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The Verigene® Respiratory Pathogens Flex Nucleic Acid Test (RP Flex) is a multiplexed qualitative test intended for the simultaneous detection and identification of multiple viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals suspected of respiratory tract infection. The test is performed on the automated Verigene System utilizing reverse transcription (RT), polymerase chain reaction (PCR), and microarray hybridization to detect gene sequences of the following organism types and subtypes:

Detecting and identifying specific viral and bacterial nucleic acids from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory infection with other clinical and laboratory findings. The results of this test should not be used as the sole basis for diagnosis, treatment, or patient management decisions.

Negative results in the presence of a respiratory illness do not preclude respiratory infection and may be due to infection with pathogens that are not detected by this test or lower respiratory tract infection that is not detected by an NPS specimen. Conversely, positive results do not rule-out infection with organisms not detected by RP Flex. The agent(s) detected may not be the definite cause of disease. The use of additional laboratory testing and clinical presentation may be necessary to establish a final diagnosis of respiratory infection.

Clinical evaluation indicates a lower sensitivity specific to RP Flex for the detection of Rhinovirus. If infection with Rhinovirus is suspected, negative samples should be confirmed using an alternative method.

Performance characteristics for Influenza A were established when Influenza A/H1 (2009 Pandemic) and A/H3 were the predominant Influenza A viruses in circulation. RP Flex may not detect novel Influenza A strains. If infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection used specifically for novel virulent influenza viruses and sent to appropriate health authorities for testing. Viral culture should not be attempted in these cases unless a biosafety level (BSL) 3+ facility is available to receive and culture specimens.

The Verigene Respiratory Pathogens Flex Nucleic Acid Test (RP Flex) 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 RP Flex, 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 RP Flex test is performed on the Verigene System, a "sample-to-result," fully automated, bench-top molecular diagnostics workstation. The System enables automated nucleic acid extraction from nasopharyngeal swabs (NPS) 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 RP Flex 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 Verigene Reader for analysis. Light scatter from the capture spots is imaged by the Verigene 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 Verigene Reader.

{
  "1. A table of acceptance criteria and the reported device performance": {
    "Influenza A": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "98.3% (58/59) (91.0-99.7)",
        "Negative Percent Agreement (95% CI)": "99.4% (2121/2134) (99.0-99.6)"
      }
    },
    "Influenza A subtype H1": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "97.8% (45/46) (88.7-99.6)",
        "Negative Percent Agreement (95% CI)": "99.7% (2138/2144) (99.4-99.9)"
      }
    },
    "Influenza A subtype H3": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "100% (13/13) (77.2-100)",
        "Negative Percent Agreement (95% CI)": "99.8% (2173/2177) (99.5-99.9)"
      }
    },
    "Influenza B": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "98.0% (49/50) (89.5-99.6)",
        "Negative Percent Agreement (95% CI)": "99.6% (2139/2147) (99.3-99.8)"
      }
    },
    "RSV A": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "100% (17/17) (81.6-100)",
        "Negative Percent Agreement (95% CI)": "99.9% (2150/2153) (99.6-99.9)"
      }
    },
    "RSV B": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "100% (173/173) (97.8-100)",
        "Negative Percent Agreement (95% CI)": "98.8% (1973/1997) (98.2-99.2)"
      }
    },
    "Parainfluenza 1": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "90.0% (27/30) (74.4-96.5)",
        "Negative Percent Agreement (95% CI)": "99.9% (2165/2167) (99.7-100)"
      }
    },
    "Parainfluenza 2": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "92.3% (12/13) (66.7-98.6)",
        "Negative Percent Agreement (95% CI)": "99.9% (2181/2184) (99.6-99.9)"
      }
    },
    "Parainfluenza 3": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "82.4% (14/17) (59.0-93.8)",
        "Negative Percent Agreement (95% CI)": "99.9% (2177/2180) (99.6-99.9)"
      }
    },
    "Parainfluenza 4": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "79.2% (19/24) (59.3-90.8)",
        "Negative Percent Agreement (95% CI)": "99.8% (2169/2173) (99.5-99.9)"
      }
    },
    "Adenovirus": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "86.0% (49/57) (74.7-92.7)",
        "Negative Percent Agreement (95% CI)": "97.2% (2081/2140) (96.5-97.9)"
      }
    },
    "Human Metapneumovirus (hMPV)": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "100% (46/46) (92.3-100)",
        "Negative Percent Agreement (95% CI)": "99.7% (2145/2151) (99.4-99.9)"
      }
    },
    "Rhinovirus": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "81.9% (407/497) (78.3-85.0)",
        "Negative Percent Agreement (95% CI)": "97.1% (1578/1625) (96.2-97.8)"
      }
    },
    "Bordetella parapertussis/bronchiseptica": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "100% (2/2) (34.2-100)",
        "Negative Percent Agreement (95% CI)": "99.9% (2290/2291) (99.8-100)"
      }
    },
    "Bordetella pertussis": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "100% (8/8) (67.6-100)",
        "Negative Percent Agreement (95% CI)": "99.9% (2187/2189) (99.7-100)"
      }
    },
    "Bordetella holmesii": {
      "Performance Criteria": "Positive Agreement ≥ 90%, Negative Agreement ≥ 95%",
      "Reported Performance (All specimens)": {
        "Positive Percent Agreement (95% CI)": "100% (1/1) (20.6-100)",
        "Negative Percent Agreement (95% CI)": "100% (2305/2305) (99.8-100)"
      }
    }
  },
  "2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)": {
    "Total specimens enrolled": 3299,
    "Specimens included in performance analysis": 3266,
    "Specimen types and provenance": {
      "Prospectively-collected fresh specimens": {
        "Count": 1069,
        "Type": "Prospective"
      },
      "Prospectively-collected frozen specimens": {
        "Count": 1317,
        "Type": "Prospective"
      },
      "Retrospectively-collected frozen specimens": {
        "Count": 520,
        "Type": "Retrospective"
      },
      "Contrived frozen specimens": {
        "Count": 360,
        "Type": "Contrived"
      }
    },
    "Country of Origin": "Not explicitly stated, but implies U.S. due to FDA submission."
  },
  "3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)": "Not specified in the provided text. The ground truth was established by comparing to an FDA-cleared molecular respiratory panel and/or PCR amplification followed by confirmatory bi-directional sequencing.",
  "4. Adjudication method (e.g. 2+1, 3+1, none) for the test set": "The method of adjudication for discrepancies between the predicate and PCR/sequencing results is not explicitly detailed. The comparison was made against a 'composite of an FDA-cleared molecular respiratory panel and analytically validated PCR with bi-directional sequencing', implying a reference standard was used for ground truth, but the steps for resolving conflicting results among these methods are not described.",
  "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": "Not applicable. This is a standalone diagnostic device, not an AI-assisted human reader study.",
  "6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done": "Yes, a standalone performance study was conducted. The clinical performance characteristics were determined by comparing the device's results to a composite reference method (FDA-cleared molecular respiratory panel and/or PCR amplification with bi-directional sequencing). The device is described as an 'automated Verigene System' which implies a standalone algorithm making the detection calls.",
  "7. The type of ground truth used (expert concensus, pathology, outcomes data, etc)": "A composite reference standard was used as ground truth: an FDA-cleared molecular respiratory panel and/or PCR amplification followed by confirmatory bi-directional sequencing.",
  "8. The sample size for the training set": "The document does not explicitly state a 'training set' size for a machine-learning model. This is a molecular diagnostic assay, and its development would typically involve analytical testing (LoD, inclusivity, exclusivity, etc.) rather than a 'training set' in the AI sense. The analytical inclusivity study used a comprehensive panel of 108 strains, and additional 28 strains from the LoD study, making a total of 136 strains for analytical inclusivity tests.",
  "9. How the ground truth for the training set was established": "For analytical studies (LoD, inclusivity, exclusivity), the 'ground truth' was based on known concentrations of characterized viral and bacterial strains (TCID50/mL or CFU/mL) in simulated NPS. For inclusivity, identification of the strains was confirmed from their source (e.g., ATCC, Zeptometrix, IRR) and in some cases, further confirmed by quantitative TaqMan real-time PCR or PCR/bi-directional sequencing."
}

