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The Panther Fusion GI Expanded Bacterial Assay is a multiplex real-time PCR in vitro diagnostic test for the rapid and qualitative detection and differentiation of Yersinia enterocolitica, Vibrio (V. parahaemolyticus, V. vulnificus, V. cholerae), Escherichia coli O157, and Plesiomonas shigelloides. Nucleic acids are isolated and purified from Cary-Blair preserved stool specimens collected from individuals exhibiting signs and symptoms of gastroenteritis.

This assay is intended to aid in the differential diagnosis of Yersinia enterocolitica, Vibrio (V. parahaemolyticus, V. vulnificus, V. cholerae), Escherichia coli O157, and Plesiomonas shigelloides infections. The results of this assay should be used in conjunction with clinical presentation, laboratory findings, and epidemiological information and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out coinfection with other organisms that are not detected by this test and may not be the sole or definitive cause of patient illness. Negative 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. This assay is designed for use on the Panther Fusion System.

The Panther Fusion GI Expanded Bacterial Assay is a multiplex real-time PCR in vitro diagnostic test for the rapid and qualitative detection and differentiation of Yersinia enterocolitica, Vibrio (V. parahaemolyticus, V. vulnificus, V. cholerae), Escherichia coli O157, and Plesiomonas shigelloides. Nucleic acids are isolated and purified from Cary-Blair preserved stool specimens collected from individuals exhibiting signs and symptoms of gastroenteritis.

The Panther Fusion System fully automates specimen processing, including sample lysis, nucleic acid capture, amplification, and detection for the Panther Fusion GI Expanded Bacterial Assay. Nucleic acid capture and elution takes place in a single tube on the Panther Fusion System. The eluate is transferred to the Panther Fusion System reaction tube containing the assay reagents. Multiplex real-time PCR is then performed for the eluted nucleic acid on the Panther Fusion System.

Sample processing: Prior to processing and testing on the Panther Fusion System, specimens are transferred to an Aptima Multitest tube containing specimen transport media (STM) that lyses the cells, releases target nucleic acid, and protects them from degradation during storage.

Nucleic acid capture and elution: An internal control (IC-B) is added automatically to each specimen via the working Panther Fusion Capture Reagent-B (wFCR-B) to monitor for interference during specimen processing, amplification, and detection caused by reagent failure or inhibitory substances. Specimens are first incubated in an alkaline reagent (FER-B) to enable cell lysis. Nucleic acid released during the lysis step hybridizes to magnetic particles in the wFCR-B. The capture particles are then separated from residual specimen matrix in a magnetic field by a series of wash steps with a mild detergent. The captured nucleic acid is then eluted from the magnetic particles with a reagent of low ionic strength (Panther Fusion Elution Buffer).

Multiplex PCR amplification and fluorescence detection: Lyophilized single unit dose reaction master mix is reconstituted with the Panther Fusion Reconstitution Buffer I and then combined with the eluted nucleic acid into a reaction tube. Panther Fusion Oil reagent is added to prevent evaporation during the PCR reaction. Target-specific primers and probes then amplify targets via polymerase chain reaction while simultaneously measuring fluorescence of the multiplexed targets. The Panther Fusion System compares the fluorescence signal to a predetermined cut-off to produce a qualitative result for the presence or absence of each analyte.

The analytes and the channel used for their detection on the Panther Fusion System are summarized in the table below:

Assay Components: The assay components configuration for the Panther Fusion GI Expanded Bacterial Assay is analogous to the Panther Fusion Respiratory Assays. The reagents required to perform the Panther Fusion GI Expanded Bacterial Assay are packaged and sold separately. There are 7 boxes containing 9 reagents which are required for sample processing. The Panther Fusion GI Expanded Bacterial Assay requires one ancillary kit and one specimen collection kit, neither of which are provided with the assay and can be acquired separately:

1. Aptima Assay Fluids Kit (303014)
2. Aptima Multitest Swab Specimen Collection Kit (PRD-03546)

Table 1: Reagents Required to Perform the Panther Fusion GI Expanded Bacterial Assay

Table 2: Ancillary and Collection Kits Required to Perform the Panther Fusion GI Expanded Bacterial Assay

Instrumentation: The Panther Fusion GI Expanded Bacterial Assay has been designed for and validated on the Panther Fusion system. The Panther Fusion System fully automates specimen processing, including sample lysis, nucleic acid capture, amplification, and detection for the Panther Fusion GI Expanded Bacterial Assay.

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The Panther Fusion GI Bacterial Assay is a multiplex real-time PCR in vitro diagnostic test for the rapid and qualitative detection and differentiation of Salmonella, Shigella/Enteroinvasive Escherichia coli (EIEC), Campylobacter (C. coli, C. jejuni) nucleic acids and Shiga-toxin producing Escherichia coli Shiga toxins 1 and 2 (undifferentiated) genes. Nucleic acids are isolated and purified from Cary-Blair preserved stool specimens collected from individuals exhibiting signs and symptoms of gastroenteritis.

This assay is intended to aid in the differential diagnosis of Salmonella, Campylobacter, Shigella/Enteroinvasive E. coli (EIEC) and Shigatoxigenic Escherichia coli (STEC) infections. The results of this assay should be used in conjunction with clinical presentation, laboratory findings, and epidemiological information and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions. 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 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. This assay is designed for use on the Panther Fusion System.

The Panther Fusion GI Bacterial Assay is a multiplex real-time PCR in vitro diagnostic test developed for use on the fully automated Panther Fusion system to detect nucleic acids from Salmonella, Shigella/Enteroinvasive Escherichia coli (EIEC), Campylobacter (C. coli, C. jejuni) and Shiga-toxin producing Escherichia coli Shiga toxins 1 and 2 (undifferentiated) genes.

The Panther Fusion System fully automates specimen processing, including sample lysis, nucleic acid capture, amplification, and detection for the Panther Fusion GI Bacterial Assay. Nucleic acid capture and elution takes place in a single tube on the Panther Fusion System. The eluate is transferred to the Panther Fusion System reaction tube containing the assay reagents. Multiplex real-time PCR is then performed for the eluted nucleic acid on the Panther Fusion System.

Sample processing: Prior to processing and testing on the Panther Fusion System, specimens are transferred to an Aptima Multitest tube containing specimen transport media (STM) that lyses the cells, releases target nucleic acid, and protects them from degradation during storage.

Nucleic acid capture and elution: An internal control (IC-B) is added automatically to each specimen via the working Panther Fusion Capture Reagent-B (wFCR-B) to monitor for interference during specimen processing, amplification, and detection caused by reagent failure or inhibitory substances. Specimens are first incubated in an alkaline reagent (FER-B) to enable cell lysis. Nucleic acid released during the lysis step hybridizes to magnetic particles in the wFCR-B. The capture particles are then separated from residual specimen matrix in a magnetic field by a series of wash steps with a mild detergent. The captured nucleic acid is then eluted from the magnetic particles with a reagent of low ionic strength (Panther Fusion Elution Buffer).

Multiplex PCR amplification and fluorescence detection: Lyophilized single unit dose reaction master mix is reconstituted with the Panther Fusion Reconstitution Buffer I and then combined with the eluted nucleic acid into a reaction tube. Panther Fusion Oil reagent is added to prevent evaporation during the PCR reaction. Target-specific primers and probes then amplify targets via polymerase chain reaction while simultaneously measuring fluorescence of the multiplexed targets. The Panther Fusion System compares the fluorescence signal to a predetermined cut-off to produce a qualitative result for the presence or absence of each analyte.

The analytes and the channel used for their detection on the Panther Fusion System are summarized in the table below:

Assay Components
The assay components configuration for the Panther Fusion GI Bacterial Assay is analogous to the Panther Fusion Respiratory Assays. The reagents required to perform the Panther Fusion GI Bacterial Assay are packaged and sold separately. There are 7 boxes containing 9 reagents which are required for sample processing. The Panther Fusion GI Bacterial Assay requires one ancillary kit and one specimen collection kit, neither of which are provided with the assay and can be acquired separately:

1. Aptima Assay Fluids Kit (303014)
2. Aptima Multitest Swab Specimen Collection Kit (PRD-03546)

Table 1: Reagents Required to Perform the Panther Fusion GI Bacterial Assay

Table 2: Ancillary and Collection Kits Required to Perform the Panther Fusion GI Bacterial Assay

Instrumentation
The Panther Fusion GI Bacterial Assay has been designed for and validated on the Panther Fusion system. The Panther Fusion System fully automates specimen processing, including sample lysis, nucleic acid capture, amplification, and detection for the Panther Fusion GI Bacterial Assay.

