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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 IMDx VanR for Abbott m2000 assay is an in vitro diagnostic assay that uses polymerase chain reaction (PCR) amplification for the qualitative detection of nucleic acids encoding the vancomycin resistance genes vanA and/or vanB. The assay is performed directly on human perirectal swabs, rectal swabs, or stool specimens from patients at risk for Vancomycin Resistant Enterococcus (VRE) colonization. The IMDx VanR for Abbott m2000 assay detects the presence of vanA and vanB genes that can be associated with vancomycin-resistant enterococci. The IMDx VanR for Abbott m2000 assay can be used as an aid to identify. prevent and control vancomycin-resistant colonization in healthcare settings. The IMDx VanR for Abbott m2000 assay is not intended to diagnose VRE infection nor to guide or monitor treatment of infection. Culture methods are necessary to recover organisms for epidemiology typing and confirmation testing.

The IMDx VanR for Abbott m2000 assay is a PCR-based assay that targets regions unique to the vanA and vanB vancomycin resistance genes that may be associated with vancomycin resistant Enterococcus (VRE). Detection of the vanA and vanB genes is measured by the presence of fluorescently-labeled oligonucleotide probes that generate a fluorescent signal when specifically bound to amplified vanA and/or vanB PCR products. Differentiation of vanA from vanB is attained by labeling the oligonucleotide probes with different colored fluorescent dyes. The amplification cycle at which fluorescent signal is detected by the Abbott m2000rt is inversely proportional to the vanA and vanB DNA target level present in the sample.

The IMDx VanR for Abbott m2000 assay includes reagents for the detection of the assay process control, which contains inactivated bacteria, unrelated to enterococci, and is introduced into each specimen during sample preparation. The process control (also acting as an internal control (IC)) is co-extracted with the specimen and co-amplified in the same PCR reaction as the vanA and vanB targets. The IC demonstrates that the entire assay process has proceeded within specification.

Here's an analysis of the provided information, focusing on the acceptance criteria and the study proving the device meets them:

Acceptance Criteria and Device Performance for IMDx VanR for Abbott m2000

The document provided, K123753, describes the IMDx VanR for Abbott m2000 assay, an in vitro diagnostic device for detecting vancomycin resistance genes. The acceptance criteria are implicitly derived from the performance goals demonstrated in the clinical studies, as explicit pre-defined acceptance criteria are not directly stated in the summary. The performance is reported as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) based on comparison to a "gold standard" method.

1. Table of Acceptance Criteria and Reported Device Performance

Note on Acceptance Criteria: The document does not explicitly state numerical acceptance criteria (e.g., "Sensitivity must be >X%"). Instead, the clinical performance study aims to demonstrate that the device performs comparably and effectively for its intended use, implying that the reported percentages of sensitivity, specificity, PPV, and NPV are deemed acceptable for supporting substantial equivalence to the predicate device.

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

• Test Set (Clinical Performance Study):
  • Peri-rectal swabs: 587 samples
  • Rectal swabs: 444 samples (further broken down into prospective and retrospective collections)
    • Prospective: 400 samples
    • Retrospective: 44 samples
  • Stool specimens: 469 samples
  • Total Clinical Samples: 587 + 444 + 469 = 1500 samples
• Data Provenance: Samples were collected from "five geographically diverse test sites within the United States." The study included both prospective and retrospective collection for rectal swabs.

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

The document does not specify the number or qualifications of experts used to establish the ground truth. It states that the ground truth was "enriched culture combined with confirmation of the molecular basis of vancomycin resistance of isolates using an alternate PCR method." This implies laboratory personnel with expertise in microbiology and molecular diagnostics, but no specific number or detailed qualifications are provided.

4. Adjudication Method for the Test Set

The document does not describe a formal adjudication method (e.g., 2+1, 3+1, none) for the test set. The ground truth was established by a combination of enriched culture and an alternate PCR method, implying a direct comparison against these established laboratory techniques rather than a human consensus process.

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

No, an MRMC comparative effectiveness study was not done. This study focuses on the in vitro diagnostic performance of the assay itself (device vs. reference method) rather than evaluating human reader performance with and without AI assistance.

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

Yes, the clinical performance study evaluates the IMDx VanR for Abbott m2000 assay in a standalone manner. The assay is an automated PCR-based diagnostic test, and its results are compared directly to the ground truth (enriched culture + alternative PCR). There is no human interpretation of images or other data being assisted by the algorithm; the assay itself generates the result.

7. The Type of Ground Truth Used

The ground truth used was a combination of enriched culture combined with confirmation of the molecular basis of vancomycin resistance of isolates using an alternate PCR method. This is a highly robust ground truth for detecting the presence of vanA and/or vanB genes and is considered a reference standard in microbiology.

