TSH: The IOS™ TSH Test Cartridge is to be used for the quantitative determination of thyroid stimulating hormone (TSH, thyrotropin) levels in serum using the Biocircuits IOS™ system.

Thyroid Controls: The IOS™ Thyroid Controls Kit is to be used to assist in monitoring accuracy and precision in the IOS™ thyroid assays.

Device Description

Thyroid stimulating hormone (TSH) is a glycoprotein with a molecular weight of about 28,000 daltons that is secreted by the anterior pituitary gland. TSH interacts with a specific receptor on the thyroid gland cell surface, stimulating production and secretion of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Secretion of TSH is regulated by two factors: 1) a hormone secreted by the hypothalamus called thyrotropin releasing hormone (TRH) which stimulates the pituitary to produce and release TSH; and 2) the concentration of unbound thyroid hormones T4 and T3 in the interstitial fluid of the brain. An increase of the concentrations of T4 and T3 inhibits the production and secretion of TSH, while a decrease in T4 and T3 levels stimulates production and secretion of TSH, forming a negative feedback mechanism. Failure at any level of regulation of the hypothalamic-pituitary-thyroid axis will result in either under-production (hypothyroidism) or over-production (hyperthyroidism) of T4 and/or T3.

Primary hypothyroidism is associated with low thyroid hormone levels and elevated TSH levels, while secondary (pituitary) and tertiary (hypothalamic) forms of hypothyroidism are associated with both low levels of T4 and/or T3 and low-to-undetectable levels of TSH. All three forms of hypothyroidism can be differentiated by the patient's TSH response to TRH.

Primary hyperthyroidism is associated with high levels of thyroid hormones and very low or undetectable levels of TSH. The TRH challenge test has been used to confirm primary hyperthyroidism. More recently, sensitive TSH assays have been developed which can differentiate overtly thyrotoxic patients from euthyroid individuals.

TSH is composed of two noncovalently linked subunits, designated "alpha" and "beta". The alpha portion is essentially identical to the alpha subunits of human luteinizing hormone (hLH), human follicle stimulating hormone (hFSH), and human chorionic gonadotropin (hCG), differing only in carbohydrate moieties. The beta subunits of each of these hormones is structurally unique and contains the biologic and immunologic specificity. Both subunits are needed for biological activity.

The Biocircuits IOS™ TSH assay uses a monoclonal antibody against the beta subunit of TSH to specifically capture the patient TSH, and a polyclonal antibody also against the beta subunit for the enzyme conjugate. This allows specific determination of the concentration of TSH without cross-reactivity with other glycoprotein hormones.

Principle of the Test:

TSH: The IOS™ TSH test is a two-site sandwich immunoassay. TSH in the patient sample binds to monoclonal anti-TSH antibody in the test cartridge. After a short incubation time, excess sample is washed away and enzyme-labeled polyclonal anti-TSH antibody (conjugate) is added, which binds to any antibody-bound TSH, forming an antibody-antigen-labeled antibody sandwich. After another short incubation time, excess conjugate is washed away and substrate is added. The rate of the enzyme-substrate reaction is directly proportional to the amount of conjugate bound, which is directly proportional to the amount of TSH present in the patient sample. All reagents necessary to perform the test are dried in the IOSTM cartridge, and are rehydrated by the addition of patient sample by the operator, or by the addition of buffer by the instrument.

To perform a test, the operator inserts an IOS™ TSH cartridge into the IOS™ instrument. When prompted, the operator adds sample to the sample well and starts the test sequence. The instrument draws the cartridge inside to be incubated. Patient sample flows into the incubation/reaction chamber where patient TSH binds to anti-TSH antibody. At the end of the sample incubation time, excess patient sample is washed away using buffer added by the instrument. Buffer is also added by the instrument to rehydrate dried conjugate in a separate reagent chamber for the next step; the rehydrated conjugate is then allowed to enter the incubation/reaction chamber and bind to antibody-bound TSH. At the end of the conjugate incubation time, excess conjugate is washed away by buffer. Buffer is used to rehydrate the substrate necessary for signal generation and quantitation of TSH in a second reagent chamber; rehydrated substrate is then allowed to enter the incubation/reaction chamber. The fluorescent signal produced is read as a rate by front-surface fluorometry, compared to the rates produced by a series of calibrators stored in instrument memory, and the amount of TSH present in the patient sample is calculated from the stored calibration curve.

