interpretation of results.

4. Adjudication method

Not applicable. These are analytical tests performed by automated systems; there is no human interpretation or adjudication involved in generating the primary test result.

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 for in vitro diagnostic assays on automated analyzers, not AI-assisted human reader studies. The "AI" would refer to the algorithms within the analytical unit, not a system designed to assist human readers.

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

Yes, the entire document focuses on the standalone performance of the analytical systems and assays. The results are generated directly by the device/analyzer without human intervention for interpretation beyond loading samples and performing quality control.

7. The type of ground truth used

• For Glucose, Sodium, TSH (Quantitative assays): The ground truth for these quantitative measurements is based on reference methods, known concentrations in calibrators and controls, or comparative methods (e.g., flame photometry for sodium, or existing cleared assays on predicate devices).
• For Methadone (Qualitative/Semi-quantitative assay): Ground truth is established by known concentrations relative to a cutoff (e.g., 225 ng/mL for negative control, 375 ng/mL for positive control) and confirmed by a "confirmatory method such as gas chromatography/mass spectrometry (GC-MS)".

8. The sample size for the training set

Not explicitly specified. These are not AI/ML models in the typical sense that require a distinct "training set." The development of reagents and analytical platforms involves extensive R&D and optimization, but the validation studies described here are for demonstrating performance and equivalence, not for "training" an algorithm in a machine learning context.

9. How the ground truth for the training set was established

Not applicable, as a distinct "training set" with established ground truth in the context of machine learning model development is not typically associated with the development and validation of these types of in vitro diagnostic reagents and analyzers. The principles are generally based on established biochemical reactions, electrochemical measurements, or immunoassays.

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The DxA 5000 is a high-speed, modular, automated sample handling system that performs pre-analytical and postanalytical sample processing and storage. The automation system also sorts, routes, and presents sample tubes to analyzers for analysis. The DxA 5000 also consolidates a variety of analytical instruments, such as an Immunoassay analyzer, into a unified workstation on a track system.

The DxI 800 Access Immunoassay System is a microcomputer controlled, random and continuous access analyzer that includes an external computer. This computer stores the system user interface (UI) software and allows the operator to interface with and direct the instrument software. The UniCel DxI 800 System uses enzyme immunoassays (utilizing paramagnetic particle solid phase and chemiluminescent detection) for the quantitative or qualitative or qualitative determination of various analyte concentrations found in human body fluids. The UniCel DxI 800 System is an in vitro diagnostic device for use in the clinical laboratory.

The Access Ferritin assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of ferritin levels in human serum and plasma (heparin) using the Access Immunoassay Systems. Measurements of ferritin aid in the diagnosis of diseases affecting iron metabolism.

The Access Folate assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of folic acid levels in human serum and plasma (heparin) or red blood cells using the Access Immunoassay Systems. Folate levels in serum and plasma (heparin) or red blood cells are used to assess folate status. The serum folate level is an indicator of recent folate intake. A low RBC folate value can indicate a prolonged folate deficiency. Folic acid measurements are used in the diagnosis and treatment of megaloblastic anemia.

The Access TSH (3rd IS) assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of human thyroid-stimulating hormone (thyrotropin, TSH, hTSH) levels in human serum and plasma using the Access Immunoassay Systems. This assay is capable of providing 3rd generation TSH results. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

The Access Vitamin B12 assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of vitamin B12 levels in human serum and plasma (heparin) using the Access Immunoassay Systems. Measurements obtained by this device are used in the diagnosis and treatment of gastrointestinal malabsorption.

The DxA system is a high throughput automated sample handling system which can perform the pre and post analytical processing of sample tubes. DxA can identify and track samples, perform centrifugation, decapping, delivery of samples to connected analyzers, recapping, storing in either non-refrigerated or refrigerated storage, and sorting to output racks.

The DxA integrates perianalytic (pre and post analysis) functions with analytical instruments (Beckman Coulter, and other manufacturer's) via a track system to provide fully integrated testing solutions.

This document focuses on the substantial equivalence of the DxA 5000 automated sample handling system and related immunoassay tests (Ferritin, Folate, TSH, Vitamin B12) to previously cleared devices. It describes engineering performance studies rather than clinical efficacy studies. Therefore, many of the typical clinical study criteria requested (like multi-reader multi-case studies, effect size of human improvement with AI, number of experts for ground truth, sample size for training sets) are not applicable or detailed in this submission.

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

1. A table of acceptance criteria and the reported device performance

The document states that "The acceptance criteria were met for all method comparisons thereby demonstrating the following:"

2. Sample size used for the test set and the data provenance

• Sample Size: The document does not specify the exact sample sizes used for the method comparison studies. It mentions that the studies utilized CLSI EP09, which is a guideline for method comparison and bias estimation using patient samples, but the number of samples is not disclosed.
• Data Provenance: Not specified in the provided text (e.g., country of origin, retrospective/prospective). However, given it's a 510(k) submission for an in vitro diagnostic device, the studies are typically conducted in a controlled laboratory setting, often in a prospective manner or using banked samples that meet specific criteria.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

This information is not applicable and not provided in the document. The acceptance criteria and performance relate to the comparability of the new automation system and immunoassay tests against predicate devices, not against a "ground truth" established by experts for diagnostic accuracy in a clinical setting in the way an AI imaging device might. The "ground truth" here is the performance of the predicate device/system.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

This information is not applicable and not provided. Adjudication methods are typically used in studies where human readers are interpreting data (e.g., medical images) and their interpretations need to be reconciled to establish a consensus ground truth. This is an engineering/analytical performance study for a laboratory automation system and immunoassay tests.