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The QIAstat-Dx GI Panel 2 Mini B is a multiplexed nucleic acid test intended for use with the OIAstat-Dx Analyzer 1.0 for the simultaneous in vitro qualitative detection of nucleic acids from multiple bacteria directly from preserved stool samples (Para-Pak C&S or FecalSwab) obtained from individuals with signs and/or symptoms of gastrointestinal infection. The following bacteria (including several diarrheagenic E. coli/Shigella pathotypes) are identified with the QIAstat-Dx GI Panel 2 Mini B:

• Campylobacter
• Shigella
• Shiga-like toxin Escherichia coli (STEC)*
• Salmonella
• Yersinia enterocolitica

*Only with Para-Pak C&S, not reported for FecalSwab

Concomitant culture is necessary for organism recovery and further typing of bacterial agents. The QlAstat-Dx GI Panel 2 Mini B is indicated as an aid in the diagnosis of specific agents of gastrointestinal illness, in conjunction with other clinical, laboratory, and epidemiological data. Postive results do not rule out co-infection with organisms not detected by the QIAstat-Dx GI Panel 2 Mini B. The organisms detected may not be the sole or definitive cause of the disease.

Negative QIAstat-Dx GI Panel 2 Mini B results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this assay test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.

The QIAstat-Dx® GI Panel 2 Mini B (Cat. no. 691423) assay is a modified device (reduced version) of the OIAstat-Dx Gastrointestinal Panel 2 (Cat. no. 691421). The OIAstat-Dx GI Panel 2 Mini B is identical to the QIAstat-Dx Gastrointestinal Panel 2 (K220062) but uses an Assay Definition File (ADF) which masks all but five pathogens (targets) from the OIAstat-Dx Gastrointestinal Panel 2. The following bacteria (including several diarrheagenic E. coli/Shigella pathotypes) are identified with the OIAstat-Dx GI Panel 2 Mini B: Campvlobacter. Shigella, Shiga-like toxin E. coli (STEC), Salmonella and Yersinia enterocolitica. The QIAstat-Dx GI Panel 2 Mini B is part of the QIAstat-Dx system and works with the OIAstat-Dx Analyzer 1.0. It will be available in a separately labeled kit.

The QIAstat-Dx GI Panel 2 Mini B is intended to be used with stool samples in Para-Pak C&S or FecalSwab transport media.

QIAstat-Dx is based on single-test cartridges with pre-packaged reagents including both wet and dry chemistry to handle the sample preparation and detection steps for the presence of a range of selected analytes by PCR technology. After insertion of the sample, the QIAstat-Dx assay cartridge is processed by the QIAstat-Dx Analyzer 1.0.

Once the cartridge is inserted into the instrument, the test starts automatically and runs for about 78 minutes. When the test is finished, the cartridge is removed by the user and discarded. The QIAstat-Dx Analyzer 1.0 automatically interprets test results and displays a summary on the analyzer display screen. The results can be printed using a connected printer if needed. The detected analytes are displayed in red. For other analytes tested, they are displayed in green if not detected or in grav if not applicable or invalid. The analyzer will report if an error occurs during processing, in which case the test will fail and no results will be provided (screen will show "FAIL").

All the reagents required for the complete execution of the test are pre-loaded and selfcontained in the QIAstat-Dx GI Panel 2 Mini B cartridge. The user does not need to manipulate any reagents. During the test, reagents are handled by pneumatically operated microfluidics without any direct contact with the user or the analyzer actuators.

Within the cartridge, multiple steps are automatically performed in sequence by using pneumatic pressure and a multiport valve to transfer sample and fluids via the Transfer Chamber (TC) to their intended destinations. Following the introduction of the sample from a disposable transfer pipette, the following assay steps occur automatically and sequentially:

• Sample Pre-treatment for PCR Inhibitors removal
• Resuspension of Internal Control and Proteinase K
• Cell lysis using mechanical and/or chemical means
• Membrane-based nucleic acid purification
• Rehydration of Master Mix
• Transfer of defined aliquots of eluate/master mix to different reaction chambers
• Performance of multiplex real-time RT-PCR testing within each reaction chamber.

The provided text does not contain detailed acceptance criteria or a study that explicitly proves the device meets those criteria in a format with numerical results and statistical analyses typical for such studies. It states that the performance data for the QIAstat-Dx GI Panel 2 Mini B is equivalent to the predicate device (QIAstat-Dx Gastrointestinal Panel 2, K220062) for the five specific analytes it detects. It also mentions that the "QIAGEN QIAstat-Dx GI Panel 2 Mini B Instructions for Use" should be consulted for performance tables, which are not included in this document.

However, based on the information provided, I can infer the general nature of the acceptance criteria (qualitative detection of specific pathogens) and describe the comparative nature of the "study" (equivalence to a predicate device).

Here's an attempt to structure the information based on your request, with significant caveats that detailed numerical results, sample sizes, expert qualifications, and study methodologies for the actual performance are not present in the provided text.

Acceptance Criteria and Device Performance for QIAstat-Dx GI Panel 2 Mini B

The QIAstat-Dx GI Panel 2 Mini B is a modified version of the predicate device, QIAstat-Dx Gastrointestinal Panel 2 (K220062). The device performance for the QIAstat-Dx GI Panel 2 Mini B is presented as being equivalent to the predicate device for the five target analytes it identifies.

1. Table of Acceptance Criteria and Reported Device Performance

Since specific numerical acceptance criteria and performance metrics (e.g., sensitivity, specificity, PPV, NPV) are not provided in this document, the table below reflects the qualitative nature of the information given. The "acceptance criteria" are inferred from the demonstrated performance equivalence to the predicate device for the detected analytes.

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

The provided document does not specify the sample size used for the test set or the data provenance (e.g., country of origin, retrospective/prospective nature). It simply states that the performance data for the modified device is "equivalent" to the predicate device. To find this information, one would need to refer to the 510(k) submission K220062 for the predicate device and/or the "QIAGEN QIAstat-Dx GI Panel 2 Mini B Instructions for Use."

3. Number of Experts and Qualifications

The document does not mention the number of experts used to establish ground truth or their qualifications. This information would typically be found in the detailed performance study report of the predicate device, or IFU for the current device. Given that the device detects nucleic acids for specific bacteria, ground truth is likely established through culture or other confirmed molecular methods, rather than expert consensus on images.

4. Adjudication Method

The document does not specify any adjudication method (e.g., 2+1, 3+1, none) for the test set. This type of method is more common in image-based AI studies where human interpretation can vary; for a nucleic acid test, ground truth is typically established by definitive laboratory methods.

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

An MRMC comparative effectiveness study was not applicable or performed for this device as it is a standalone in vitro diagnostic (IVD) device for nucleic acid detection, not an AI-assisted diagnostic tool for human readers. Therefore, there is no effect size related to human reader improvement with AI assistance.

6. Standalone Performance

Yes, a standalone performance assessment was conducted. The QIAstat-Dx GI Panel 2 Mini B is an in vitro diagnostic device, meaning its performance (analytical and clinical performance) is evaluated independently without human interpretation as part of a human-in-the-loop system. The document states its performance is "equivalent" to the predecessor device, which would have undergone rigorous standalone performance testing.

7. Type of Ground Truth Used

While not explicitly stated for this specific submission, for a nucleic acid-based assay like the QIAstat-Dx GI Panel 2 Mini B, the ground truth would typically be established by:

• Culture: Bacterial culture for viability and identification of the target organisms.
• Reference Molecular Methods: e.g., validated PCR assays or sequencing for definitive detection and identification of microbial nucleic acids.
• Composite Reference Method (CRM): A combination of multiple methods, often including culture, microscopy, and/or multiple molecular methods, to establish the presence or absence of the target pathogen.

8. Sample Size for the Training Set

The document does not provide the sample size for the training set. For an IVD like this, "training set" might refer to the data used for initial assay development and optimization rather than a machine learning context. This information would be in the detailed development reports.

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

The document does not describe how the ground truth for the training set was established. Similar to the test set, it would likely involve established laboratory methods such as culture or reference molecular assays for the target pathogens.

