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The Xpert® Carba-R Assay, performed on the GeneXpert® Instrument Systems, is a qualitative in vitro diagnostic test designed for the detection and differentiation of the blakes, blaypy, blaxx -8, and blang gene sequences associated with carbapenem-non-susceptibility. The test utilizes automated real-time polymerase chain reaction (PCR).

The Xpert Carba-R Assay is intended as an aid to infection of carbapenem-non-susceptible bacteria that colonize patients in healthcare settings. A negative Xpert Carba-R Assay result does not preclude the presence of other resistance mechanisms.

The Xpert Carba R-Assay is for use with the following sample types:

Pure Colonies
The assay is performed on carbapentible pure colonies of Enterobacteriaceae. Acinetobacter baumannii. or Pseudomonas aeruginosa, when grown on blood agar or MacConkey agar. For testing pure colonies, the Xpert Carba-R Assay should be used in conjunction with other laboratory tests including phenotypic antimicrobial susceptibility testing.

The identification of a blawy, blayin metallo-beta-lactamase gene (i.e., the genes that encode the INP, NDM, and VIM metallo-beta-lactamases, respectively) may be used as an aid to clinicians in determining appropriate therapeutic strategies for patients with known or suspected carbapenem-non- susceptible bacterial infections.

Rectal and Perirectal Swab Specimens
The assay is performed on rectal swab specimens from patients at risk for intestinal colonization with carbapenem-non-susceptible bacteria. Concomitant cultures are necessary to recover organisms for epidemiological typing, antimicrobial susceptibility testing, and for further confirmatory bacterial identification.

The Xpert Carba-R Assay, when performed on rectal and perirectal swab specimens, is not intended to guide or monitor treatment for carbapenem-non-susceptible bacterial infections or to determine infection from carbapenem-nonsusceptible bacteria.

The Xpert Carba-R Assay is an automated real-time polymerase chain reaction (PCR) in vitro diagnostic test for qualitative detection of the blakpo, blaymy, blavny, blaoxa-as, and blamp gene sequences from rectal or perirectal swab specimens or isolates of pure cultures of carbapenem-non-susceptibility gram-negative bacteria. The Xpert Carba-R Assay is intended as an aid for infection control for monitoring the spread of carbapenem-non-susceptible organisms in healthcare settings.

The Xpert Carba-R Assay is performed on the Cepheid GeneXpert® Instrument Systems (GeneXpert Dx, GeneXpert Infinity-48, GeneXpert Infinity-48s, and GeneXpert Infinity-80 systems). The GeneXpert Instrument System platform automates sample preparation, amplification and real-time detection.

The GeneXpert Instrument Systems require the use of single-use, disposable cartridges (the Xpert Carba-R cartridges) that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained and specimens never come into contact with working parts of the instrument modules, cross-contamination between samples is minimized.

The Xpert Carba-R Assay cartridges contain reagents for the detection of blaxpy blayDM blaym, blacks, and blandp gene sequences. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are controls utilized by the GeneXpert Instrument System platform. The SPC is present to control for adequate processing of the target bacteria and to monitor the presence of inhibitors in the real-time PCR reaction to reduce the possibility of false negative results. The PCC verifies reagent rehydration, real-time PCR tube filling in the cartridge, probe integrity, and dye stability.

The single-use, multi-chambered fluidic cartridges are designed to complete sample preparation and real-time PCR for the detection of the blakpc, blaNDM, blagxA-48 and blamp gene sequences from rectal or perirectal swab specimens or isolates of pure cultures of carbapenem-non- susceptibility gram-negative bacteria in approximately 50 minutes. The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems and the GeneXpert Infinity Systems, have 1 to 80 randomly accessible modules, depending upon the instrument, that are each capable of performing separate sample processing and real-time PCR and RT- 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 RT-PCR and detection.

Rectal or perirectal swab specimens or bacterial isolates from culture are placed into a sample reagent. The sample is transferred to the sample chamber of the disposable fluidic cartridge (the Xpert Carba-R cartridge). The user initiates a test from the system user interface and places the cartridge into the GeneXpert instrument platform, which performs hands-off real-time, multiplex PCR for detection of the blakers, blayDM blaym, blacks, and blamp gene sequences. The results are automatically generated at the end of the process in a report that can be viewed and printed.

Here's an analysis of the provided text, focusing on the acceptance criteria and the study that proves the device meets them, structured according to your request.

Device Name: Xpert® Carba-R Assay

1. Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a numbered or bulleted list with corresponding performance numbers for each criterion, as would be ideal in a formal acceptance criteria table. However, based on the non-clinical and clinical studies presented, we can infer the acceptance criteria and the device's performance against them, particularly focusing on the clinical performance as that's often tied to regulatory acceptance.

The primary measure of clinical performance for this diagnostic device is Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) against a reference method. Analytical criteria include Limit of Detection (LoD), inclusivity (analytical reactivity), and analytical specificity (cross-reactivity).

Inferred Acceptance Criteria and Reported Device Performance (with direct performance data as provided):

(Note: "N/A" for PPA signifies no True Positives were observed in the prospective study for IMP and VIM, which is reflected in the CI. The acceptance threshold is inferred based on typical diagnostic performance expectations for such devices.)

