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The Verigene Enteric Pathogens Nucleic Acid Test (EP) is a multiplexed, qualitative test for simultaneous detection and identification of common pathogenic enteric bacteria, viruses and genetic virulence markers from liquid or soft stool preserved in Cary-Blair medium, collected from individuals with signs and symptoms of gastrointestinal infection. The test is performed on the automated Nanosphere Verigene System utilizing reverse transcription (RT), polymerase chain reaction (PCR), and array hybridization to detect specific gastrointestinal microbial nucleic acid gene sequences associated with the following pathogenic bacteria and viruses:

• · Campylobacter Group (composed of C. coli, C. jejuni, and C. lari)
• · Salmonella species
• · Shigella species (including S. dysenteriae, S. boydii, S. sonnei, and S. flexneri)
• · Vibrio Group (composed of V. cholerae and V. parahaemolyticus)
• · Yersinia enterocolitica
• Norovirus GI/GII
• Rotavirus A

In addition, EP detects the Shiga toxin 1 gene and Shiga toxin 2 gene virulence markers. Shiga toxin producing E. coli (STEC) typically harbor one or both genes that encode for Shiga Toxins 1 and 2.

EP is indicated as an aid in the diagnosis of specific agents of gastrointestinal illness, in conjunction with other clinical, laboratory, and epidemiological information; however, is not to be used to monitor these infections. EP also aids in the detection and identification of acute gastroenteritis in the context of outbreaks.

Due to the limited number of positive specimens collected for certain organisms during the prospective clinical study, performance characteristics for Yersinia enterocolitica, Vibrio Group and Shigella species were primarily established with contrived specimens.

Concomitant culture is necessary for organism recovery and further typing of bacterial agents.

EP results should not be used as the sole basis for diagnosis, treatment management decisions. Confirmed positive results do not rule out co-infection with other organisms that are not detected by this test, and may not be the sole or definitive cause of patient illness. Negative EP results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.

The Verigene Enteric Pathogens Nucleic Acid Test (EP) is a molecular assay that relies on detection of specific nucleic acid targets in a microarray format. For each of the bacterial or viral nucleic acid sequences detected by EP, unique Capture and Mediator oligonucleotides are used, 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 a region that binds to a different portion of the same nucleic acid targets and also have a sequence that allows binding of a gold nanoparticle probe. 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 EP test is performed on the Verigene System, a "sample-to-result," fully automated, benchtop molecular diagnostics workstation. The System enables automated nucleic acid extraction from unformed stool specimens (liquid or soft) preserved in Cary-Blair media and detection of analyte-specific target nucleic acids. The Verigene System consists of two components: the Verigene Reader and the Verigene Processor SP.

The Reader is the Verigene System's user interface and serves as the central control unit for all aspects of test processing, automated imaging, and result generation using a touch-screen control panel and a barcode scanner. The Verigene Processor SP executes the test procedure, automating the steps of (1) Sample Preparation and Target Amplification - cell lysis and magnetic bead-based bacterial and viral nucleic acid isolation and amplification, and (2) Hybridization- detection and identification of analyte-specific nucleic acid 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 finally loads the specimen into the Test Cartridge for hybridization. Single-use disposable test consumables and a self-contained Verigene Test Cartridge are used for each sample tested with the EP assay.

To obtain the test results after test 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 targeted nucleic acid sequence/analyte. This determination is made by means of software-based decision algorithm resident in the Reader.

Here's an analysis of the provided text regarding the acceptance criteria and study for the Verigene® Enteric Pathogens Nucleic Acid Test (EP):

1. Table of Acceptance Criteria and Reported Device Performance

The document primarily focuses on overall agreement rates rather than explicitly stated acceptance criteria with specific thresholds for positive and negative agreement. However, we can infer performance targets from the reported results and the nature of medical device studies aiming for high accuracy.

Notes on Acceptance Criteria: Based on typical FDA clearance for diagnostic devices, the acceptance criteria would generally be a pre-defined lower bound for the confidence interval of the positive and negative agreement (e.g., >90% or >95% for the lower bound of the 95% CI). While not explicitly stated here, the reported percentages (and confidence intervals where provided) demonstrate that the device aimed for and largely achieved very high agreement rates. The low numbers of positive clinical specimens for some targets (Rotavirus A, Shigella spp., Vibrio spp., Y. enterocolitica) led to the use of contrived specimens to establish performance, which is a common practice when clinical prevalence is low.

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

• Total Valid Specimens: 1940

  • 1294 prospectively-collected fresh specimens
  • 34 prospectively-collected frozen specimens
  • 203 selected samples
  • 409 simulated specimens

• Data Provenance:

  • Country of Origin: United States (multi-site prospective investigation study at eight (8) U.S. institutions).
  • Retrospective/Prospective: Primarily prospective (1294 fresh, 34 frozen specimens). There were also "selected samples" (203) and "simulated specimens" (409), which would not be considered purely prospective clinical data. The phrase "selected samples" often implies retrospectively identified samples with known disease status.

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 used or their qualifications for establishing ground truth.

4. Adjudication Method for the Test Set

The document does not specify an adjudication method. It states that "The viral comparator methods were a composite of a real-time RT-PCR assay and conventional PCR assays with confirmatory bi-directional sequencing." This implies a reference standard rather than an adjudication process between multiple readers.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This study is for a diagnostic test (Verigene EP) and compares its performance against reference laboratory methods, not human readers.

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

Yes, the study described is a standalone performance study. The Verigene EP test is an automated system that produces results directly from the specimen ("sample-to-result") without human interpretation of images or complex data that would necessitate a "human-in-the-loop" assessment. The performance is assessed by comparing the device's output to a reference method.

7. The Type of Ground Truth Used

The ground truth for the clinical study was established using PCR-based viral reference methods, specifically:

• A composite of a real-time RT-PCR assay.
• Conventional PCR assays with confirmatory bi-directional sequencing.

For bacterial targets and Shiga toxin genes, while not explicitly detailed in the clinical study section, it can be inferred that similar robust molecular or culture-based methods served as the reference standard.

8. The Sample Size for the Training Set

The document does not explicitly state the sample size for a training set. The clinical study described is primarily for performance evaluation (test set). For a molecular diagnostic device like this, the development and training of the underlying detection algorithm would typically occur during the assay development phase, using internal validation samples, and may not have a "training set" in the same way an AI/ML image analysis algorithm would. Analytical performance studies (LoD, inclusivity, cross-reactivity) are part of establishing the robustness of the assay's detection mechanism.

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

As no specific training set is outlined in the context of this 510(k) summary, the method for establishing its ground truth is also not described. For the analytical studies (e.g., LoD, inclusivity, cross-reactivity), the "ground truth" is inherently defined by using characterized microbial strains, known concentrations, and well-established molecular and microbiological techniques to prepare the samples.

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