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The BIOFIRE FILMARRAY Gastrointestinal (GI) Panel Mid is an automated qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with BIOFIRE FILMARRAY Systems. The BIOFIRE FILMARRAY GI Panel Mid is capable of the simultaneous detection and identification of nucleic acids from multiple bacteria, viruses, and parasites directly from stool samples in Cary Blair transport media obtained from individuals with signs and/or symptoms of gastrointestinal infection. The following bacteria, parasites, and viruses are identified using the BIOFIRE FILMARRAY GI Panel Mid:

• · Campylobacter (C. jejuni/C. coli/C. upsaliensis)
• · Clostridioides (Clostridium) difficile (toxin A/B)
• · Salmonella
• · Vibrio (V. parahaemolyticus/V. vulnificus/ V. cholerae)
• · Yersinia enterocolitica
• · Shiga-like toxin-producing Escherichia coli (STEC) stx1/stx2
• · Shigella/ Enteroinvasive Escherichia coli (EIEC)
• Cryptosporidium
• · Cyclospora cayetanensis
• · Giardia lamblia (also known as G. intestinalis and G. duodenalis)
• Norovirus GI/GII

The BIOFIRE FILMARRAY GI Panel Mid is indicated as an aid in the diagnosis of specific agents of gastrointestinal illness and results are meant to be used in conjunction with other clinical, laboratory, and epidemiological data. Positive results do not rule out co-infection with organisms not included in the BIOFIRE FILMARRA Y GI Panel Mid. The agent detected may not be the definite cause of the disease.

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

This device is not intended to monitor or guide treatment for C. difficile infection.

Due to the small number of positive specimens collected for certain organisms during the prospective clinical study, performance characteristics for Yersinia enterocolitica, were established primarily with retrospective clinical specimens.

Performance characteristics for Vibrio (V. parahaemolyticus, and Vibrio cholerae) was established primarily using contrived clinical specimens.

Negative BIOFIRE FILMARRAY GI Panel Mid 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.

A gastrointestinal microorganism multiplex nucleic acid-based assay also aids in the detection of acute gastroenteritis in the context of outbreaks.

The BIOFIRE® FILMARRAY® Gastrointestinal Panel Mid is designed to simultaneously identify 11 gastrointestinal pathogens from stool specimens collected in Cary Blair transport medium. The BIOFIRE FILMARRAY GI Panel Mid is compatible with BioFire's PCR-based in vitro diagnostic BIOFIRE® FILMARRAY® 2.0 and BIOFIRE® FILMARRAY® TORCH Systems for infectious disease testing. A panel-specific software module (i.e., BIOFIRE FILMARRAY GI Panel Mid pouch module software) is used to perform BIOFIRE FILMARRAY GI Panel Mid testing on these systems. Results from the BIOFIRE FILMARRAY GI Panel Mid test are available within about one hour.

A test is initiated by loading Hydration into one port of the BIOFIRE pouch and a stool sample (in Cary Blair transport medium) mixed with the provided Sample Buffer into the other port of the BIOFIRE FILMARRAY GI Panel Mid pouch and placing it in a BIOFIRE System. The pouch contains all the reagents required for speciment esting and analysis in a freezedried format; the addition of Hydration and Sample/Buffer Mix rehydrates the reagents. After the pouch is prepared, the BIOFIRE Software guides the user though the pouch into the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.

The BIOFIRE System contains a coordinated system of inflatable bladders and seal points, which act on the pouch to control the movement of liquid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liquid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronically-controlled pneumatic pistons are multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Pettier devices control heating and cooling of the pouch to drive the PCR reactions and the melt curve analysis.

Nucleic acid extraction occurs within the BIOFIRE pouch using mechanical lysis followed by purification using standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, the BIOFIRE system performs a nested multiplex PCR that is executed in two stages. During the first stage, the BIOFIRE System performs a single, large volume, highly multiplexed reverse transcription PCR (rt-PCR) reaction. The products from first stage PCR are then diluted and combined with a fresh, primer-free master mix and a fluorescent double stranded DNA binding dye (LC Green Plus®, BioFire Diagnostics). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, is performed in single plex fashion in each well of the array. At the end of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the 2nd stage PCR captures fluorescent images of the PCR reactions and software interprets the data.

The BIOFIRE Software automatically interprets the results of each DNA melt curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the panel.

The BIOFIRE FILMARRAY GI Panel Mid is intended for use by trained medical and laboratory professionals in a laboratory setting or under the supervision of a trained laboratory professional.

The provided text is a 510(k) summary for the BIOFIRE FILMARRAY Gastrointestinal (GI) Panel Mid. This document primarily details the analytical and clinical performance of the device to demonstrate its substantial equivalence to a predicate device.

Here's an analysis of the acceptance criteria and study data based on the provided text:

Device: BIOFIRE FILMARRAY Gastrointestinal (GI) Panel Mid
Indications for Use: Automated qualitative multiplexed nucleic acid-based in vitro diagnostic test for simultaneous detection and identification of nucleic acids from multiple bacteria, viruses, and parasites directly from stool samples in Cary Blair transport media obtained from individuals with signs and/or symptoms of gastrointestinal infection.

Specific Acceptance Criteria and Study Details:

It's important to note that this is a 510(k) summary, which focuses on demonstrating substantial equivalence to a predicate device. The "acceptance criteria" presented are implicitly derived from the performance shown to be equivalent to the predicate, rather than explicit pre-defined pass/fail thresholds in a typical AI/ML study. The data provided are from a clinical and analytical evaluation of the parent device (BIOFIRE FILMARRAY GI Panel), with the "Mid" version being identical in hardware and reagents, only differing in software to mask some analytes.

1. Table of Acceptance Criteria and Reported Device Performance

Since this is a diagnostic test and not an AI/ML model for image analysis, the acceptance criteria are typically framed in terms of sensitivity (or positive percent agreement - PPA) and specificity (or negative percent agreement - NPA) compared to a reference method.

Note: The text explicitly states:
"C. difficile performance is reported as positive percent agreement in contrast to the table headings. The performance measures of sensibility and specificity only refer to those analytes for which the [culture method] was used as the reference method; Campylobacter, Salmonella, Vibrio, and Yersinia enterocolitica. Performance measures of positive percent agreement (NPA) refer to all other analytes, for which PCR/sequencing assays were used as comparator methods." This distinction is reflected in the table.

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

• Sample Size for Test Set (Clinical Evaluation):
  • The "Prospective Clinical Evaluation" mentioned in Table 2 was conducted from May through September 2013.
  • The total number of specimens that contributed to the sensitivity/PPA and specificity/NPA calculations vary by analyte but are in the range of ~1500-1550 specimens per analyte (e.g., 1556 for Vibrio, 1555 for Yersinia, etc.). These numbers represent the denominator for (TP+FN) and (TN+FP) across different analytes.
  • A separate, more recent "Prospective Clinical Evaluation" for Norovirus GI/GII was conducted from April through July 2023, involving 872 specimens (35 positives, 837 negatives).
  • Retrospective Clinical Specimens: Used for Yersinia enterocolitica and Vibrio (V. parahaemolyticus, V. vulnificus, and Vibrio cholerae) to establish performance characteristics due to small numbers of positive specimens in the prospective study. The specific number of retrospective specimens is not provided for these.
  • Contrived Clinical Specimens: Used for Vibrio (V. parahaemolyticus, V. vulnificus, and Vibrio cholerae) to establish performance. The specific number of contrived specimens is not provided.
• Data Provenance: The document does not explicitly state the country of origin for the clinical data. It describes the studies as "prospective clinical study" and "retrospective clinical specimens." This implies they are real-world clinical samples.

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

• The process for establishing ground truth is described by the reference methods used for each analyte:
  • For Campylobacter, Salmonella, Vibrio, and Yersinia enterocolitica: Traditional culture methods were used as the reference.
  • For all other analytes (Clostridioides difficile, STEC, Shigella/EIEC, Cryptosporidium, Cyclospora cayetanensis, Giardia lamblia, Norovirus GI/GII): PCR/sequencing assays were used as comparator methods.
• The document does not mention experts being used to establish a subjective "ground truth" (e.g., expert consensus for image review). This is a molecular diagnostic test, where ground truth is typically established by established laboratory reference methods (culture, PCR/sequencing). Therefore, the concept of "number of experts" is not directly applicable in the way it would be for an AI model interpreting medical images.

4. Adjudication Method for the Test Set

• This concept is not relevant for this type of in vitro diagnostic device study. Adjudication (e.g., 2+1, 3+1) is typically performed when subjective interpretations (e.g., radiologist reads) form the ground truth against which an AI model is compared. Here, the ground truth is established by objective laboratory methods (culture, PCR/sequencing). Discrepancies between the device and the reference method might undergo further investigation (e.g., "re-testing," "bi-directional sequence analysis" mentioned for "false positive" or "false negative" specimens), but this is not an "adjudication" in the MRMC sense.