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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 and genetic virulence markers from liquid or soft stool preserved in Cary-Blair media, 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:

• Campylobacter Group (comprised of C. coli. C. jejuni. and C. lari) .
• . Salmonella species
• Shigella species (including S. dysenteriae, S. boydii, S. sonnei, and S. flexneri) .
• Vibrio Group (comprised of V. cholerae and V. parahaemolyticus) .
• . Yersinia enterocolitica

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 l 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, or other patient 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 which relies on detection of specific nucleic acid targets in a microarray format. For each of the bacterial nucleic acid sequences detected by EP, 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 a region which bind to a different portion of the same nucleic acid targets and also have a sequence which 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, bench-top 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 bacterial-specific target DNA. The Verigene System consists of two components: the Verigene Reader and the Verigene Processor SP.

The Reader is the Verigene System's user interface, which serves as the central control unit for all aspects of test processing, automated imaging, and result generation using a touchscreen 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 DNA isolation and amplification, and (2) Hybridizationdetection 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 finally loads the specimen into the Test Cartridge for hybridization. Single-use disposable test consumables and a self-contained Verigene Test Cartridge are utilized 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 bacterial nucleic acid sequence/analyte. This determination is made by means of software-based decision algorithm resident in the Reader.

Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text:

Device: Verigene® Enteric Pathogens Nucleic Acid Test (EP)
Purpose: Multiplexed, qualitative test for simultaneous detection and identification of common pathogenic enteric bacteria and genetic virulence markers from liquid or soft stool preserved in Cary-Blair media.

1. Acceptance Criteria and Reported Device Performance

The document describes analytical and clinical performance studies, which serve to establish the device's meeting of performance criteria. The tables provided in the original document directly illustrate the reported performance against implied acceptance metrics (e.g., target agreement percentages).

Table of Acceptance Criteria and Reported Device Performance:

Since specific acceptance criteria values (e.g., "must achieve X% sensitivity") are not explicitly stated as distinct criteria, I will list the performance metrics presented in the document as reported performance, implying they met the internal acceptance thresholds for regulatory submission. The precision and reproducibility results are strong indicators of meeting defined criteria for consistency.

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

• Clinical Study (Method Comparison):

  • Total Specimens Tested with EP Test: 1975
  • Valid/Evaluable Specimens: 1852 (after excluding 98 specimens and 25 indeterminate "No Call" specimens).
  • Data Provenance:
    • Country of Origin: United States (7 U.S. institutions involved in prospective investigation study).
    • Retrospective/Prospective: Primarily prospective collection of fresh and frozen Cary-Blair specimens. Additionally, simulated frozen seeded Cary-Blair specimens were used (408 specimens, prepared from deidentified prospectively-collected glycerol stocks from 12 clinical specimen acquisition sites).

• Precision Study (Internal): 14-member simulated sample panel tested daily in duplicate by 2 operators for 4 non-consecutive days, yielding 224 total results.

• Reproducibility Study (External): 14 unique samples tested daily in triplicate by 2 operators for 5 non-consecutive days at 3 external sites, yielding 1260 total results.

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

The document does not specify the number or qualifications of experts used to establish the ground truth. It states that the EP test results were compared to "reference methods, including bacterial culture and automated phenotype identification for the bacterial targets and broth enrichment followed by EIA and PCR amplification/BDS for Stx1/Stx2 typing." This implies laboratory professionals following established protocols, but no specifics on "experts" or their qualifications for ground truth establishment beyond standard lab procedures.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method for discrepancies in the clinical test set results (e.g., by multiple experts). It simply states the comparison to reference methods. For the analytical studies (LoD, reactivity), "expected results" were confirmed by replicate testing and quantitative definitions.

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

There is no indication of a multi-reader multi-case (MRMC) comparative effectiveness study being done, nor any mention of human readers assisting or being assisted by the AI/device. This device is a diagnostic test intended to be performed by laboratory personnel, not an AI for image interpretation or clinical decision support with physician assistance. Therefore, an effect size of human readers improving with AI vs. without AI assistance is not applicable to this type of device.

6. Standalone Performance

The entire clinical performance section (pages 10-11) describes the standalone performance of the Verigene EP test against reference methods. This means the algorithm/device's performance (results from the Verigene System) without human intervention in result interpretation beyond what is normally done in a lab setting (e.g., verifying automated calls as per standard operating procedures).

7. Type of Ground Truth Used

The ground truth for the clinical study was established using reference laboratory methods, specifically:

• Bacterial targets: Bacterial culture and automated phenotype identification.
• Stx1/Stx2 typing: Broth enrichment followed by EIA and PCR amplification/BDS.

For artificial/simulated specimens, the ground truth was the known composition of the seeded samples.

8. Sample Size for the Training Set

The document describes the analytical and clinical validation of the device. There is no information provided regarding a "training set" or the process of machine learning model development. This is a molecular diagnostic test, likely based on established probes and detection algorithms, not a deep learning AI model that requires a distinct training phase. The "Cutoff Verification" section mentions assessing 3800 data points (1120 expected positive) from LoD testing to verify the assay cutoff, which is more akin to internal algorithm parameter tuning rather than machine learning training.

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

As noted above, there is no explicit mention of a training set in the context of machine learning model development. If "training" refers to internal development and optimization of the assay's detection parameters and algorithms, the ground truth would have been established through controlled laboratory experiments (e.g., precisely known concentrations of target organisms, pure cultures, etc.) similar to the analytical studies described.

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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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The Verigene® Clostridium difficile Nucleic Acid Test (CDF) is a qualitative multiplexed in vitro diagnostic test for the rapid detection of toxin A (tcdA), toxin B (tcdB), and tcdC gene sequences of toxigenic Clostridium difficile and for presumptive identification of PCR ribotype 027 strains from unformed (liquid or soft) stool specimens collected from patients suspected of having C. difficile infection (CDI). Presumptive identification of the PCR ribotype 027 strain of C. difficile is by detection of the binary toxin (cdt) gene sequence and the single base pair deletion at nucleotide 117 in the tcdC gene encodes for a negative regulator in C. difficile toxin production. The test is performed on the Verigene System and utilizes automated specimen preparation and polymerase chain reaction (PCR) amplification, combined with a nanoparticle-based array hybridization assay to detect the toxin gene sequences associated with toxin-producing C. difficile.

The CDF Test is indicated for use as an aid in the diagnosis of CDI. Detection of PCR ribotype 027 strains of C. difficile by the CDF Test is solely for epidemiological purposes and is not intended to guide or monitor treatment for C. difficile infections. Concomitant culture is necessary only if further typing or organism recovery is required.