Thyroid Controls: The use of materials derived from human blood to monitor quality control of clinical chemistry testing in the clinical laboratory has been widely established over the past several years. (1) The Biocircuits IOS™ Thyroid Controls are two levels of blood-based material for use with Biocircuits IOSTM thyroid assays test cartridges (T4/TU, T4, or TSH),

To run a control, the operator inserts the Thyroid Control Cartridge (packaged with the controls) into the IOS™ instrument. The instrument reads the lot number and ranges of acceptable values for the control solutions from the Control Cartridge barcode, and then ejects the Control Cartridge. The operator then inserts a test cartridge and follows the instrument prompts to identify the control level, apply control solutions, and begin the test sequence. The IOS™ instrument performs the required buffer additions to rehydrate assay reagents and perform wash steps as necessary, reads the fluorescence signal generated, and calculates and prints the control result just as it would if the cartridge were used to test a patient sample.

AI/ML Overview

This looks like a 510(k) premarket notification for a TSH assay rather than an AI/ML powered device. While it contains performance data and a comparison to a predicate device, it does not involve the typical elements of an AI/ML study such as training sets, ground truth establishment by experts, or MRMC comparative effectiveness studies. Therefore, many of the requested fields cannot be filled.

Here's an analysis based on the provided text, focusing on the available information:

Acceptance Criteria and Device Performance for Biocircuits IOS™ TSH Test Cartridges

Device Name: Biocircuits IOS™ TSH Test Cartridges

Predicate Device: Stratus ultra-sensitive hTSH test (Dade International)

Intended Use: Quantitative determination of thyroid stimulating hormone (TSH, thyrotropin) levels in serum using the Biocircuits IOS™ system.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical targets in the document. Instead, the study aims to demonstrate substantial equivalence to the predicate device and acceptable precision and accuracy for diagnostic use. The reported performance is as follows:

Performance Metric	Acceptance Criteria (Implicit)	Reported Device Performance (Biocircuits IOS™ TSH Assay)
Accuracy (Correlation with Predicate Device - Manufacturer Lab)	High correlation (e.g., r > 0.95) and regression line close to y=x when compared to a commercially available fluorescent enzyme immunoassay (implied predicate or well-established method).	Correlation coefficient (r): 0.98Line of regression: y = 0.141 + 1.07xSample Range: ≤ 0.173 uIU/mL to 26.30 uIU/mL
Accuracy (Correlation with Predicate Device - Physician's Office Lab)	High correlation (e.g., r > 0.95) and regression line close to y=x when compared to the predicate method.	Correlation coefficient (r): 0.978Line of regression: y = 0.255 + 0.922xSample Range: ≤ 0.173 uIU/mL to 23.06 uIU/mL
Precision (Manufacturer Lab - Within-day)	Acceptable within-day variability (e.g., %CV < 15% or as per clinical standards for TSH).	Control Level 1 (0.78 uIU/mL): 6.4% CVControl Level 2 (12.02 uIU/mL): 9.9% CVControl Level 3 (23.60 uIU/mL): 11.3% CV
Precision (Manufacturer Lab - Between-day)	Acceptable between-day variability (e.g., %CV < 15% or as per clinical standards for TSH).	Control Level 1 (0.78 uIU/mL): 13.6% CVControl Level 2 (12.02 uIU/mL): 9.2% CVControl Level 3 (23.60 uIU/mL): 11.3% CV
Precision (Physician's Office Lab - Overall)	Acceptable overall variability in a typical clinical setting.	Control Level 1 (0.773 uIU/mL): 9.2% CVControl Level 2 (12.93 uIU/mL): 13.8% CV
Thyroid Controls Ranges	Established ranges should encompass expected variations for quality control.	TSH Control Level 1: Mean 0.78 uIU/mL, Range 0.45 - 1.11TSH Control Level 2: Mean 12.02 uIU/mL, Range 8.48 - 15.56

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

Accuracy (Manufacturer Lab): 206 patient samples. Data provenance is "manufacturer's laboratories," implying a retrospective or prospectively collected internal sample set. Country of origin not specified, but typically assumed to be the US for FDA submissions unless otherwise stated.
Accuracy (Physician's Office Lab): 43 patient samples. Data provenance is "typical physicians' office laboratory" and "manufacturer's laboratory" (for predicate method). The samples were "split and sent," indicating a prospective collection for this specific comparative study. Country of origin not specified.
Precision (Manufacturer Lab): 10 replicates for within-day, 40 replicates (over multiple days) for between-day, using 3 control levels.
Precision (Physician's Office Lab): 23 replicates for Control Level 1, 18 replicates for Control Level 2, collected over twelve working days.
Thyroid Controls Ranges: 40 cartridges each for two control levels, tested over at least 10 days, using several IOS™ instruments.