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

This information is not applicable and not provided. MRMC studies are relevant for imaging devices where human readers are involved in the diagnostic process. This document concerns a laboratory automation system and immunoassay tests, not an AI-assisted diagnostic imaging tool.

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

The studies described are for the performance of the integrated system (DxA 5000 connected to the DxI 800 Access Immunoassay System running specific assays). While the system operates largely automatically (an "algorithm only" in the sense that the mechanical and analytical processes are automated), its performance is compared to a human-operated predicate system or another automated system. This is not an "AI algorithm only" study in the context of diagnostic decision support, but rather an automated analytical system comparison.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

The "ground truth" in this context is the performance of the legally marketed predicate devices/systems:

• Power Processor Sample Processing System (K110413) for the DxA 5000's automation features.
• Beckman Coulter UniCel® DxI 800 Access® Immunoassay System (K023764), Access® Ferritin assay (K926221), Access® Folate assay (K060774), Access® HYPER sensitive hTSH assay (K042281), and Access® Vitamin B12 assay (K955436) for the immunoassay performance in conjunction with the automation system.

The study aimed to demonstrate that the new device system yielded results "within specifications" when compared to the predicate, implying the predicate's performance served as the benchmark or "ground truth" for equivalence.

8. The sample size for the training set

This information is not applicable and not provided. This is a 510(k) submission for laboratory equipment and assays, not a machine learning/AI device requiring a "training set" in the computational sense. The "development" for such systems involves rigorous engineering, analytical validation, and verification based on established chemical, biological, and mechanical principles.

9. How the ground truth for the training set was established

This information is not applicable for the reasons stated in point 8.

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The cobas pro integrated solutions is an IVD device used for the quantitation of clinical chemistry and Ion Selective Electrolyte parameters from various biological fluids.

Glucose HK Gen.3 is an in vitro test for the quantitative determination of glucose in human serum, plasma, urine and CSF on Roche/Hitachi cobas c systems. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia and pancreatic islet cell tumors.

The ISE indirect Na for Gen. 2 is intended for the quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. Sodium measurements are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance.

Elecsys TSH immunoassay 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 and pituitary disorders. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The cobas pro integrated solutions (cobas pro) is a fully automated, random-access, software controlled system intended for in vitro quantitative analysis of analytes in body fluids. It will typically be used in clinical laboratories with large workload. The system consolidates clinical chemistry, homogenous and heterogeneous immunoassays as well as electrolyte testing within one workplace. It consists of a high throughput sample distribution unit (core unit) and different analytical units for ISE (cobas pro ISE analytical unit), clinical chemistry (c 503 analytical unit) and immunoassay (e 801 analytical) testing. The system hardware is comprised of new or previously cleared members of the Roche/Hitachi cobas c or Elecsys families of analyzers. The instrument software is unique to the cobas pro and was developed from previous generations of Roche/Hitachi instrument systems.

Here's a breakdown of the acceptance criteria and study information for the cobas pro integrated solutions device, specifically focusing on the Glucose HK Gen.3, ISE indirect Na for Gen.2, and Elecsys TSH assays.

Preamble: This document describes a Traditional 510(k) Premarket Notification for the cobas pro integrated solutions. The core purpose is to show that previously cleared Glucose, Sodium, and TSH assays, when run on the new cobas pro integrated solutions system, are substantially equivalent to their predicate devices. Therefore, the acceptance criteria and studies presented are largely comparative or validation studies demonstrating consistent performance with previously cleared devices and established analytical standards.

1. Table of Acceptance Criteria and Reported Device Performance

Given that this is a 510(k) submission demonstrating substantial equivalence to pre-existing predicate devices for assays and a new integrated system, the acceptance criteria are generally focused on meeting established performance claims or showing equivalence within acceptable statistical limits. The summary provided focuses on the reported device performance which is then implicitly compared to internal acceptance criteria (often relative to the predicate device or CLSI guidelines).

Note on Acceptance Criteria: The document explicitly states "All samples met the predetermined acceptance criterion" for precision studies. For LoQ, it states "LoQ determined at maximum allowable %TE (total error) of no more than 20% (Glucose and TSH) and 30% (Sodium)." For endogenous interference, it was "recovery of 100±10%". For exogenous interference (common drugs for Elecsys TSH), it was "± 10% of the reference value". For method comparisons, the slope, intercept, and correlation coefficients approaching 1 or 0 respectively, indicate strong agreement, satisfying the intent of substantial equivalence. Specific numerical acceptance criteria are not always stated outright but are implied by the study design and conclusion of meeting criteria.

