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The Xpert® vanA test performed on the GeneXpert® Instrument Systems is a qualitative in vitro diagnostic test designed for detection of the vanA gene sequence associated with vancomycin resistance in bacteria obtained from rectal swab specimens from patients at risk for intestinal colonization with vancomycin-resistant bacteria. The test utilizes automated real-time polymerase chain reaction (PCR) to detect the vanA gene that is frequently associated with vancomycin-resistant enterococci (VRE). The Xpert vanA test is intended to aid in the recognition, prevention, and control of vancomycin-resistant organisms that colonize patients in healthcare settings. The Xpert vanA test is not intended to diagnose infections caused by vancomycin-resistant bacteria nor to guide or monitor treatment for vancomycin-resistant bacterial infections. Concomitant cultures are necessary to recover organisms for identification of vancomycin-resistant bacteria, antimicrobial susceptibility testing, and for epidemiological typing.

The Xpert van4 test is an automated in vitro diagnostic test for the qualitative detection of the vanA gene sequence associated with vancomycin resistance in bacteria obtained directly from rectal swab specimens. The specimen is collected on a double swab, one of which is placed in a tube containing sample reagent. Following brief vortexing, the content of the sample reagent is transferred to the uniquely labeled Sample Chamber of a disposable fluidic cartridge (the Xpert vanA cartridge). The user initiates a test from the user interface of the GeneXpert® instrument system platform and places the cartridge with sample into the GeneXpert® instrument system which performs hands-off real-time, multiplex polymerase chain reaction (PCR) for the detection of vanA DNA.

In the GeneXpert® Instrument Systems (comprised of the GeneXpert® Dx System, GeneXpert® System with Touchscreen, and GeneXpert® Infinity System), sample preparation, amplification, and real-time detection are all fully automated and completely integrated. The platform requires the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained, cross-contamination between samples is minimized.

Depending on the specific instrument, a GeneXpert® instrument system may contain 1-80 modules, each of which are randomly accessible and capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE thermocycler for performing real-time PCR and detection.

The Xpert van4 test includes reagents for the detection of the gene for vancomycin resistance (van4) as well as an internal sample processing control (SPC) to control for adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR assay. The SPC also ensures that the PCR conditions (temperature and time) are appropriate for the amplification reaction and that the PCR reagents are functional. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.

The Xpert van 4 test performed on the GeneXpert® Instrument Systems provides results in less than 45 minutes.

Each instrument in the GeneXpert® instrument family is equipped with a Windows OS-based personal computer that is preloaded with software applications for running the tests and viewing the results, as described in Table 1.

The provided text describes a 510(k) premarket notification for the Cepheid Xpert vanA test. This submission is for a modification to an already cleared device (Xpert vanA, K092953) to include the GeneXpert Infinity System instruments. As such, the document primarily focuses on demonstrating that the performance of the modified device is equivalent to the predicate device and does not present a full de novo study with a comprehensive set of acceptance criteria and performance statistics like sensitivity and specificity against a clinical ground truth.

Here's an analysis of the available information:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state formal acceptance criteria with numerical targets for the verification studies. Instead, it describes "verification studies" aiming to show equivalence to the predicate device. The performance is reported qualitatively as "100% agreement of reportable results" and "no statistically significant differences in Ct values."

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

The document mentions "both contrived positive (vancomycin-resistant (vanA) Enterococcus faecalis cells added to negative matrix) and negative matrix only) samples" for functional testing. However, it does not specify the sample size for these contrived samples.

The data provenance is from verification studies conducted by the manufacturer (Cepheid) to demonstrate the performance of the Xpert vanA test on the GeneXpert Infinity System instruments. The samples are contrived, meaning they were prepared in a laboratory setting, rather than derived from a patient population (i.e., not prospective or retrospective clinical data in the traditional sense).

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

Given that the test set consisted of "contrived positive" and "negative matrix only" samples, the ground truth was established by the known composition of these laboratory-prepared samples. There is no mention of external experts or clinical adjudication for these ground truths, as the samples were artificially created with a defined vanA status.

4. Adjudication Method for the Test Set

No explicit adjudication method is mentioned. For contrived samples with a known composition, formal adjudication by a panel of experts is typically not performed or necessary. The "ground truth" is inherent in the preparation of the samples.

