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The Joint Biological Agent Identification and Diagnostic System (JBAIDS) Anthrax Detection System is a real-time polymerase chain reaction (PCR) test system intended for the qualitative in vitro diagnostic (IVD) detection of target DNA sequences on the pXO1 plasmid (Target 1) and the pXO2 plasmid (Target 2) from Bacillus anthracis. The system can be used to test the following:

• Human whole blood collected in sodium citrate from individuals suspected of having anthrax
• Positive blood cultures
• Cultured organisms grown on blood agar plates.
  The JBAIDS Anthrax Target 2 assay is used as a supplementary test only after a positive result with the Target 1 Assay.
  The JBAIDS Anthrax Target 1 and Target 2 Assays are run on the JBAIDS instrument using the Diagnostic Wizard. Results are for the presumptive identification of B. anthracis, in conjunction with culture and other laboratory tests. The following considerations also apply:
• The diagnosis of anthrax infection must be made based on history, signs, symptoms, exposure likelihood, and other laboratory evidence, in addition to the identification of pXO1 and pXO2 targets either from cultures or from direct blood specimens.
• The assays have not been evaluated with blood from individuals without clinical signs or symptoms who were presumed exposed and who subsequently developed anthrax (inhalation or other forms of the disease), or from individuals with any form of anthrax (inhalational, cutaneous, or gastrointestinal).
• The level of plasmid targets that would be present in blood from individuals with early systemic infection is unknown.
• The definitive identification of B. anthracis from colony growth, liquid blood culture growth, or from blood specimens requires additional testing and confirmation procedures in consultation with public health or other authorities for whom reports are required.
  The safety and effectiveness of other types of tests or sample types (not identified as "For in vitro diagnostic use") have not been established.

The Joint Biological Agent Identification and Diagnostic System (JBAIDS) Anthrax Detection System is a fully integrated IVD system composed of the portable JBAIDS instrument, laptop computer and software, the JBAIDS Anthrax Detection Kit with two different freeze-dried PCR assays for detection of pathogenic Bacillus anthracis DNA. The system has been validated using four different sample preparation kits for isolating DNA from whole blood (IT 1-2-3TM Platinum Path, QFLOWdma, FLOW Sample Purification Kits), positive blood cultures (IT I-2-3TM SWIPE Sample Purification Kit), and plate cultures (IT 1-2-3™ Platinum Path and SWIPE Sample Purification Kits). Use of the JBAIDS DNA Extraction Control Kit is also recommended.
Prior to testing, specimens are processed using BioFire Diagnostic's IT 1-2-3 Sample Purification Kits. The resulting purified sample is added to Target 1 Unknown and Target 1 Inhibition Control vials, along with reconstitution buffer. Target 1 Positive Control and Negative Control vials are prepared using reconstitution buffer and water. When B. anthracis DNA is present, a fragment of B. anthracis DNA is amplified. The amplicon is detected by fluorescence using a specific hydrolysis probe. Each probe is labeled on one end with a fluorescent reporter moiety (6-carboxyfluorescein (6-FAM)) and elsewhere with a quencher moiety (carboxy tetramethylrhodamine (TAMRA)). When the probe is intact, the quencher absorbs the light emitted by the reporter moiety. During PCR, the probe hybridizes to the target sequence before the exonuclease activity of Taq polymerase hydrolyzes the probe, separating the fluorophore from the quencher and permitting detection of the fluorescent signal generated by the reporter. The fluorescent signal increases as additional templates are amplified and more probes are hydrolyzed.
JBAIDS Software analyzes the fluorescence amplification curves and reports results as positive, negative, uncertain or inhibited. A failure of the Positive or Negative Control will result in the entire run being called invalid. Retesting is required to resolve uncertain, invalid or inhibited results. The Target 2 assay is used as a supplementary test only after a positive result is obtained with the Target 1 assay.