• Serum Repeatability CV: 0.4%-9.2%
• Serum Intermediate Precision CV: 0.5%-10.0%
• Urine Repeatability CV: 0.4%-8.3%
• Urine Intermediate Precision CV: 0.7%-8.5%
• CSF Repeatability CV: 0.4%-3.0%
• CSF Intermediate Precision CV: 0.5%-3.5%
  ISE indirect Na (N=84 per application):
• Plasma Repeatability CV: 0.3%-0.6%
• Plasma Intermediate Precision CV: 0.5%-1.5%
• Serum Repeatability CV: 0.3%-0.5%
• Serum Intermediate Precision CV: 0.5%-1.7%
• Urine Repeatability CV: 0.3%-0.5%
• Urine Intermediate Precision CV: 0.6%-4.8%
  Elecsys TSH (N=84):
• Repeatability CV: 1.6%-6.3%
• Intermediate Precision CV: 2.4%-11.7% |
  | Analytical Sensitivity | LoQ: Total error not more than 20% (Glucose, TSH), 30% (Na). | Glucose HK Gen.3: LoB: 0.2 mg/dL, LoD: 0.4 mg/dL, LoQ: 1.4 mg/dL.
  Claimed: LoB: 2 mg/dL, LoD: 2 mg/dL, LoQ: 2 mg/dL.
  ISE indirect Na: LoB: 3.50 mmol/L, LoD: 4.42-4.51 mmol/L, LoQ: 11.8-12.2 mmol/L.
  Claimed: LoB: 3.5 mmol/L, LoD: 4.5 mmol/L, LoQ: 12.2 mmol/L.
  Elecsys TSH: LoB: 0.0013-0.0015 µIU/mL, LoD: 0.00282-0.00348 µIU/mL, LoQ: 0.00386-0.00495 µIU/mL.
  Claimed: LoB: 0.0025 µIU/mL, LoD: 0.005 µIU/mL, LoQ: 0.005 µIU/mL. |
  | Linearity/Reportable Range | Deviations within predetermined acceptance criteria. | Glucose HK Gen.3: Serum (R2=0.9999), Urine (R2=0.9997), CSF (R2=0.9992) linear in claimed range (2.0-750 mg/dL).
  ISE indirect Na: Plasma (R2=0.9998), Serum (R2=0.9998), Urine (R2=0.9999) linear in claimed range (80-180 mmol/L for S/P, 20-250 mmol/L for U).
  Elecsys TSH: Serum (R2=0.9972) linear in range 0.004-118 uIU/mL. |
  | High Dose Hook Effect | No hook effect observed up to a specified concentration. | Elecsys TSH: No hook effect up to 1466 uIU/mL TSH. |
  | Endogenous Interference | Recovery of 100 ± 10%. | Glucose HK Gen.3: No interference from albumin, bilirubin, hemolysis, IgG, lipemia, etc. at specified high concentrations.
  ISE indirect Na: No interference from bilirubin, hemolysis, lipemia at specified high concentrations.
  Elecsys TSH: No interference from biotin, lipemia, hemoglobin, bilirubin, rheumatoid factor, immunoglobulins at specified high concentrations. |
  | Exogenous Interference (Drugs) | ± 10% of the reference value in comparison to unspiked samples. | ISE indirect Na: No interference from various common and special drugs at specified concentrations.
  Elecsys TSH: No interference from common and special drugs at specified concentrations. |
  | Analytical Specificity/Cross-Reactivity | % cross-reactivity near zero. | Elecsys TSH: hGH, hCG, LH, FSH showed 0.000% cross-reactivity at high tested concentrations. |
  | Method Comparison to Predicate | Strong correlation (slope ≈ 1, intercept ≈ 0, high R/tau values) indicating substantial equivalence to predicate device/reference method. | Glucose HK Gen.3: Slope close to 1.0, intercept close to 0, strong correlation (Pearson r/Kendall tau close to 1) comparing to cobas c 501.
  ISE indirect Na: Slope close to 1.0, intercept close to 0, strong correlation (Pearson r close to 1) comparing to cobas c 501 ISE and Flame Photometer.
  Elecsys TSH: Slope = 1.018 (LCL/UCL: 1.004/1.025), Intercept = -0.0018 µIU/mL (LCL/UCL: -0.0040/-0.0001), Pearson r = 0.999, Kendall tau = 0.977 when compared to predicate Elecsys TSH on cobas 8000. |
  | Sample Matrix Comparison | Acceptable recovery of analyte values and strong correlation between different sample types (e.g., serum vs. various plasma anticoagulants). | Glucose HK Gen.3: Strong correlation (slope near 1, intercept near 0, r near 1) comparing serum to serum tube with separation gel, and various plasma anticoagulants (K2EDTA, Li-Heparin, NaF/K-Oxalate, NaF/Na2-EDTA, NaF/Citrate/Na2-EDTA, KF/Na2-EDTA).
  ISE indirect Na: Strong correlation (Slope = 1.015, Intercept = -2.69, r = 0.998) between Serum and Li-Heparin Plasma.
  Elecsys TSH: Strong correlation (slope near 1, intercept near 0, r near 1) comparing serum to Li-Heparin, K2-EDTA, and K3-EDTA plasma. |
  | Stability | Stability data supports Roche Diagnostic's claims as reported in the package inserts. (Implied: device maintains performance over its claimed shelf life and in-use stability.) | Stability data for Glucose HK Gen.3, ISE indirect Na, and Elecsys TSH was provided in prior 510(k)s (K061048, K060373, and K190773 respectively) and supports the claims. |