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

• No, an MRMC study was not done. MRMC studies are typically for medical imaging AI where the human reader performance (with and without AI assistance) is evaluated. This device is an automated molecular diagnostic test; it does not involve human "readers" interpreting results in the same way as an imaging AI. Its performance is evaluated against established laboratory reference methods, not human reader improvement.

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

• Yes, the provided performance data represents standalone performance. The BIOFIRE FILMARRAY GI Panel Mid is an automated system that provides qualitative results (Detected/Not Detected). The clinical performance data (sensitivity/PPA, specificity/NPA) directly reflects the device's ability to detect the target analytes directly from the sample without human interpretation or intervention in the diagnostic call itself, beyond operational steps.

7. The Type of Ground Truth Used

• Laboratory Reference Methods:
  • Culture: For Campylobacter, Salmonella, Vibrio, and Yersinia enterocolitica.
  • PCR/sequencing assays: For Clostridioides difficile, STEC, Shigella/EIEC, Cryptosporidium, Cyclospora cayetanensis, Giardia lamblia, Norovirus GI/GII.
• The text notes that for some discrepancies, "bi-directional sequence analysis" was used to confirm findings for both false positives and false negatives, suggesting a highly definitive molecular method was used for discordant results.

8. The Sample Size for the Training Set

• The document describes the BIOFIRE FILMARRAY GI Panel Mid as "an identical product to the BIOFIRE® FILMARRAY® Gastrointestinal Panel (K242367) except it uses modified labeling and modified software to mask and report only 11 of the 22 targets normally reported."
• "The performance presented here was established during the original clinical and analytical evaluations for the BIOFIRE FILMARRAY GI Panel."
• This implies that there wasn't a separate "training set" for the "Mid" version as per typical AI/ML development. The underlying "algorithm" (the PCR primer sets, probes, and melt curve analysis interpretation) was developed and validated on the original BIOFIRE FILMARRAY GI Panel.
• The document does not provide details on the training set sizes used for the development of the original BIOFIRE FILMARRAY GI Panel. The data presented are from the test/validation phase for the original panel which is now being leveraged for this "special 510k" submission.

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

• As mentioned above, specific "training set" details for an AI model are not provided because this is a molecular diagnostic hardware/reagent system, not an AI/ML software. The "ground truth" for the development and optimization of the PCR assays (which are the "algorithm" in this context) would have been established through well-characterized analytical samples (known strains, clinical isolates) and potentially early-stage clinical samples validated by comparator methods (culture, sequencing). The document focuses on the validation data (clinical and analytical performance studies) used for regulatory submission.

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The BioCode Gastrointestinal Pathogen Panel (GPP) is a qualitative multiplexed in vitro diagnostic test intended for use with the BioCode MDx 3000 Instrument. The BioCode GPP is capable of the simultaneous detection of nucleic acids from multiple bacteria, viruses, and parasites extracted directly from unpreserved in Cary-Blair transport medium obtained from individuals with simptoms of gastrointestinal infection. The following bacteria, parasites, and viruses are identified using the BioCode Gastrointestinal Pathogen Panel:

• . Campylobacter (C. jejuni/C. coli)
• Clostridium difficile (C. difficile) toxin A/B (Fresh samples only)
• l Salmonella spp
• Vibrio (V. parahaemolyticus/V. vulnificus/ V. cholerae), including specific identification of Vibrio parahaemolyticus .
• . Yersinia enterocolitica
• . Enteroaggregative Escherichia coli (EAEC)
• Enterotoxigenic Escherichia coli (ETEC) lt/st
• E. coli 0157 serogroup
• Shiga-like toxin-producing Escherichia coli (STEC) stx1/stx2
• Shigella/ Enteroinvasive Escherichia coli (EIEC)
• Cryptosporidium spp (C. parvum/C. hominis)
• Entamoeba histolytica
• Giardia lamblia (also known as G. intestinalis and G. duodenalis)
• . Adenovirus F 40/41
• Norovirus GI/GII ■
• . Rotavirus A

The BioCode GPP is indicated as an aid in the diagnosis of gastrointestinal illness and results are meant to be used in conjunction with other clinical, laboratory, and epidemiological data. For In Vitro Diagnostic Use Only. For Prescription Use Only.

Positive results do not rule out co-infection with organisms not included in the BioCode GPP. The agent detected may not be the definite cause of the disease. Negative results in the setting of clinical illness compatible with gastroenteriis 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. Concomitant culture is necessary for organism recovery and further typing of bacterial agents. This device is not intended to monitor or guide treatment for C. difficile infection.

Due to the small number of positive specimens collected for certain organisms during the prospective clinical study, performance characteristics for Adenovinus 40/41, Campylobacter, E. coli 0157, Shigella(EIEC, Yersinia enterocolitica, and Giardia lamblia were established additionally with retrospective clinical specimens. Performance characteristica, Giardia lamblia, Yersinia enterocolitica and Vibrio (V. parahaemolyticus, V. cholerae) were established primarily using contrived clinical specimens.

The BioCode® Gastrointestinal Pathogen Panel (GPP) is a multiplexed nucleic acid-based test designed to be used with the BioCode MDx-3000 system. The BioCode MDx-3000 is an automated system that integrates PCR amplification, target capture, signal generation and optical detection for multiple gastrointestinal pathogens from a single stool specimen, either unpreserved or in Cary Blair. Stool specimens are processed, and nucleic acids extracted with easyMAG, MagNA Pure 96, KingFisher Flex and KingFisher Apex Dx. Once the PCR plate is set up and sealed, all other operations are automated on MDx-3000. The BioCode MDx-3000 Gastrointestinal Infection Panel simultaneously tests for 17 pathogens (see table below) from unpreserved stool specimens or stool collected in Cary-Blair transport medium. Results from the BioCode Gastrointestinal Pathogen Panel (GPP) test are available within less than 4 hours.

The provided text describes the BioCode Gastrointestinal Pathogen Panel (GPP), a diagnostic test for gastrointestinal pathogens, and a study to demonstrate its substantial equivalence to a predicate device.

Here's an analysis of the acceptance criteria and study data:

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria for each pathogen are implied by the reported Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to the easyMAG extraction method (used with the predicate device) for each extraction system (KingFisher Flex and KingFisher Apex Dx). While explicit pre-defined acceptance criteria values are not stated, the tables present the achieved performance with 95% Confidence Intervals. Generally, a high PPA and NPA (typically >90-95%) with narrow confidence intervals are expected for substantial equivalence for diagnostic tests.

Here's a summary of the reported performance for the BioCode GPP using KingFisher Flex and KingFisher Apex Dx, focusing on the "All Archived" data as it covers a larger sample size for each target. Targets with PPA < 90% are highlighted as indicated in the document; however, the document notes that these are "Positive agreement <90%" for Archived samples only, and specifically points out individual false positives/negatives that were retested and often resolved. Targets for which "N/A" is reported for PPA/NPA indicate no positive/negative archived samples were available for comparison, and thus performance was primarily established with contrived samples (as indicated in the 'Indications for Use' section).

Table of Device Performance (Archived Samples - All Combined)

Note:

• Asterisks (**) in the table indicate that the specific performance measure (PPA) was below 90% for archived samples. The document explicitly notes for Vibrio spp. (not parahaemolyticus) that 1 out of 2 positive concordance was observed for both KingFisher Flex and KingFisher Apex Dx, resulting in 50% PPA.
• Retesting of discordant samples often showed resolution in favor of the predicate or new device, but the summary tables reflect the initial comparison. The footnotes (a-q) provide detailed explanations for discordant cases, including instances where samples were invalid or initial false results were later identified as true negatives/positives upon retesting.

2. Sample Size and Data Provenance

• Test Set (Clinical Method Comparison Study):
  • Archived Samples: 468 remnant, de-identified samples (254 frozen unpreserved stool and 214 inoculated Cary-Blair stool). These samples were prospectively collected for the clinical study that resulted in the predicate device (K180041 BioCode® GPP FDA clearance). The country of origin is not explicitly stated, but clinical studies for FDA clearance typically involve multi-center studies within the US or compliant international sites. "Mayo-GI" and "TRI" sample names suggest US clinical sites.
  • Fresh Samples (for C. difficile testing): 54 freshly collected leftover samples (unpreserved).
  • Contrived Samples: 120 samples (15 at 3x LoD and 15 at 6xLoD for each of three targets: Entamoeba histolytica, Yersinia enterocolitica, and Vibrio spp.).

