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The GeneSTAT.MDx Coccidioides Assay is a qualitative real-time polymerase chain reaction (PCR) in vitro diagnostic test for the detection of nucleic acids from Coccidioides immitis and Coccidioides posadasii. The assay does not differentiate between these two species. The assay is performed on bronchial alveolar lavage (BAL) or bronchial wash (BW) specimens from patients presenting with respiratory signs and symptoms consistent with coccidioidomycosis. The GeneSTAT.MDx Coccidioides Assay is intended to be used along with clinical findings and other laboratory results as an aid in the diagnosis of coccidioidomycosis in patients with possible or probable exposure to Coccidioides immitis or Coccidioides posadasii.

The GeneSTAT.MDx Coccidioides Assay is a qualitative real-time PCR-based assay to detect target Coccidioides spp. DNA from bronchial alveolar lavage (BAL) or bronchial wash (BW) samples. The sample is prepared by a lysis and extraction process, with the extracted DNA then tested with the GeneSTAT.MDx Coccidioides assay on the GeneSTAT System.

The GeneSTAT System is a real-time PCR nucleic acid testing platform. The GeneSTAT system consists of:

• The single-use, disposable, assay-specific Test Module cartridge that contains the real-time PCR reagents, internal control, reaction wells, and test parameters. The single-use cartridge contains all the necessary reagents for amplification and detection of the Coccidioides target DNA as well as a human DNA control sequence that is used to monitor the presence of inhibitors in the PCR reaction and to ensure that the sample preparation process is adequate. All information to run the assay as well as lot number and expiration date is contained on the Radio-Frequency Identification (RFID) tag on the cartridge. The cartridge contains two PCR reaction wells. One well contains PCR reagents for amplification and detection of Coccidioides DNA and the human gene internal control (Reaction Well 1). The second well (Reaction Well 2) contains the same reagents for amplification/detection of Coccidioides DNA as used in Reaction Well 1 but does not contain the PCR reagents to detect the internal control.
• The GeneSTAT Analyzer instrument that performs the mechanical, optical, and fluidic actions upon the Test Module to perform the PCR reactions. The instrument generates, analyzes, and transmits results to a connected pre-configured computer for presentation to the user. One single-use Test Module can be tested at a time in each GeneSTAT Analyzer. Up to four GeneSTAT Analyzers can be connected to single computer.
• A MS Windows based laptop computer
• The associated software and firmware required to run the test, analyze the results, and present the results to the user.
• The Performance Verification Test Cartridges (PVT) that are used to periodically verify that the analyzer is functioning within acceptable limits. A successful PVT run is required to activate the analyzer. The PVT should be run at minimum every six months, and it is recommended that a PVT should be run monthly.

Here's a breakdown of the acceptance criteria and the study details for the GeneSTAT.MDx Coccidioides Assay, based on the provided text:

Acceptance Criteria and Device Performance for GeneSTAT.MDx Coccidioides Assay

1. Table of Acceptance Criteria and Reported Device Performance

The direct acceptance criteria for clinical performance are not explicitly stated as numerical targets before the study in the provided text (e.g., "minimum 90% sensitivity"). Instead, the study presents the observed performance, and the FDA's conclusion implies these results were deemed acceptable for classification. Therefore, the table below consolidates the clinical performance from the comparison studies as the de facto "reported device performance" that met the classification requirements. For analytical studies, "acceptable" as stated in the text is considered the acceptance criteria, and specific numerical results are provided where available.

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

A. Clinical Test Set:

• Prospective Samples:
  • Sample Size: 231 (189 BAL, 42 BW)
  • Data Provenance: Prospective collection from four geographically diverse regions endemic for Coccidioides in the United States: Phoenix, AZ, Albuquerque, NM, Tucson, AZ, and North Hollywood, CA. Samples were collected fresh and tested prospectively at three of the sites.
• Retrospective Samples:
  • Sample Size: 100 (51 positive: 27 BAL, 24 BW; 49 negative: 38 BAL, 11 BW)
  • Data Provenance: Frozen, de-identified BAL/BW specimens. Selected from previously confirmed negative and positive samples for Coccidioides infection. Implied to be from the same (or similar) endemic regions in the United States as the prospective samples, given the context of the study.

B. Analytical Test Set (Example: Reproducibility)

• Sample Size:
  • Between-site reproducibility: 90 replicates for each reactivity level (Moderate Positive, Low Positive, Negative BAL) across 3 sites. Total 270 replicates tested qualitatively.
  • Within-laboratory repeatability: 48 replicates for each reactivity level (Moderate Positive, Low Positive, Negative BAL). Total 144 replicates tested qualitatively.
• Data Provenance: Samples were contrived (spiked with attenuated C. posadasii spherules) in negative BAL sample matrix. Operators at internal and external test sites performed the testing. The origin of the negative BAL matrix itself is not specified but is assumed to be clinical samples from a relevant geographical origin, potentially within the US.

