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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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For the in-vitro diagnostic quantitative determination of free and protein bound salivary cortisol in human saliva as an aid in the assessment of Cushing Syndrome and Addison's Disease. Measurements of cortisol in saliva are used in the diagnosis and treatment of disorders of the adrenal gland.

The kit consists of a 96 well GARGG (Goat Anti-Rabbit Gamma Globulin) coated microplate (12x8 breakable strip wells), seven ready-to-use calibrators (range 0.1-30 ng/ml) of gravimetrically prepared cortisol from a commercial source (Steraloids) and compared and traced to NIST cortisol, low and high controls, anti-Cortisol (rabbit), 10X concentrated Cortisol (analog)-peroxidase, substrate solution, stop reaction solution and 10X concentrated wash solution.

Here's a breakdown of the acceptance criteria and study information for the Pantex AM/PM Salivary Cortisol EIA Kit, based on the provided text:

The provided text focuses on the analytical performance of the Pantex AM/PM Salivary Cortisol EIA Kit and its equivalence to a predicate device. It demonstrates the device's ability to accurately and reliably measure salivary cortisol levels.

1. Table of Acceptance Criteria and Reported Device Performance

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

• Precision/Reproducibility:
  • Intra-assay: 20 replicates for low, medium, and high samples.
  • Inter-assay: Mean of average duplicates for 12 separate assays.
  • Inter-lot: Duplicate measurements of 5 saliva pools and 3 saliva controls using 3 different lots.
  • Repeatability: 3 saliva pools tested over 20 days (2 assays/day).
• Linearity: 10 sample concentrations (dilutions).
• Recovery: 10 saliva samples.
• Expected Reference Values (for establishing normal range): 152 male saliva samples and 152 female saliva samples (Total 304 samples).
• Detection Limits (LoB, LoD, LoQ): 120 measurements of "cortisol free free salvia" (clarified as cortisol-free saliva) and low-level cortisol samples.
• Analytical Specificity/Cross Reactivity: Each compound tested at 10,000 ng/mL (or 1000 ng/mL for some) in an unspecified number of samples.
• Method Comparison: 160 samples compared between the new device and the predicate device.
• Interferences Studies: 3 levels of Cortisol (low, medium, high) spiked with high concentrations of 5 interfering substances (alcohol, caffeine, nicotine, food, gum extracts). The number of individual replicates per interferent is detailed in the tables (typically 4 levels of interferent tested with each of the 3 cortisol pools).

Data Provenance: The document does not explicitly state the country of origin of the data or whether the samples were retrospective or prospective, except for the "Expected Reference Values" study which collected 304 samples (presumably from individuals) to establish a new reference range. Given the context of a 510(k) submission, these studies are typically conducted internally or by contract research organizations (CROs) for the device manufacturer.

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

The device is an in-vitro diagnostic (IVD) assay for quantitative measurement of salivary cortisol. The "ground truth" for such devices is typically established through:

• Reference materials: Calibrators and controls are traced to NIST cortisol.
• Known concentrations: For linearity, recovery, and interference studies, known concentrations of cortisol or interferents are added to samples.
• Comparison to a legally marketed predicate device: This is a key method for demonstrating substantial equivalence.

Therefore, for the analytical performance studies, no external human experts were used to establish "ground truth" in the way a radiologist would read an image. The ground truth relies on laboratory standards, analytical methods, and comparison to an established device.

4. Adjudication Method for the Test Set

Not applicable. This is an in-vitro diagnostic test, not a subjective interpretation task requiring adjudication by human readers.

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

No, an MRMC comparative effectiveness study was not done. The device is a quantitative immunoassay, not an AI-assisted diagnostic intended for human reader interpretation.

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

Yes, the studies presented are standalone performance evaluations of the assay itself. The Pantex AM/PM Salivary Cortisol EIA Kit is an automated/semi-automated laboratory test using an enzyme immunoassay principle; its performance is determined by the output of the instrument reading the optical density, not by human interpretation of individual cases. It functions as an "algorithm only" in the sense that it provides a quantitative result based on chemical reactions and optical measurement, without human clinical interpretation being part of the device's performance claim.