8. The Sample Size for the Training Set

The document does not explicitly state the sample size for a "training set." This type of molecular diagnostic assay typically undergoes extensive analytical validation (e.g., LOD, reactivity, cross-reactivity) using characterized strains and spiked samples, and then its clinical performance is evaluated on a distinct clinical test set. It's possible that data from these extensive analytical studies could be considered analogous to training data for method optimization, but a defined "training set" in the context of machine learning is not applicable here as it's a rule-based PCR assay, not an AI/ML algorithm.

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

As noted above, a traditional "training set" as understood in AI/ML is not described. However, for the analytical studies (e.g., Analytical Reactivity, Challenge Study), the ground truth was established using "well-characterized vancomycin-resistant Enterococcus strains and/or clinical isolates" and other organisms. These strains would have their vanA/vanB status, and other genetic characteristics, confirmed through standard microbiological and molecular methods (e.g., sequencing, biochemical tests, established PCR assays).

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The BD GeneOhm™ VanR Assay is a qualitative in vitro test for the rapid detection of vancomycin-resistance (vanA and vanB) genes directly from perianal or rectal swabs. The BD GeneOhm™ VanR Assay detects the presence of the vanA and vanB genes that can be associated with vancomycin-resistant enterococci (VRE). The assay is performed on an automated real-time PCR instrument with perianal or rectal swabs from individuals at risk for VRE colonization. The BD GeneOhm™ VanR Assay can be used as an aid to identify, prevent and control vancomycin-resistant colonization in healthcare settings. The BD GeneOhm™ VanR Assay is not intended to diagnose VRE infections nor to guide or monitor treatment for VRE infections. Concomitant cultures are necessary to recover organisms for epidemiological typing, susceptibility testing and for further confirmatory identification.

Following specimen lysis, the vanA and vanB genetic targets, if present, are amplified. Amplification of the Internal Control (IC), a DNA fragment of 294-bp including a 254-bp sequence not found in VRE, will also take place unless PCR inhibitory substances are present. The amplified DNA targets are detected with molecular beacon probes, hairpin-forming single-stranded oligonucleotides labelled at one end with a quencher and at the other end with a fluorescent reporter dye (fluorophore). In the absence of target, the fluorescence is quenched. In the presence of target, the hairpin structure opens upon beacon/target hybridization, resulting in emission of fluorescence. For the detection of the vanA amplicon, the molecular beacon probe contains the fluorophore FAM at the 5' end and the nonfluorescent quencher moiety DABCYL at the opposite 3' end of the oligonucleotide. For the detection of the vanB amplicon, the molecular beacon probe contains the fluorophore Texas Red at the 5' end and the quencher DABCYL at the 3' end. For the detection of the IC amplicon, the molecular beacon probe contains the fluorophore TET at the 5' end and the quencher DABCYL at the 3' end. Each beacon-target hybrid fluoresces at a wavelength characteristic of the fluorophore used in the particular molecular beacon probe. The amount of fluorescence at any given cycle, or following cycling, depends on the amount of specific amplicon present at that time. The SmartCycler® software simultaneously monitors the fluorescence emitted by each molecular beacon probe, interprets all data, and provides a final result at the end of the cycling program.

Here's a summary of the acceptance criteria and study details for the BD GeneOhm™ VanR Assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria in terms of specific performance thresholds (e.g., "Sensitivity must be >X%"). Instead, the study aims to demonstrate substantial equivalence to the predicate device. The performance is reported in terms of observed sensitivity and specificity (or Positive Percent Agreement and Negative Percent Agreement). The tables below summarize the overall clinical performance across all sites.

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

• Sample Size (Test Set):
  • Direct/Enriched Culture Comparison: 2156 specimens (1316 perianal and 834 rectal specimens). 2150 reportable results.
  • Direct Culture Comparison: 2152 specimens (1314 perianal and 832 rectal specimens). 2146 reportable results.
• Data Provenance: The study was a "multisite prospective investigational study" conducted across "Five (5) medical centers." The country of origin is not explicitly stated, but the submission is to the US FDA, implying US-based or internationally accepted clinical trial standards. The study design is prospective.

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

The document does not specify the number or qualifications of experts involved in establishing the ground truth. The reference method involved a multi-step microbiological process. While it implicitly requires expert laboratory personnel to perform and interpret these complex tests, no specific "expert" panel for ground truth adjudication is mentioned.

