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The FilmArray Gastrointestinal (GI) Panel is a qualitative multiplexed in vitro diagnostic test intended for use with FilmArray systems. The FilmArray 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 FilmArray GI Panel:

• · Campylobacter (C. jejuni/C. coli/C. upsaliensis)
• · Clostridium difficile (C. difficile) toxin A/B
• Plesiomonas shigelloides
• · Salmonella
• · Vibrio (V. parahaemolyticus/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) stx1/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 FilmArray 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 FilmArray 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 FilmArray 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 and identification of acute gastroenteritis in the context of outbreaks.

The FilmArray Gastrointestinal (GI) Panel is a multiplex nucleic acid test designed to be used with FilmArray systems. The FilmArray GI pouch contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex PCR with DNA melt analysis. The FilmArray Gastrointestinal (GI) Panel simultaneously conducts 22 tests for the identification of GI pathogens from stool specimens collected in Cary Blair transport medium (Table 1). Results from the FilmArray GI Panel test are available within about one hour.

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

The FilmArray instrument 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. 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 FilmArray pouch using mechanical and chemical lysis followed by purification using standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, a nested multiplex PCR is executed in two stages. During the first stage, a single, large volume, highly multiplexed reverse transcription PCR (rt-PCR) reaction is performed. 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 Defense, LLC). 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 each well of the array. At the conclusion of the 240 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 array captures fluorescent images of the PCR2 reactions and software interprets the data.

The FilmArray 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 text describes the FilmArray Gastrointestinal (GI) Panel, a qualitative multiplexed in vitro diagnostic test for the simultaneous detection and identification of nucleic acids from multiple bacteria, viruses, and parasites directly from stool samples. The document focuses on demonstrating substantial equivalence of the FilmArray GI Panel for use with the FilmArray 2.0 system to a previously cleared FilmArray GI Panel (K140407) used with the original FilmArray system.

The acceptance criteria are not explicitly stated as clear thresholds in the provided document. However, the study aims to demonstrate concordance and reproducibility between the modified system (FilmArray 2.0) and the current (predicate) system for all listed analytes, indicating that performance should be comparable to or better than the predicate device.

The reported device performance (FilmArray GI Panel for use with FilmArray 2.0) is detailed in two main studies: Clinical Performance and Reproducibility, comparing it against the original FilmArray system.

1. Table of Acceptance Criteria and Reported Device Performance

Since explicit acceptance criteria are not provided, I will derive implied criteria from the study results and present the reported performance against these implied criteria.

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

• Clinical Performance Study (Modified System vs. Current System):

  • Sample Size: A total of 104 specimens were selected for testing on both the current and modified systems. Each analyte was represented 3-5 times.
  • Data Provenance:
    • Specimens previously obtained during the FilmArray GI prospective clinical evaluation: This indicates a mix of prospective clinical data. The country of origin is not explicitly stated but implies US-based clinical trials, given FDA submission.
    • Archived specimens collected from external medical facilities and reference laboratories: This suggests retrospective data from various sources (country not specified).
    • Contrived clinical specimens: Used for rare GI analytes (Entamoeba histolytica, Vibrio spp., and V. cholerae).

• Low Analyte Study (Replicate Testing at LoD):

  • Sample Size: 20 replicates per system were tested for most analytes at Limit of Detection (LoD). For Vibrio/Vibrio cholerae and Adenovirus F41 (second test), 40 replicates were tested (initial 20 + an additional 20).
  • Data Provenance: Not specified, but likely laboratory-generated contrived samples given the nature of LoD testing.

• Reproducibility Study:

  • Sample Size: A panel of contrived stool samples was tested. Each analyte was evaluated at three different concentrations (Negative, Low Positive, Moderate Positive). "108 data points per sample" were generated, implying a significant number of runs. For each organism, there were 36 runs per site/system (3 sites * 1 system/site * x replicates/run, over 4 days), leading to 108 data points for each condition (concentration x organism). For example, C. difficile had 108 data points for moderate positive, 108 for low positive, and 108 for negative.
  • Data Provenance: Contrived stool samples, likely prepared in a laboratory setting. Tested at three different test sites. Country of origin not specified.