7. The Type of Ground Truth Used

The ground truth for the analytical performance studies primarily relied on:

• Known concentrations/reference standards: For precision, linearity, recovery, detection limits, and analytical specificity, the accuracy is determined against samples with known, carefully prepared concentrations or certified reference materials (e.g., NIST cortisol).
• Comparison to a predicate device: For method comparison, the reference is the performance of the legally marketed predicate device (Salimetrics HS Salivary Cortisol EIA Kit).
• Spiked samples: For recovery and interference studies, known amounts of analyte or interferents were spiked into samples.

8. The Sample Size for the Training Set

Not applicable in the context of an enzyme immunoassay kit. There is no machine learning algorithm that requires a "training set" in the conventional sense. The "training" of such a device refers to its development and optimization based on chemical and biological principles, using reagents, controls, and calibration curves as part of its design for accurate measurement.

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

Not applicable. As explained above, there isn't a "training set" for an EIA kit in the machine learning context. The "ground truth" during the development and optimization of the kit would be based on fundamental analytical chemistry principles, known concentrations of cortisol, and established practices for immunoassay development and validation.

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Immunoassay for the in vitro quantitative determination of cortisol in human serum, plasma, urine, and saliva. The determination of cortisol is used for the recognition and treatment of functional disorders of the adrenal gland.

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

Elecsys Cortisol CalSet is used for calibrating the quantitative Elecsys Cortisol assay on the Elecsys immunoassay analyzers.

(1) The Elecsys Cortisol Assay is a two step competitive immunoassay with streptavidin microparticles and electrochemiluminescence detection. Results are determined using a calibration curve that is generated specifically on each instrument by a 2 point calibration and a master curve provided with the reagent bar code.
(2) The Elecsys Cortisol CalSet is a lyophilized product consisting of human serum with added cortisol (synthetic) in two concentration ranges. During manufacture, the analyte is spiked into the matrix at the desired concentration levels.

The provided text describes a 510(k) summary for the Elecsys Cortisol Test System (K070788), a modified device, comparing it to a predicate device (K043175). The key modifications appear to be the addition of new platforms (cobas e 411 and cobas e 601 analyzers) and some refined details regarding sensitivity and expected values for saliva.

Since this is an in-vitro diagnostic (IVD) device, the acceptance criteria are related to analytical performance characteristics rather than clinical outcomes or diagnostic accuracy in the way a medical imaging AI would be. The "study" mentioned isn't a single large clinical trial in the traditional sense, but rather a series of analytical performance evaluations summarized in the comparison tables.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the performance of the predicate device (K043175), with the modified device (K070788) aiming to demonstrate "substantial equivalence." The table below highlights key performance characteristics where data or changes are specifically mentioned. For many features, the modified device performance is simply stated as "Same" as the predicate.

Study Proving Acceptance Criteria:

The study that proves the device meets the acceptance criteria is the comparison study detailed in the 510(k) submission, which involved generating the performance data for the modified Elecsys Cortisol Test System (K070788) on the new platforms (cobas e 411 and cobas e 601 analyzers) and ensuring these results are substantially equivalent to the predicate device (K043175). The text explicitly states: "The Elecsys Cortisol Test System (modified) is substantially equivalent to other devices legally marketed in the United States. The Elecsys Cortisol Test System (modified) is equivalent to the Elecsys Cortisol Test System (K043175)." The comparison table provides the evidence for this claim, showing "Same" for many features, or updated, comparable data for others (e.g., precision, sensitivity, expected values).

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

• Test Set Sample Size:
  • Precision (Saliva): Not explicitly stated how many individual samples were used for the precision testing, but results are presented at multiple concentration levels, implying repeat measurements on specific samples/pools (e.g., "Between-run" data shows CVs at 5 different concentrations).
  • Expected Values (Saliva): 154 healthy individuals.
  • Specific sample sizes for other analytical performance characteristics (e.g., measuring range, sensitivity) are not explicitly provided in the summary.
• Data Provenance: Not specified in the provided text (e.g., country of origin, retrospective or prospective).