4. Adjudication Method for the Test Set

No explicit adjudication method (like 2+1 or 3+1) is described for the test set. The ground truth (Reference Method) was established through a defined laboratory protocol involving direct culture, enriched culture, phenotypic identification of Enterococcus colonies, vancomycin resistance testing (MIC method), and genotypic characterization of vanA or vanB genes using alternative PCR. This is a sequential, algorithm-driven process rather than an independent expert adjudication.

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

No, an MRMC comparative effectiveness study was not done. This device is a molecular diagnostic assay, not an imaging-based diagnostic tool that typically involves human reader interpretation. The comparison is between the automated PCR assay and a laboratory reference method.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) was Done

Yes, the performance characteristics presented are for the standalone algorithm (BD GeneOhm™ VanR Assay). The device is a "qualitative in vitro test for the rapid detection of vancomycin-resistance (vanA and vanB) genes directly from perianal or rectal swabs" performed on "an automated real-time PCR instrument." The reported performance metrics (sensitivity, specificity etc.) are the direct output of this automated system compared to the reference method.

7. The Type of Ground Truth Used

The ground truth used was a "Reference Method" consisting of:

• Direct Culture complemented by Enriched Culture.
• Inoculation onto Bile Esculin Azide agar supplemented with 6 µg/mL vancomycin (BEAV).
• Phenotypic identification of presumptive Enterococcus colonies (PYR test, commercial tests for species identification).
• Vancomycin resistance determined using an MIC method.
• Genotypic characterization of vanA and vanB genes using alternative PCR for confirmed vancomycin-resistant enterococcal isolates.

A "vanA- and/or vanB-containing VRE positive specimen" was defined as a specimen with vancomycin-resistant enterococci from culture with vanA and/or vanB genes identified by alternative PCR. A negative specimen was defined as negative by both direct and enriched culture methods.

8. The Sample Size for the Training Set

The document provided (510(k) summary) does not specify a separate "training set" for the BD GeneOhm™ VanR Assay. Clinical performance studies typically involve a "test set" to evaluate the device against a reference method. For molecular assays, assay development involves extensive internal validation and optimization with various samples, but these are generally not described as a "training set" in the same way machine learning models would have one. The focus here is on the performance of the developed assay on a clinical validation cohort.

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

As no specific "training set" is described for this type of device in the provided document, the method for establishing its ground truth is not detailed. However, the ground truth for the clinical validation (test set), as described in point 7, involved a comprehensive microbiological and molecular reference method. This rigorous reference method would implicitly guide the development and optimization of the assay during its pre-clinical phase.

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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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The IDI-VanR® Assay is a qualitative in vitro test for the rapid detection of vancomycinresistance (vanA and vanB) genes directly from rectal swabs. The IDI-vanR® Assay detects the presence of the vanA and vanB genes that can be associated with vancomycin-resistant enterococci (VRE). The assay is performed on an automated realtime PCR instrument with rectal swabs from patients at risk for VRE colonization. The IDI-VanR® Assay can be used as an aid to identify, prevent and control vancomycinresistant colonization in healthcare settings. Concomitant cultures are necessary to recover organisms for epidemiological typing, susceptibility testing and for further confirmatory identification. The IDI-VanR® Assay is not intended to diagnose VRE infections nor to guide or monitor treatment for VRE infections.

Following specimen lysis, amplification of the vanA and vanB targets occurs. Amplification of the IC, a DNA fragment of 294-bp including a 254-bp sequence not found in VRE, will also take place unless there are PCR inhibitory substances. The amplified DNA targets are detected with molecular beacons, a hairpin-forming single-stranded oligonucleotides labelled at one end with a quencher and at the other end with a fluorescent reporter dye (fluorophore). In the absence of target, the fluorescence is quenched. In the presence of target, the hairpin structure opens upon beacon/target hybridization, resulting in emission of fluorescence. For the detection of vanA amplicons, the molecular beacon contains the fluorophore FAM at the 5' end and the non-fluorescent quencher moiety DABCYL at the opposite end of the oligonucleotide. For the detection of the vanB amplicons, the molecular beacon contains the fluorophore Texas Red at the 5' end and the quencher DABCYL at the 3' end. For the detection of the Internal Control (IC) amplicons, the molecular beacon contains the fluorophore TET at the 5' end and the quencher DABCYL at the 3' end. Each beacon-target hybrid fluoresces at a wavelength characteristic of the fluorophore used in the particular molecular beacon. The amount of fluorescence at any given cycle, or following cycling, depends on the amount of specific amplicons present at that time. The SmartCycler® software simultaneously monitors the fluorescence emitted by each beacon, interprets all data, and provides a final result at the end of the cycling program.