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

• Glucose HK Gen.3 (Precision):
  • Sample Size: 84 measurements for each control level (PreciControl ClinChem Multi 1 and 2) and 5 human serum samples per application (serum, urine, CSF). So, for repeatability and intermediate precision, 84 measurements for 2 controls + 5 samples, across serum, urine, and CSF applications.
  • Data Provenance: Human serum, plasma, urine, and CSF samples. These were "native, single donors as well as pools." The study was conducted in-house by Roche Diagnostics (implied by the submission).
• ISE indirect Na (Precision):
  • Sample Size: 84 measurements for each control level (PreciControl ClinChem Multi 1 and 2, Liquichek 1 and 2) and 5 human plasma, serum, and urine samples per application. So, for repeatability and intermediate precision, 84 measurements for controls + 5 samples, across Li-Heparin Plasma, Serum, and Urine.
  • Data Provenance: Human Li-Heparin plasma, serum, and urine samples. These were "native, single donors as well as pools." Conducted in-house by Roche Diagnostics.
• Elecsys TSH (Precision):
  • Sample Size: 84 measurements for each control level (PreciControl Universal, PC Thyro Sensitive) and 5 human serum samples.
  • Data Provenance: Human serum samples. These were "native, single donors as well as pools." Conducted in-house by Roche Diagnostics.
• Analytical Sensitivity (LoB, LoD, LoQ) for all assays:
  • Sample Size:
    • LoB: ≥ 60 measurements of analyte-free samples.
    • LoD: 60 measurements (5 low-analyte concentration samples, measured in duplicate over 6 runs, 3 days).
    • LoQ: ≥ 60 measurements per sample type (samples with low analyte concentration measured over 3 to 5 days).
  • Data Provenance: Not explicitly stated for specific blanks or low-concentration samples beyond "analyte-free" or "low-analyte concentration". Conducted in-house by Roche Diagnostics.
• Linearity/Assay Reportable Range:
  • Glucose HK Gen.3: Three high analyte human serum, urine, and CSF samples diluted to 12 levels.
  • ISE indirect Na: Three high analyte human serum, urine, and CSF samples diluted to multiple aliquot concentrations.
  • Elecsys TSH: Three high analyte human serum samples diluted to concentrations covering the measuring range.
  • Data Provenance: Human serum, urine, CSF samples. Conducted in-house by Roche Diagnostics.
• Endogenous Interference:
  • Glucose HK Gen.3: Plasma and urine samples, glucose levels ~79.5 mg/dL and ~116.3 mg/dL.
  • ISE indirect Na: Human plasma, serum, and urine samples. Low (~124 mmol/L) and high (~151 mmol/L) for S/P; low (26.3 mmol/L) and high (188 mmol/L) for urine.
  • Elecsys TSH: Human serum samples with TSH concentrations ~0.462 uIU/mL, ~3.95 µIU/mL, and ~7.54 µIU/mL.
  • Data Provenance: Human samples. Conducted in-house by Roche Diagnostics.
• Exogenous Interference (Drugs):
  • ISE indirect Na: Two sample pools (low and high concentration ISE indirect Na).
  • Elecsys TSH: Two human serum samples (~0.5 uIU/mL and ~8 uIU/mL TSH).
  • Data Provenance: Human samples. Conducted in-house by Roche Diagnostics.
• Analytical Specificity/Cross-Reactivity (Elecsys TSH):
  • Sample Size: Native human serum sample pool.
  • Data Provenance: Human serum samples. Conducted in-house by Roche Diagnostics.
• Method Comparison to Predicate:
  • Glucose HK Gen.3: 74 native human serum samples, 67 native human urine samples, 75 native CSF samples.
  • ISE indirect Na: 120 human Lithium heparin plasma samples (vs cobas c 501 ISE), 118 human Lithium heparin plasma (vs Flame Photometer), 120 human serum (vs cobas c 501 ISE), 120 human serum (vs Flame Photometer), 120 human urine (vs cobas c 501 ISE/Flame Photometer).
  • Elecsys TSH: 138 samples (129 native human serum, 9 diluted human serum samples; single donors and pools).
  • Data Provenance: Native human samples (serum, plasma, urine, CSF), some diluted. Conducted in-house by Roche Diagnostics.
• Sample Matrix Comparison:
  • Glucose HK Gen.3: At least 39 serum/plasma pairs for each anticoagulant type (K2-EDTA, Li-Heparin, NaF/K-Oxalate, NaF/Na2-EDTA, NaF/Citrate/Na2-EDTA, KF/Na2-EDTA plasma tubes) + serum vs. serum tube with separation gel.
  • ISE indirect Na: 50 serum/Li-Heparin plasma pairs.
  • Elecsys TSH: Minimum of 56 serum/plasma pairs for Li-Heparin, K2-EDTA, K3-EDTA plasma tubes. Serum separation tubes from 3 manufacturers, blood from five donors were used.
  • Data Provenance: Native human samples. Conducted in-house by Roche Diagnostics.

3. Number of Experts and Qualifications for Ground Truth

This submission concerns in vitro diagnostic (IVD) devices for quantitative measurements of analytes. For such devices, "ground truth" is typically established by:

• Reference methods (e.g., flame photometry for Sodium reference),

• Previously cleared and validated predicate devices,

• Known concentrations in control materials or spiked samples, or

• The inherent chemical/physical measurement by the device itself (for analytical performance criteria like precision, linearity).