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

Not applicable. This document describes an in vitro diagnostic device (IVD) for measuring TSH levels. The "ground truth" for TSH concentration in patient samples is established by quantitative measurement using a reference or predicate method, not by expert consensus or interpretation of images/data by human experts.

4. Adjudication Method for the Test Set

Not applicable. See point 3. The comparison is objective, based on quantitative agreement between two assay methods.

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

Not applicable. This is an IVD device, not an AI/ML-powered diagnostic tool requiring human interpretation. Therefore, there is no "human reader" component to improve "with AI vs without AI assistance."

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

Yes, in a sense. The performance data presented (precision, accuracy comparing to the predicate) represents the standalone performance of the Biocircuits IOS™ TSH assay device itself. It quantifies TSH levels without human intervention beyond sample loading and initiating the test. There isn't an "algorithm" in the AI/ML sense, but rather a biochemical assay with automated measurement and calculation.

7. The Type of Ground Truth Used

The ground truth for both accuracy studies was established by comparison to a predicate method (a commercially available fluorescent enzyme immunoassay). For the clinical performance, the predicate method's results on the same split patient samples served as the reference. For the precision studies, the "mean" values of the control materials served as the reference point for assessing variability.

8. The Sample Size for the Training Set

Not applicable. This is not an AI/ML device that requires a "training set" in the context of machine learning. The device is a "reagents for thyroid stimulating hormone assay." The "training" for such a device would involve method development, calibration curve generation, and reagent optimization, which are parts of standard IVD development, not AI/ML model training. The document refers to "calibrators stored in instrument memory" and "factory-generated" calibration, which implies a pre-established calibration curve used by the instrument's software.

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

Not applicable. As per point 8, there is no AI/ML "training set" in the conventional sense. The "ground truth" for calibration (which is analogous to what a training set aims to achieve for an AI model) would be established by measuring known concentrations of TSH standards (calibrators) using the assay, and then fitting a curve to these values to translate raw signal into TSH units.

Summary

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K961566

NOV 1 8 1996

510(k) Summary of Safety and Effectiveness

A. Submitter: Biocircuits Corporation 1324 Chesapeake Terrace Sunnyvale, CA 94089 (408) 745-1961 Contact: Sheila J. Ramerman Date Prepared: October 25, 1996

Device Names:
Proprietary Name:	Biocircuits IOS™ TSH Test CartridgesBiocircuits IOS™ Thyroid Controls
Common Name:	Reagents for thyroid stimulating hormone assayQuality control materials (assayed and unassayed)
Classification Name:	Thyroid stimulating hormone test systemQuality control materials (assayed and unassayed)

C. Legally Marketed Device:

The IOS™ TSH Test Cartridges are substantially equivalent to the Stratus ultra-sensitive hTSH test currently manufactured and distributed by Dade International (formerly Baxter Dade).

D. Device Description:

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Principle of the Test:

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E. Intended Use:

TSH: The IOS™ TSH Test Cartridge is to be used for the quantitative determination of thyroid stimulating hormone (TSH, thyrotropin) levels in serum using the Biocircuits IOS™ system.

Thyroid Controls: The IOS™ Thyroid Controls Kit is to be used to assist in monitoring accuracy and precision in the IOS™ thyroid assays.

F. Comparison with the Predicate Device:

Table I summarizes the comparative features of both the IOS™ and Stratus TSH assays.