The Verigene C. difficile Nucleic Acid Test (CDF) 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 CDF, 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 a region which bind to a different portion of the same nucleic acid targets and also have a sequence which 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 CDF Test is performed on the Verigene System, a "sample-to-result", fully automated, bench-top molecular diagnostics workstation. The System consists of two components: the Verigene Reader and the Verigene Processor SP. The Reader is the user interface, serving as the central control unit for test processing, automated imaging, and result generation. The Processor SP automates sample preparation, target amplification, and hybridization-detection.

The medical device being described is the Verigene® Clostridium difficile Nucleic Acid Test (CDF), which is a qualitative multiplexed in vitro diagnostic test for the rapid detection of toxin B (tcdB), and tcdC gene sequences of toxigenic Clostridium difficile and for presumptive identification of PCR ribotype 027 strains from unformed (liquid or soft) stool specimens collected from patients suspected of having C. difficile infection (CDI).

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct predefined numerical targets in the provided text. Instead, the study's findings demonstrate the performance, which then implies the met "acceptance criteria." The main performance metrics provided are for sensitivity, specificity, and accuracy against reference methods.

Note: The acceptance criteria were not explicitly stated with specific numerical thresholds but are inferred from the reported performance which were considered sufficient for substantial equivalence.

2. Sample size used for the test set and the data provenance

• Sample Size for Clinical (Method Comparison) Test Set: 1,875 specimens were evaluated in the clinical study (n=1875). For specific comparisons, some samples were excluded due to inconclusive or missing reference results:
  • 6 specimens were not PCR-ribotyped.
  • 2 specimens were not sequenced for tcdC Bi-Directional Sequencing (BDS).
• Data Provenance: The data was collected from a multi-site prospective investigation study at five U.S. institutions.
  • This indicates the data is prospective and collected within the United States.

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

The text does not explicitly state the "number of experts" or their "qualifications" used to establish the ground truth. The ground truth for the clinical test set was established through a combination of reference culture followed by cell cytotoxicity testing on isolates, and subsequent strain typing by PCR Ribotyping and Bi-Directional Sequencing (BDS) at a central laboratory and an external third-party site. This suggests laboratory professionals and/or researchers were involved, but their specific expert qualifications (e.g., years of experience) are not detailed.

4. Adjudication method for the test set

The text describes using a "central laboratory" for initial culture and cytotoxin B testing, and an "external third-party site" for PCR Ribotyping. Bi-Directional Sequencing was done either on culture-confirmed isolates or DNA extracted during PCR Ribotyping. There isn't a described "adjudication method" in the sense of multiple experts reviewing and reaching a consensus on cases where initial results varied. Instead, the ground truth was established hierarchically and sequentially using definitive laboratory methods. For instance, if C. difficile was isolated from direct culture and was cytotoxin positive, it was deemed "toxigenic C. difficile positive." If not, enriched culture was used.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is an automated molecular diagnostic test, not an AI-assisted diagnostic device that human readers interpret. Therefore, the concept of "human readers improving with AI vs. without AI assistance" is not applicable.

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

Yes, a standalone study was done. The Verigene CDF Test operates on the Verigene System, which is described as a "sample-to-result, fully automated, bench-top molecular diagnostics workstation." The results are generated by a "software-based decision algorithm resident in the Reader." The performance data presented (analytical and clinical) represent the standalone performance of this automated device and its algorithm.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth used for the clinical (method comparison) study was a combination of:

• Reference Culture: Inoculation onto CCFA-D and CCMB-Tal media.
• Cell Cytotoxicity Testing: Performed on isolates from the cultures.
• Molecular Strain Typing:
  • PCR Ribotyping (at an external third-party site, with Agilent 2100 Bioanalyzer for added discrimination).
  • Bi-Directional Sequencing (BDS) of the tcdC gene.

This constitutes a robust, multi-faceted laboratory-based "reference standard" or "gold standard."

8. The sample size for the training set

The document does not provide information on the sample size for a training set. As this device is a molecular diagnostic test based on PCR and hybridization, it is likely designed and validated using analytical samples and clinical samples, but the term "training set" in the context of machine learning (where algorithms learn from data) is not used. The "cutoff verification" mentioned in analytical testing involved 59 C. difficile strains to verify cut-off values for the two-tiered filter algorithm, which might be considered an internal validation step, but not a "training set" in the common AI sense.

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

As no "training set" is explicitly mentioned in the context of the device's development or a machine learning approach, the method for establishing its ground truth is not described. The analytical studies (LoD, reactivity, specificity, etc.) utilized independently-confirmed C. difficile strains and other microorganisms with known characteristics.

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The Verigene® CYP2C19 Nucleic Acid Test (CYP2C19 Test), performed using the sample-to-result Verigene System, is a qualitative multiplexed in vitro diagnostic test for the simultaneous detection and identification of an individual's CYP450 2C19 genotype in genomic deoxyribonucleic acid (DNA) obtained from EDTA-anticoagulated whole blood samples. The Verigene CYP2C19 Nucleic Acid Test (CYP2C19 Test) is indicated for use in clinical laboratories upon prescription by the attending physician as an aid to clinicians in determining therapeutic strategy for therapeutics that are metabolized by the CYP450 2C19 gene product, specifically *2, *3, and *17. The Verigene CYP2C19 Nucleic Acid Test (CYP2C19 Test) is not indicated to be used to predict drug response or non-response.

The Verigene® System is comprised of test consumables and shared instrumentation. All Verigene tests are formatted in self-contained test-specific Verigene Test Cartridges which serve to analyze a nucleic acid sample that is presented to them. Nucleic acids are prepared directly from a whole blood specimen using magnetic glass particles and input automatically into a Test Cartridge inside the Verigene Processor SP. Test progress is tracked and directed by the Verigene Reader instrument, which serves as a central control unit for each Verigene System. Genomic DNA is extracted from the white blood cells in a whole blood specimen, fragmented and denatured. This fragmented, single-stranded genomic DNA hybridizes to complementary sequence-specific DNA oligonucleotides, known as capture oligonucleotides, arrayed on the surface of a substrate (glass slide). A second DNA oligonucleotide is then hybridized to the captured genomic DNA that was captured initially. This oligonucleotide is known as a mediator oligonucleotide containing two sequence domain is complementary to the genomic DNA target and a second domain is complementary to a common oligonucleotide attached to a signal generating gold nanoparticle probe. After washing away any DNA not affixed to the captures, the probe is exposed to the captured mediator/target compound where it hybridizes to any captured mediators. Presence of the gold nanoparticle probes at a particular location on the substrate is assessed optically. The Verigene CYP2C19 Nucleic Acid Test is designed to detect and genotype the CYP450 2C19 *2, *3 and *17 alleles. The test report lists the alleles and provides which genotype was detected in the specimen. The CYP2C19 Test algorithm automatically calculates each of the allele results using a preset normalized ratio of the signal of wild type capture locations on the microarray to the mutant capture locations on the microarray.