The GeneOhm Sciences Canada, Inc. IDI-VanR™ Assay is a qualitative in vitro test for the rapid detection of vancomycin-resistance (vanA and vanB) genes directly from rectal swabs, used as an aid to identify, prevent and control vancomycinresistant colonization in healthcare settings.

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

Acceptance Criteria and Device Performance

The document does not explicitly state pre-defined acceptance criteria in terms of specific sensitivity and specificity thresholds that the device must meet. Instead, it presents the device's performance in comparison to a predicate device and culture technique, implying that substantial equivalence to the predicate (Remel Bile Esculin Azide agar with 6 ug/mL vancomycin (BEAV)) serves as the primary "acceptance criterion" for market clearance.

However, based on the presented clinical performance data, we can infer the reported performance of the IDI-VanR™ Assay.

• Overall Sensitivity: 97.3% (95% CI: 92.2%-99.4%)
• Overall Specificity: 91.4% (95% CI: 89.3%-93.2%)
• Negative Predictive Value (NPV): 99.6% (95% CI: 98.9%-99.9%)
• Positive Predictive Value (PPV): 59.1% (95% CI: 51.6%-66.4%)

Detailed breakdown by gene (Table 1):

• Sensitivity VanA': 97.1% (95% CI: 91.6-99.4%) (Note: VanA' includes vanA alone and vanA+B PCR results considered true positive where culture was vanA positive.)
• Sensitivity VanB: 57.1% (95% CI: 1.8-90.1%) (Acknowledged as low due to low number of vanB positive specimens).
• Specificity (combined for vanA, vanB, vanA+B, negative): 91.4% (This specificity seems to be derived from the overall calculation in Table 2, not solely from Table 1's detailed breakdown, as a direct calculation from Table 1's "Negative" row would be different if only negative cultures were considered.)

Unresolved Rate:

• Initial: 0.2% (2/968)
• After repeat testing: 0.1% (1/968) |

Note on "Acceptance Criteria": In 510(k) submissions, the primary "acceptance criterion" is often substantial equivalence to a predicate device. The performance metrics presented are to demonstrate that the new device is as safe and effective as the predicate. While specific numerical targets might not be explicitly stated as "acceptance criteria," regulatory bodies assess if the presented performance is acceptable for the intended use and comparable to established methods.

Study Details:

1. Sample sizes used for the test set and data provenance:

   • Total Sample Size: 968 rectal swab specimens.
   • Data Provenance: Clinical trials were performed at four investigational sites. The country of origin is not explicitly stated for all sites, but the submitter is GeneOhm Sciences Canada, Inc., suggesting at least some Canadian sites. The study appears to be prospective as it evaluates the performance of the IDI-VanR™ Assay against culture technique in a clinical trial setting.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • The document does not specify the number of experts or their qualifications for establishing the ground truth. The ground truth (comparator method) was the "Remel Bile Esculin Azide agar with 6 ug/mL vancomycin (BEAV) with phenotypic identification of presumptive Enterococcus colonies and determination of vancomycin and teicoplanin resistance (CLSI, M7-A6 and M100-S15)." This implies that laboratory personnel trained in microbiology and following established clinical guidelines (MMWR, CDC, CLSI) performed the ground truth testing.

3. Adjudication method for the test set:

   • The document does not describe a formal adjudication method (e.g., 2+1, 3+1). The ground truth was established by the predicate culture method, and the device's results were compared against this. Any discrepancies would typically be resolved by retesting or further investigation according to the study protocol, though this specific detail is not provided.

4. 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 is not an AI/CAD device. The IDI-VanR™ Assay is a nucleic acid amplification test (real-time PCR) for detecting specific genes. Therefore, an MRMC study with human readers and AI assistance is not applicable to this device.

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

   • Yes, the performance presented is for the device operating stand-alone. The IDI-VanR™ Assay is an in vitro diagnostic test, and its results (positive/negative for vanA/vanB) are generated by an automated real-time PCR instrument and software. The reported sensitivity and specificity refer to the device's performance as a primary diagnostic tool against the reference method.

6. The type of ground truth used:

   • The ground truth used was culture technique (Remel Bile Esculin Azide agar with vancomycin) combined with phenotypic identification of Enterococcus colonies and determination of vancomycin and teicoplanin resistance according to established clinical and laboratory standards (MMWR, CDC, CLSI M7-A6 and M100-S15). This is a well-accepted and standard method for identifying VRE.

7. The sample size for the training set:

   • The document does not mention a training set. This is typical for in vitro diagnostic tests like PCR assays. These types of assays are based on established molecular biology principles and validated against known controls and clinical samples without a "training set" in the machine learning sense. The assay's parameters (e.g., primer and probe design, cycling conditions) would be developed and optimized in a lab setting, not through machine learning training on a large dataset.