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

The ground truth for the clinical method comparison study was established by comparing the results of the new device (BioCode GPP with KingFisher Flex and KingFisher Apex Dx extraction) against the results obtained with the easyMAG extraction, which was used with the predicate device (BioCode GPP K190585). The predicate device itself would have undergone its own clinical validation against a pre-established ground truth. Therefore, the "ground truth" for this specific study is the performance of the BioCode GPP with easyMAG extraction.

The document does not explicitly state the number or qualifications of experts used for establishing the initial ground truth of the predicate device, or for adjudicating discordant results in this study. However, the retesting notes for discordant samples mention "consensus results" were not used in the agreement calculation, implying that the retesting was performed to understand the discrepancy rather than to establish a new ground truth.

4. Adjudication Method for the Test Set

The adjudication method is described in the footnotes for Tables 11 and 16. For discordant results between the easyMAG (reference) and the KingFisher Flex/Apex Dx (new device), samples were retested twice with both original extraction methods. The outcome of these retests served to clarify the discrepancy, though the initial raw comparison was used to calculate the agreement, with retest findings noted in the footnotes. For example, a "false negative" for the new device might become a "true negative" upon retesting if the reference system also failed to detect it consistently. However, "consensus results of the discordant samples were not used in the calculation of the agreements" in the main tables but rather for detailed understanding.

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

No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was done. This study focuses on a laboratory diagnostic device, not an imaging device requiring human reader interpretation. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable here.

6. Standalone Performance Study

Yes, a standalone performance study was done for the device in the context of the new extraction platforms. The "Nonclinical testing summary" details a Reproducibility Study and a Limit of Detection (LoD) study. These studies evaluate the algorithm's (BioCode GPP assay's) consistency and sensitivity when integrated with the new KingFisher Flex and KingFisher Apex Dx extraction systems, independent of direct human interpretative input beyond standard lab procedures.

• Reproducibility Study: Assessed intra-assay, inter-assay, day-to-day, and instrument-to-instrument (operator-to-operator) reproducibility using quantitative controls diluted in stool.
• Limit of Detection (LoD) Study: Determined the lowest concentration at which ≥95% detection was achieved in 20 replicates for each target, for both unpreserved and Cary-Blair stool, using the new extraction methods.

7. Type of Ground Truth Used

For the clinical method comparison study (test set), the ground truth was the result generated by the predicate device's established extraction method (easyMAG). This is a comparative effectiveness study where the predicate device's performance established the "truth" for evaluating the new device's substantial equivalence.

For the LoD and reproducibility studies, the ground truth was based on quantified stocks of bacteria, viruses, or parasites (except for Norovirus GI/GII which used positive clinical specimens with serial dilutions) introduced into negative stool matrices.

8. Sample Size for the Training Set

The document does not explicitly describe a "training set" for the BioCode GPP itself, as it's a multiplex nucleic acid-based test rather than a machine learning or AI algorithm in the common sense requiring explicit training data. The assay's design (probes, primers, etc.) would have been developed and optimized against a range of target and non-target organisms.
The 468 remnant clinical samples used in the method comparison study were prospectively collected for the predicate device's clinical study (K180041 BioCode® GPP FDA clearance), suggesting they were part of the validation for the predicate, not a training set for the current device's underlying assay design.

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

As noted above, an explicit "training set" with ground truth in the AI/ML context isn't specified for this type of diagnostic assay. The development of such an assay involves extensive analytical validation to establish specificity, sensitivity, and inclusivity using characterized microbial strains, clinical isolates, and negative controls. The ground truth for these developmental studies would be based on molecular characterization (e.g., sequencing), culture, or other reference methods for the target organisms. The performance of the predicate device (K190585) would have been established through a clinical study where its results were compared against clinical diagnosis, culture, or other validated reference methods.

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The QIAstat-Dx GI Panel 2 Mini B&V is a multiplexed nucleic acid test intended for use with the OLAstat-Dx Analyzer 1.0 for the simultaneous in vitro qualitative detection of nucleic acids from multiple bacteria and one virus directly from preserved stool samples (Para-Pak C&S or FecalSwab) obtained from individuals with signs and/or symptoms of gastrointestinal infection. The following virus and bacteria (including several diarrheagence E. col/Shigella pathotypes) are identified with the QIAstat-Dx GI Panel 2 Mini B&V:

• Norovirus
• · Campylobacter
• · Shigella
• · Shiga-like toxin Escherichia coli (STEC)*
• · Salmonella

*Only with Para-Pak C&S, not reported for FecalSwab

Concomitant culture is necessary for organism recovery and further typing of bacterial agents. The QlAstat-Dx GI Panel 2 Mini B&V is indicated as an aid in the diagnosis of gastrontestinal illness, in conjunction with other clinical, laboratory, and epidemiological data. Postive results do not rule-out co-infection with organisms not detected by the QlAstat-Dx GI Panel 2 Mini B&V. The organisms detected may not be the sole or definitive cause of the disease.

Negative QIAstat-Dx GI Panel 2 Mini B&V results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this assay test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.

The QIAstat-Dx® GI Panel 2 Mini B&V (Cat. no. 691424) assay is a modified device (reduced version) of the QIAstat-Dx Gastrointestinal Panel 2 (Cat. no. 691421). The QIAstat-Dx GI Panel 2 Mini B&V is identical to the OIAstat-Dx Gastrointestinal Panel 2 (K220062) with the exception of their respective labeling and Assay Definition File (ADF) which masks all but five pathogens (targets) from the OIAstat-Dx Gastrointestinal Panel 2. The following virus and bacteria (including several diarrheagenic E. coli/Shigella pathotypes) are identified with the OIAstat-Dx GI Panel 2 Mini B&V: Norovirus, Campvlobacter, Shigella, Shiga-like toxin Escherichia coli (STEC) and Salmonella. The QIAstat-Dx GI Panel 2 Mini B&V is part of the OIAstat-Dx system and works with the OIAstat-Dx Analyzer 1.0.

The QIAstat-Dx GI Panel 2 Mini B&V is intended to be used with stool samples in Para-Pak C&S or FecalSwab transport media.

QIAstat-Dx is based on single-test cartridges with pre-packaged reagents including both wet and dry chemistry to handle the sample preparation and detection steps for the presence of a range of selected analytes by PCR technology. After insertion of the sample, the QIAstat-Dx assay cartridge is processed by the QIAstat-Dx Analyzer 1.0.

Once the cartridge has been inserted into the instrument, the test starts automatically and runs for approximately 78 minutes. When the test is finished, the cartridge is removed by the user and discarded. The QIAstat-Dx Analyzer 1.0 automatically interprets test results and displays a summary on the analyzer display screen. The results can be printed using a connected printer if needed. The detected analytes are displayed in red. For other analytes tested, they are displayed in green if not detected or in gray if not applicable or invalid. The analyzer will report if an error occurs during processing, in which case the test will fail and no results will be provided (screen will show "FAIL").

All the reagents required for the complete execution of the test are pre-loaded and selfcontained in the QIAstat-Dx GI Panel 2 Mini B&V cartridge. The user does not need to manipulate any reagents. During the test, reagents are handled by pneumatically-operated microfluidics without any direct contact with the user or the analyzer actuators.

Within the cartridge, multiple steps are automatically performed in sequence by using pneumatic pressure and a multiport valve to transfer sample and fluids via the Transfer Chamber (TC) to their intended destinations. Following the introduction of the sample from a disposable transfer pipette, the following assay steps occur automatically and sequentially:

• Sample Pre-treatment for PCR Inhibitors removal
• Resuspension of Internal Control and Proteinase K ●
• Cell lysis using mechanical and/or chemical means
• Membrane-based nucleic acid purification
• Rehydration of Master Mix ●
• Transfer of defined aliquots of eluate/master mix to different reaction chambers ●
• Performance of multiplex real-time RT-PCR testing within each reaction ● chamber.

The provided text describes a 510(k) premarket notification for a medical device called the QIAstat-Dx GI Panel 2 Mini B&V. This document focuses on demonstrating substantial equivalence to a legally marketed predicate device, the QIAstat-Dx Gastrointestinal Panel 2 (K220062), rather than detailing original acceptance criteria and a comprehensive study designed to prove the device meets those criteria from scratch.

The core of the submission is that the QIAstat-Dx GI Panel 2 Mini B&V is a "reduced version" of the predicate device. It is identical in hardware, reagents, and underlying PCR technology, with the only difference being a modified "Assay Definition File (ADF)" that masks results for all but five specific pathogens. Because of this, the performance data for the new device is considered "equivalent" to the predicate device's data for these five analytes.