This submission focuses on the analytical and clinical performance of the Verigene® CYP2C19 Nucleic Acid Test. Here's a breakdown based on your request:

1. Table of Acceptance Criteria and Reported Device Performance

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

The document describes several test sets used for different studies:

• Analytical Sensitivity / LOD: 7 individual whole blood samples, each with a different genotype. Tested in replicates of 40 (total 280 tests). The data provenance is not specified, but it refers to "individual whole blood samples," suggesting clinical samples. The study appears to be prospective in nature, designed specifically for this validation.
• Interference Testing: 5 individual whole blood samples, each with a different genotype. Tested in 30 replicates per specimen for each interfering substance (total 150 tests per substance, with 5 substances and a control, leading to 900 measurements in Table 2). Data provenance is not specified, but it refers to "EDTA-anticoagulated whole blood samples," suggesting clinical samples. This study appears to be prospective.
• Specimen Stability Study: 35 EDTA whole blood samples. Tested once at 5, 10, 12, and 15 day time points (total 140 tests). Data provenance is not specified (e.g., "freshly-collected whole blood samples"). This study appears to be prospective.
• Carry-over / Cross-contamination: Whole blood specimens containing different genotypes. Tested sequentially on ten Verigene instruments, repeated in triplicate (total number of samples not explicitly stated, but includes "*1/*2, followed by *1/*1, then *1/*17, then *1/*1" repeated in triplicate). Data provenance is not specified. This study appears to be prospective.
• Precision Study: 8 unique whole blood specimens. Each tested in duplicate twice daily by two operators over 12 non-consecutive days at one site (48 replicates per specimen, total 384 data points). Data provenance is not specified. This study appears to be prospective.
• Reproducibility Study: The same 8-member panel of specimens as the Precision Study. Tested in duplicate twice daily by two operators over 5 non-consecutive days at three sites (60 replicates per specimen, total 480 data points). Data provenance is not specified. This study appears to be prospective.
• Method Comparison Study: 670 unique human whole blood samples, collected in EDTA. Data provenance is not specified, but the samples are "human whole blood samples," implying clinical origin. The study appears to be prospective, specifically for method comparison.

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

The ground truth for all performance studies (Analytical Sensitivity, Interference, Precision, Reproducibility, Method Comparison) was established by bi-directional sequencing (BDS). This is a laboratory method, not reliant on human experts for interpretation in the same way imaging studies might be. Therefore, the concept of "number of experts" and their "qualifications" for ground truth establishment is not applicable here.

4. Adjudication Method for the Test Set

Not applicable for this type of laboratory test. The ground truth (bi-directional sequencing) is considered definitive. When the device produced "No Calls" initially, these samples were re-tested, and if successful, contributed to the "Final Call Rate." In the Reproducibility study, the two final "No Call" results were considered discordant. For the Method Comparison study, one sample with an initial and final no-call on the Verigene test had a BDS result of *1/*2, indicating this was a definite discrepancy.

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

No, an MRMC comparative effectiveness study was not conducted. This device is a molecular diagnostic test that provides a genotype result, not an imaging device requiring human reader interpretation.

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

Yes, the performance studies detailed (Analytical Sensitivity, Interference, Stability, Carry-over, Precision, Reproducibility, Method Comparison) represent the standalone performance of the Verigene® CYP2C19 Nucleic Acid Test. The system is described as "sample-to-result" with "automated DNA extraction" and the "Test algorithm automatically calculates each of the allele results." This indicates minimal human intervention in the final result generation once the sample is loaded.

7. The Type of Ground Truth Used

The primary ground truth used for all performance evaluations was bi-directional sequencing (BDS). This is a highly accurate molecular method for determining specific DNA sequences, considered the gold standard for genotyping.

8. The Sample Size for the Training Set

The document does not specify a separate training set or its sample size. This is common for diagnostic tests like this, especially when the underlying technology (genotyping microarray and algorithm) is based on established scientific principles rather than a machine learning model that requires explicit training data in the context of regulatory submissions. The algorithm's parameters are likely "preset" based on scientific design and internal development/optimization rather than a distinct, large-scale training dataset as seen with AI/ML systems.

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

Since no explicit "training set" is described in the context of this 510(k) summary, the method for establishing its ground truth is also not provided. The device's "preset normalized ratio of the signal of wild type capture locations on the microarray to the mutant capture locations on the microarray" implies that the underlying genetic science and expected signal profiles for specific alleles dictate the algorithm's basis, rather than being "trained" on a dataset in the AI/ML sense.

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The Verigene® Gram-Positive Blood Culture Nucleic Acid Test (BC-GP) performed using the sample-to-result Verigene System is a qualitative, multiplexed in vitro diagnostic test for the simultaneous detection and identification of potentially pathogenic gram-positive bacteria which may cause bloodstream infection (BSI). BC-GP is performed directly on blood culture bottles identified as positive by a continuousmonitoring blood culture system and which contain gram-positive bacteria. BC-GP detects and identifies the following bacterial genera and species: Staphylococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdunensis, Enterococcus faecalis, Enterococcus faecium, Streptococcus spp., Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Listeria spp.

In addition. BC-GP detects the mecA resistance marker, inferring mecA-mediated methicillin resistance, and the vanA and vanB resistance markers, inferring vanA/vanB-mediated vancomycin resistance. In mixed growth, BC-GP does not specifically attribute van-mediated vancomycin resistance to either E. faecalis or E. faecium, or mecAmediated methicillin resistance to either S. aureus or S. epidermidis.

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

The Verigene® Gram-Positive Blood Culture Nucleic Acid Test (BC-GP) 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-GP test. Capture and Mediator olizonucleotides are utilized for gold nanoparticle probe-based endpoint detection. The Canture oligonucleotides bind to a specific portion of the nucleic acid target and are themselves bound onto a substrate in the microarray. The Mediator oligonucleotides bind to a different portion of the same nucleic acid target and allow binding of a gold nanoparticle probe to a portion complementary to 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.

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

The Reader is the Verigene System's user interface, which serves as the central control unit for all aspects of test processing and results generation. The Reader's graphical user interface guides the user through test processing and test results using a barcode scanner. The user inserts the Test Cartridge into the Verigene Processor SP, which executes the test procedure, automating the steps of ( ) Sample Preparation - Cell lysis and magnetic bead-bacterial DNA isolation from blood culture samples and (2) Hybridization - Detection and identification of bacterialspecific DNA in a microarray format by using gold nanoparticle probe-based technology.

After test processing is complete, to obtain the test results the user removes the Test Cartridge from the Processor SP, removes the reagent pack from the substrate holder, 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 decisions regarding the presence (Detected) or absence (Not Detected) of a bacterial nucleic acid sequence/analyte.

The user is asking for information about the acceptance criteria and study data for the "Verigene® Gram-Positive Blood Culture Nucleic Acid Test (BC-GP)".

Here's a breakdown of the requested information based on the provided text:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly state "acceptance criteria" in a tabular format with corresponding "reported device performance" for this specific 510(k) submission (K122514). This submission is an expansion of the intended use for a previously cleared device (K113450) and largely refers back to the original submission for detailed performance characteristics.

However, the document describes a study to support the expanded use (analytical testing of additional culture bottles) and reports the performance of the device in that study. I can create a table based on the findings of this specific study as it relates to the suitability of the additional bottle types.

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Sample Size for Test Set: For the analytical testing of additional culture bottles, the study inoculated each of the six additional bottle types with representative strains into seven replicates each.
• Data Provenance: The document does not specify the country of origin of the data, nor does it explicitly state whether the study was retrospective or prospective. Given it involved controlled inoculations into specific bottle types to test performance, it would be considered a prospective analytical study within a lab setting rather than clinical data provenance.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

The document does not mention the use of experts or their qualifications for establishing ground truth in this analytical study. Ground truth in this context (testing specific bacterial strains in culture bottles) would typically be established by controlled inoculation of known bacterial strains, confirmed by standard microbiological identification methods, rather than expert consensus on interpretation.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

The document does not mention any adjudication method. For an analytical study involving known bacterial inoculations, adjudication by experts for ground truth is generally not applicable in the same way it would be for interpreting complex clinical images or diagnoses.