• No human "experts" (like radiologists interpreting images) were used to establish ground truth in the context of these analytical performance studies. The "ground truth" is analytical, derived from established chemical/instrumental methods and reference standards.

4. Adjudication Method for the Test Set

Since this is an IVD device for quantitative measurements and the studies are analytical performance evaluations based on instrumental precision, accuracy, and comparison to established methods or predicate devices, there is no adjudication method (e.g., 2+1, 3+1) involving human experts as would be seen in diagnostic imaging studies. The data points are quantitative measurements from the instruments themselves or reference methods. Statistical analysis (e.g., regression, CVs, SDs) is used to assess performance against pre-defined criteria.

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

No MRMC comparative effectiveness study was done. This type of study, involving multiple human readers interpreting cases with and without AI assistance, is relevant for diagnostic imaging AI algorithms where human interpretation is part of the clinical pathway. This submission is for an in vitro diagnostic (IVD) measurement system, not an AI-powered diagnostic imaging tool that assists human readers. The comparative studies involved comparing the new system's analytical performance against predicate IVD systems or reference methods, not human readers.

6. Standalone Performance Study (Algorithm Only)

The entire non-clinical performance evaluation could be considered analogous to a "standalone" performance study, as it describes the analytical performance of the device itself (the integrated system with its assays) without human intervention in the measurement process. The device provides quantitative results, and these results are directly evaluated for precision, linearity, sensitivity, interference, and agreement with predicate devices or reference methods. There is no "human-in-the-loop" aspect to the core measurement and output of these IVD assays.

7. Type of Ground Truth Used

The ground truth used for these analytical studies consists of:

• Known concentrations: For studies like linearity, analytical sensitivity (LoB, LoD, LoQ), and interference, samples prepared with known concentrations of analytes or interferents serve as the ground truth.
• Reference methods: For method comparison studies, well-established and often independently validated reference methods (e.g., flame photometry for sodium measurement) serve as the ground truth or gold standard for comparison.
• Predicate device results: For demonstrating substantial equivalence, the results obtained from a legally marketed predicate device (which itself has established ground truth capabilities) serve as the comparative ground truth.
• Internal statistical controls: For precision studies, consistent and stable control materials are used, where the expected range or value is the "ground truth" against which repeatability and intermediate precision are measured.

8. Sample Size for the Training Set

This document describes the non-clinical performance evaluation for a 510(k) submission, primarily for demonstrating analytical performance and substantial equivalence. It does not describe the development or training of an AI algorithm based on machine learning, so there is no specific "training set" in the context of AI/ML models. The data presented here are validation data for the analytical performance of the assay and integrated system.

For a traditional IVD device, method development involves internal studies and optimization, but this is distinct from "training data" for a machine learning model. The various studies (precision, linearity, etc.) use samples/replicates as described in point 2.

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

As noted in point 8, there isn't a "training set" in the machine learning sense described in this document. If this were to refer to the developmental studies for the underlying assays (Glucose HK Gen.3, ISE indirect Na, Elecsys TSH, which are previously cleared), their ground truth would have been established during their initial development and validation process using:

• Reference materials: Certified reference materials (CRMs) with known analyte concentrations.
• Clinical samples: Patients samples characterized by confirmed diagnoses or clinical outcomes for intended use populations.
• Comparison to established methods: Correlation with existing, approved methods, often considered the "gold standard."
• Spiking and dilution experiments: Preparing samples with known added amounts of analyte.

These are standard practices in IVD assay development, ensuring the analytical and clinical performance of the individual assays before they are integrated into a new system like the cobas pro integrated solutions.

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Immunoassay for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid and pituitary disorders.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The Elecsys TSH immunoassay makes use of a sandwich test principle using monoclonal antibodies specifically directed against human TSH. The antibodies labeled with ruthenium complex) consist of a chimeric construct from human and mouse specific components. The Elecsys TSH immunoassay is used for the in vitro quantitative determination of thyroid stimulating hormone in human serum and plasma. It is intended for use on the cobas e immunoassay analyzers.

The Elecsys TSH device is an immunoassay for the in vitro quantitative determination of thyrotropin in human serum and plasma, used in the diagnosis of thyroid and pituitary disorders. It is an electrochemiluminescence immunoassay (ECLIA) intended for use on cobas e immunoassay analyzers. The key change in the updated device is a two-step approach to block biotin interference by adding an antibody to bind free biotin in the sample and changing the linker on the biotinylated capture antibody.

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

1. A table of acceptance criteria and the reported device performance

The document provides performance data across various non-clinical studies. The acceptance criteria are generally implied by "All samples met the predetermined acceptance criterion" or "All lots met the predetermined acceptance criterion" for studies like precision, LoB, LoD, LoQ, and linearity. For interference studies, the "No interference seen up to" values represent the performance vs. a defined limit. For lot-to-lot reproducibility, the comparability of SDs and CVs implicitly confirms acceptance. For method comparison, the statistical results (slope, intercept, correlation coefficient, bias) are compared against internal acceptance criteria.

