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The BD MAX Check-Points CPO Assay performed on the BD MAX System is a qualitative, automated in vitro diagnostic real-time PCR test designed for the detection and differentiation of the carbapenemase genes blakes, blayble blaymoblance and black-48, that are associated with carbapenem non-susceptibility in Gram-negative bacteria. The assay does not distinguish between the blay™ and bland genes.

The BD MAX Check-Points CPO Assay is intended as an aid to infection control in the detection of carbapenem-non-susceptible bacteria that colonize patients in healthcare settings. The BD MAX Check-Points CPO Assay is not intended to guide or monitor treatment for carbapenem-non-susceptible bacterial infections. A negative BD MAX Check-Points CPO Assay result does not preclude the presence of other resistance mechanisms.

Testing is performed on rectal swabs from patients at risk for intestinal colonisation with carbapenem nonsusceptible bacteria. This test is intended for use in conjunction with clinical presentation, laboratory findings, and epidemiological information. Results of this test should not be used as the sole basis for patient management decisions. Concomitant cultures are necessary to recover organisms for epidemiological typing, antimicrobial susceptibility testing, and for further confirmatory bacterial identification.

The BD MAX Check-Points CPO Assay detects the presence of carbapenemase genes in Gram-negative bacteria and includes an internal Sample Processing Control.

Rectal swab specimens are collected from patients using ESwab. After sampling they are transported to the laboratory in the Amies transport media of the ESwab. The ESwab is vortexed and a 50 µl aliquot is transferred to the Sample Buffer Tube using a pipette with disposable filter tip. The Sample Buffer Tube is closed with a septum cap and vortexed. Once the worklist is generated and the clinical specimen is loaded on the BD MAX system, along with a BD MAX Check-Points CPO Reagent Strip and BD MAX PCR Cartridge, the run is started and no further operator intervention is required. The BD MAX System automates sample preparation, including target organism lysis, DNA extraction and concentration, reagent rehydration, target nucleic acid sequence amplification and detection using real-time PCR. The interpretation of the signal is performed automatically by the BD MAX System. The assay also includes a Sample Processing Control that is provided in the Extraction Tube and subjected to extraction, concentration and amplification steps. The Sample Processing Control monitors for the presence of potential inhibitory substances as well as system or reagent failures.

Following enzymatic cell lysis at an elevated temperature, the released nucleic acids are captured on magnetic affinity beads. The beads, with the bound nucleic acids, are washed and the nucleic acids are eluted. Eluted DNA is neutralized and transferred to the Master Mix Tube to rehydrate the PCR reagents. After rehydration, the BD MAX System dispenses a fixed volume of PCR-ready solution into the BD MAX PCR Cartridge. Microvalves in the BD MAX PCR Cartridge are sealed by the system prior to initiating PCR to contain the amplification mixture thus preventing evaporation and contamination. The amplified DNA targets are detected using hydrolysis (TaqMan®) probes, labeled at one end with a fluorescent reporter dve (fluorophore) and at the other end with a quencher moiety. Probes labeled with different fluorophores are used to detect amplicons for the carbapenemase genes KPC, VIM, OXA-48, NDM, IMP and the Sample Processing Control in five different optical channels of the BD MAX System.

The VIM and IMP genes are combined in one optical channel of the BD MAX system, all other genes have a separate optical channel. When the probes are in their native state, the fluorescence of the fluorophore is quenched due to its proximity to the quencher. However, in the presence of target DNA, the probes hybridize to their complementary sequences and are hydrolyzed by the 5'-3' exonuclease activity of the DNA polymerase as it synthesizes the nascent strand along the DNA template. As a result, the fluorophores are separated from the quencher molecules and fluorescence is emitted. The BD MAX System monitors these signals at each cvcle and interprets the data at the end of the program to report the final results.

The provided document describes the performance characteristics of the BD MAX Check-Points CPO Assay. This device is a qualitative, automated in vitro diagnostic real-time PCR test for the detection and differentiation of specific carbapenemase genes (blaKPC, blaVIM/blaIMP, blaOXA-48, and blaNDM).