Here's a breakdown of the acceptance criteria and study information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The submission primarily focuses on demonstrating equivalence of a new DNA extraction method (Platinum Path) to an existing one (QFLOWdna) for use with the JBAIDS Anthrax Detection Kit. Therefore, the "acceptance criteria" are implicitly defined by the performance of the predicate device with the QFLOWdna kit, and the "reported device performance" is how the new Platinum Path kit compares.

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

• Clinical Performance (Surrogate Whole Blood):

  • Sample Size: 100 surrogate whole blood specimens (50 spiked with B. anthracis, 50 not spiked). Each sample was processed by both new (Platinum Path) and old (QFLOWdna) extraction methods and then tested.
  • Data Provenance: Prospectively collected from febrile volunteers in the USA (November 2012 to April 2013). These were surrogate specimens spiked with inactivated B. anthracis, not true clinical anthrax samples.

• Limit of Detection:

  • Sample Size: 20 independent whole blood specimens, each spiked with B. anthracis at the LoD level.
  • Data Provenance: Not explicitly stated, but implied to be laboratory-prepared samples for analytical validation.

• Reproducibility:

  • Sample Size: A panel of 12 blood samples (4 medium positive, 4 low positive, 4 negative). Each sample was tested twice a day for four days at each of three testing sites. Total individual tests for each target would be 12 samples * 2 tests/day * 4 days * 3 sites = 288 for each target (Target 1 and Target 2).
  • Data Provenance: Multicenter study, locations are "Site 1, Site 2, Site 3." Country of origin not explicitly stated, but typically assumed to be domestic for FDA submissions unless otherwise specified.

• Detection of Direct Culture Samples:

  • Sample Size: 10 B. anthracis colonies and 10 non-B. anthracis colonies.
  • Data Provenance: Not explicitly stated, but implied to be laboratory-prepared cultures.

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

The ground truth for the surrogate clinical specimens and analytical studies was established by:

• Spiking Status: Knowing which samples were spiked with inactivated B. anthracis and at what concentration, and which were not. This is a controlled laboratory process, not dependent on human expert interpretation for definitive classification.
• Predicate Device Performance: For the surrogate clinical specimens, the "correct result" was defined by the JBAIDS result when processed with the QFLOWdna kit, which is the predicate/established method. This avoids the need for external expert consensus on the B. anthracis status of a sample that has already been spiked.

Therefore, no external clinical experts were used to establish the ground truth in the traditional sense for these studies. The ground truth was based on the controlled spiking of samples and comparison to an established method.

4. Adjudication Method for the Test Set

Not applicable in the traditional sense. The "ground truth" for the surrogate clinical specimens was determined by the results from the predicate extraction method (QFLOWdna), and for the analytical studies, it was determined by the known spiking status of the samples. There was no need for expert adjudication of conflicting results as the comparison was against a predetermined "truth."

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 a molecular diagnostic test for B. anthracis DNA, not an imaging device that would typically involve human readers interpreting images. The study focuses on the analytical and clinical (surrogate) performance of the extraction method and PCR kit.

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

Yes, the studies presented are standalone (algorithm only). The JBAIDS system, with its software, analyzes the fluorescence amplification curves and reports results (positive, negative, uncertain, inhibited). The operators were blinded to the analyte content, meaning their human "interpretation" was limited to running the instrument and following its automated output. The performance metrics (PPA, NPA, LoD, reproducibility) are based directly on the device's output.

7. The Type of Ground Truth Used

• Clinical Performance (Surrogate Whole Blood): Known spiking status of the samples from a laboratory perspective, and the performance of the predicate DNA extraction method (QFLOWdna) as the "correct result" for comparison.
• Limit of Detection: Known concentration of spiked B. anthracis in laboratory-prepared whole blood specimens.
• Reproducibility: Known concentration of spiked B. anthracis (medium, low, or unspiked).
• Detection of Direct Culture Samples: Known identity of the bacterial colonies (either B. anthracis or non-B. anthracis) through laboratory culture and identification.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" for the device itself. This submission is for modifications to an existing device (the JBAIDS Anthrax Detection Kit) by adding compatibility with a new sample purification kit (IT 1-2-3 Platinum Path). The JBAIDS system and its algorithm were presumably developed and validated previously. The studies described here are a validation of the new sample preparation method, not the training of a new algorithm.