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

   • As there is no mention of a training set, this question is not applicable. The assay's fundamental design is based on known genetic sequences (vanA and vanB) and molecular detection methods, not on data-driven training. Development would involve extensive analytical validation using characterized bacterial strains and clinical samples to optimize performance characteristics.

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For the visual or spectrophotometric detection of the vanA and vanB genes in determining vancomycin resistance in enterococci isolated from culture.

The Velogene™ Genomic Identification Assay for VRE (Vancomycin Resistant Enterococci) is an in vitro, DNA probe based, diagnostic device that utilizes Cycling Probe™ Technology (CPT) to generate a spectrophotometric or visual result. Results can be generated 90 minutes after primary isolation. The Velogene™ Genomic Identification Assay for VRE (hereafter may be referred to as the Velogene™ assay) utilizes a fluorescein labeled, biotinylated DNA-RNA-DNA chimeric probe providing an RNase H cleavable linkage when bound to the complementary sequence of the van A or vanB gene. RNase H cleaves the RNA portion of the chimeric probe when it is hybridized to the target DNA. The uncleaved probe (vanA and vanB negative) is detected by binding of the fluoresceinated probe to a solid surface and attachment of an antifluorescein antibody conjugated with horseradish peroxidase, which converts a substrate to a colored end product. Cleavage of the probe (vanA or vanB positive) prevents binding of the probe-anti-fluorescein antibody enzyme complex, thus preventing formation of the colored end product. A vancomycin-resistant isolate (i.e. vanA or vanB gene is present) will produce a colorless result (or OD650 of ≤0.14). A vancomycin-sensitive isolate (i.e. vanA and vanB gene are absent) will produce a distinctly blue color (or OD650 of >0.14). Each Velogene™ assay kit contains supplies sufficient to process 48 samples and consists of two separate reagent kits: a VRE Lysis/Cycle Kit and a VRE Microwell Detection Kit.

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

1. Table of Acceptance Criteria and Reported Device Performance

The submission does not explicitly state pre-defined acceptance criteria (e.g., minimum sensitivity, specificity, or agreement metrics that needed to be met). Instead, it presents the results of a comparative study and implies that the observed agreement rate was sufficient for substantial equivalence.

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

• Sample Size: 518 isolates
• Data Provenance: The study was conducted at "3 geographically distributed U.S. sites" using "routinely submitted samples for microbiological identification." This indicates the data was prospective or at least collected in a routine clinical setting.

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

The document does not specify the number of experts or their qualifications for establishing the ground truth. The ground truth was based on the predicate device, Vancomycin Screen Agar, which is a growth-based test. Interpretation of this test would typically be performed by trained laboratory personnel, but no specifics are given regarding expert review or reconciliation.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication method (e.g., 2+1, 3+1). The "ground truth" was established by the predicate device (Vancomycin Screen Agar), and the Velogene™ assay's results were compared against this. It's implied that the results of the Vancomycin Screen Agar were considered definitive for the purpose of this comparison.

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

A Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not applicable and therefore not performed. This device is a standalone diagnostic assay (an in vitro DNA probe test) that provides a direct result (colorless or blue, or OD650 reading). It does not involve human readers interpreting images or data where AI assistance would improve human performance.

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

Yes, a standalone performance evaluation was done for the Velogene™ Genomic Identification Assay for VRE. The study compared the results of the Velogene™ assay (an "algorithm only" in the sense of a chemical/molecular assay without human interpretation of complex visuals) directly against the predicate device. The assay itself generates a direct spectrophotometric or visual result without human interpretation beyond reading the color or OD650 value.

7. The Type of Ground Truth Used

The ground truth used for the comparative study was the phenotypic result from a legally marketed predicate device: Vancomycin Screen Agar (Brain Heart Infusion (BHI) Agar with 6 ug/mL vancomycin). This is a growth-based test that identifies vancomycin resistance.

8. The Sample Size for the Training Set

The document does not provide information on a separate training set or its sample size. This type of submission (510(k)) for an IVD kit often focuses on clinical validation rather than a deep dive into the development and training of a machine learning model, which is not applicable here as it's a chemical assay. The comparison is the validation study.

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

Since no separate training set is mentioned in the provided text, and the device is a molecular assay, the concept of establishing ground truth for a "training set" as it would apply to a machine learning algorithm is not relevant to this submission. The "ground truth" for the overall evaluation was the predicate device's results, against which the Velogene™ assay was compared.

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