2. Sample Size and Data Provenance

• Test Set Sample Sizes:

  • Prospective Clinical Study (Perirectal Swab Specimens): 924 eligible specimens (from an initial 963 enrolled).
  • Contrived Clinical Study (Perirectal Swab Matrix): 432 specimens.
  • Perirectal vs. Rectal Swab Equivalence Study: 201 eligible specimens (from an initial 207 enrolled).
  • Analytical Sensitivity (LoD): 20 replicates for each target (10 carbapenemase-producing organisms) at each concentration level, tested over 4 days, then 10 verification replicates at each estimated LoD.
  • Analytical Reactivity (Inclusivity): 72 samples, tested in triplicate at approximately 3X LoD.
  • Analytical Specificity (Cross-reactivity): 62 carbapenem-susceptible/non-susceptible bacterial strains, 24 commensal bacterial strains/enteric microorganisms, human cells. Tested in triplicate.
  • Carry-Over Contamination: 102 tests (50 high positive, 52 negative).
  • Competitive Interference: Replicates of eight for each combination.
  • Potentially Interfering Substances: 8 replicates of positive samples and 8 replicates of negative samples tested per substance (24 substances).
  • Reproducibility: 11 samples x 4 replicates/day x 6 days x 2 operators x 3 sites = 1584 total tests (though 144 replicates per sample type for analysis).

• Data Provenance:

  • Prospective Clinical Study: "Five geographically diverse sites" collected specimens. This implies a multi-center study, likely in the US, given the FDA submission. The study involved patient samples ("subjects who were hospitalized or in a long-term care facility"). This is prospective data collection.
  • Contrived Clinical Study: Prepared in perirectal matrix, likely laboratory-based data using spiked samples. This is non-clinical/laboratory data.
  • Perirectal vs. Rectal Swab Equivalence Study: "one site enrolling fresh prospectively collected rectal and perirectal swab specimens from consented subjects who were hospitalized in-patients." This is prospective data collection, from a single center.
  • Other non-clinical studies (Analytical, Reproducibility, etc.) are laboratory-based and generated data, not patient-derived.

3. Number of Experts and Qualifications (for Ground Truth)

The document does not explicitly state the number of experts or their specific qualifications (e.g., "radiologist with 10 years of experience") used for establishing the ground truth.

For the clinical studies, the reference method involved:

• Culturing the MacConkey enrichment broth.
• Screening for carbapenem-non-susceptible organisms.
• Confirmation by disk diffusion method (per CLSI document M02 and M100).
• DNA extraction, quantification, and amplification with specific primers.
• Confirmation of amplicon size on Agilent 2100 Bioanalyzer.
• For positive cases, sending the amplicon to an independent laboratory for reference bi-directional sequencing analysis, which was validated for detection of the five targets.

While "experts" are implicitly involved in performing and interpreting these complex laboratory procedures, their specific number, roles, and detailed qualifications are not detailed.

4. Adjudication Method for the Test Set

The document mentions discordant analysis for the prospective clinical study.

• "For specimens with discordant results (the Xpert Carba-R Assay was positive for a target gene but a carbapenem-non-susceptible organism was not isolated by reference culture), discordant analysis was performed using bi-directional sequencing on DNA extracted directly from the MacConkey enrichment broth."
• This indicates a process of re-evaluation of discrepancies, but it's not a formal multi-reader, consensus-based adjudication process for initial ground truth establishment. It's a method for clarifying "false positive" results by seeking further molecular evidence in the original sample. No mention of 2+1 or 3+1 for human readers or direct adjudication of AI outputs is present.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is a diagnostic assay (molecular test), not an AI system assisting human readers with interpreting images or other data. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" is not applicable here.

6. Standalone Performance

Yes, the studies primarily evaluate the standalone performance of the Xpert Carba-R Assay. The device is a "qualitative in vitro diagnostic test designed for the detection and differentiation of gene sequences." Its performance metrics (PPA, NPA, LoD, specificity, reproducibility) are reported for the device itself, not in conjunction with human interpretation of its results, beyond the clinical correlation implied by its "aid to infection control" indication. It's an "algorithm only" in the sense that it provides a direct qualitative result (DETECTED/NOT DETECTED) based on its PCR analysis.

7. Type of Ground Truth Used

The ground truth for the clinical studies (prospective and contrived) was established by a reference method combination of:

• Culture: MacConkey enrichment broth culture followed by disk diffusion method (per CLSI M02/M100) to confirm carbapenem non-susceptibility.
• DNA Sequencing: Bi-directional DNA sequence analysis of purified and amplified DNA from isolated colonies or, in discordant cases, directly from the MacConkey enrichment broth.

For the analytical studies, the ground truth was established by precise laboratory preparations (e.g., known concentrations of bacterial strains for LoD, well-characterized strains for reactivity and specificity).

8. Sample Size for the Training Set

The document describes premarket clinical trials and analytical studies for testing and validation. There is no mention of a separate "training set" or "training data" in the context of machine learning or AI models. This device is a molecular diagnostic assay (PCR-based), not an AI algorithm that undergoes data-driven training. The development of such a device involves assay design, optimization, and then extensive analytical and clinical validation, but not "training" in the AI sense.

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

As noted above, there is no mention of a "training set" for an AI model. For the development and validation of the PCR assay itself, ground truth for optimization and development would implicitly have been established through a combination of:

• Known Reference Strains: Using well-characterized bacterial strains with confirmed genetic markers.
• Synthetic Oligonucleotides: Designing and testing probes and primers against known sequences.
• Internal Laboratory Experiments: Repeated testing and refinement to achieve desired assay performance characteristics before formal validation studies.

These are common practices in the development of molecular diagnostic assays, but they are not described as AI-style "training" with a dedicated "training set."

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