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Precision (Repeatability & Intermediate Precision): The test set involved 2 replicates per run for 21 days, across 2 runs per day, for PreciControl Universal, PC Thyro Sensitive, and 5 human serum samples. This is a prospective study design for precision. Sample types were native, single human donors as well as pools.
• Lot-to-Lot Reproducibility: 2 replicates of each of 5 human serum samples per run, 2 runs per day, for 21 days (7 days per lot, n=28 determinations per lot). Prospective design. Sample types were native, single human donors as well as pools.
• Limit of Blank (LoB): Five blank samples with two replicates each per run, for 6 runs on ≥ 3 days (total 60 determinations for analyte free samples). Prospective design.
• Limit of Detection (LoD): Five low analyte samples with two replicates each per run, for 6 runs on ≥ 3 days (total 60 replicates per sample per reagent lot). Prospective design.
• Limit of Quantitation (LoQ): 25 replicates per sample per reagent lot, over 5 days (1 run per day). Prospective design.
• Linearity/Assay Reportable Range: Three high analyte human serum samples were diluted and measured in 3-fold determination within a single run. Prospective design.
• High Dose Hook Effect: Three human serum samples spiked with analyte, dilution series performed, measured in one-fold determination. Prospective design.
• Endogenous Interference: Varied by interferent. For Biotin, Lipemia, Hemoglobin, Bilirubin, RF, IgG, IgM, samples were spiked with interfering substances and diluted into a dilution pool in 10% increments. The number of individual samples/pools is not explicitly stated but implies multiple. Prospective design.
• Analytical Specificity/Cross-Reactivity: A native human serum sample pool was used for each potential cross-reacting compound. Prospective design.
• Exogenous Interferences (Drugs): Two human serum samples (native serum pools) were used. Prospective design.
• Sample Matrix Comparison: A minimum of 56 serum/plasma pairs per sample material (Li-heparin, K2-EDTA, K3-EDTA plasma) were tested in singleton. For PST/SST, blood from five donors was used, measured in duplicate. Prospective design.
• Method Comparison to Predicate: 138 samples (129 native human serum samples and 9 diluted human serum samples, single donors as well as pools diluted) were measured in singleton. Prospective design.

Data Provenance: The document does not explicitly state the country of origin for the human serum and plasma samples. However, the manufacturer, Roche Diagnostics, operates globally with establishments in Mannheim and Penzberg, Germany, and Indianapolis, USA. The studies typically indicate the use of "human serum" or "human serum samples" without further geographic specification. All described studies appear to be prospective experimental designs conducted in a laboratory setting for device validation.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This device is an in vitro diagnostic immunoassay testing for a quantifiable biomarker (TSH), not an imaging device or a device requiring expert interpretation of complex clinical data to establish ground truth for its performance characteristics. The ground truth for such assays is established through analytical methods and reference standards (e.g., spectrophotometry for linearity, spiked samples for interference, reference materials for precision, comparison to a predicate device). No human experts are used to "establish primary ground truth" in the sense of clinical diagnosis for these analytical performance studies. The ground truth is the actual concentration of the analyte, or the known characteristics of the samples (e.g., spiked amount of interferent).

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

Not applicable. As described above, this is an in vitro diagnostic analytical performance study, not a clinical study requiring adjudication of diagnoses or interpretations by 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 device is an automated immunoassay, an in vitro diagnostic (IVD) test, not an imaging device or AI-driven diagnostic tool that would involve human "readers" or AI assistance.

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

Yes, the studies described are all standalone performance studies of the Elecsys TSH immunoassay system. It's an automated device (cobas e immunoassay analyzer) that provides quantitative results without human intervention in the measurement process itself, beyond sample loading and general operation/maintenance.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

The ground truth used for these analytical studies includes:

• Known concentrations: For LoB, LoD, LoQ, and linearity, the samples are either analyte-free, at known low concentrations, or dilutions from known high concentrations.
• Spiked samples: For interference studies (endogenous and exogenous), known amounts of interfering substances are added to samples.
• Reference materials/standards: For precision, controls with defined concentrations are used. Traceability is to the 2nd IRP WHO Reference Standard 80/558.
• Comparison to a legally marketed predicate device: For method comparison, the results of the new device are compared quantitatively to those of the predicate device.
• Clinical samples (native human serum/plasma): These are used to assess the device's performance across a range of physiological concentrations and in real-world matrices for studies like precision, linearity, and matrix comparison.

8. The sample size for the training set

This document describes a 510(k) submission for a revised immunoassay, not a machine learning or AI-based device. Therefore, there is no "training set" in the context of algorithm development. The development of the assay itself would have involved extensive R&D and analytical testing to optimize reagents and protocols, but this is distinct from training an AI model on a dataset.

9. How the ground truth for the training set was established

Not applicable, as there is no "training set" in the AI/ML context for this device. The assay's performance characteristics are established through the non-clinical studies detailed in the summary.

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AFIAS TSH-SP, for use in conjunction with the AFIAS-6/SP Analyzer, is an immunofluorometric test system intended for in vitro diagnostic use at clinical laboratories and Point-of-Care (POC) sites for the quantitative measurement of thyroid stimulating hormone (TSH) levels in serum, sodium-heparinized plasma samples. The test system is intended for use as an aid in the diagnosis of thyroid or pituitary disorders.

AFIAS-6/SP Analyzer is a fluorescence-scanning instrument for in vitro diagnostic use at clinical laboratories and Pointof-Care (POC) sites in conjunction with various in vitro diagnostic AFIAS immunoassays for measuring the concentration of designated analytes in serum or plasma samples.