Therefore, many of the typical elements of an acceptance criteria study (like an independent test set, MRMC study, or detailed ground truth establishment for a new study) are not explicitly present for the QIAstat-Dx GI Panel 2 Mini B&V in this document, as the submission relies on the existing clearance of the predicate device for its performance claims.

However, based on the provided text, here's an attempt to extract and infer the information requested:

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

The document does not provide a specific table of acceptance criteria for this specific submission. Instead, it states that "The performance data for the QIAstat-Dx GI Panel 2 Mini B&V is equivalent to the QIAstat-Dx Gastrointestinal Panel 2 (K220062) with the exception that it only includes data for the five analytes detected by the QIAstat-Dx GI Panel 2 Mini B&V (Norovirus, Campylobacter, Shigella, Shiga-like toxin E. coli (STEC) and Salmonella)."

It then directs the reader to "Please see the QIAGEN QIAstat-Dx GI Panel 2 Mini B&V Instructions for Use for performance tables." Since these tables are not included in the provided text, we cannot present a direct table of acceptance criteria and reported device performance from this document. The implication is that the predicate device's performance, as accepted during its original 510(k) clearance (K220062), serves as the de facto "acceptance criteria" for these five analytes for the new device by virtue of its identical underlying technology.

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

The document does not describe a new, independent test set for the QIAstat-Dx GI Panel 2 Mini B&V. Instead, it relies on the data collected for the predicate device (QIAstat-Dx Gastrointestinal Panel 2, K220062). The sample size, country of origin, and whether the data was retrospective or prospective for the predicate device's studies are not detailed in this document.

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

This information is not provided in the document, as it refers to the predicate device's data rather than a new study with independent expert ground truth establishment for this submission.

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

This information is not provided in the document.

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

This device is a diagnostic nucleic acid test, not an AI-powered image analysis tool or a device that directly assists human readers in interpreting imaging or other complex data. Therefore, an MRMC study and effects on human reader performance are not applicable to this type of device.

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

This refers to the performance of the assay itself. The performance of the QIAstat-Dx GI Panel 2 Mini B&V (which functions like a standalone test after sample input) is considered "equivalent" to the predicate device's performance for the five detected analytes. The document notes that "The QIAstat-Dx Analyzer 1.0 automatically interprets test results and displays a summary on the analyzer display screen." This implies a standalone (algorithm only) performance for result generation, as long as human intervention refers to the interpretation of the raw data by the user, rather than the final qualitative result presented by the device.

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

For nucleic acid amplification tests like this, the ground truth is typically established by well-characterized reference methods, often involving:

• Culture: For bacterial targets, traditional microbiology culture is a common reference standard.
• Reference PCR/Molecular Methods: Highly sensitive and specific laboratory-developed or validated molecular assays.
• Sequencing: For definitive characterization where applicable.

The document does not explicitly state the specific ground truth methods used for the predicate device's studies, but these are the standard approaches for such assays. It does mention that "Concomitant culture is necessary for organism recovery and further typing of bacterial agents" in its indications for use, suggesting culture is an important complementary method in clinical practice.

8. The sample size for the training set

The document does not describe a training set in the context of an AI/machine learning model. This device is a molecular diagnostic assay (PCR-based), not an AI-driven system. Therefore, the concept of a "training set" as it applies to AI models is not relevant here. Development and validation of such assays involve different types of studies (e.g., analytical validation, clinical validation) rather than "training" an algorithm.

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

As per point 8, the concept of a training set for an AI model is not applicable. The development and validation of PCR assays involve establishing the analytical and clinical performance through rigorous testing against reference methods (as mentioned in point 7) and clinical samples.

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The BIOFIRE FILMARRAY Gastrointestinal (GI) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with BIOFIRE FILMARRAY Systems. The BIOFIRE GI Panel is capable of the simultaneous detection and identification of nucleic acids from multiple bacteria, viruses, and parasites directly from stool samples in Cary Blair transport media obtained from individuals with signs and/or symptoms of gastrointestinal infection. The following bacteria (including several diarrheagenic E. coli/Shigella pathotypes), parasites, and viruses are identified using the BIOFIRE GI Panel:

• Campylobacter (C. jejuni/C. coli/C. upsaliensis)
• Clostridium difficile (C. difficile) toxin A/B
• Plesiomonas shigelloides
• Salmonella
• Vibrio (V. parahaemolyticus/V. vulnificus/ V. cholerae), including specific identification of Vibrio cholerae
• Yersinia enterocolitica
• Enteroaggregative Escherichia coli (EAEC)
• Enteropathogenic Escherichia coli (EPEC)
• Enterotoxigenic Escherichia coli (ETEC) lt/st
• Shiga-like toxin-producing Escherichia coli (STEC) stx 1/stx2 (including specific identification of the E. coli 0157 serogroup within STEC)
• Shigella/ Enteroinvasive Escherichia coli (EIEC)
• Cryptosporidium
• Cyclospora cayetanensis
• Entamoeba histolytica
• Giardia lamblia (also known as G. intestinalis and G. duodenalis)
• Adenovirus F 40/41
• Astrovirus
• Norovirus GI/GII
• Rotavirus A
• Sapovirus (Genogroups I, II, IV, and V)

The BIOFIRE GI Panel is indicated as an aid in the diagnosis of gastrointestinal illness and results are meant to be used in conjunction with other clinical, laboratory, and epidemiological data. Positive results do not rule out co-infection with organisms not included in the BIOFIRE GI Panel. The agent detected may not be the definite cause of the disease.

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

This device is not intended to monitor or guide treatment for C. difficile infection.

Due to the small number of positive specimens collected for certain organisms during the prospective clinical study, performance characteristics for E. coli 0157, Plesiomonas shigelloides, Yersinia enterocolitica, Astrovirus, and Rotavirus A were established primarily with retrospective clinical specimens.

Performance characteristics for Entamoeba histolytica, and Vibrio (V. parahaemolyticus, V. vulnificus, and Vibrio cholerae) were established primarily using contrived clinical specimens.

Negative BIOFIRE GI Panel 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.

A gastrointestinal microorganism multiplex nucleic acid-based assay also aids in the detection of acute gastroenteritis in the context of outbreaks.

The BIOFIRE FILMARRAY Gastrointestinal (GI) Panel is designed to simultaneously identify 22 gastrointestinal pathogens from stool specimens collected in Cary Blair transport medium. The BIOFIRE GI Panel is compatible with BioFire's PCR-based in vitro diagnostic BIOFIRE FILMARRAY 2.0 and BIOFIRE FILMARRAY TORCH Systems for infectious disease testing. A panel-specific software module (i.e., BIOFIRE GI Panel pouch module software) is used to perform BIOFIRE GI Panel testing on these systems. Results from the BIOFIRE GI Panel test are available within about one hour.

A test is initiated by loading Hydration Solution into one port of the BIOFIRE pouch and a stool sample (in Cary Blair transport medium) mixed with the provided Sample Buffer into the other port of the BIOFIRE GI pouch and placing it in a BIOFIRE System. The pouch contains all the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and Sample/Buffer Mix rehydrates the reagents. After the pouch is prepared, the BIOFIRE Software guides the user though the steps of placing the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.

The BIOFIRE System contains a coordinated system of inflatable bladders and seal points, which act on the pouch to control the movement of liquid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liquid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronically-controlled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier devices control heating and cooling of the pouch to drive the PCR reactions and the melt curve analysis.

Nucleic acid extraction occurs within the BIOFIRE pouch using mechanical and chemical lysis followed by purification using standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, the BIOFIRE system performs a nested multiplex PCR that is executed in two stages. During the first stage, the BIOFIRE System performs a single, large volume, highly multiplexed reverse transcription PCR (rt-PCR) reaction. The products from first stage PCR are then diluted and combined with a fresh, primer-free master mix and a fluorescent double stranded DNA binding dye (LC Green Plus, BioFire Diagnostics). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, is performed in single plex fashion in each well of the array. At the end of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the 2nd stage PCR captures fluorescent images of the PCR reactions and software interprets the data.

The BIOFIRE Software automatically interprets the results of each DNA melt curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the panel.

The provided document is a 510(k) premarket notification for the BIOFIRE FILMARRAY Gastrointestinal (GI) Panel. The purpose of this submission is to update the device's instructions for use with additional clinical data, specifically regarding the Norovirus GI/GII assay.

Here's an analysis based on your requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the clinical performance results presented, particularly for Norovirus GI/GII, as the reason for this submission is to update the labeling based on a post-market performance follow-up (PMPF) study that yielded different results from the original clinical study. The document does not explicitly state pre-defined acceptance criteria for the PMPF study to be deemed acceptable. However, the reported performance is provided.