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

This is an in-vitro diagnostic device (IVD) measuring a biochemical marker (cortisol). The "ground truth" for such a device is established through highly accurate reference methods and the intrinsic concentration of the analyte in samples, not typically through human expert adjudication like in diagnostic imaging. Therefore:

• Number of Experts: Not applicable in the context of IVD performance studies.
• Qualifications of Experts: Not applicable.

4. Adjudication Method for the Test Set

Not applicable for an IVD device measuring analyte concentration. Analytical performance is evaluated against quantitative measurements and statistical methods, not by human adjudication of qualitative results.

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

• No, an MRMC comparative effectiveness study was not done. This type of study is typically for evaluating the diagnostic performance of systems (often imaging AI) where multiple human readers interpret cases with and without AI assistance. This device is an IVD for quantitative determination of cortisol.

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

• Yes, the performance data presented is standalone algorithm performance. The Elecsys Cortisol Test System is an automated immunoassay. The reported performance characteristics (e.g., measuring range, sensitivity, precision) reflect the algorithm's direct measurement capabilities without direct human interpretation in the results generation. Humans operate the instrument and interpret the final quantitative values, but the performance metrics themselves are tied to the automated assay's analytical capabilities.

7. The Type of Ground Truth Used

• For sensitivity, measuring range, and precision, the ground truth is the known concentration of cortisol in control samples or spiked samples, or the statistical evaluation of repeated measurements of real patient samples.
• For expected values (saliva), the ground truth is derived from quantitative measurements in a population of healthy individuals.
• The "Traceability / Standardization" section states the device is "Standardized against the Enzymun-Test Cortisol method. This in turn was standardized via ID-MS." Isotope Dilution Mass Spectrometry (ID-MS) is often considered a "gold standard" or highly accurate reference method for quantitative measurements, providing the ultimate ground truth for concentration.

8. The Sample Size for the Training Set

• Not explicitly stated and likely not applicable in the same way as machine learning models. This is an immunoassay system, not a machine learning algorithm that is "trained" on a dataset in the modern sense. The "training" for such a system involves the development and optimization of the assay reagents, protocols, and calibration curves. The development would involve numerous samples, but there isn't a distinct "training set" for an algorithm in this context. The "master curve provided with the reagent bar code" is key to the assay's function, implying significant development and standardization data for its creation.

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

• As above, the concept of a "training set" doesn't directly apply. However, the accuracy of the assay's measurements (which forms its "ground truth" for operation) is based on:
  • Standardization against ID-MS: This indicates a robust method for establishing accurate concentration values.
  • Calibration curves: These are established using calibrators with known concentrations, which are themselves traceable to highly accurate methods. The Elecsys Cortisol CalSet is a "lyophilized product consisting of human serum with added cortisol (synthetic) in two concentration ranges," where the "analyte is spiked into the matrix at the desired concentration levels." These "desired concentration levels" would be the ground truth for calibration.

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An enzyme immunoassay for the quantitative in vitro diagnostic measurement of active free cortisol (hydrocortisone and hydroxycorticosterone) in saliva. Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.

The DRG Salivary Cortisol ELISA KIT is based on the competition principle and the microplate separation. An unknown amount of Cortisol present in the sample and a fixed amount of Cortisol coniugated with horseradish peroxidase compete for the binding sites of mouse polyclonal Cortisol-antiserum coated onto the wells. After one hour incubation the microplate is washed to stop the competition reaction. After addition of the TMB substrate solution the concentration of Cortisol is inversely proportional to the optical density measured.

Here's an analysis of the provided text regarding the DRG Salivary Cortisol ELISA, focusing on acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied through the performance data presented, as explicit criteria (e.g., "must achieve X correlation") are not stated. The performance is reported against other commercially available methods or standard analytical techniques.

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

The "test set" in this context refers to the samples used for method comparison and performance evaluation.