AFIAS TSH-VB, for use in conjunction with the AFIAS-6/VB Analyzer, is an immunofluorometric test system intended for in vitro diagnostic use at clinical laboratories and Point-of-Care (POC) sites for the quantitative measurement of thyroid stimulating hormone (TSH) levels in sodium-heparinized or EDTA venous whole blood samples. The test system is intended for the monitoring of TSH levels in euthyroid and hypothyroid individuals.

AFIAS-6/VB Analyzer is a fluorescence-scanning instrument for in vitro diagnostic use at clinical laboratories and Pointof-Care (POC) sites in conjunction with various in vitro diagnostic AFIAS immunoassays for measuring the concentration of designated analytes in venous whole blood samples.

AFIAS TSH-SP as well as AFIAS TSH-VB Test Cartridge is a plastic structure molded in the form of a disposable, self-contained, unitized device which houses the 'lyophilized detection buffer', the 'diluent i.e. reconstitution buffer' as well as the 'test strip'; all of which are integral components of the test. The test cartridge is an elongated structure having 140 mm length. 17 mm width and 17 mm height.

'AFIAS TSH-SP ID Chip' as well as 'AFIAS TSH-VB ID Chip' is a flat, rectangular device with its main body measuring 24 mm × 20 mm × 3 mm. Another rectangular portion measuring 12 mm × 10 mm × 2 mm protrudes out from the apical side of the main body. The ID Chip is an electronic memory device fitted into a plastic matrix. Lot-specific 'ID Chip' is an integral component of the test.

AFIAS-6/SP as well as AFIAS-6/VB analyzer is a compact, bench-top, automated, fluorometric analyzer measuring 42 cm (L) x 33.6 cm (W) x 29.3 cm (H). AFIAS-6 weighs 15.1 kg. Either analyzer is a flourometer instrument of closed-system analyzer type.

Here's an analysis of the provided text, outlining the acceptance criteria and study details for the AFIAS TSH devices:

Acceptance Criteria and Device Performance for AFIAS TSH-SP and AFIAS TSH-VB

Note: The document presents acceptance criteria implicitly through performance study results and comparisons to a predicate device. Specific numerical acceptance criteria (e.g., "CV must be 0.95 or higher). | 0.9998 (Serum vs. Sodium heparin plasma), 0.9997 (Serum vs. Di-Potassium EDTA plasma) | 0.9998 (Sodium heparin venous whole blood vs. Di-Potassium EDTA venous whole blood) |
| Clinical Method Comparison (Correlation Coefficient) | High correlation (e.g., >0.95 or higher) with predicate device. | 0.9994 | 0.9999 |
| Clinical Method Comparison (Weighted Deming Regression Slope) | Close to 1 (e.g., 0.9-1.1) to indicate agreement with predicate. | 0.976 | 0.909 |
| Clinical Method Comparison (Weighted Deming Regression Y-intercept) | Close to 0 to indicate agreement with predicate. | -0.003 | 0.012 |