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

This question is not applicable to this submission. The Xpert vanA test is a qualitative in vitro diagnostic test that uses automated real-time PCR to detect the vanA gene sequence. It is a fully automated system, and human interpretation of results is minimal (typically reading a "detected" or "not detected" output). There is no "AI" or "human reader" component in the diagnostic process that would warrant an MRMC study or an assessment of human reader improvement with AI assistance.

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

Yes, the performance evaluated here is essentially standalone (algorithm only). The Xpert vanA test is an automated system where sample preparation, amplification, and real-time detection are fully integrated. The "device performance" refers to the automated output of the system.

7. The Type of Ground Truth Used

The ground truth for the verification studies was based on known, contrived samples. For the "contrived positive" samples, the ground truth was the presence of vanA positive Enterococcus faecalis cells. For "negative matrix only" samples, the ground truth was the absence of vanA.

8. The Sample Size for the Training Set

This document does not provide information about a "training set." This submission focuses on verification studies for a modification to a previously cleared device. Diagnostic devices like this typically undergo extensive development and validation, but the details of the initial development (including training sets for algorithms, if any) are not part of this specific 510(k) summary for a modification. The test is based on PCR, not machine learning that would require a distinct "training set."

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

Since no training set is mentioned or applicable in the context of this PCR-based diagnostic device and modification, how its ground truth was established is not provided in the document.

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The Cepheid Xpert® vanA Assay performed in the GeneXpert® Dx System is a qualitative in vitro diagnostic test designed for rapid detection of the vanA gene sequence associated with vancomycin resistance in bacteria obtained from rectal swab specimens from patients at risk for intestinal colonization with vancomycin-resistant bacteria. The test utilizes automated real-time polymerase chain reaction (PCR) to detect the vanA gene that is frequently associated with vancomycin-resistant enterococci (VRE). The Xpert vanA Assay is intended to aid in the recognition, prevention, and control of vancomycin-resistant organisms that colonize patients in healthcare settings. The Xpert vanA Assay is not intended to diagnose infections caused by vancomycin-resistant bacteria nor to guide or monitor treatment for vancomycin-resistant bacterial infections. Concomitant cultures are necessary to recover organisms for identification of vancomycin-resistant bacteria, antimicrobial susceptibility testing and for epidemiological typing.

The Cepheid Xpert vanA Assay is a rapid, automated in vitro diagnostic test for qualitative detection of the vanA gene sequence associated with vancomycin resistance in bacteria obtained directly from rectal swab specimens. The Xpert vanA Assay system performs real-time multiplex polymerase chain reaction (PCR) for detection of DNA after an initial sample processing step. The assay is performed on the Cepheid GeneXpert® Dx System. The specimen is collected on a double swab, one of which is placed in a tube containing elution reagent. Following brief vortexing, the eluted material and two single-use reagents (Reagent 1 and Reagent 2) that are provided with the assay are transferred to different, uniquely-labeled chambers of the disposable fluidic cartridge (the Xpert vanA cartridge). The user initiates a test from the system user interface and places the cartridge into the GeneXpert® Dx System instrument platform, which performs hands-off realtime, multiplex polymerase chain reaction (PCR) for detection of DNA. In this platform, additional sample preparation, amplification, and real-time detection are all fullyautomated and completely integrated. The GeneXpert® System consists of a GeneXpert instrument, personal computer, and the multi-chambered fluidic cartridges that are designed to complete sample preparation and real-time PCR for detection of the vanA gene that is associated with vancomycin-resistant enterococci (VRE) in less than 45 minutes. Each instrument system has 1 to 16 randomly accessible modules that are each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids, an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and detection. The Xpert vanA Assay includes reagents for the detection of the vanA resistant gene as well as an internal sample processing control (SPC) to control for adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR assay. The SPC also ensures the PCR conditions (temperature and time) are appropriate for the amplification reaction and that the PCR reagents are functional. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.

Here's an analysis of the provided text regarding the acceptance criteria and study for the Xpert vanA Assay:

Acceptance Criteria and Device Performance for Xpert vanA Assay

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria in terms of numerical thresholds for sensitivity, specificity, or agreement. Instead, it demonstrates "substantial equivalence" to predicate devices (a PCR assay and a culture method) and the "current standard of care." The reported performance metrics are presented from clinical comparison studies.

For the purpose of this response, I will interpret the achieved performance relative to the reference standard as the demonstrated effectiveness that led to acceptance.