• Normal Range Study: 109 saliva samples. Adult male and female apparently healthy subjects, ages 20 to 80 years. Morning collection. (Provenance not specified, but likely domestic to DRG International, Inc. in NJ, USA, or related clinical sites). Prospective in nature.
• Method Comparison (Study 1 vs. LIA): 114 saliva samples. Subjects ages 40 to 70 years. (Provenance not specified). Retrospective implied as samples were "run".
• Method Comparison (Study 2 vs. EIA): 72 saliva samples. Men ages 40 to 70 years. (Provenance not specified). Retrospective implied.
• Method Comparison (Study 3 vs. LC-MS): 28 saliva samples. (Provenance not specified). Retrospective implied.
• Expanded Method Comparison (Study 1 vs. LIA): 40 saliva samples. Subjects ages 25-65 years. (Provenance not specified). Retrospective implied.
• Expanded Method Comparison (Study 2 vs. EIA): 40 saliva samples. Men and women ages 25-65 years. (Provenance not specified). Retrospective implied.
• Sensitivity: This is typically an in-vitro measurement using dilutions of known concentrations, not patient samples.
• Specificity: In-vitro evaluation of various steroid compounds.
• Reproducibility (Intra- and Inter-Assay): 4 saliva samples for intra-assay; commercial control samples for inter-assay.
• Reproducibility (Inter-Lot): 5 saliva samples.
• Recovery: 3 saliva samples with endogenous cortisol spiked with known amounts.
• Linearity: 3 saliva samples serially diluted.

The provenance regarding country of origin is not explicitly stated for any of the patient samples, but given the manufacturer's location, US-based samples are a reasonable assumption for a US regulatory submission. All studies appear to be retrospective analyses of collected samples.

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

This type of diagnostic device (ELISA kit for cortisol) doesn't typically rely on human expert interpretation of images or complex data for "ground truth" in the way an AI imaging device would. Instead, the ground truth for method comparison studies is established by:

• Reference method: Commercial LIA, EIA, and LC-MS methods. These methods are themselves established, and their results are treated as the "ground truth" for comparison.
• Known concentrations: For sensitivity, specificity, recovery, and linearity studies, known concentrations of cortisol or interfering substances are used.

Therefore, the concept of "experts establishing ground truth for the test set" is not directly applicable in the same way as for subjective diagnostic tasks. The performance is compared against existing, validated analytical methods.

4. Adjudication Method for the Test Set

Not applicable. As explained above, the "ground truth" for this type of device is established through comparison with recognized analytical methods or known sample concentrations, not through expert adjudication of subjective findings.

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 ELISA kit, a laboratory diagnostic test measuring a biochemical marker. It does not involve human "readers" or "AI assistance" in the interpretation of complex data (like medical images) where MRMC studies are relevant.

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

This is an in vitro diagnostic (IVD) kit. Its performance is inherently standalone, in that it provides a quantitative result based on the chemical reaction. There's no "human-in-the-loop" component in the interpretation of the raw assay signal (optical density) to derive the cortisol concentration once the assay is run and the standard curve is established. The device itself is the "algorithm only" (chemical reaction and measurement) to produce the result.

7. The Type of Ground Truth Used

The ground truth for the performance studies was primarily established by:

• Reference analytical methods: Commercially available LIA (Luminescence Immunoassay) and EIA (Enzyme Immunoassay) methods, and a reference LC-MS (Liquid Chromatography-Mass Spectrometry) method.
• Known concentrations: For sensitivity, specificity (known cross-reactants), recovery (spiked samples with known added cortisol), and linearity (serum samples with known dilutions).

8. The Sample Size for the Training Set

This document describes a premarket notification (510(k)) for a traditional IVD device. The language "training set" is typically associated with machine learning or AI algorithm development. For an ELISA kit, there isn't a "training set" in that sense. The kit's reagents, protocols, and standard curve parameters are developed through R&D experiments and optimization processes, but this is not typically referred to as a "training set" for an algorithm. The reported studies (method comparison, reproducibility, etc.) are essentially validation studies for the finalized product.

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

As there isn't a "training set" for an algorithm in the AI sense, this question is not directly applicable. The "ground truth" for the development and optimization of the ELISA kit would involve established biochemical principles and highly controlled experiments using known concentrations of cortisol and other substances, likely following established laboratory practices for assay development.