G. Performance Data:

TSH Test Cartridges:

Non-clinical testing performed in the manufacturer's laboratories gave the following results:

1. Precision

A laboratory study performed at the manufacturer for within-day and between-day precision in the IOS™ TSH assay used three levels of control material. The following data were obtained:

Control Level	1	2	3
Mean (uIU/mL)	0.78	12.02	23.60
SD, overall (uIU/mL)	0.11	1.18	2.67
% CV, within-day (n=10)	6.4%	9.9%	11.3%
% CV, between-day (n=40)	13.6%	9.2%	11.3%
% CV, overall	13.5%	9.8%	11.3%

2. Accuracy

A comparison of methods obtained by testing 206 patient samples in the manufacturer's laboratories using the IOS™ TSH assay and a commercially available fluorescent enzyme immunoassay gave a correlation coefficient ('r') of 0.98, with the line of regression described by the equation y = 0.141 + 1.07x. Samples tested ranged from ≤ 0.173 uTU/mL to 26.30 uIU/mL.

Clinical testing performed at a typical physician's office laboratory gave the following results:

1. Precision

A study was performed in a typical physicians' office laboratory for total precision in the IOS™ TSH assay. Data were collected over twelve working days. The following data were obtained:

Control Level	1	2
Number of replicates	23	18
Mean (uIU/mL)	0.773	12.93
SD, overall (uIU/mL)	0.071	1.78
% CV, overall	9.2%	13.8%

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2. Accuracy

A comparison of methods was also performed by users in a typical physicians' office laboratory. A total of 43 patient samples were tested using the IOS™ TSH assay in the office laboratory; the samples were split and sent to the manufacturer's laboratory for testing by the predicate method. These studies gave a correlation coefficient ('r') of 0.978, with the line of regression described by the equation y = 0.255 + 0.922x. Samples tested ranged from ≤ 0.173 uIU/mL to 23.06uIU/mL.

Thyroid Controls:

The following ranges for the IOS™ Thyroid Controls were determined in studies in the manufacturer's laboratories. To establish the ranges, the controls were tested in a total of 40 cartridges each, over at least 10 days, using several IOS™ instruments. These values only apply to this lot of IOSTM Thyroid Controls. Different lots of Thyroid Controls will likely have slightly different ranges. Your laboratory should establish its own range for these controls over time.

Analyte	Control Level 1		Control Level 2
	Mean	Range	Mean	Range
T4 (ug/dL)	8.1	6.48 - 9.72	12.9	10.32 - 15.4
T-Uptake (%)	32.4	29.25 - 35.55	39.7	36.85 - 42.55
TSH (uIU/mL)	0.78	0.45 - 1.11	12.02	8.48 - 15.56

It is self-evident from the data and information presented here that the Biocircuits IOS™ TSH Test Cartridges as as safe, effective, and perform as well as the Stratus ultra-sensitive hTSH assay in commercial distribution by Dade International.

Attachment: Table I: Assay Comparison

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Baxter STRATUS vs. Biocircuits IOS™

Assay Comparison

ATTRIBUTE	STRATUS hTSH	IOS™ TSH
Technology	Fluorometric enzyme immunoassay	Fluorometric enzyme immunoassay
Assay format	Sandwich	Sandwich
Enzyme label	Alkaline phosphatase	Alkaline phosphatase
Substrate	Methylumbelliferyl phosphate	Methylumbelliferyl phosphate
ReagentsImmobilization MediumDry	Reaction tabMonoclonal antibody only	Plastic cartridgeMonoclonal antibody, polyclonal antibodyconjugate, substrate
ReagentsWet	2 (assay-specific), loaded by operator at startof each run	1 (used for all assays), continuously on board
ReagentsDeliveryCalibrationCalibration StabilityStorage	Fully automatedUser-generated14 days (minimum)Refrigerated (2-8°C)	Fully automatedFactory-generated90 days (minimum)Room Temperature (15-30°C)
SampleTypeVolumeMeasurement Needed	Serum or plasma0.2 ml (minimum)Non-precision	Serum0.15 mLNon-precision
Operating environment	22°-32° C	15°-30° C
Data analysis	Microprocessor-controlledStored standard curves	Microprocessor-controlledStored standard curves
Data output	LCD displayPrinted alphanumeric hard copy	LCD displayPrinted alphanumeric hard copy

لاڙي

Regulation Number and Section

§ 862.1690 Thyroid stimulating hormone test system.

(a)
Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known as thyrotrophin and thyrotrophic hormone, in serum and plasma. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.(b)
Classification. Class II.