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

• Was an MRMC study done? No. This device is an in vitro diagnostic test for detecting nucleic acid sequences of bacteria directly from blood cultures, not an imaging device requiring human readers or AI assistance in interpretation in the context of an MRMC study.

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

• Standalone performance: Yes, the performance described in the document is for the standalone device (Verigene® BC-GP test on the Verigene System). The system is a "sample-to-result, fully automated" system with "automated nucleic acid extraction... and target detection," and interpretation by "Diagnostic Software/Decision Algorithm." This indicates it operates without human-in-the-loop performance for result generation. The results are "Detected" or "Not Detected" for specific analytes based on signal intensity read by the system.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

For the analytical testing of additional culture bottles, the ground truth was established by controlled inoculation of known bacterial strains. The presence or absence of specific bacterial targets was predetermined by the strains inoculated.

8. The sample size for the training set

The document does not provide information about a "training set" for the BC-GP test. This type of molecular diagnostic device is typically developed based on known genetic sequences and optimized through analytical studies, rather than machine learning models that require a distinct training set in the conventional sense. The "Performance Characteristics" section refers to K113450 for the full analytical and clinical performance data, indicating that the core technology and algorithm were established in the previous submission.

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

As there's no mention of a "training set" in the context of machine learning, ground truth establishment for such a set is not applicable here. The establishment of the assay's detection capabilities would have been through rigorous analytical validation using characterized bacterial cultures and nucleic acid controls.

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The Verigene® Gram Positive Blood Culture Nucleic Acid Test (BC-GP) performed using the sample-to-result Verigene System is a qualitative, multiplexed in vitro diagnostic test for the simultaneous detection and identification of potentially pathogenic gram-positive bacteria which may cause bloodstream infection (BSI). BC-GP is performed directly on positive blood culture using BACTEC™ Plus Aerobic/F and BacT/ALERT FA FAN® Aerobic blood culture bottles, which contain gram positive bacteria. BC-GP is indicated for use in conjunction with other clinical and laboratory findings, such as culture, to aid in the diagnosis of bacterial bloodstream infections; however, it is not used to monitor bloodstream infections.

BC-GP detects and identifies the following bacterial genera and species:
Staphylococcus spp.
Staphylococcus aureus
Staphylococcus epidermidis
Staphylococcus lugdunensis
Streptococcus spp.
Streptococcus pneumoniae
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus group
Enterococcus
faecalis
Enterococcus
faecium
Listeria spp.

In addition, BC-GP detects the mecA resistance marker, inferring mecA-mediated methicillin resistance, and the vanA and vanB resistance markers, inferring vanA/vanB-mediated vancomycin resistance. In mixed growth, BC-GP does not specifically attribute van-mediated vancomycin resistance to either E. faecium, or mecA-mediated methicillin resistance to either S. aureus or S. epidermidis.

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

The Verigene® Gram Positive Blood Culture Nucleic Acid Test (BC-GP) is a molecular assav 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-GP test, Capture and Mediator oligonucleotides are utilized for gold nanoparticle probe-based endpoint detection. The Capture oligonucleotides bind to a specific portion of the nucleic acid target and are themselves bound onto a substrate in the microarray. The Mediator oligonucleotides bind to a different portion of the same nucleic acid target and allow binding of a gold nanoparticle probe to a portion complementary to 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.

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

The Reader is the Verigene System's user interface, which serves as the central control unit for all aspects of test processing and results generation. The Reader's graphical user interface guides the user through test processing and test results using a barcode scanner. The user inserts the Test Cartridge into the Verigene Processor SP, which 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) Verigene Hybridization Test - Detection and identification of bacterial-specific DNA in a microarray format by using gold nanoparticle probe-based technology.

After test processing is complete, to obtain the test results the user removes the Test Cartridge from the Processor SP, removes the reagent pack from the substrate holder, 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 decisions regarding the presence (Detected) or absence (Not Detected) of a bacterial nucleic acid sequence/analyte.

The provided text describes the evaluation of the Verigene® Gram Positive Blood Culture Nucleic Acid Test (BC-GP). While specific "acceptance criteria" defined as a numerical threshold for performance are not explicitly stated in a single section, the document outlines the performance requirements for various aspects of the device (limit of detection, inclusivity, specificity, interference, precision, and clinical agreement). The "reported device performance" is then presented in the clinical study results, allowing for an implicit comparison against acceptable ranges for such diagnostic assays.

Here's an organized breakdown of the requested information:

1. A table of acceptance criteria and the reported device performance

The document doesn't present explicit acceptance criteria with specific numerical thresholds for each analyte. Instead, it describes general expectations for "acceptable specificity," "expected results," and "high concordance." For the purpose of this table, I will infer general performance expectations from the overall context and the nature of diagnostic assay validation (e.g., generally aiming for very high agreement for positive and negative cases, especially for critical diagnoses like bloodstream infections). The reported device performance is directly extracted from the clinical study results.

Inferred Acceptance Criteria vs. Reported Device Performance

2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)

• Test Set Sample Size:
  • Clinical Study: 1767 specimens in total were initially enrolled.
    • 1251 fresh specimens
    • 175 frozen specimens
    • 216 contrived blood culture specimens (for rare organisms).
  • 125 specimens were excluded for various reasons (e.g., training sample, culture/reference method results unavailable, sample not tested on BC-GP, QC/protocol error).
  • The total evaluable specimens for analysis are not explicitly stated as a single number after exclusions, but performance tables typically reflect data from the 1426 (1251 fresh + 175 frozen) prospectively/retrospectively collected samples + 216 contrived samples, minus the excluded non-evaluable samples where applicable to each specific analyte calculation.
• Data Provenance:
  • Country of Origin: Not explicitly stated, but the study was conducted at "five external, geographically-diverse clinical study sites," implying multiple locations within a single country (likely the USA, given the FDA context).
  • Retrospective or Prospective: The clinical study incorporated both:
    • Most specimens were collected and tested as "fresh" (implying prospective at time of collection relative to the BC-GP testing).
    • Some were "stored frozen prior to testing" (implying retrospective collection for later testing).
    • A portion was "contrived" (simulated specimens for rare organisms).

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

• The document does not specify the number of experts or their specific qualifications (e.g., "radiologist with 10 years of experience").
• However, it details the reference methods used to establish ground truth:
  • "conventional biochemical, culture, and bidirectional sequencing reference methods."
  • "culture followed by testing blood culture isolates with conventional biochemicals, Vitek2, and cefoxitin disc testing."
  • "Cefoxitin discs were used as the reference method for confirming mecA mediated resistance in S. aureus and S. epidermidis."
  • "Vancomycin resistance and the presence of vanA or vanB in E. faecium and E. faecalis was performed using vancomycin E-tests followed by bidirectional sequencing on resistant organisms."
  • This implies that the ground truth was established by laboratory professionals using established clinical microbiology techniques, but their individual expertise is not quantified.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

• The document does not explicitly describe a formal adjudication method (like "2+1" or "3+1") for resolving discrepancies between the BC-GP test and the reference methods.
• It states that "BC-GP Test results were compared with results from traditional laboratory reference methods." Discrepancies are reported (e.g., in mixed cultures, 6 "false positives" and 25 "false negatives" compared to reference culture). However, the process for investigating or resolving these discrepancies to arrive at a final "ground truth" for the discrepant cases is not detailed.
• It does mention that the "initial No-call rate in the clinical study was 4.7% (77/1642), and the final No-call rate was 1.1% (18/1642)," implying that some initial no-calls were resolved or re-tested successfully, but this isn't an "adjudication" of BC-GP vs. reference method.