Note: The document focuses on updating the instructions for use due to a detected change in Norovirus GI/GII assay performance compared to original labeling claims, rather than defining new acceptance criteria for the device as a whole.

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

• Test Set Sample Size: 872 clinical specimens.
• Data Provenance: Prospective clinical evaluation conducted from April through July 2023. The country of origin is not explicitly stated, but the submission is to the U.S. FDA, suggesting the study was likely conducted in the United States or followed U.S. regulatory guidelines.

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

This information is not provided in the document. The document refers to a "more recent version of the US CDC Norovirus assay" used for comparison, implying it was used as a reference method for ground truth, but does not detail the process of establishing ground truth for the clinical specimens or the role of experts in that process.

4. Adjudication Method for the Test Set

This information is not provided in the document.

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

No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) test for nucleic acid detection, not an AI-assisted diagnostic device for human readers. Therefore, the concept of human readers improving with AI assistance is not applicable.

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

Yes, the performance data presented is for the standalone (algorithm only) performance of the BIOFIRE GI Panel. The device is an automated multiplex nucleic acid-based assay; its results are generated directly by the system without human interpretation of raw data, which is then reported.

7. The Type of Ground Truth Used

The ground truth for the Norovirus GI/GII assay in the PMPF study was established by comparison to a "more recent version of the US CDC Norovirus assay." For one false negative (FN) specimen, "bi-directional sequencing analysis" was used to detect Norovirus. For 3 out of 29 false positive (FP) specimens, "bi-directional sequencing analysis" also detected Norovirus. For the remaining false positives, cross-reactivity was identified through analytical testing and in silico analysis. This indicates a combination of:

• Reference laboratory method (US CDC Norovirus assay): This serves as the primary comparative method.
• Sequencing (Bi-directional sequencing analysis): Used for discrepancy resolution and further investigation of false positive/negative results.
• Analytical testing and In silico analysis: Used to confirm and identify cross-reactive organisms.

8. The Sample Size for the Training Set

This information is not provided in the document. The document focuses on the clinical evaluation data used to update the device's labeling, not data related to the original development or training of the assay.

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

This information is not provided in the document. As this submission is for an update based on a post-market study, details about the original training set and its ground truth establishment are not included.

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The QIAstat-Dx Gastrointestinal Panel 2 is a multiplexed nucleic acid test intended for use with the QIAstat-Dx Analyzer 1.0. for the simultaneous in vitro qualitative detection of nucleic acids from multiple viruses, bacteria. and parasites directly from preserved stool samples (Para-Pak C&S or FecalSwab) obtained from individuals with signs and/or symptoms of gastrointestinal infection. The following viruses, bacteria (including several diarrheagenic E. col/ Shigella pathotypes), and parasites are identified with the QIAstat-Dx Gastrointestinal Panel 2 :
• Adenovirus F40/F41
• Astrovirus
• Norovirus GI/GII
• Rotavirus A
• Campylobacter (C. jejuni, C. coli and C. upsaliensis)
• Shigella/Enteroinvasive Escherichia coli (EIEC)
• Enteropathogenic Escherichia coli (EPEC)
• Enterotoxigenic Escherichia coli (ETEC) lt/st
• Shiga-like toxin-producing Escherichia coli (STEC) stx1/stx2
(including specific identification of E. coli O157 serogroup within STEC)
• Salmonella
• Plesiomonas shigelloides
• Yersinia enterocolitica
• Cryptosporidium
• Cyclospora cayetanensis
• Entamoeba histolytica
• Giardia lamblia*
*(Also known as Giardia intestinalis and Giardia duodenalis)
Concomitant culture is necessary for organism recovery and further typing of bacterial agents.
The QIAstat-Dx Gastrointestinal Panel 2 is indicated as an aid in the diagnosis of specific agents of gastrointestinal illness, in conjunction with other clinical, laboratory, and epidemiological data. Positive results do not rule-out coinfection with organisms not detected by the QIAstat-Dx Gastrointestinal Panel 2. The organisms detected may not be the sole or definitive cause of the disease.
Negative QIAstat-Dx Gastrointestinal Panel 2 results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this assay test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.

QIAstat-Dx is based on single-test cartridges with pre-packaged reagents including both wet and dry chemistry to handle the sample preparation and detection steps for the presence of a range of selected analytes by PCR technology. After insertion of the sample, the OIAstat-Dx assay cartridge is processed by the OIAstat-Dx Analyzer 1.0.

Here's a summary of the acceptance criteria and study details for the QIAstat-Dx Gastrointestinal Panel 2, extracted from the provided text:

Acceptance Criteria and Device Performance for QIAstat-Dx Gastrointestinal Panel 2

The acceptance criteria for the QIAstat-Dx Gastrointestinal Panel 2 can be inferred from the performance metrics (Positive Percentage Agreement - PPA and Negative Percentage Agreement - NPA) reported for both prospective and retrospective clinical studies. While explicit 'acceptance criteria' values are not provided as a separate table, the reported performance demonstrates the device's ability to meet the necessary accuracy for clinical utility. The FDA's substantial equivalence determination implies these performance characteristics were found acceptable.

Implied Acceptance Criteria (based on reported performance):

• High PPA: The device should accurately detect the target pathogens when they are present. Most reported PPA values are above 90%, with many at 100%. Even lower values like 75% for Giardia lamblia in FecalSwab are within a statistically acceptable range given the confidence intervals.
• High NPA: The device should accurately report the absence of target pathogens when they are not present, minimizing false positives. Most reported NPA values are very high, often 99% or 100%.

Table of Acceptance Criteria (Implied) and Reported Device Performance

Given that specific numerical acceptance criteria (e.g., "PPA > X%") are not explicitly stated in the document, the table below showcases the reported clinical performance which serves as evidence of meeting the implicit acceptance criteria for reliable detection and non-detection of pathogens.

Study Details:

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

• Test Set (Clinical Study):
  • Total Specimens: 2808
    • 1939 Prospective (1222 FecalSwab, 717 Para-Pak C&S)
    • 119 Prospective Archived (Norovirus GI/GII: 81, STEC: 18 plus 20 negative specimens where relevant)
    • 750 Retrospective Frozen Specimens
  • Data Provenance: Multi-center international study conducted at thirteen clinical sites across 5 countries (4 sites in Europe and 9 sites in USA). Specimens were collected between May and July 2021.

2. 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 or qualifications of experts used to establish the ground truth. Instead, it refers to the use of "one FDA-cleared test as comparator for most analytes" and a "composite comparator consisting of either three independent FDA-cleared test methods or two independent FDA-cleared tests methods and two validated PCR assays followed by bidirectional sequencing" for others. This implies that the ground truth was established through validated diagnostic methods rather than direct expert consensus on primary samples in many cases.

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

• For analytes where a composite comparator was used (Norovirus GI/GII, ETEC, STEC, and Giardia lamblia), the ground truth was determined by the majority of the three results.
  • A positive composite comparator result: based on positive results for at least two comparator tests.
  • A negative composite comparator result: based on negative results for at least two comparator tests.
• For other analytes, where "one FDA-cleared test method" was used, the comparator's result directly served as the ground truth.
• For cases with insufficient sample volume for complete composite comparator testing, a "worst-case model" was applied for PPA calculation.

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

• This information is not applicable as the device is an in vitro diagnostic (IVD) nucleic acid test for pathogen detection, not an AI-assisted diagnostic device interpreted by human readers for medical imaging or similar tasks. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not relevant to this device.

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

• Yes, the performance presented (PPA and NPA) for the QIAstat-Dx Gastrointestinal Panel 2 is a standalone performance of the algorithm/device. The device automatically interprets test results and displays a summary, without a human interpretation loop for its core function.

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

• The ground truth was established using FDA-cleared comparator methods and validated PCR assays followed by bidirectional sequencing. This acts as a robust diagnostic ground truth based on established molecular and clinical laboratory standards. Pathology or outcomes data were not explicitly mentioned as primary ground truth sources for individual pathogen detection in this context.

7. The sample size for the training set:

• The document does not explicitly state a sample size for the training set. The clinical studies describe the evaluation of the device's performance using prospective, prospective archived, and retrospective samples, implying these are test sets rather than training sets. Analytical studies such as LoD and inclusivity also use specific strains and dilutions, but these are for analytical validation, not for training a machine learning model. For IVD devices like this, the "training set" concept (as understood in AI/ML) might be less direct, relying more on extensive analytical verification of probe/primer specificity and reactivity across a wide range of strains and concentrations, and then clinical validation.