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The Elecsys Cortisol is an immunoassay for the in-vitro quantitative determination of cortisol in serum, plasma, urine and saliva. The determination of cortisol is used for the recognition and treatment of functional disorders of the adrenal gland. The electrochemiluminescence immunoassay "ECLIA" is intended for use on the Roche Elecsys 1010/2010 and MODULAR ANALYTICS E170 (Elecsys module) immunoassay analyzers.

The Elecsys Cortisol Assay is a two step sandwich immunoassay with streptavidin microparticles and electrochemiluminescence detection. Results are determined using a calibration curve that is generated specifically on each instrument by a 2 point calibration and a master curve provided with the reagent bar code.

Here's an analysis of the acceptance criteria and supporting study for the Elecsys® Cortisol Immunoassay System, based on the provided 510(k) summary:

Device: Elecsys® Cortisol Immunoassay System

1. Table of Acceptance Criteria and Reported Device Performance

The submission focuses on demonstrating substantial equivalence to a predicate device rather than setting explicit acceptance criteria in the way a clinical trial might for a new drug. Instead, it provides performance characteristics of the new device and compares them to the predicate, implying that performance comparable to the predicate (and within acceptable analytical ranges for this type of test) is the "acceptance criteria."

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

• Sample Size (Method Comparison): 326 samples
• Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. It is implied to be a direct comparison of patient samples run on both systems.

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

This type of immunoassay does not typically involve expert readers for establishing ground truth in the way medical imaging devices do. The "ground truth" for the method comparison is the measurement obtained from the predicate device (Salimetrics HS Salivary Cortisol Enzyme). The results are compared statistically, not against a human interpretation.

4. Adjudication Method for the Test Set

Not applicable for this type of quantitative immunoassay comparison. Adjudication is typically used in subjective interpretation tasks (e.g., radiology readings) to reconcile differing expert opinions. Here, the comparison is direct numerical data.

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

No, an MRMC study was not done. MRMC studies are relevant for devices that involve human interpretation, often assisted by AI, to assess the impact of the device on human performance. This is a standalone quantitative assay.

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

Yes, the device is a standalone quantitative immunoassay platform. Its performance characteristics (precision, sensitivity, method comparison) are inherently "standalone," meaning they represent the device's performance without human interpretive intervention.

7. The Type of Ground Truth Used

For the method comparison, the "ground truth" was the results obtained from the predicate device (Salimetrics HS Salivary Cortisol Enzyme). For other performance metrics like precision and sensitivity, the ground truth is established through standard laboratory practices using known controls and calibrators, often with traceability to a reference method (e.g., ID-MS for the Elecsys Cortisol).

8. The Sample Size for the Training Set

The document does not specify a separate "training set" in the context of machine learning or AI. For immunoassay development, there are typically reagent optimization phases and validation studies that involve numerous samples and controls, but these are not usually referred to as "training sets" in the same way as in AI/ML development. The provided data for method comparison is a validation dataset.

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

As there's no explicitly defined "training set" in the AI/ML sense, this question is not directly applicable. If considering the development and optimization of the immunoassay itself, the "ground truth" would be established using reference materials, calibrators, and possibly samples with known cortisol concentrations (e.g., measured by ID-MS or another highly accurate reference method).

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Salimetrics HS-Cortisol kit is a competitive immunoassay specifically designed for the quantitative in vitro diagnostic measurement of salivary cortisol. This kit may be used to measure adrenal cortical function and as a screen for Cushing's and Addison's disease. Saliva cortisol accurately reflects the amount of serum cortisol in the circulation. This kit is not intended for use with serum or plasma samples.

Test Principle- A microtitre plate is coated with rabbit antibodies to cortisol. Cortisol in standards and unknowns compete with cortisol linked to horseradish peroxidase for the antibody binding sites. After incubation, unbound components are washed away. Bound cortisol peroxidase is measured by the reaction of the peroxidase enzyme on the substrate tetramethylbenzidine (TMB). This reaction produces a blue color. A vellow color is formed after stopping the reaction with sulfuric acid. Optical density is read on a standard plate reader at 450 nm. The amount of cortisol peroxidase detected is inversely proportional to the amount of cortisol present. The optical density readings of the calibrators are used to form a standard curve to which the optical densities of the controls and samples are compared.