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

• No, a multi-reader multi-case (MRMC) comparative effectiveness study was NOT done.
• This device is an automated molecular diagnostic assay, not an imaging device that requires human "readers" or interpretation in the same way an AI for radiology would. Its performance is compared directly against established laboratory reference methods, not against human reader performance, nor is it designed to "assist" human readers in a direct interpretation task. The "Reader" component of the Verigene System is an automated instrument for analyzing the microarray, not a human.

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

• Yes, the provided study describes standalone performance of the algorithm.
• The Verigene BC-GP test is a "sample-to-result, fully automated, bench-top molecular diagnostics workstation." The entire process, from sample preparation to target detection and result generation, is automated by the Verigene System. The clinical study evaluates the performance of this automated system (algorithm only) against traditional culture-based reference methods. There is no human "in-the-loop" for interpreting the BC-GP test results; the system generates "Detected" or "Not Detected" calls.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

• The ground truth for the clinical study was established using a combination of traditional microbiological reference methods and gold-standard molecular techniques:
  • Culture: Isolation and identification of microorganisms through conventional culture methods.
  • Biochemicals: Conventional biochemical tests for species identification.
  • Vitek2: An automated system for microbial identification and antimicrobial susceptibility testing.
  • Cefoxitin Disk Diffusion: For mecA-mediated methicillin resistance.
  • Vancomycin E-tests: For vancomycin resistance.
  • Bidirectional Sequencing: For vanA and vanB resistance markers.
  • This represents a robust and well-accepted set of methods for establishing ground truth in clinical microbiology.

8. The sample size for the training set

• The document mentions "Training Sample" as a reason for exclusion from the evaluable clinical dataset (e.g., 5 at OSU, 4 at LIJ), but it does not specify the total sample size used for the training set for the BC-GP device itself.
• The "Assay Cutoff" section mentions that "a set of bacterial strains were tested to represent all the analytes detected by the BC-GP Test" to initially determine cutoff values, and "A set of retrospective blood culture specimens were then tested with the BC-GP Test to verify the previously determined cut off values." This internal process would constitute a form of training or optimization, but the specific number of samples for this phase is not provided.
• The clinical study mentions the exclusion of 125 specimens, some labeled as "Training Sample" (indicating they were likely used for internal development or training purposes prior to the formal clinical evaluation).

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

• For the "Assay Cutoff" determination (an internal optimization process analogous to training), the ground truth was established by:
  • "Blood culture bottles were spiked with each individual organism and grown in automated blood culture instruments to 'bottle ring.'"
  • "The test decisions from each test were compiled to generate a data set that was used to initially determine BC-GP Assay Test cutoff values."
  • The verification of these cutoffs used "retrospective blood culture specimens" where "Results were analyzed using logistic fit and ROC statistics. The results obtained from this the cutoff determination matched the results from culture-based biochemical results, thus verifying the final cutoff values."
• This indicates that for the internal optimization/training phases, the ground truth was established by known spiked organisms and confirmed by culture-based biochemical results.

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The Verigene® Staphylococcus Blood Culture (BC-S) Nucleic Acid Test performed using the sample-to-result Verigene System is a qualitative, multiplexed in vitro diagnostic test for the simultaneous detection and identification of potentially pathogenic gram-positive bacterial species Staphylococcus aureus ("SA") and Staphylococcus epidermidis ("SE") which may cause bloodstream infection (BSI). In addition, the BC-S test detects the mecA resistance marker inferring mecA-mediated methicillin/oxacillin resistance. In mixed growth, the BC-S Test does not specifically attribute mecA-mediated methicillin/oxacillin resistance to either SA or SE.

The BC-S test is performed directly on positive blood culture using BACTEC™ Plus Aerobic/F and BacT/ALERT FA FAN® Aerobic blood culture bottles, which contain gram-positive cocci in clusters (GPCCL) observed on Gram stain. Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing, differentiation of mixed growth, association of the mecA gene to an organism, or for epidemiological typing.

The BC-S test is indicated for use in conjunction with other clinical and laboratory findings, such as culture, to aid in the diagnosis of bacterial bloodstream infections; however, it is not used to monitor bloodstream infections.

The Verigene Staphylococcus Blood Culture Nucleic Acid Test (BC-S) 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-S test, Capture and Mediator oligonucleotides are utilized for gold nanoparticle probe-based endpoint detection. The Capture oligonucleotides bind to a specific portion of the nucleic acid target and are themselves bound onto a substrate in the microarray. The Mediator oligonucleotides bind to a different portion of the same nucleic acid target and allow binding of a gold nanoparticle probe to a portion complementary to 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.

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

The Reader is the Verigene System's user interface, which serves as the central control unit for all aspects of test processing and results generation. The Reader's graphical user interface guides the user through test processing and test results using a barcode scanner.

The user inserts the Test Cartridge into the Verigene Processor SP, which executes the test procedure, automating the steps of ( ) Sample Preparation - Cell lysis and magnetic bead-based bacterial DNA isolation from blood culture samples and (2) Verigene Hybridization Test - Detection and identification of bacterial-specific DNA in a microarray format by using gold nanoparticle probe-based technology.

After test processing is complete, to obtain the test results the user removes the Test Cartridge from the Processor SP, removes the reagent pack from the substrate holder, 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 decisions regarding the presence (Detected) or absence (Not Detected) of a bacterial nucleic acid sequence/analyte.

This document describes the regulatory submission for the Verigene® Staphylococcus Blood Culture Nucleic Acid Test (BC-S) and its performance characteristics.

Here's an analysis of the provided text to extract the requested information:

1. Table of Acceptance Criteria and the Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" for the clinical performance in a pass/fail sense with numerical targets. However, the "Method Comparison Study" results can be interpreted as the device's reported performance against a reference standard. The goal implicitly is high agreement with the reference methods.

2. Sample size used for the test set and the data provenance:

• Test Set Sample Size: 330 culture-positive, gram-positive (GPCCL) blood culture specimens from patients.
• Data Provenance:
  • Country of Origin: Not explicitly stated, but the study was conducted at "five external clinical sites," implying clinical settings within a country, likely the US given the FDA submission.
  • Retrospective or Prospective: Prospective, as subjects were "individuals receiving routine care requiring blood culture testing" and "specimens from these patients were identified for BC-S testing."

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

• Number of experts: Not explicitly stated.
• Qualifications of experts: The ground truth was established using "reference method results obtained from the standard biochemical bacterial detection and susceptibility techniques utilized in routine clinical practice." This implies standard microbiology laboratory personnel and practices, rather than a panel of individual experts.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

• No explicit adjudication method is mentioned for the test set. The comparison was made against "reference method results obtained from the standard biochemical bacterial detection and susceptibility techniques utilized in routine clinical practice," suggesting a direct comparison rather than a consensus process.

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:

• No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic test for bacterial identification and resistance markers, not an imaging analysis tool that relies on human reader interpretation of images. The study focuses on the device's performance against standard microbiological methods.

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

• Yes, the performance data presented (analytical and clinical) represents the standalone performance of the Verigene® Staphylococcus Blood Culture Nucleic Acid Test (BC-S) and the Verigene® System. The system is described as a "sample-to-result, fully automated, bench-top molecular diagnostics workstation," implying minimal human intervention beyond setting up the test. The "Method Comparison Study" directly compares the device's output to standard laboratory results.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

• The ground truth used was reference method results obtained from standard biochemical bacterial detection and susceptibility techniques utilized in routine clinical practice. This essentially means the results from conventional microbiology tests (e.g., culture, biochemical identification, antimicrobial susceptibility testing) performed in clinical laboratories.