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" in a separate section with specific numerical thresholds for sensitivity and specificity. However, based on the presentation of "Performance Results" with 95% Confidence Intervals (CI), it's implied that the device is deemed acceptable if these performance metrics are sufficiently high and demonstrate clinical utility. The general expectation for diagnostic assays is high sensitivity and specificity.

Since direct acceptance criteria are not provided, I will present the reported performance, which implicitly met the FDA's requirements for substantial equivalence.

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

• Test Set Size:

  • Prospective Specimens: 1486 initially collected, 1473 eligible for clinical evaluation after excluding unreportable ones.
  • Contrived Specimens: 166.
  • Analytical Inclusivity: 93 strains (containing 97 target genes).
  • Analytical Specificity: 26 organisms tested.
  • Interfering Substances: 29 substances tested.
  • Reproducibility Studies (Inter-lab, Inter-lot, Intra-lab): Varied sample sizes per gene and concentration level, typically involving 60-120 replicates for positives and 72-100 for negatives per study type.
  • Carry-over Contamination: 166 negative specimens.
  • Mixed Infection/Competitive Interference: 13 specimens.

• Data Provenance:

  • Clinical (Prospective) Study: Samples collected from "five (5) geographically diverse clinical centers" as part of routine patient care. This indicates prospective collection from real-world clinical settings, likely within the country of the clinical centers (not explicitly stated, but generally implied to be within the jurisdiction of the submitting company or where clinical trials are feasible).
  • Contrived Study: Specimens were prepared by spiking "well-characterized strains into unique negative rectal swab matrix." This is a laboratory-based study design.

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

• The document does not mention the number or qualifications of experts involved in establishing the ground truth for the clinical specimens.
• The ground truth for the clinical (prospective) study was established by a "reference method" consisting of:
  • Bacterial culture for recovery of non-susceptible isolates from rectal swab specimens.
  • Followed by detection of antibiotic resistance genes by PCR and sequencing.
  • Bacterial culture protocol included both direct plating and overnight enrichment.
• For contrived specimens, ground truth was also established by PCR and sequencing of the spiked strains.
• For analytical inclusivity, strains were either from "public collections and well-characterized clinical isolates," implying previous expert characterization.

4. Adjudication Method for the Test Set:

• The document does not describe an adjudication method involving multiple experts for the clinical test set results.
• The comparison is between the BD MAX device results and the reference method (culture + PCR/sequencing), which serves as the established ground truth. Discrepancies would typically be reviewed by laboratory personnel, but a formal multi-expert adjudication process is not detailed.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, and the effect size of how much human readers improve with AI vs without AI assistance:

• No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done.
• This device is an automated in vitro diagnostic real-time PCR test, not an AI-assisted imaging or diagnostic tool that involves human readers interpreting results with or without AI assistance. The results are interpreted automatically by the BD MAX System.

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

• Yes, this entire study is a standalone performance evaluation of the algorithm/device itself.
• The "BD MAX System automates sample preparation, including target organism lysis, DNA extraction and concentration, reagent rehydration, target nucleic acid sequence amplification and detection using real-time PCR."
• "The interpretation of the signal is performed automatically by the BD MAX System."
• The performance tables directly compare the BD MAX Check-Points CPO (the device's output) to the gold standard reference method.

7. The type of ground truth used:

• Expert Consensus + Laboratory Reference Method for Clinical Specimens: For prospective clinical specimens, the ground truth was established by a bacterial culture-based reference method including PCR and sequencing. While not explicitly "expert consensus" in the sense of multiple independent interpretations, the reliance on established laboratory techniques (culture, PCR, sequencing) for genetic characterization is a form of highly reliable, validated ground truth in molecular diagnostics.
• Molecular Characterization for Contrived Specimens: For contrived specimens, the ground truth was based on the known molecular characteristics of the spiked strains, confirmed by PCR and sequencing.
• Known Strain Characteristics for Analytical Studies: For inclusivity, specificity, LoD, and reproducibility studies, the ground truth was based on the known genetic profile and concentration of the bacterial strains used, confirmed by standard molecular methods (e.g., PCR and sequencing for gene presence).

