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The IOS Free Thyroxine Test Cartridges are intended to be used for the quantitative determination of free (not protein bound) thyroxine (thyroid hormone) in serum for the diagnosis and treatment of thyroid diseases. They are intended to be used with the Biocircuits IOS® instrument in clinical laboratories, physician office laboratories, and other alternate sites of use close to the point of patient care.

The IOS Controls are to be used to assist in monitoring accuracy and precision in the IOS immunoassay test cartridges.

The IOS Free T4 assay is a sequential immunoassay in which free T4 in the patient serum sample first binds to a monoclonal anti-T4 antibody; this free T4:anti-T4 complex is then captured by polyclonal goat-anti-mouse immobilized on the plastic surface. Excess ('uncomplexed') anti-T4 antibody also binds to the surface. After an incubation period, any excess sample and unbound anti-T4 antibody are removed. In the second step, alkaline phosphatase-labeled T4 ('conjugate') is added, and the conjugate binds to T4 binding sites on the uncomplexed anti-T4 antibody. After another incubation period, excess conjugate is washed away and substrate is added. The substrate reacts with the conjugate bound to uncomplexed anti-T4 antibody and produces a fluorescent signal. The level of fluorescence is directly proportional to the amount of conjugate bound to the uncomplexed anti-T4 antibody and inversely proportional to the amount of free T4:T4 antibody complex, and thus inversely proportional to the amount of free T4 present in the serum sample. All the reagents necessary to perform the test are dried in the IOS Free T4 Test Cartridge, and are rehydrated by 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 Free T4 Test 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 and adds buffer to dilute the serum. The diluted serum rehydrates the dried reagent (mouse anti-T4 antibody) in the sample well. A short incubation period allows the serum and reagents to react. This mixture then flows into the incubation/ reaction chamber, where binding to the solid phase occurs. At the end of the incubation time, excess mixture is aspirated out of the incubation/reaction chamber by the instrument. Buffer is used to rehydrate conjugate in a separate chamber; rehydrated conjugate is allowed to enter the reaction chamber to bind to uncomplexed T4 antibody. At the end of this incubation time, excess conjugate is washed away by buffer dispensed by the instrument. Buffer is also used to rehydrate the substrate necessary for signal generation and quantitation in a third chamber: rehydrated substrate is then allowed to enter the incubation/reaction chamber. The signal produced is read as a rate by front-surface fluorometry, compared to the signal produced by a series of calibrators stored in instrument memory, and the amount of free T4 present in the patient sample is calculated from the stored calibration curve.

IOS 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. The Biocircuits IOS Controls are two levels of blood-based material for use with Biocircuits IOS Test Cartridges.

To run a control, the operator inserts the 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 Cartidge barcode, and then ejects the Control Cartidge. 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.

Here's an analysis of the provided 510(k) summary regarding the Biocircuits IOS® Free Thyroxine Test Cartridges and IOS Controls, focusing on the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct pass/fail thresholds in this summary. However, the performance data presented is implicitly compared to what would be considered acceptable for a diagnostic device of this type, especially in relation to the predicate device. The primary performance metrics presented are precision and accuracy (correlation with a predicate device).

Note: The summary states: "It is self-evident from the data and information presented here that the Biocircuits IOS Free Thyroxine Test Cartridges are as safe, effective, and perform as well as the Dade Stratus Free Thyroxine Fluorometric Immunoassay manufactured and distributed by Dade International, Inc." This implies the reported performance met the unstated acceptance criteria for substantial equivalence.

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

• Accuracy (Manufacturer's Lab): 119 patient samples.
  • Data Provenance: "manufacturer's laboratories." Includes "pooled human serum spiked with T4 to obtain high concentrations of free T4." (Likely retrospective, but not explicitly stated if all 119 were patient-derived or if spiked samples were included in that count.)
• Accuracy (Physician's Office Lab): 68 patient samples.
  • Data Provenance: "clinical testing performed in a typical physicians' office laboratory." Samples were "split and sent to the manufacturer's laboratory for testing by both the IOS and a commercially available fluorescent enzyme immunoassay." Includes "pooled human serum spiked with T4 to obtain high concentrations of free T4." (Likely retrospective patient samples, with spiked samples used for wider range coverage.)
• Precision (Manufacturer's Lab): "n=10" for within-day, "n=40" for between-day for 3 control levels. This refers to the number of replicates tested.
• Precision (Physician's Office Lab): "number of replicates 44" for control level 1, "40" for control level 2.
• Control Range Establishment (Manufacturer's Lab): Each control level was tested in "80 cartridges, over at least 3 days, using several IOS instruments."

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

This type of immunoassay (Free Thyroxine Test) relies on comparison with a predicate device and established laboratory methods. No human experts were used to establish ground truth for the test set in the traditional sense (e.g., radiologists interpreting images). The "ground truth" for accuracy was established by comparing the results of the new device to those obtained from a "commercially available fluorescent enzyme immunoassay" (the Dade Stratus Free Thyroxine Fluorometric Enzyme Immunoassay, and later generalized to "a commercially available fluorescent enzyme immunoassay").

4. Adjudication Method for the Test Set

Not applicable. The ground truth was based on a laboratory reference method, not expert consensus requiring 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

Not applicable. This is an in-vitro diagnostic device (immunoassay) and does not involve human readers for interpretation in the context of imaging or similar tasks where MRMC studies are typically employed. "AI" is not mentioned in the context of assisting human interpretation in this document.

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

Yes, the performance studies presented (precision and accuracy) are of the standalone device performance. The device (IOS Free Thyroxine Test Cartridges with the IOS instrument) provides quantitative results directly. The human "in-the-loop" is the operator performing the test and adding samples, but not interpreting the raw signal in a way that requires AI assistance or a complex human-algorithm interaction for diagnostic output.

7. The Type of Ground Truth Used

The ground truth used for accuracy was comparison against a legally marketed predicate device (the Dade Stratus Free Thyroxine Fluorometric Enzyme Immunoassay and "a commercially available fluorescent enzyme immunoassay"). This is a common approach for establishing substantial equivalence for in-vitro diagnostic devices. For precision, the ground truth is simply the statistical distribution of repeated measurements on control materials.

8. The Sample Size for the Training Set

No explicit training set is mentioned. For in-vitro diagnostic assays, "training" in the machine learning sense is not typically applicable. Instead, the device's calibration curve and operational parameters are established during development and manufacturing. The document mentions "Factory-generated" calibration and "stored standard curves" which would be developed using known concentrations of analytes, but no sample size for this internal process is provided.

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

As above, there isn't a "training set" in the machine learning context. The calibration for the device (what it would 'learn' in a broad sense) is "Factory-generated" and "stored standard curves." This process would involve running samples with precisely known concentrations of free T4 (standards or calibrators) to establish the relationship between the fluorescent signal and the analyte concentration. This is a fundamental part of developing any quantitative assay. The known concentrations of these calibrators serve as the 'ground truth' for the instrument's internal calibration.

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