8. The sample size for the training set:

• The document does not explicitly state the sample size for a "training set." The performance data section focuses on "Analytical Testing" and "Clinical Testing" (Method Comparison Study, Reproducibility Study). In vitro diagnostic tests like this typically undergo extensive analytical validation (LOD, inclusivity, exclusivity, etc.) using characterized strains and then clinical validation with patient samples. The term "training set" is more common in machine learning contexts, which this device does not appear to primarily utilize in the same way. The strains used for "Analytical Reactivity (Inclusivity)" and "Analytical Specificity (Exclusivity)" could be considered part of developmental data but aren't explicitly called a training set.

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

• As a "training set" is not explicitly mentioned in the context of machine learning model training, the method for establishing its ground truth is not provided. However, the ground truth for the analytical validation (inclusivity/exclusivity) would have been established by standard microbiological characterization of the bacterial strains used (e.g., genetic sequencing, biochemical tests, culture).

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The Verigene® Respiratory Virus Plus Nucleic Acid Test (RV+) on the Verigene® System is a qualitative nucleic acid multiplex test intended to simultaneously detect and identify multiple respiratory virus nucleic acids in nasopharyngeal (NP) swab specimens from individuals with signs and symptoms of respiratory tract infection. The following virus types and subtypes are identified using the RV+: Influenza A, Influenza A subtype H1, Influenza A subtype H3, 2009 H1N1, Influenza B, Respiratory Syncytial Virus (RSV) subtype A, and RSV subtype B. The test is not intended to detect Influenza C virus. Detecting and identifying specific viral nucleic acids from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection, if used in conjunction with other clinical and laboratory findings.

Negative results for Influenza A, Influenza B, or RSV do not preclude influenza virus or RSV infection and should not be used as the sole basis for diagnosis, treatment, or patient management decisions. Conversely, positive results do not rule-out bacterial infection or co-infection with other viruses. The agent detected may not be the definite cause of disease. The use of additional laboratory testing and clinical presentation must be considered in order to obtain the final diagnosis of respiratory viral infection.

Performance characteristics for Influenza A Virus were established when Influenza A/H3, A/H1, and 2009 H1N1 were the predominant Influenza A viruses circulating. These characteristics may vary when other Influenza A viruses are emerging.

If infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions used specifically for novel virulent influenza viruses and sent to state or local health department for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

The entire RV+ test is performed on the Verigene® System, which is a bench-top molecular diagnostics workstation that consists of two instruments, the Verigene Processor SP and the Verigene Reader. The Verigene Processor SP performs the assay steps on each sample by using a robotic pipettor to transfer and mix reagents within and between separate testing modules designed for nucleic acid extraction, target amplification, and the Verigene Hybridization Test. The Verigene Hybridization Test module is the same as in the original Verigene System with added modules for nucleic acid extraction and RT-PCR target amplification. Key functions of the Verigene Processor SP include: 1) Reading of the barcode identification label on inserted Test Consumables to maintain positive identification of patient samples throughout processing. 2) Facilitation of nucleic acid extraction, multiplex RT-PCR target amplification, and the Verigene Hybridization Test. 3) Real-time communication of test processing status to the Reader.

The Verigene Reader is the same instrument as in the FDA-cleared RVNATSP. It is a free-standing instrument with a touch screen control panel and a wand-based barcode scanner. It utilizes a graphical user interface to guide the user through the process of ordering tests and reporting results. There are no serviceable parts and no user calibration is required. Interaction with the touch screen is minimized through barcode use. This instrument also serves as the reader of the Test Cartridges using advanced optics. The key functions of the Verigene Reader include: 1) Entry and tracking of specimen identification numbers via manual keyboard input or via barcode-reader wand. 2) Test selection for each specimen. 3) Automated transfer of specimen processing instructions on Test Cartridge-specific basis to linked Processor SP unit(s). A single Reader unit can control up to 32 Processor units. 4) Automated imaging and analysis of Test Cartridges. 5) Results display. 6) Results report generation.

RV+ consumables within each single-use disposable test kit include: (i) Tip Holder Assembly; (ii) Extraction Tray; (iii) Amplification Tray; and (iv) RV+ Test Cartridge. The kit components are inserted into the corresponding module of the Verigene Processor SP prior to each test, and the sample is added to the Extraction Tray. Patient information is entered into the Reader to initiate the test procedure.

1. Tip Holder Assembly - The robotic pipettor picks up pipettes from the Tip Holder Assembly. The pipettes are used for mixing and transferring reagents within the test procedure.
2. Extraction Tray – Nucleic acids are extracted from the sample by using magnetic bead-based methods within the Extraction Tray. Each Tray contains reagents for a single extraction procedure. A robotic pipette transfers reagents to designated wells within the Extraction Tray to affect the steps of lysis, capture of nucleic acids onto the magnetic beads, washing, and eluting the isolated nucleic acids from the magnetic beads.
3. Amplification Tray – The isolated nucleic acids are amplified by using multiplex RT-PCR within the Amplification Tray. Each Tray contains reagents for a single multiplex RT-PCR procedure. A robotic pipette transfers the reagents to a specific well within the Amplification Tray. A set thermal profile is then initiated to perform all of the amplification related steps including UDG-based decontamination, reverse transcription, and multiplex PCR in a single tube. Upon completion, an aliquot of the amplified sample is mixed with hybridization buffer containing the virus specific mediator probes. The sample is then transferred to the Test Cartridge.
4. RV+ Test Cartridge for Verigene Hybridization Test – The virus-specific and subtype-specific amplicons are detected and identified within a Test Cartridge by using specific nucleic acid probes in conjunction with gold nanoparticle probe-based detection technology. Each Test Cartridge is a self-contained, laboratory consumable that consists of two parts. The upper housing of each cartridge is called the "reagent pack" and contains reservoirs filled with the detection reagents. When in place with the 'substrate holder', the reagent pack creates an air-tight hybridization chamber surrounding the region of the substrate containing a target-specific capture array. As each step of the test is completed, old reagents are moved out of the hybridization chamber and new reagents are added from the reagent pack via microfluidic channels and pumps. Once the test is complete, the Test Cartridge is removed from the Verigene Processor SP unit and the reagent pack is snapped off and discarded. The remaining slide is now ready for imaging and analysis in the Verigene Reader.
5. End-point detection on the Verigene Reader: The test slide is inserted into the Verigene Reader wherein it is illuminated along its side. The gold-silver aggregates at the test sites scatter the light, which is in turn captured by a photosensor. The relative intensity arising from each arrayed test site is tabulated. Net signals, defined as the absolute signal intensities with background signals subtracted, are compared with thresholds determined by negative controls within the slide in order to arrive at a decision regarding the presence or absence of target. These results are linked to the test and patient information entered at the beginning of each test session to provide a comprehensive results file.

Here's an analysis of the acceptance criteria and the study proving the device meets those criteria, based on the provided text:

Acceptance Criteria and Device Performance for Verigene® Respiratory Virus Plus Nucleic Acid Test (RV+)

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria in terms of specific sensitivity and specificity thresholds. Instead, it presents the "Performance Characteristics" from a methods comparison study, and the acceptance is implied by the FDA's clearance of the device (K103209). Therefore, the "acceptance criteria" here are interpreted as the observed performance deemed acceptable for FDA clearance, and the "reported device performance" refers to the results from the clinical methods comparison study.

