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The IBL International Cortisol Saliva Luminescence Immunoassay is intended for the in-vitro diagnostic quantitative determination of Cortisol in human saliva and for use as an aid in the diagnosis and treatment of adrenal disorders. The device is not intended for point-of-care settings.

Cortisol (also known as hydrocortisone, compound F) is the main glucocorticoid in humans and is produced in the zona fasciculata of the adrenal cortex. 90 % of the circulating cortisol are bound to corticoid binding globulin (CBG, Transcortin), ca. 7 % are bound to albumin and only 1-3 % are unbound. Only the latter part represents the active form of cortisol. The free cortisol is released in saliva and is excreted via the kidneys as a small part among the metabolites of cortisol. The level of free cortisol in blood regulates mainly its secretion in the adrenal cortex in a negative feedback mechanism via CRH (corticotropin releasing hormone) in the hypothalamic region and the ACTH in the pituitary gland, but it is also affected by different situations above all by stress.

In humans, there is a physiological fluctuation of cortisol achieving the highest level in the morning and the lowest during the night. This fluctuation of cortisol plasma level is reflected in saliva normally with a peak in the first 90 minutes after waking up. The cortisol measurement is indicated in adrenal disorders. Due to the diurnal fluctuations of cortisol, a salivary sample collection is an easy method without the stress of repeated venipunctures.

Test principle:
Luminescence immunoassay based on the competition principle. An unknown amount of antigen present in the sample and a fixed amount of enzyme labelled antigen compete for the binding sites of the antibodies coated onto the wells. After incubation the wells are washed to stop the competition reaction. After addition of the luminescence substrate solution the intensity of the luminescence measured is inversely proportional to the amount of the antigen in the sample. Results of samples can be determined directly using the standard curve.

Device composition:
The device is available in two sizes, 96 tests and 960 tests.

The device consists of an antibody coated 96 well Microtiter Plate, seven Standards (range 0.015 - 3.20 µg/dL, equivalent to 0.15 - 32 ng/mL calibrated to the NIST cortisol), two Controls, Enzyme Conjugate (Cortisol coupled to peroxidase), Chemiluminescence Reagent 1 and 2, 10x concentrated Wash Buffer, Adhesive Foils.

The provided document describes the IBL International Cortisol Saliva Luminescence Immunoassay, a device for in-vitro diagnostic quantitative determination of Cortisol in human saliva, intended as an aid in diagnosing and treating adrenal disorders. The device's performance was evaluated through various analytical studies and a method comparison with a predicate device.

Here's a breakdown of the requested information:

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

The document does not explicitly present a table of "acceptance criteria" separate from the "reported device performance." Instead, it describes various performance characteristics and their outcomes, implying that the achieved outcomes met the internal acceptance criteria for substantial equivalence. I will synthesize the reported performance characteristics that implicitly serve as 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)

• Detection Limits (LoB, LoD/LoQ): Five different samples, tested five times in duplicate during three days.
• Specificity (Cross-reactivity): Three different human saliva samples, spiked with interfering substances in six different concentrations. Tested once in duplicate during eight days.
• Linearity: Two different human saliva samples, mixed to produce intermediate concentrations. Tested in duplicate during two days.
• Recovery: Three different human saliva samples, spiked with six different cortisol concentrations. Tested in duplicate during one day.
• Precision: Seven human saliva pools, determined in triplicate, over 20 days of testing.
• Analytical Specificity (Interferences): Three different human saliva samples, tested in duplicate during one day.
• Sample Freezing Claim: Not explicitly stated how many samples were used, but described conceptually with "mean CV" figures.
• Sample Stability: Five samples (low, medium, high concentration).
• Reference Interval Study: 325 prospectively collected samples from apparently healthy individuals. Origin: one collection site within the United States.
• Method Comparison Study: 169 human saliva samples. Data provenance not explicitly stated, but implies laboratory testing with provided samples rather than external clinical trial data.

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)

For this in-vitro diagnostic device, "ground truth" is established by the analytical reference methods and measured concentrations, not by expert consensus on clinical images or diagnoses.

• Traceability: Ground truth for standards is established by the National Institute of Standards and Technology (NIST) using their standard reference material (Ref. 921) for cortisol.
• Method Comparison: The predicate device, Pantex INC. AM/PM Salivary cortisol EIA (K102841), serves as the comparator or "reference" for evaluating the proposed device's performance. The "ground truth" for these samples is the value obtained from the predicate device.

No medical experts (e.g., radiologists) were involved in establishing the "ground truth" in the traditional sense for this type of analytical device. The "truth" is based on established chemical assay methodologies and traceable standards.

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

Not applicable for this type of in-vitro diagnostic device. Adjudication methods are typically used in clinical studies involving interpretation of subjective data (e.g., images) by multiple human readers. For this device, performance is based on quantitative analytical measurements.

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 that provides a quantitative measurement of cortisol in saliva. It is not an AI-powered image analysis tool or a device used by human readers for interpretation. Therefore, no MRMC study was conducted, and there's no concept of human readers improving with/without AI assistance.

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

This refers to the device's inherent analytical performance. The various analytical studies (LoB, LoD, LoQ, linearity, recovery, precision, specificity, stability) effectively represent the "standalone" performance of the immunoassay without human interpretive input affecting the quantitative result. The device itself performs the measurement.

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

The ground truth for the analytical performance studies (such as linearity, recovery, and precision) is derived from:

• Carefully prepared samples with known concentrations of cortisol (e.g., standards, spiked samples).
• Comparisons against a legally marketed predicate device whose performance characteristics are already established and accepted by regulatory bodies.
• Traceability to Certified Reference Materials (NIST Cortisol reference material).

For the reference interval study, the "ground truth" is the observed cortisol levels in a cohort of healthy individuals selected based on specific inclusion/exclusion criteria.

8. The sample size for the training set

Not applicable in the context of machine learning or AI models with distinct training sets. This is a traditional immunoassay kit. The "training" for the assay itself involves internal method development and optimization, which would use many samples, but these are not formally designated as a "training set" like in AI/ML.

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

Not applicable as it's not an AI/ML model needing a separate training set with ground truth. The development and validation of the immunoassay rely on standard laboratory practices, including using calibrated reference materials and internal quality controls.

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