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The BioCode Gastrointestinal Pathogen Panel (GPP) is a qualitative, gastrointestinal microorganism multiplexed nucleic acid-based assay capable of detecting of nucleic acids from the following organisms in unpreserved stool and Cary-Blair media:

• Adenovirus 40/41 ●
• Campylobacter (C. jejuni, C. coli) ●
• Clostridium difficile (C. difficile) toxin A/B (from fresh specimens only) ●
• Cryptosporidium (C. parvum, C. hominis) 0
• Entamoeba histolytica ●
• Escherichia coli (E. coli) 0157 ●
• Enterotoxigenic E. coli (ETEC) LT/ST ●
• Enteroaggregative E. coli (EAEC) 0
• Giardia lamblia (also known as G. intestinalis and G. duodenalis) ●
• Norovirus GI/GII ●
• Rotavirus A ●
• Salmonella spp. .
• Shiga-like Toxin producing E. coli (STEC) stx1/stx2 ●
• Shigella (S. boydii, S. sonnei, S. flexneri, S. dysenteriae)/EIEC ●
• Vibrio spp. (V. cholerae, V. parahaemolyticus, V. vulnificus), specific identification of V. ● parahaemolyticus
• Yersinia enterocolitica

The BioCode Gastrointestinal Pathogen Panel (GPP) 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 BioCode Gastrointestinal Pathogen Panel (GPP). The agent detected may not be the 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.

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 Campylobacter spp., E. coli 0157, Shigella/EIEC, Yersinia enterocolitica, and Adenovirus 40/41 were established primarily with retrospective clinical specimens.

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

The BioCode Gastrointestinal Pathogen Panel (GPP) is a multiplex nucleic acid test designed to be used with the BioCode MDx 300 system. The BioCode MDx 3000 is an automated system that integrates PCR amplification, target capture, signal generation and optical detection for nultiple gastrointestinal pathogens from a single stool speciment or in Cary Blair. Stool specimens are processed and nucleic acids extracted with easyMAG, an automated system. Once the PCR plate is set up and sealed, all other operations are automated on MDx 3000. The BioCode Gastrointestinal Pathogen 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 test are available within less than 5 hours.

Here's a breakdown of the acceptance criteria and study details for the BioCode Gastrointestinal Pathogen Panel (GPP) based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for the clinical performance metrics (PPA and NPA). Instead, it presents the calculated agreement rates and their 95% confidence intervals from the clinical study. The reproducibility study, however, does have clear acceptance criteria defined (>= 95% detection for positive targets, and >= 95% non-detection for negative targets).

Here's a table summarizing the reported clinical performance. Note that "Acceptance Criteria" for clinical performance are inferred based on general expectations for diagnostic assays submitted to the FDA; explicit numerical targets were not provided in the text for these. The Reproducibility section does state explicit criteria.

2. Sample Sizes and Data Provenance

• Clinical Study (Prospective):

  • Sample Size: 1558 leftover, de-identified samples.
  • Data Provenance: Prospectively collected from patients in the United States (Baltimore, MD; Tampa, FL; Memphis, TN; Los Angeles, CA). Samples collected between January 2015 and August 2017.
  • Specimen Breakdown:
    • Unpreserved (Fresh): 237 samples
    • Unpreserved (Frozen): 960 samples
    • Cary-Blair (Fresh): 361 samples
  • Inoculated Cary-Blair Samples: 400 unpreserved stool samples from Sites 1 and 2 were thawed and inoculated into Cary-Blair to supplement numbers for specific analytes (pg 21).

• Pre-selected Archived Specimens (Category III):

  • Sample Size: 260 preselected archived specimens.
  • Data Provenance: Archived clinical specimens that were previously tested positive by different methods (retrospective). These were spiked with known positives and randomized with negative specimens. (pg 23)

• Contrived Specimens (Category IV):

  • Sample Size: 612 samples total, with 485 positive samples.
  • Data Provenance: Prepared using specimens previously tested negative for all BioCode GPP analytes, then spiked at levels of up to 3X LOD or greater. (pg 25)

• Asymptomatic Volunteers (Clinical Specificity):

  • Sample Size: 125 clinical stool samples.
  • Data Provenance: Collected from healthy asymptomatic donors from Tampa General Hospital and University of Maryland. (pg 30-31)

• Reproducibility Study:

  • Sample Size: 7 contrived samples (6 positive, 1 negative control) extracted in triplicate and each assayed in singlet over 10 runs per site. Total 90 replicates per target. (pg 32)
  • Data Provenance: Performed at 3 sites. (pg 32)

• Limit of Detection (LoD):

  • Sample Size: 20 replicates for each tested organism and sample type (unpreserved stool and Cary-Blair). (pg 35)

• Interfering Substances:

  • Each sample extracted in triplicate and tested in singlet. (pg 37)

• Cross Contamination/Sample Carryover:

  • Five complete runs in "checkerboard" pattern. (pg 50)

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the number or qualifications of experts used to establish ground truth for the clinical test set. Instead, it relies on reference methods for clinical performance evaluation (pg 13).

4. Adjudication Method for the Test Set

The document does not describe an adjudication method involving human experts. For the clinical study, the reference method for each target pathogen was used as the ground truth. In some cases, discrepancies between the BioCode GPP and the initial reference method were subjected to bidirectional sequencing or additional rounds of sequencing for "confirmation" (e.g., footnotes on pages 14, 15, 17, 22), which can be considered a form of analytical adjudication to determine the true state of the specimen.