8. The sample size for the training set:

• The document does not provide information on a specific training set size because this is a molecular diagnostic assay, not a machine learning model that undergoes a distinct "training" phase with labeled data in the same way.
• The development of such an assay involves extensive research and development to design primers and probes, optimize reaction conditions, and establish thresholds, but this is a different process than training an AI algorithm on a dataset. The analytical studies (LoD, inclusivity, specificity) demonstrate the robustness and limits of the assay design.

9. How the ground truth for the training set was established:

• As mentioned above, there isn't a "training set" in the AI/ML sense for this type of device.
• The design of the assay (primers, probes) would have been based on established scientific knowledge of carbapenemase gene sequences and validated against known reference strains with confirmed gene presence/absence through sequencing and other molecular characterization techniques. This iterative process of design and validation ensures the assay's ability to detect the target genes accurately.

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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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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 blaker, blaNDM, blayIM, blackA-48, and blanny 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. The Xpert Carba-R Assay is not intended to guide or monitor treatmannon-susceptible bacterial infections. 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:

Rectal Swab Specimens

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

Pure Colonies

The assay is performed on carbapenen-non-susceptible pure colonies of Enterobacter baumanni, 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 Xpert Carba-R Assay is an automated real-time polymerase chain reaction (PCR) in vitro diagnostic test for qualitative detection of the blaxpc, blaym, blaoxa-a8, and blamp gene sequences from rectal swab specimens. The Xpert Carba-R Assay is intended as an aid for infection control for monitoring the spread of carbapenem-nonsusceptible 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 blakec, blanDM, blaym, blaox 8-8, and blance 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 blaker, blanny, blaoxA-48. and blank gene sequences from rectal swab specimens 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 realtime 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 swab specimens 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 blaker, blaypy, blaym, blaoxy-48, and blane gene sequences. The results are automatically generated at the end of the process in a report that can be viewed and printed.

Here’s a summary of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Device: Xpert® Carba-R Assay

Indications for Use: Qualitative in vitro diagnostic test for the detection and differentiation of blaKPC, blaNDM, blaVIM, blaOXA-48, and blaIMP gene sequences associated with carbapenem-non-susceptibility. Intended as an aid to infection control for detecting carbapenem-non-susceptible bacteria colonizing patients in healthcare settings (rectal swab specimens). Also for use with carbapenem-non-susceptible pure colonies of Enterobacteriaceae, Acinetobacter baumannii, or Pseudomonas aeruginosa.

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" for the clinical performance in a separate, clear table. However, the reported performance metrics in the clinical study can be considered as the evidence demonstrating the device meets an implicit acceptance level for regulatory approval. Regulatory bodies typically look for high Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA). Based on the "Prospective Specimen Results" section (Table 5-11), here are the key performance metrics:

Note on IMP PPA: The PPA for IMP is "N/A" with 0 True Positives (TP) among the prospective specimens, which indicates a very low prevalence of this target in the prospective cohort.

Contrived Specimen Performance (Table 5-14):

The reproducibility study (Table 5-15) shows high overall agreement, typically 100% for negative and moderate positive samples, and ranging from 86.1% to 97.2% for low positive samples, indicating consistent performance across sites and operators.

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

• Prospective Clinical Study:
  • Initial Enrollment: 802 rectal swab specimens.
  • Eligible for Inclusion: 785 specimens.
  • Final Dataset: 755 specimens after exclusions (including 16 Stenotrophomonas maltophilia due to intrinsic resistance).
  • Provenance: Five geographically diverse sites (three across the United States and two in Europe). Data was collected prospectively from subjects hospitalized or in long-term care facilities.
• Contrived Clinical Study:
  • Sample Size: 432 contrived specimens prepared in rectal swab matrix.
  • Provenance: This data is laboratory-generated, not from human subjects.

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

The document refers to a "reference culture laboratory" and an "independent laboratory for reference bi-directional sequencing analysis" for establishing ground truth. It does not explicitly state the number of experts or their specific qualifications (e.g., "radiologist with 10 years of experience"). However, the methodologies employed (culture, disk diffusion, CLSI document standards, PCR, and bi-directional DNA sequencing) imply the involvement of qualified laboratory professionals and molecular biologists.