Reproducibility/Precision Study:
The document also presents reproducibility data, interpreted as another form of acceptance criteria for device performance stability.

• Total Agreement for all panel members across all 3 sites: 97.2% - 100% (95% CI range from 90.3% - 99.7% to 95.0% - 100.0%).
• "No Call" rate: 1.6% (14/864)
• "Pre-analytical error" failure rate: 0.2% (2/864)

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

• Sample Size for Test Set: 1022 prospectively-collected specimens were used for the methods comparison study.
• Data Provenance:
  • Country of Origin: Not explicitly stated, but the study was conducted at "three collection hospital sites" and shipped to "Nanosphere" (located in Northbrook, IL, USA) for processing and then to "testing sites." Given the FDA submission from a US-based company, it is highly probable the data is from the USA.
  • Retrospective or Prospective: The samples were collected prospectively during the 2008-2009 and 2009-2010 respiratory seasons. Residual specimens were then de-identified, frozen, and shipped to Nanosphere, then shipped to testing sites.

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

• Number of Experts: Not explicitly stated as "experts." The ground truth was established using a combination of methods:
  • Culture-based methods confirmed with an FDA-cleared Direct Fluorescent Antibody (DFA) test for Influenza A, Influenza B, and RSV.
  • Bidirectional sequencing for Influenza A subtyping (H3, H1, 2009 H1N1) and RSV subtyping (RSV A, RSV B).
  • For discordant results between RV+ and culture/DFA, bidirectional sequencing and/or NAAT (Nucleic Acid Amplification Test) was used for resolution.
• Qualifications of Experts: Not specified. The reference methods mentioned are laboratory-based standard tests, implying qualified laboratory personnel perform these tests, but no specific "expert" role or qualifications (e.g., years of experience) are detailed.

4. Adjudication Method for the Test Set

The adjudication method for the test set involved a multi-step process for resolving discrepancies:

• Initial comparison of RV+ results against culture-based methods confirmed with FDA-cleared DFA.
• For Influenza A subtyping and RSV subtyping, bidirectional sequencing was used as the primary comparative method.
• For discordant results between RV+ and culture/DFA, further clarification was sought using bi-directional sequencing and/or NAAT.
• Specific notes for individual discrepancies (e.g., footnote comments below the tables) illustrate this process, where sequencing or repeat testing with NAAT/culture informed the final ground truth. This resembles a tie-breaker adjudication approach for discordant results.

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 mentioned. This study focuses on the standalone performance of the RV+ device against established laboratory methods, not on comparing human reader performance with and without AI assistance. The device itself is a molecular diagnostic test, not an AI-powered image analysis tool for human readers.

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

• Yes, a standalone performance study was conducted. The methods comparison study evaluated the RV+ system (which includes sample preparation, target amplification, and a Verigene Hybridization Test with automated imaging and analysis, generating results automatically) as a direct comparison against standard laboratory ground truth methods. The Verigene System is described as a "bench-top molecular diagnostics workstation" that automates various steps and provides "results display" and "results report generation." This indicates a standalone performance evaluation of the device as a diagnostic tool without continuous human-in-the-loop adjustments to the test outcome.

7. The Type of Ground Truth Used

The ground truth used was a composite gold standard primarily consisting of:

• Culture-based methods confirmed with an FDA-cleared DFA test: For general detection of Influenza A, Influenza B, and RSV.
• Bidirectional sequencing: For subtyping of Influenza A (H3, H1, 2009 H1N1) and RSV (RSV A, RSV B), and for resolution of discordant results.
• NAAT (Nucleic Acid Amplification Test): Used for further clarification in cases of culture/DFA discordance.

This approach uses a combination of established laboratory diagnostic techniques.

8. The Sample Size for the Training Set

The document does not report a separate training set or its sample size for the Verigene® Respiratory Virus Plus Nucleic Acid Test (RV+). The provided information focuses on the validation studies (analytical and methods comparison) for the final trained/developed device. Molecular diagnostic tests like this one are typically developed through iterative optimization and then validated, rather than having a distinct "training set" in the machine learning sense for the final product evaluation.

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

Since a distinct "training set" is not reported in the context of device development as per the provided text, the method for establishing its ground truth is also not applicable or reported. The focus is on the performance evaluation of the already developed device using the methods comparison and reproducibility studies.

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The Verigene® Respiratory Virus Nucleic Acid Test on the Verigene SP System (RVNATsp) is a qualitative multiplex in vitro diagnostic test for the detection and identification of Influenza A Virus, Influenza B Virus, and Respiratory Syncytial Virus (RSV) nucleic acids purified from nasopharyngeal swab specimens obtained from patients symptomatic for viral upper respiratory infection. The test is intended to be used on the Verigene SP System as an aid in the differential diagnosis of Influenza A, Influenza B, and RSV infections. The test is not intended to detect Influenza C virus.

Negative results do not preclude influenza virus or RSV infection and should not be used as the sole basis for treatment or other management decisions. It is recommended that negative test results be confirmed by culture.

Performance characteristics for Influenza A Virus were established when Influenza A/H3 and A/H1 were the predominant Influenza A viruses in circulation. As Influenza A viruses emerge, performance characteristics may vary.

If infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent Influenza viruses and sent to state or local health department for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

Not Found

This document is a 510(k) clearance letter for the "Verigene® Respiratory Virus Nucleic Acid Test on the Verigene SP System (RVNATSP)." It describes the device's intended use and substantial equivalence to a predicate device. However, it does not contain the detailed study information, acceptance criteria, or performance data typically found in a clinical study report or a more comprehensive 510(k) submission summary.

Therefore, many of the requested fields cannot be directly answered from this document.

Here's what can be extracted and what cannot:

1. A table of acceptance criteria and the reported device performance

• Cannot be extracted: This document does not provide acceptance criteria or detailed performance data (e.g., sensitivity, specificity, accuracy). It only mentions that performance characteristics for Influenza A Virus were established for specific subtypes.

2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Cannot be extracted: The document does not specify the sample size, data provenance, or whether the study was retrospective or prospective.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

• Cannot be extracted: The document does not mention experts, their number, or qualifications related to establishing ground truth for the test set.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

• Cannot be extracted: The document does not describe any adjudication method.

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

• N/A: This device is a diagnostic nucleic acid test, not an AI-assisted imaging device. Therefore, an MRMC study comparing human readers with and without AI assistance is not applicable to this type of device.

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

• Applicable, but details not provided: As an in vitro diagnostic test, the "algorithm only" performance (i.e., the diagnostic test itself) is what is assessed. However, the performance metrics (sensitivity, specificity) are not provided in this letter.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

• Implicitly standard of care/reference method, but not explicitly stated: For a nucleic acid test, the ground truth would typically be established by a highly sensitive and specific reference method, such as culture or another validated molecular test. The document mentions "Negative results do not preclude influenza virus or RSV infection and should not be used as the sole basis for treatment or other management decisions. It is recommended that negative test results be confirmed by culture," which suggests culture might be part of the ground truth or a confirmatory method. However, the specific method for establishing ground truth for the primary study is not explicitly detailed.

8. The sample size for the training set

• Cannot be extracted: This document does not provide details about a training set since it's a 510(k) clearance letter, not a full study report for an AI/machine learning device.

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

• Cannot be extracted: As above, details about a training set or its ground truth establishment are not present.

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