Note: The document emphasizes that the device is "as safe, as effective, and performs as well as the current standard of care," which implies the stated performance metrics meet the (unspecified) acceptance levels for substantial equivalence.

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

• Sample Size for Test Set: A total of 1231 specimens were tested in the clinical comparison study.
• Data Provenance: The study was a multi-site prospective investigation study conducted at three US institutions.

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

The document does not specify the "number of experts" used in the typical sense of radiologists or other clinicians reviewing images. Instead, the ground truth was established through a multi-step laboratory process:

• Reference Culture: Performed by a central laboratory.
• Bi-directional Sequencing Confirmation: Performed on vancomycin-resistant E. faecalis or E. faecium isolates, sent to a second reference laboratory using alternative vanA specific primers.
• Identification and Susceptibility Testing: Presumptive VRE was definitively identified using the API20S strip (BioMérieux, France) and VRE isolates were tested for susceptibility to glycopeptides using vancomycin E-test strips and agar dilution for teicoplanin.

While specific "expert qualifications" (e.g., years of experience for individual technicians/scientists) are not detailed, the process involves established laboratory protocols and confirmation by multiple methods and reference laboratories, implying a high level of expertise in molecular biology and microbiology.

4. Adjudication Method for the Test Set

The adjudication method was a multi-step laboratory confirmation process, rather than a typical clinical adjudication by multiple human reviewers. The ground truth was established by:

• Reference Culture: Starting with bile esculin azide broth with vancomycin, followed by subculture to agar.
• Presumptive Identification: Gram stain, catalase, and pyr test.
• Definitive Identification: API20S strip.
• Susceptibility Testing: Vancomycin E-test strips and agar dilution for teicoplanin.
• Final Confirmation: Bi-directional sequencing of vanA-positive isolates using independent primers.

This layered approach serves as the "adjudication" to establish the most accurate ground truth for VRE colonization with the vanA gene.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a MRMC comparative effectiveness study was not done.

This device is an in vitro diagnostic (IVD) PCR assay, which produces an objective "Positive" or "Negative" result for the presence of the vanA gene. It does not involve human readers interpreting complex data like medical images, so a study comparing human reader performance with and without AI assistance is not applicable.

6. Standalone Performance Study

Yes, a standalone performance study was done.

The clinical comparison study directly evaluated the Xpert vanA Assay's performance (algorithm only, without human-in-the-loop adjustments to the result) against the established reference culture and bi-directional sequencing gold standard. The reported Percent Positive Agreement, Percent Negative Agreement, Accuracy, PPV, and NPV are all measures of the standalone performance of the device.

7. Type of Ground Truth Used

The ground truth used was a combination of expert consensus laboratory methods:

• Reference culture: Phenotypic detection of vancomycin-resistant enterococci (VRE) growth on selective media.
• Definitive identification and susceptibility testing: Using established laboratory methods (API20S, E-test strips, agar dilution).
• Bi-directional sequencing confirmation: Genetic confirmation of the vanA gene using independent primers.

This provides a robust, multi-faceted ground truth derived from both phenotypic and genotypic characteristics.

8. Sample Size for the Training Set

The document does not specify a sample size for a training set. This is common for IVD assays based on established molecular biology principles (PCR), where the assay design is driven by known genetic targets rather than machine learning on large, annotated datasets requiring separate training and test sets.

The "non-clinical studies" (analytical reactivity, sensitivity, linearity, specificity, interfering substances) describe laboratory-based testing of known strains and samples to characterize the assay's fundamental performance. These experiments might involve optimizing assay parameters, but not in the context of a "training set" for a machine learning algorithm.

For example:

• Analytical Reactivity: Tested 30 vancomycin-resistant enterococci strains and 20 vancomycin-sensitive enterococci strains.
• Analytical Sensitivity (LoD): Used 4 to 10 replicates for estimation and 20 replicates for confirmation.
• Linearity: Used replicates of 4 at each of 6 serial dilutions.
• Analytical Specificity: Tested 42 bacterial and fungal strains.

These are not "training sets" in the AI sense, but rather validation sets for internal development and characterization.

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

As there is no explicit training set described in the context of a machine learning algorithm, the question of how its ground truth was established is not directly applicable.

The "ground truth" for the analytical studies (e.g., whether a strain is vanA positive or negative, or its CFU/mL concentration) was established by standard microbiological and genetic methods (e.g., strain identification, sequencing, quantitative culturing methods).

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