4. Adjudication Method for the Test Set

For prospective specimens:

• The Xpert Carba-R Assay was evaluated against a reference method consisting of:
  1. Culture: MacConkey enrichment broth.
  2. Confirmation of carbapenem non-susceptibility: Disk diffusion method (per CLSI document M02 and M100) on isolated colonies.
  3. Molecular Confirmation: DNA extracted from non-susceptible isolates was purified, quantified, amplified with primers specific to the 5 target genes, and confirmed for appropriate amplicon size on an Agilent 2100 Bioanalyzer.
  4. Sequencing: If bands corresponded to expected amplicon sizes, the amplicon was sent to an independent laboratory for reference bi-directional sequencing analysis, which was validated for detecting the five targets.
• Discordant Analysis: For specimens where the Xpert Carba-R Assay was positive but a carbapenem-non-susceptible organism was not isolated by reference culture (False Positives based on initial reference), bi-directional sequencing on DNA extracted directly from the MacConkey enrichment broth was performed to confirm the presence of the gene sequences. This acts as an adjudication step.

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

No MRMC comparative effectiveness study was mentioned in this document. The device is an automated in vitro diagnostic test, so there is no "human reader" component in its direct output or interpretation in the way an imaging AI system would interact with a radiologist. Therefore, improvement of human readers with AI assistance is not applicable to this device.

6. Standalone (Algorithm Only) Performance Study

Yes, a standalone study was performed. The clinical studies (both prospective and contrived) directly evaluated the performance of the Xpert Carba-R Assay (the algorithm/device) against the reference method without human intervention in the interpretation of the Xpert Carba-R results. The reported PPA and NPA values represent the standalone performance of the device.

7. Type of Ground Truth Used

The ground truth for the test set was established using a multi-faceted approach:

• Expert Reference Method: A combination of culture (MacConkey enrichment broth followed by plating and disk diffusion based on CLSI standards) and molecular methods (PCR for specific gene amplification and bi-directional DNA sequence analysis).
• Outcomes Data: Not directly applicable here; the ground truth is based on the presence or absence of specific gene sequences and organism characteristics.
• Expert Consensus: While not explicitly stated as "expert consensus," the use of a multi-step reference method involving culture, phenotypic susceptibility testing, and sequencing performed by specialized laboratories implies a high standard of expert-driven verification. The discordant analysis further indicates a rigorous process to resolve discrepancies against the initial reference standard.

8. Sample Size for the Training Set

The document does not explicitly state the sample size of a "training set" for the Xpert Carba-R Assay. This is typical for in vitro diagnostic devices that are based on established molecular biology principles (like PCR) and analytical validation (LoD, reactivity, specificity) rather than machine learning models that require distinct training sets. The development process would involve extensive analytical testing to optimize primers and probes, which could be considered an iterative development phase but not a formal "training set" in the AI/ML sense.

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

As no explicit "training set" is described in the context of an AI/ML model, the establishment of ground truth for a training set is not detailed. However, for a PCR-based assay, the development process would involve establishing the analytical robustness of the assay, including:

• Analytical Sensitivity (Limit of Detection - LoD): Determined by using carbapenemase-producing organisms seeded into negative human rectal swab matrix at varying concentrations and verified with known positive and negative replicates.
• Analytical Reactivity (Inclusivity): Evaluated against a panel of 72 well-characterized bacterial strains with known resistance markers in rectal swab matrix, tested at concentrations (e.g., 3x LoD).
• Analytical Specificity (Cross-reactivity): Evaluated against a panel of 62 carbapenem-susceptible bacteria with other resistance mechanisms, 24 commensal/enteric microorganisms, and human cells at defined concentrations.

These analytical studies use panels with known characteristics (verified through methods like individual PCR assays, DNA sequence analysis, or Check-Points array) to ensure the assay correctly identifies targets and avoids off-target detection. This rigorous analytical characterization serves a similar purpose to "ground truth establishment" for refining a diagnostic assay's performance.

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