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

No MRMC study was mentioned. The device is a "multiplex nucleic acid-based assay," indicating an automated laboratory test, not an imaging AI diagnostic that assists human readers. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply here.

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

Yes, the studies presented are for the standalone performance of the BioCode Gastrointestinal Pathogen Panel (GPP) system, without human interpretation or assistance beyond typical laboratory operational procedures. The results, as quantitative fluorescence intensity (MFI) values, are processed by the BioCode MDx 3000 system to determine positive or negative results.

7. Type of Ground Truth Used

• Clinical Study (Prospective):

  • Reference standard methods: Culture, FDA-cleared NAAT (Nucleic Acid Amplification Test), or Composite results of two PCR/sequencing assays (pg 13).
  • For discrepancies, bidirectional sequencing or additional rounds of sequencing were used as further confirmation/adjudication (e.g., footnotes on pages 14, 15, 17, 22).

• Archived Specimens: Previously tested positive by different methods, and verified using analyte-specific PCR followed by bi-directional sequencing performed by Applied BioCode, Inc. (pg 23).

• Contrived Specimens: Known concentrations of quantified bacteria, viruses, or parasites spiked into negative clinical matrix. (pg 25)

8. Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning. This device is a molecular diagnostic assay, not a machine learning algorithm that is trained on a dataset. The studies described are performance validation studies for an established assay.

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

Since this is not a machine learning device trained on a "training set," this question is not applicable. The device's probes and primers for detecting targets are designed based on known genetic sequences, not through a data-driven training process like that used for AI/ML.

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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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The Prodesse® ProGastro SSCS Assav is a multiplex real time PCR in vitro diagnostic test for the qualitative detection and differentiation of Salmonella, Shigella, and Campylobacter (C. jejimi and C. coli only, undifferentiated) nucleic acids and Shiga Toxin 1 (stxl) and Shiga Toxin 2 (stx2) genes. Shiga toxin producing E. coli (STEC) typically harbor one or both genes that encode for Shiga Toxins I and 2. Nucleic acids are isolated and purified from preserved stool specimens obtained from symptomatic patients exhibiting signs and symptoms of gastroenteritis. This test is intended for use, in conjunction with clinical presentation and epidemiological risk factors, as an aid in the differential diagnosis of Salmonella, Shigella, Campylobacter jejuni/Campylobacter coli, and STEC infections in humans.

The results of this test 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 are not detected by this test, and may not be the sole or definitive cause of patient illness. Negative ProGastro SSCS Assay results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.

The ProGastro SSCS Assay enables detection and differentiation of Salmonella, Shigella, Campylobacter (C. jejuni and C. coli only, undifferentiated) and an Internal Control in the SSC Mix and Shiga Toxin Producing E. coli (STEC, stx1 and stx2 differentiated) and an Internal Control in the STEC Mix.

An overview of the procedure is as follows:

• 1. Collect raw stool specimens from symptomatic patients and place into Cary Blair Transport Medium or ParaPak C&S (C&S) Transport Medium .
• 2. Add the Gastro RNA/DNA Internal Control (GIC) to every sample to monitor for inhibitors present in the specimens.
• 3. Perform isolation and purification of nucleic acids using a NucliSENS easyMAG System and the Automated Magnetic Extraction Reagents (bioMérieux).
• 4. Add purified nucleic acids to the SSC Mix included in the ProGastro SSCS Assay Kit. The SSC Mix contains target-specific oligonucleotide primers and probes for detection of Salmonella, Shigella, and Campylobacter (C. jejuni and C. coli only). The primers and probes are complementary to highly conserved regions of genetic sequences for these organisms. The probes are dual-labeled with a reporter dye and a quencher (see table below).
• 5. Add purified nucleic acids to the STEC Mix included in the ProGastro SSCS Assay Kit. The STEC Mix contains target-specific oligonucleotide primers and probes for detection of Shiga Toxin 1 and 2 genes (stxl and stx2). The primers and probes are complementary to highly conserved regions of these genes. The probes are dual-labeled with a reporter dye and a quencher (see table below).
• 6. Perform amplification of DNA in a Cepheid SmartCycler II instrument. In this process, the probe anneals specifically to the template followed by primer extension and amplification. The ProGastro SSCS Assay is based on Tagman reagent chemistry, which utilizes the 5' - 3' exonuclease activity of Taq polymerase to cleave the probe thus separating the reporter dye from the quencher. This generates an increase in fluorescent signal upon excitation from a light source. With each cycle, additional reporter dye molecules are cleaved from their respective probes, further increasing fluorescent signal. The amount of fluorescence at any given cycle is dependent on the amount of amplification products present at that time. Fluorescent intensity is monitored during each PCR cycle by the real-time instrument.

Here's a breakdown of the acceptance criteria and study information for the ProGastro SSCS Assay:

The document provided details the clinical performance and analytical performance (reproducibility and precision) of the ProGastro SSCS Assay. The primary acceptance criteria for clinical performance are presented as Sensitivity, Specificity, Positive Percent Agreement (PPA), and Negative Percent Agreement (NPA). For analytical performance, it focuses on the agreement with expected results and the Coefficient of Variation (CV) for Ct values.

1. Table of Acceptance Criteria and Reported Device Performance

Clinical Performance (Prospective Study):

Clinical Performance (Retrospective Study):

Reproducibility (Across 3 Sites, 2 Operators/Site, 5 Days - Total 90 runs per condition):

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