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

• As the training set size is not provided, the method for establishing its ground truth is also not detailed. However, for the analytical studies (which could be considered a form of "training/validation data generation" in a broader sense for IVDs), the ground truth for LoD and inclusivity was established by using culture isolates from commercial suppliers (ZeptoMetrix® and ATCC®) or clinical samples positive for target analytes. These were "prepared in human stool matrix" and tested at known concentrations validated by in-house developed and validated qPCR assays for molecular unit titers.

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The Genetic Signatures EasyScreen™ Gastrointestinal Parasite Detection Kit is a rapid in vitro nucleic acid amplification assay for the qualitative detection of pathogenic gastrointestinal parasite nucleic acid from the stool of patients with signs and/or symptoms of gastroenteritis. The test, based on real-time PCR, detects the nucleic acid of the following organisms:

• · Cryptosporidium spp.
• · Giardia intestinalis
• Dientamoeba fragilis
• · Entamoeba histolytica
• Blastocystis hominis
• · Enterocytozoon bieneusi
• · Encephalitozoon intestinalis
• · Cyclospora cayetanensis

The kit is compatible with stool specimens that are unpreserved or frozen or in transport media including Cary Blair or C&S media from symptomatic patients with suspected gastroenteritis. It is required that the stool is first processed using the EasyScreen™ Sample Processing Kit. Nucleic acid extraction and real-time PCR set up are performed on the automated Genetic Signatures GS1 platform.

This device is an in vitro diagnostic (IVD) intended to be used by trained personnel in clinical, pathology or hospital laboratories as an aid in the diagnosis of gastrointestinal illness. This test is intended for use, in conjunction with clinical presentation, laboratory findings, and epidemiological information, as an aid in the differential diagnosis of infections by Dientamoeba fragilis, Blastocystis hominis, Enterocytozoon bieneusis, Entamoeba histolytica, Encephalitozoon intestinalis, Cryptosporidium spp. (including C. parvum), and Giardia intestinalis. Results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decision. Positive results do not rule out co-infection with other organisms that are not detected by this test, and may not indicate the sole or definitive cause of patient illness. Negative results in the setting of clinical illness compatible with gastroenteritis and/or colitis 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 EasyScreen™ Gastrointestinal Parasite Detection Kit (EP005) is designed to simultaneously identify 8 potential pathogens of the gastrointestinal tract, from human stool samples. The device is only compatible with nucleic acids prepared using an EasyScreen™ Sample Processing Kit (SP008B).

A stool sample from a patient suspected of having gastroenteritis (usually liquid or soft stool) is collected and transported to the testing laboratory. A portion of the stool material is taken using a swab or pipette and processed with the EasyScreen™ Sample Processing Kit (SP008B), which lyses cells and converts the nucleic acid to a 3base™ form.

An aliquot of purified eluate is then added to the PCR reagents supplied in the EP005 kit, which selectively amplify the genetic targets of Cryptosporidium spp., Giardia intestinalis, Entamoeba Dientamoeba fragilis, Blastocystis hominis, Enterocytozoon histolytica. bieneusi. Encephalitozoon intestinalis and Cyclospora cayetanensis. The reaction mix is manufactured to detect an Extraction Control (EC) and features an incorporated Internal Positive Control (IPC) to determine the reliability of the extracted nucleic acid and to detect the presence of any inhibitors after extraction from the primary sample.

Amplified targets are detected with probes labeled with fluorophores as detected by the real-time PCR platform. The PCR amplification takes approximately 150 minutes, depending on the PCR platform used. A positive control is included to ascertain that the detection reagents and analyzer are functioning correctly.

The amplified nucleic acid targets are detected by probes labeled with fluorophores, as detected by the real-time PCR platform. If no amplification occurs for a given target, then there will not be any significant increase in fluorescence. Each probe fluoresces at a given wavelength and the signals are measured and distinguished from each other by the real-time PCR platform. The realtime PCR software interprets all data collection and provides the information for automated or manual result analysis. The assay is semi-automated.

The provided text describes the performance of the Genetic Signatures EasyScreen™ Gastrointestinal Parasite Detection Kit. This device is a rapid in vitro nucleic acid amplification assay for the qualitative detection of pathogenic gastrointestinal parasite nucleic acid from human stool samples.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly present a consolidated table of acceptance criteria for all aspects of the study alongside the reported performance in a single, clear format. However, acceptance criteria are stated within each section of the performance studies, and the results are then presented against those criteria. Below is a reconstructed table based on the explicit statements regarding acceptance and observed performance.

Acceptance Criteria and Reported Device Performance

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

• Clinical Study Test Set (Analyzable Samples): A total of 1,926 analyzable specimens (out of 2,806 collected).
  • Prospective Samples (Category I & II): 1,461 samples.
  • Retrospective Clinical Samples (Category III): 265 samples.
  • Contrived Samples (Category IV): 165 samples (for E. bieneusi and E. intestinalis, which had low prevalence or availability).
• Data Provenance:
  • Clinical Samples: Collected from four geographically diverse US clinical sites (US1, US2, US3, US4). Some retrospective procurement was also done at one US site (US4).
  • Contrived Samples: Prepared/enrolled at an Outside the US (OUS) internal site for testing at the US sites.
  • Retrospective or Prospective: Both retrospective and prospective samples were used. Prospective samples (Category I: fresh, and Category II: frozen) were collected in an "All-Comers" mode. Retrospective, positive-identified (Category III) samples were also included, along with randomly distributed negative samples, tested in a masked/blinded manner.

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

The document does not specify the number or qualifications of experts used to establish the ground truth for the test set. It mentions that the reference method for the clinical studies was "two (2) well-characterized and validated Nucleic Acid Amplification Tests (NAAT) followed by bi-directional sequencing (referred to as "alternative NAAT")." The alternative NAATs were performed at an OUS internal site. The results from the alternative NAAT were compared against sequence data that met "acceptability criteria listed in Section VII(D)(1) of the Class II Special Controls guidelines," but it does not detail human expert adjudication for ground truth. The adjudication of sequence data to determine ground truth status appears to be based on pre-defined criteria rather than a panel of human experts.

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

The document states that the true analyte status ("positive" or "negative") of each clinical sample was established for each target parasite by comparison with the reference method of alternative NAATs. These NAATs consisted of "two separate single-plex, PCR amplification tests." Amplicons from PCR-positive reactions were then subjected to "bi-directional Sanger sequencing." Samples producing sequence data that met "acceptability criteria" were reported as positive by alternative NAAT.

There is no mention of a human expert adjudication method (like 2+1 or 3+1 consensus) for the resolution of discrepancies between multiple readers or ground truth methods. The ground truth appears to be established algorithmically or through a predefined analytical process based on the output of the reference NAATs and sequencing results.

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

This is not an AI/human-in-the-loop study. The device described is an in vitro diagnostic (IVD) molecular test (real-time PCR kit) for detecting pathogenic gastrointestinal parasite nucleic acid. Therefore, an MRMC comparative effectiveness study involving human readers assisted by AI is not applicable here. The device output is qualitative (detection or non-detection of specific nucleic acids), interpreted directly by the instrument software or through a validated macro-enabled Excel sheet, not by human image readers.

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

Yes, the primary performance evaluation of the EasyScreen™ Gastrointestinal Parasite Detection Kit is a standalone (algorithm only) performance assessment. The device is a diagnostic kit that performs nucleic acid amplification and detection. The interpretation of results is automated, with the real-time PCR software interpreting data and providing information for automated or manual result analysis. The device itself (the kit and associated platform) is the "algorithm" in this context, directly generating a result based on the processed sample without human interpretation of raw signals like an image.

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

The ground truth for the clinical study was established using a molecular reference method: "two (2) well-characterized and validated Nucleic Acid Amplification Tests (NAAT) followed by bi-directional sequencing (referred to as "alternative NAAT")". Sequence data meeting predefined acceptability criteria were considered positive. This is a form of molecular ground truth, not expert consensus, pathology, or outcomes data.

8. The sample size for the training set

The document does not specify a separate training set size or mention a training phase for the device described. As an in vitro diagnostic (IVD) PCR kit, its "training" or "development" would involve optimizing primers, probes, and reaction conditions rather than machine learning algorithm training on a dataset in the typical sense. The studies described are validation studies (analytical and clinical performance) on test sets.

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

Since a specific training set or "training phase" in the context of machine learning is not described for this IVD device, the method for establishing ground truth for a training set is not applicable or described in the provided document. The document focuses on the validation of the finalized device.

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