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

The document does not mention the use of experts to establish ground truth. For the clinical performance study, the "ground truth" seems to be established through the "original characterization" of the specimens or by reference laboratory results. For contrived specimens, the ground truth is inherently known from how they were prepared. Therefore, information on the number or qualifications of experts is not applicable here.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method for determining ground truth in the clinical studies. For specimens with discrepancies between the modified and current systems, explanations (e.g., analyte levels below LoD) were provided, but a formal adjudication process (like 2+1 or 3+1 expert review) is not mentioned. For contrived samples, ground truth is established by design.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. The FilmArray GI Panel is an in vitro diagnostic test for direct pathogen detection, not an imaging device or AI algorithm requiring human interpretation. Therefore, a study comparing human readers with and without AI assistance is not applicable. The study compares the performance of an automated diagnostic system (FilmArray 2.0) against another version of the same automated system (original FilmArray).

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

Yes, the studies presented describe the standalone performance of the FilmArray GI Panel for use with FilmArray 2.0. The device itself is an automated system that performs nucleic acid extraction, PCR, and analysis, with the software automatically interpreting results. There is no human "in-the-loop" for the diagnostic interpretation phase of the device's function. The comparison is between two versions of this automated system.

7. The Type of Ground Truth Used

• Clinical Performance Study:

  • Reference Methods / Original Characterization: For clinical specimens, the ground truth was established by "original characterization" or by the "source laboratory" before being used in the comparison study. For example, some specimens were "originally characterized as positive" or the analyte "had not been reported in this specimen by the source laboratory." Specific details of these reference methods are not provided, but they likely refer to standard laboratory tests used to initially identify the pathogens.
  • Contrived Specimens: For certain rare analytes, ground truth was established by preparing "contrived clinical specimens" (i.e., known positive samples spiked with the organism).

• Low Analyte Study & Reproducibility Study:

  • Contrived Samples: The ground truth for these studies was established by creating "contrived samples" or "spiked with various concentrations" of known analytes. This means the presence and concentration of the target organisms were precisely controlled and known.

8. The Sample Size for the Training Set

The provided document describes a validation study for an existing device (FilmArray GI Panel 2.0) against its predicate (FilmArray GI Panel). It does not describe the development or training of a new algorithm. Therefore, information on a "training set" for an algorithm is not applicable in this context, as the document focuses on demonstrating substantial equivalence rather than original algorithm development.

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

As no training set is described (see point 8), this information is not applicable.

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The FilmArray Gastrointestinal (GI) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with the FilmArray Instrument. The FilmArray 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 FilmArray 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) It/st .
• Shiga-like toxin-producing Escherichia coli (STEC) stx1/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 FilmArray GI Panel 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 FilmArray 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 O157, 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 FilmArray Gl 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 noninfectious 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 and identification of acute gastroenteritis in the context of outbreaks.

The FilmArray Gastrointestinal (GI) Panel is a multiplex nucleic acid test designed to be used with the FilmArray Instrument. The FilmArray GI pouch contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex PCR with DNA melt analysis. The FilmArray Gastrointestinal (GI) Panel simultaneously conducts 22 tests for the identification of GI pathogens from stool specimens collected in Cary Blair transport medium (Table 1). Results from the FilmArray GI Panel test are available within about one hour.

A test is initiated by loading Hydration Solution into one port of the FilmArray pouch and a stool sample (in Cary Blair transport medium) mixed with the provided Sample Buffer into the other port of the FilmArray GI pouch and placing it in the FilmArray Instrument. The pouch contains all of 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 FilmArray Software guides the user though the steps of placing the pouch into the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.

The FilmArray Instrument 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 FilmArray pouch using mechanical and chemical Ivsis followed by purification using standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, the FilmArray performs a nested multiplex PCR that is executed in two stages. During the first stage, the FilmArray 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®, BioFire). 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 singleplex fashion in each well of the array. At the conclusion of the 2nd stage PCR, the arrav 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 200 stage PCR captures fluorescent images of the PCR reactions and software interprets the data.

The FilmArray 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 FilmArray Gastrointestinal (GI) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test for 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.

1. Table of Acceptance Criteria and Reported Device Performance:

The document lists "Positive Percent Agreement (PPA)" and "Negative Percent Agreement (NPA)" as performance measures, which can be interpreted as sensitivity and specificity. While acceptance criteria are not explicitly stated as numerical thresholds for PPA and NPA, a general expectation for diagnostic assays is high agreement with the reference method. The reported performance varies by analyte. For the purpose of this output, the reported device performance for selected analytes is presented below. A comprehensive table for all analytes can be found in Table 6 of the provided document.