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

The text does not specify the number or qualifications of experts used to establish the ground truth.

For clinical studies, the ground truth was established by:

• Fungal culture followed by Coccidioides-specific DNA probe hybridization (AccuProbe, Hologic, Marlborough, MA) for all samples.
• For the retrospective samples, an independent real-time PCR and bi-directional sequencing method was additionally used for confirmation, and only samples concordant by both culture and the reference lab PCR/sequencing were included.

While these methods inherently involve expert interpretation and laboratory personnel, the document does not quantify the number of experts or detail their specific qualifications (e.g., mycologist, molecular biologist, board-certified pathologists, etc., or their years of experience).

4. Adjudication Method for the Test Set

The text does not describe an adjudication method in the typical sense of multiple human readers reviewing discordant results. Instead, for the clinical test sets:

• Discordant samples (e.g., the false positive in the prospective study, or false positives in the retrospective study) were investigated by independent real-time PCR and bi-directional sequencing method to confirm the Coccidioides DNA status and verify the true positive/negative status of the sample.
• For the analytical studies, if an initial invalid result occurred, the sample was re-tested per assay instructions. Similarly, initial false positives or false negatives in analytical specificity or control checks were re-tested (often at higher concentrations) to confirm the final result.

This implies a process of re-testing and confirmation using an orthogonal method rather than a multi-expert consensus adjudication of a single interpretation.

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

No, a Multi Reader Multi Case (MRMC) comparative effectiveness study was not done.

This device is an in vitro diagnostic (IVD) assay, not an imaging or interpretive device that typically involves human readers or their interaction with AI. The studies assess the standalone performance of the assay compared to established laboratory methods (fungal culture, PCR/sequencing), not how human interpretation improves with AI assistance. Therefore, there is no mention of human readers or an effect size for human improvement with AI assistance.

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

Yes, a standalone study was done.

The entire analytical and clinical performance evaluation of the GeneSTAT.MDx Coccidioides Assay is a standalone assessment of the device's ability to detect Coccidioides DNA directly from samples. The GeneSTAT System, with its associated software and firmware, performs the PCR reactions, analyzes the results, and presents them to the user. While a human operator initiates the run and performs sample preparation, the interpretation of the raw signals and generation of the "Coccidioides DNA Detected" or "Not Detected" results is performed by the algorithm within the device.

The clinical studies specifically compare the GeneSTAT.MDx Coccidioides assay's output directly against the "gold standard" ground truth (fungal culture/DNA probe/reference PCR/sequencing) without human intervention in the interpretation of the assay's output.

7. The Type of Ground Truth Used

The ground truth used for the clinical studies was a combination of:

• Fungal culture followed by Coccidioides-specific DNA probe hybridization (AccuProbe). This is a laboratory-based method.
• For retrospective samples, this was further cross-referenced and confirmed by validated PCR assay with bi-directional sequencing. This is also a laboratory-based molecular method.

Therefore, the ground truth relies on laboratory diagnostic methods (culture, DNA probe, reference PCR/sequencing), which are considered highly reliable for the presence or absence of the organism's DNA. It is not directly pathology (histology), expert consensus on clinical presentation only, or patient outcomes data as the primary ground truth.

8. The Sample Size for the Training Set

The document does not specify a separate "training set" sample size for the algorithm itself. PCR-based assays like the GeneSTAT.MDx Coccidioides Assay typically do not undergo a separate "training" phase in the same way machine learning algorithms do, especially for the core detection logic.

However, the "cut-off values for the assay Coccidioides result and the internal control were established and verified by analyzing contrived samples and clinical BAL/BW samples known to be positive and negative for Coccidioides." This process of establishing and verifying cut-offs effectively acts as a form of "calibration" or optimization using a dataset of known samples, which could be functionally considered a "training" or "development" dataset. The size of this specific dataset for cut-off establishment is not stated.

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

Given the above, if we consider the "cut-off establishment" samples as a form of training set:

The ground truth for these samples was established by their known status for Coccidioides (i.e., known positive or negative). This would have been determined either by:

• Contrived samples: Artificially prepared samples with known concentrations of Coccidioides (e.g., spiked attenuated C. posadasii spherules).
• Clinical BAL/BW samples known to be positive and negative for Coccidioides: These would have been characterized using established laboratory methods such as fungal culture and/or reference molecular methods similar to those used for the clinical validation studies.

The document states this process validates the cut-offs, which are then applied to the performance evaluation.

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