2. Sample Size and Data Provenance

• Limit of Blank (LoB):
  • Test Set Sample Size: 5 unique blank/TSH-depleted human serum samples (for TSH-SP) and 5 unique blank/TSH-depleted whole blood samples (for TSH-VB). Each tested in 5 replicates, with 3 lots on 3 analyzers for 3 days, leading to 75 replicates per lot/analyzer.
  • Data Provenance: Not explicitly stated (e.g., country). Appears to be laboratory-controlled samples (TSH-depleted).
• Limit of Detection (LoD):
  • Test Set Sample Size: 5 unique low TSH-spiked human serum samples (for TSH-SP) and 5 unique low TSH-spiked whole blood samples (for TSH-VB). Each tested in 5 replicates, with 3 lots on 3 analyzers for 3 days, leading to 75 replicates per lot/analyzer.
  • Data Provenance: Not explicitly stated (e.g., country). Appears to be laboratory-controlled samples (TSH-spiked).
• Limit of Quantitation (LoQ):
  • Test Set Sample Size:
    • TSH-SP: 5 low TSH-spiked serum samples, tested in 2 replicates daily in two runs, for 21 successive days (total 210 measurements per sample per lot/analyzer combination).
    • TSH-VB: 4 low TSH-spiked venous whole blood samples, tested in 5 replicates daily in two runs, for 5 successive days (total 200 measurements per sample per lot/analyzer combination).
  • Data Provenance: Not explicitly stated (e.g., country). Appears to be laboratory-controlled samples (TSH-spiked).
• Linearity and Reportable Range:
  • Test Set Sample Size: 22 test samples each for TSH-SP (serum) and TSH-VB (whole blood), prepared by mixing high and TSH-depleted samples. Each tested in triplicate.
  • Data Provenance: Not explicitly stated (e.g., country). Laboratory-prepared samples.
• Susceptibility to High-dose Hook Effect:
  • Test Set Sample Size: 12 spiked samples (TSH concentrations 25 to 3000 µIU/ml). Tested in triplicate.
  • Data Provenance: Not explicitly stated (e.g., country). Laboratory-prepared samples.
• Analytical Specificity:
  • Test Set Sample Size: Samples spiked with various interferants/cross-reactants. Specific number of samples not detailed, but substances and concentrations are listed.
  • Data Provenance: Not explicitly stated (e.g., country). Laboratory-prepared samples.
• Site-to-Site Precision/Reproducibility:
  • Test Set Sample Size:
    • TSH-SP: 4 serum samples (TSH levels ~0.5, ~5.0, ~15.0 & ~55.0 µIU/ml). Each tested in 5 replicates, with 3 lots on 3 analyzers (1 per site) by 9 operators (3 per site). Total 15 replicates per sample per site, 45 replicates per sample combined.
    • TSH-VB: 4 whole blood samples (TSH levels ~0.5, ~5.0, ~15.0 & ~55.0 µIU/ml). Each tested in 5 replicates, with 3 lots on 3 analyzers (1 per site) by 9 operators (3 per site). Total 15 replicates per sample per site, 45 replicates per sample combined.
  • Data Provenance: External point-of-care sites. Not explicitly stated (e.g., country). Uses clinical samples (Clinical Serum Sample 1, 2, Clinical Venous Whole Blood Sample 1, 2) and spiked samples (Spiked Serum Sample 3, 4, Spiked Venous Whole Blood Sample 3, 4).
• Matrix Comparison:
  • Test Set Sample Size:
    • TSH-SP: 81 matched serum vs. sodium heparin plasma samples; 79 matched serum vs. Di-Potassium EDTA plasma samples.
    • TSH-VB: 63 matched sodium heparin venous whole blood vs. Di-Potassium EDTA venous whole blood samples.
  • Data Provenance: Clinical samples from same study subjects. Not explicitly stated (e.g., country).
• Adult Reference Interval:
  • Test Set Sample Size:
    • TSH-SP: 128 apparently healthy adults (65 males, 63 females, age 21-70 years) for serum samples.
    • TSH-VB: 133 apparently healthy adults (69 males, 64 females, age 21-70 years) for sodium heparin venous whole blood samples.
  • Data Provenance: Not explicitly stated (e.g., country). Appears to be prospective collection of healthy adult samples.
• Clinical Method Comparison:
  • Test Set Sample Size:
    • TSH-SP: 183 serum samples (including 22 spiked).
    • TSH-VB: 157 sodium heparinized venous whole blood samples (including 22 spiked).
  • Data Provenance: Clinical sites (three point-of-care sites). Samples collected from across the three study sites. Not explicitly stated (e.g., country).

3. Number of Experts and Qualifications for Ground Truth

• The document describes in vitro diagnostic devices for measuring TSH levels. The performance studies for these types of devices primarily rely on established analytical methods and reference standards rather than expert human interpretation of images or clinical cases.
• No "experts" were used to establish ground truth in the typical sense of a diagnostic imaging study (e.g., radiologists interpreting images). Instead, ground truth is established by:
  • Reference testing (e.g., predicate device, or other established laboratory methods) for method comparison studies.
  • Known concentrations for spiked samples (LoD, LoQ, Linearity, Hook Effect, Analytical Specificity).
  • Large cohorts of 'apparently healthy adults' for reference intervals.

4. Adjudication Method

• None specified. For in vitro diagnostic assays, ground truth is typically analytical (known concentrations, reference method results) rather than requiring adjudication of human interpretations.

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

• No. This is an in vitro diagnostic (IVD) test, not an imaging device that requires human interpretation. Therefore, an MRMC study comparing human readers with and without AI assistance is not applicable. The precision study did involve multiple operators at POC sites using the device, but this is different from an MRMC study for diagnostic interpretation.

6. Standalone Performance Study

• Yes. All the analytical and clinical studies described (LoB, LoD, LoQ, Linearity, Hook Effect, Analytical Specificity, Site-to-Site Precision, Matrix Comparison, and Reference Interval determination) assess the algorithm/device performance in a standalone manner. The "human-in-the-loop" aspect is limited to the operator performing the test according to instructions, not interpreting results in a diagnostic imaging sense.
• The Clinical Method Comparison study also implicitly evaluates standalone performance by comparing the device's results to a predicate device.

7. Type of Ground Truth Used

• Known concentrations: For LoB, LoD, LoQ, Linearity, Hook Effect, and Analytical Specificity, ground truth is established by preparing samples with known or precisely characterized TSH concentrations (e.g., TSH-depleted, TSH-spiked samples).
• Predicate device results: For Clinical Method Comparison, the results from the Access Fast hTSH (on the Access 2 system) are used as the reference/ground truth for comparison.
• Statistically derived from healthy population: For Adult Reference Interval determination, ground truth is derived from the statistical distribution (2.5th and 97.5th percentiles) of TSH levels in a large cohort of apparently healthy adults.

8. Sample Size for the Training Set

• The document does not explicitly describe a "training set" in the context of machine learning or AI models, as this is an IVD device and the performance studies focus on analytical validation.
• However, the calibration process for the device (Lot-specific master calibration curve encoded in an ID chip) implies that a set of characterized samples would have been used by the manufacturer to establish these curves. The size of this internal calibration data set is not provided in this document.

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

• As above, due to this being an IVD device and not an AI/ML model with a distinct "training set" in the conventional sense, this information is not explicitly provided.
• The calibration curves provided on the ID chips would have been established by the manufacturer using a reference method and a range of TSH standards/samples with known concentrations. This would involve a comprehensive analytical process to ensure accuracy and precision across the measuring range.

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