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

• Prospective Clinical Study:
  • Sample Size: 1556 residual stool specimens. Originally 1578 were acquired, but 22 were excluded.
  • Data Provenance: The study was multi-center, conducted at four geographically distinct U.S. study sites (Pacific, North Central, Great Lakes, and Northeast regions). The data is prospective.
• Archived Specimens:
  • Sample Size: 222 preselected archived clinical specimens.
  • Data Provenance: Retrospective, as these were archived specimens. Countries of origin are not specified beyond being "clinical specimens."
• Contrived Specimens:
  • Sample Size: Varies by analyte, but generally tested using at least 50 spiked specimens for each organism or 75 unspiked specimens. For example, for Entamoeba histolytica, 50 positive and 75 negative contrived specimens were used.
  • Data Provenance: Created in the laboratory using residual negative specimens from the prospective clinical study, spiked with known organisms.

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 of experts used or their qualifications for establishing the ground truth. It refers to "appropriate comparator/reference methods," which include "standard manual and automated microbiological/biochemical identification methods" for bacteria and "PCR with Bi-directional Sequencing" for other pathogens. These methods likely rely on trained laboratory personnel, but no explicit mention of "experts" and their qualifications (e.g., "radiologist with 10 years of experience") is made in the context of ground truth establishment for the clinical performance study.

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

The document describes a discrepancy resolution process. For the clinical study, if the FilmArray GI Panel result differed from the initial reference/comparator method, bi-directional sequence analysis was performed. Specifically, for discrepant results in mixed infections (where the FilmArray detected organisms not found by reference methods), bi-directional sequence analysis was used to confirm the presence of the analyte. This suggests an adjudication method based on a higher-tier molecular technique (sequencing) for discordant results. However, a formal "X+Y" adjudication method where multiple initial readers are involved is 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:

This is an in vitro diagnostic device (nucleic acid-based assay), not an AI-powered diagnostic imaging device or an assay with a human "reader" component that would involve interpretation (like a radiologist reading an image). Therefore, a multi-reader multi-case (MRMC) comparative effectiveness study involving human readers and AI assistance is not applicable and was not performed. The device provides an automated "Detected" or "Not Detected" result.

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

Yes, the clinical evaluation presented is a standalone performance study. The FilmArray GI Panel is an automated nucleic acid test that provides results directly. The software automatically interprets the results and provides a test result for each organism on the panel (Page 3). There is no human-in-the-loop component for result interpretation for the primary output of the device.

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

The ground truth was established using a combination of:

• Bacterial Culture with Microbiological/Biochemical Identification: For most bacterial targets (e.g., Campylobacter, E. coli O157, Plesiomonas shigelloides, Salmonella, Vibrio, Yersinia enterocolitica, STEC, ETEC, EPEC, EIEC/Shigella, EAEC).
• PCR with Bi-directional Sequencing: For viruses and parasites, and for confirming discrepant bacterial results from culture (e.g., for Norovirus, Sapovirus, Cryptosporidium, Giardia lamblia). Bi-directional sequencing was also used to identify species within bacterial groups when standard methods couldn't.

8. The sample size for the training set:

The document does not explicitly mention a "training set" in the context of machine learning or algorithm development for interpretation. This is a molecular diagnostic assay, and its performance is based on the specificity of its primers and probes and the robustness of the PCR and melt curve analysis. The development process would involve extensive optimization and testing of these components. However, the document does describe analytical studies such as Limit of Detection (LoD) and Inclusivity/Exclusivity tests, which involve testing a large number of isolates and contrived samples to define the operational characteristics of the assay. For instance, the inclusivity study evaluated 270 isolates representing the diversity of FilmArray GI Panel analytes.

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

As noted above, a traditional "training set" in the machine learning sense is not described. However, the "ground truth" for the analytical studies (Limit of Detection, Inclusivity, Exclusivity) was established by:

• Quantified organism preparations: For LoD studies, organisms were spiked at known concentrations into negative sample matrix.
• Well-characterized isolates/strains: For inclusivity, a collection of 270 isolates representing the diversity of relevant species/serotypes was used. Their identity would have been confirmed by standard microbiological and molecular methods.
• Bioinformatics/in silico analysis: For organisms not empirically tested, in silico analysis of sequence data was used to predict reactivity against the assay primers, effectively serving as a computational "ground truth."

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