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The Verigene® Gram Negative Blood Culture Nucleic Acid Test (BC-GN), performed using the sample-to-result Verigene System, is a qualitative multiplexed in vitro diagnostic test for the simultaneous detection and identification of selected gram-negative bacteria and resistance markers. BC-GN is performed directly on blood culture media using blood culture bottles identified as positive by a continuous monitoring blood culture system and which contain gram-negative bacteria as determined by gram stain.

BC-GN detects and identifies the following:

BC-GN will not distinguish Escherichia coli from Shigella spp. (S. dysenteriae, S. flexneri, S. boydii, and S. sonnei)

BC-GN is indicated for use in conjunction with other clinical and laboratory findings to aid in the diagnosis of bacterial bloodstream infections; however. is not used to monitor these infections. Sub-culturing of positive blood cultures is necessary to recover organisms for antimicrobial susceptibility testing (AST), for identification of organisms not detected by BC-GN, to detect mixed infections that may not be detected by BC-GN, for association of antimicrobial resistance marker genes to a specific organism, or for epidemiological typing.

The Verigene Gram Negative Blood Culture Nucleic Acid Test (BC-GN) is a molecular assay which relies on detection of specific nucleic acid targets in a microarray format. For each of the bacterial nucleic acid sequences detected by the BC-GN test, unique Capture and Mediator oligonucleotides are utilized, with gold nanoparticle probe-based endpoint detection. The Capture oligonucleotides are covalently bound to the microarray substrate and hybridize to a specific portion of the nucleic acid targets. The Mediator oligonucleotides have regions which bind to a different portion of the same nucleic acid targets and also have sequences which allow binding of gold nanoparticle probes. Specific silver enhancement of the bound gold nanoparticle probes at the capture sites results in gold-silver aggregates that scatter light with high efficiency and provide accurate detection of target capture.

The BC-GN test is performed on the Verigene System, a sample-to-result, fully automated. bench-top molecular diagnostics workstation consisting of two components: the Verigene Reader and the Verigene Processor SP. For the BC-GN test, the Verigene System allows automated nucleic acid extraction from positive bacteria-containing blood culture specimens and target detection of bacteria-specific DNA. The BC-GN test utilizes single-use disposable test consumables and a self-contained Verigene Test Cartridge for each sample tested.

The Reader is the Verigene System's central control unit and user interface, and, with a touch-screen control panel and barcode scanner, guides the user through test processing. imaging, and test result generation. The Verigene Processor SP executes the test procedure. automating the steps of (1) Sample Preparation- cell lysis and magnetic bead-based bacterial DNA isolation from blood culture samples, and (2) Hybridization-- detection and identification of bacterial-specific DNA in a microarray format by using gold nanoparticle probe-based technology. Once the specimen is loaded by the operator, all other fluid transfer steps are performed by an automated pipette that transfers reagents between wells of the trays and loads the specimen into the Test Cartridge for hybridization. Single-use disposable test consumables and a self-contained Verigenc Test Cartridge are utilized for each sample tested with the BC-GN test.

To obtain the test results after processing is complete. the user removes the Test Cartridge from the Processor SP, and inserts the substrate holder into the Reader for analysis. Light scatter from the capture spots is imaged by the Reader and intensities from the microarray spots are used to make a determination regarding the presence (Detected) or absence (Not Detected) of a bacterial nucleic acid sequence/analyte. This determination is made by means of software-based decision algorithm resident in the Reader.

The Nanosphere Verigene® Gram Negative Blood Culture Nucleic Acid Test (BC-GN) is a qualitative multiplexed in vitro diagnostic test designed for the simultaneous detection and identification of selected gram-negative bacteria and resistance markers directly from positive blood culture media.

Here's an analysis of its acceptance criteria and the supporting studies:

1. Table of Acceptance Criteria (Performance Goals) and Reported Device Performance (Method Comparison Study)

The document does not explicitly state "acceptance criteria" as a set of predefined thresholds for performance metrics. However, the "Method Comparison" study presents the device's performance against reference methods, which implicitly serve as the comparison points for its effectiveness. The reported performance metrics are Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA), along with their 95% Confidence Intervals.

Note: The document does not explicitly state numerical acceptance criteria. The "implied acceptance criterion" section is a general interpretation based on typical regulatory expectations for diagnostic accuracy.