Kit Description- The kit consists of an antibody coated 96 well plate, six calibrators at a concentration of 1.800, 0.600, 0.200, 0.067. 0.022, and 0.007 µg/dL of NIST(National Institute of Standards and Technology) cortisol, two controls representing a high (1.00 ug/dL) and low (0.100 ug/dL) level of salivary cortisol, the enzyme conjugate (1600X concentrate), assay diluent containing a pH indicator, wash buffer(10X concentrate), tetramethylbenzidine substrate solution, stop solution, and kit insert.

Here's a breakdown of the acceptance criteria and study information for the Salimetrics HS Salivary Cortisol Enzyme Immunoassay Kit:

Acceptance Criteria and Reported Device Performance

The device's acceptance criteria are framed in comparison to a predicate device (Diagnostic Systems Laboratory Active Cortisol EIA, K850141), focusing on quantitative performance characteristics.

Study Information

1. Sample Sizes and Data Provenance:

   • Test Set:
     • Intra-assay Precision: 12 replicates for each of 4 levels (HS Salivary Cortisol EIA) and 3 levels (Predicate).
     • Inter-assay Precision: Mean of average duplicates for 12 separate runs for each of 4 levels (HS Salivary Cortisol EIA) and 3 levels (Predicate).
     • Sensitivity: 10 sets of duplicates at 0 µg/dL standard.
     • Linearity of Dilution: 3 saliva samples for HS Salivary Cortisol EIA, 2 samples for Predicate. Each diluted up to 1:16.
     • Recovery: 7 saliva samples for HS Salivary Cortisol EIA, 3 samples for Predicate.
     • Correlation with Serum: 68 matched samples (saliva and serum) from presumed normal adults.
     • Specificity: Tested various compounds at specific concentrations (e.g., up to 66,000 ng/mL for Transferrin).
   • Data Provenance: Not explicitly stated (e.g., country of origin). The studies appear to be prospective, laboratory-based analytical performance studies conducted by the manufacturer. No indication of retrospective data or data from clinical sites is provided for these specific performance characteristics.

2. Number of Experts and Qualifications for Ground Truth:

   • For the analytical performance studies (precision, sensitivity, linearity, recovery, specificity), ground truth is established by the known concentrations of calibrators, spiked samples, and controlled dilutions. This does not involve human experts in the way clinical diagnostic studies might.
   • For the correlation with serum, the ground truth for serum cortisol measurements was established by the predicate device (Diagnostic Systems Laboratory Active Cortisol EIA). The "presumed normal adults" served as the source of samples, and their "normality" would be based on standard clinical criteria, but no specific number or qualification of experts establishing this normality is mentioned.

3. Adjudication Method: Not applicable for these analytical performance studies, as the ground truth is based on known values, reference methods (predicate device for comparison), or established analytical protocols.

4. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study: No, this type of study was not performed. The submission focuses on the analytical performance of an immunoassay kit, not on the diagnostic performance of human readers with or without AI assistance.

5. Standalone (Algorithm Only) Performance Study: Yes, the entire submission describes the standalone performance of the HS Salivary Cortisol Enzyme Immunoassay Kit. It is a laboratory diagnostic device, and its performance is evaluated independent of human interpretation beyond the technical execution of the assay.

6. Type of Ground Truth Used:

   • Analytical Ground Truth: For precision, sensitivity, linearity, and recovery, the ground truth is based on known concentrations of standards, controls, and spiked substances.
   • Comparative Ground Truth: For correlation with serum, the predicate device (Diagnostic Systems Laboratory Active Cortisol EIA) served as the reference method for serum cortisol levels against which salivary cortisol measurements from the new device were compared.

7. Sample Size for Training Set: Not applicable. This device is an immunoassay kit, not a machine learning or AI algorithm that requires a training set in the conventional sense. The "training" of the assay refers to the internal calibration curve generated with the provided calibrators.

8. How Ground Truth for the Training Set Was Established: Not applicable. As it's an immunoassay kit, the concepts of "training set" and "ground truth for training" do not apply. The calibrators provided in the kit have NIST-traceable cortisol concentrations, establishing their "ground truth" for the assay's internal calibration.

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