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For in vitro diagnostic use in the quantitative determination of total testosterone (bound and unbound) in serum using the ADVIA Centaur and ADVIA Centaur XP systems.

Measurements of testosterone are used in the diagnosis and treatment of disorders involving the male sex hormones (androgens), including primary and secondary hypogonadism, delayed or precocious puberty, impotence in males and, in females, hirsutism (excessive hair) and virilization (masculinization) due to tumors, polycystic ovaries, and adrenogenital syndromes.

The ADVIA Centaur TSTO assay consists of the following:
ADVIA Centaur TSTO Primary Reagent ReadyPack
ADVIA Centaur TSTO Lite Reagent: acridinium ester-labeled testosterone in buffered saline with preservatives
ADVIA Centaur TSTO Solid Phase: polyclonal rabbit antitestosterone antibody bound to monoclonal mouse antirabbit antibody covalently coupled to paramagnetic particles in buffered saline with sodium azide (0.1%) and preservatives
Probe Wash: buffered saline with sodium azide (0.1%) and preservatives
ADVIA Centaur TSTO Ancillary Reagent ReadyPack
ADVIA Centaur TSTO Releasing Agent: steroid releasing agent (~0.1 µg/mL) in buffered saline with sodium azide (0.1%) and preservatives
Cal E Low and High Calibrators: (After reconstitution) low or high levels of cortisol, progesterone and testosterone in human plasma with sodium azide (0.1%) and preservatives

The methodology is Competitive immunoassay using direct chemiluminescent technology.

The Siemens Healthcare Diagnostics Inc. ADVIA Centaur TSTO assay is a device for the quantitative determination of total testosterone in serum. The submission (K133491) is for a modification to the assay due to the qualification of a new polyclonal rabbit anti-testosterone pool. This is a Class I (Reserved) device, product code CDZ, and is regulated under 21 CFR 862.1680.

Here's an analysis of the acceptance criteria and study in relation to the modified device:

1. Table of Acceptance Criteria and Reported Device Performance:

The document describes specific performance characteristics rather than explicit "acceptance criteria" with numerical thresholds for each test. However, we can infer the acceptance for some based on the reported results and the comparison to an existing predicate device. The primary acceptance for this submission is demonstrating "substantial equivalence" to the predicate device.

2. Sample Sizes Used for the Test Set and Data Provenance:

• Precision:
  • Sample Size: Human specimen pools, three levels of controls, and one in-house serum control. Each sample assayed in 2 replicates per run, 2 runs per day for 20 days (total of 80 replicates per sample type).
  • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective). Implicitly, this is a prospective study conducted during device development/modification.
• Linearity:
  • Sample Size: 9 serially diluted samples. Each sample assayed in triplicate.
  • Data Provenance: Not explicitly stated. Implicitly, prospective.
• Method Comparison:
  • Sample Size: 120 serum samples.
  • Data Provenance: Not explicitly stated. Implicitly, prospective.
• Reference Interval Verification:
  • Sample Size: 20 female and 20 male apparently healthy donors (serum samples).
  • Data Provenance: Not explicitly stated. Implicitly, prospective.
• Detection Limit:
  • Sample Size: Not specified beyond "series of results" for LoB and "smallest amount" for LoD.
  • Data Provenance: Not explicitly stated. Implicitly, prospective.
• Endogenous Interference:
  • Sample Size: Two sample pools (one low, one high testosterone), spiked with potential interferents. Samples tested in replicates of three (3).
  • Data Provenance: Not explicitly stated. Implicitly, prospective.
• Cross-Reactivity:
  • Sample Size: One low testosterone sample and one Multi-Diluent 3 sample (~0 ng/dL), spiked with potential cross-reactants. Tested in replicates of 6 per sample.
  • Data Provenance: Not explicitly stated. Implicitly, prospective.

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

Ground truth in this context refers to the true concentration of testosterone or the presence/absence of interferents/cross-reactants. For in vitro diagnostic assays like this, the "ground truth" is typically established by:

• Reference Methods: Often a gold-standard method (e.g., mass spectrometry) or a well-validated reference assay. While not explicitly mentioned as a separate ground truth determination step for the test samples themselves (rather, the predicate device is the comparison), it's assumed that the predicate device and the methods for spiking samples are based on established and accurate measurements.
• Known Concentrations: For linearity, interference, and cross-reactivity studies, the "ground truth" is the known concentration of the analyte or interferent/cross-reactant that was spiked into the samples.

The document does not mention the use of human experts (e.g., radiologists) for adjudication or establishing ground truth in the way it would be for imaging diagnostics. The ground truth here is analytical, based on chemical and laboratory standards.

4. Adjudication Method for the Test Set:

Not applicable. This is an in vitro diagnostic device reporting quantitative measurements, not a diagnostic imaging device requiring expert consensus for interpretation. The performance is assessed statistically against predefined analytical standards or comparative methods.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size with vs. without AI Assistance:

Not applicable. This is an in vitro diagnostic assay for measuring testosterone levels, not an AI-assisted diagnostic imaging device or a device involving human interpretation of complex data for a "case." Therefore, an MRMC study and AI assistance effect size are not relevant to this submission.

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

Yes, the studies described are standalone device performance studies. The ADVIA Centaur TSTO assay is an automated diagnostic instrument. The performance characteristics (precision, linearity, method comparison, etc.) are evaluated based solely on the output of the instrument (the "algorithm" or assay chemistry) itself, without human intervention in the result determination process beyond running the assay and interpreting the quantitative data.

7. The Type of Ground Truth Used:

The ground truth used in these studies is primarily:

• Known concentrations: For linearity, interference, and cross-reactivity studies, the ground truth is established by spiking samples with known quantities of the analyte or interfering substances.
• Predicate Device Measurements: For method comparison, the results from the predicate device (unmodified ADVIA Centaur TSTO assay) serve as the comparative "ground truth" to demonstrate substantial equivalence.
• Defined Reference Ranges: For reference interval verification, the "ground truth" is the established reference intervals for males and females.

8. The Sample Size for the Training Set:

This document does not specify a separate "training set" in the context of machine learning or AI. For in vitro diagnostic assays, the assay parameters are developed and optimized through extensive R&D, often using a multitude of samples, but these are not typically referred to as a "training set" in the AI sense. The submission describes the validation of a modified device. The original development of the predicate device would have involved internal "training" or optimization, but those details are not provided here.

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

As there is no "training set" described in the AI/machine learning sense, this question is not directly applicable. For the development of the assay (which is analogous to training in a broader sense), the ground truth would have been established through methodologies such as:

• Reference methods: Using gold standard analytical techniques to accurately quantify testosterone.
• Highly purified standards: Using precisely weighed and quantified testosterone standards to calibrate the assay and ensure accurate measurement.
• Gravimetric and volumetric preparations: For preparing calibrators, controls, and spiked samples, relying on accurate laboratory techniques to establish known concentrations.

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