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

• Sample Size for Test Set: A total of 1412 specimens were analyzed in the method comparison study.
  • 604 prospectively-collected fresh specimens
  • 272 prospectively-collected frozen specimens
  • 239 selected frozen specimens
  • 297 simulated frozen specimens
• Data Provenance: The study was conducted at thirteen (13) investigational sites. The document does not specify the countries of origin for these sites or the data itself, but such clinical trials for FDA submissions are typically conducted in the US or under comparable regulatory frameworks. The inclusion of "prospectively-collected fresh specimens" and "prospectively-collected frozen specimens" indicates prospective data collection, while "selected frozen specimens" and "simulated frozen specimens" indicate retrospective or artificially prepared samples. This suggests a mixed approach to sample collection.

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

The document does not explicitly state the number of experts used to establish ground truth or their specific qualifications (e.g., "radiologist with 10 years of experience"). Instead, it describes the methods used to establish ground truth:

• For bacterial organisms: "standard culture-based automated phenotypic bacterial identification reference methods." This implies that the ground truth was established by clinical microbiology laboratories following established protocols, likely interpreted by qualified clinical microbiologists or medical laboratory scientists.
• For resistance markers: "the combination of PCR amplification and bidirectional sequencing confirmation." This indicates molecular biology techniques, which would also be performed and interpreted by appropriately trained laboratory personnel.

4. Adjudication Method for the Test Set

The document does not mention an explicit "adjudication method" involving multiple human readers for the test set results. The ground truth was established using standard reference laboratory methods, not through an adjudication process of human interpretations of the device's output. The device's results were directly compared to these reference methods.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not reported. This device is an in vitro diagnostic test (an algorithm-only device without human-in-the-loop performance being evaluated in the clinical study presented) rather than an imaging or interpretive AI device where human reader performance is typically assessed and compared to AI-assisted performance. The study focuses on the agreement of the device's output with standard reference methods. Therefore, an effect size of human readers improving with AI vs. without AI assistance is not applicable here.

6. Standalone (Algorithm-Only Without Human-in-the-Loop Performance) Study

Yes, the method comparison study directly assesses the standalone performance of the Verigene BC-GN test (algorithm only). The device's results are automatically generated by the Verigene System (Reader and Processor SP) and then compared to the ground truth established by reference laboratory methods, without human intervention in the interpretation of the device's output that would then be compared to human interpretation.

7. Type of Ground Truth Used

The ground truth used was:

• Culture-based automated phenotypic bacterial identification reference methods for bacterial organisms.
• PCR amplification and bidirectional sequencing confirmation for resistance markers.

8. Sample Size for the Training Set

The document does not explicitly specify a "training set" in the context of machine learning model development. This device appears to be a molecular diagnostic assay using a microarray and a software-based decision algorithm, rather than a system heavily reliant on a continuously learning or adaptable AI model that would typically have a distinct training phase with a specific dataset.

However, analytical studies involved extensive testing that could be considered analogous to developing and refining the device's performance characteristics:

• Analytical Sensitivity (LOD): Tested 12 bacterial strains.
• Analytical Reactivity (Inclusivity): Tested 195 strains of 44 different organisms (including 79 with resistance markers).
• Analytical Specificity (Exclusivity): Tested 172 "non-BC-GN panel" organisms.
• Competitive Inhibition / Mixed Growth: Multiple studies involving combinations of bacterial organisms.
• Precision/Repeatability: 18-member panel tested for 864 replicates.
• Reproducibility: 18-member panel tested for 1620 replicates across 3 external sites.

These studies contribute to the design and validation of the test's targets, probes, and decision algorithm, but a "training set" in the context of statistical machine learning for inferential models is not presented.

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

As noted in point 8, a distinct "training set" with ground truth in the typical machine learning sense is not explicitly described. For the analytical studies (e.g., LOD, inclusivity, exclusivity), the ground truth for bacterial identification and resistance marker presence would have been established using well-characterized laboratory strains and standard microbiological and molecular identification techniques. These involve:

• Pure cultures: For LOD and inclusivity, known bacterial strains are used.
• Conventional identification methods: Such as cell morphology, growth characteristics, biochemical tests, and potentially 16S rRNA sequencing for difficult or novel strains.
• Molecular techniques for resistance markers: Such as PCR and sequencing to confirm the presence and identity of specific resistance genes.

These methods are the gold standards in microbiology for characterizing bacteria and their genetic elements, forming the basis of the device's design and analytical performance evaluation.

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