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

Since there is no explicit mention of a "training set" for a new algorithm within this submission, this question is not directly applicable. The JBAIDS Anthrax Detection System already existed and was previously cleared (K051713 and K071188). The ground truth for its initial development and validation would have followed similar principles of known positive and negative samples, likely through spiking and confirmed cultures, as is typical for molecular diagnostic assays.

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The Joint Biological Agent Identification and Diagnostic System (JBAIDS) Plague Detection Kit is a real-time polymerase chain reaction (PCR) test kit intended for the qualitative in vitro diagnostic (IVD) detection of target DNA sequences of Yersinia pestis. The kit can be used to test human whole blood collected in sodium citrate or sputum collected aseptically from individuals greater than 18 years of age suspected of having septic or pneumonic plague. In addition, positive blood cultures and colonies may be tested. The JBAIDS Plague Target 2 assay is used as a supplementary test only after a positive result with the Target I Assay.

The JBAIDS Plague Target 1 and Target 2 assays are run on the JBAIDS instrument using the Diagnostic Wizard. Results are for the presumptive identification of Y. pestis in conjunction with culture and other laboratory tests. The definitive identification of Y. pestis from colony growth, liquid blood culture growth, or from blood or sputum specimens requires additional testing and confirmation procedures in consultation with public health or other authorities for whom reports are required.

The diagnosis of plague must be made based on history, signs, symptoms, exposure likelihood, and other laboratory evidence in addition to the identification of Y. pestis from cultures or directly from whole blood or sputum specimens.

The JBAIDS Plague Detection Kit is intended for use by trained clinical laboratory personnel who have received specific training on the use of the JBAIDS Plague Detection Kit. The level of Y. pestis that would be present in blood or sputum from individuals with early systemic infection is unknown. Due to the difficulty in obtaining clinical specimens, these assays were not evaluated with blood or sputum from individuals with septic or pneumonic plague.

The Joint Biological Agent Identification and Diagnostic System (JBAIDS) Plague Detection System is a fully integrated IVD system composed of the portable JBAIDS instrument, laptop computer and software and the JBAIDS Plague Detection Kit with two different freeze-dried PCR assays for detection of Yersinia pestis DNA. The system has been validated using four different sample preparation kits for isolating DNA from wole blood (IT 1-2-3TM Platinum Path and QFLOWdana Sample Purification Kits), sputum (IT 1-2-3TM Platinum Path and IT 1-2-3TM VIBE), positive blood cultures (IT 1-2-3TM SWIPE Sample Purification Kit), and plate cultures (IT 1-2-3™ Platinum Path and SWIPE Sample Purification Kits). Use of the JBAIDS DNA Extraction Control Kit is also recommended.

Prior to testing, specimens are processed using BioFire Diagnostic's IT 1-2-3 Sample Purification Kits. The resulting purified sample is added to Target 1 Unknown and Target 1 Inhibition Control vials, along with reconstitution buffer. Target 1 Positive Control and Negative Control vials are prepared using reconstitution buffer and water. When Y. pestis DNA is present, a fragment of Y. pestis DNA is amplified. The amplicon is detected by fluorescence using a specific hydrolysis probe. Each probe is labeled on one end with a fluorescent reporter moiety (6-carboxyfluorescein (6-FAM)) and elsewhere with a quencher moiety (carboxy tetramethylrhodamine (TAMRA)). When the probe is intact, the quencher absorbs the light emitted by the reporter moiety. During PCR, the probe hybridizes to the target sequence before the exonuclease activity of Taq polymerase hydrolyzes the probe, separating the fluorophore from the quencher and permitting detection of the fluorescent signal generated by the reporter. The fluorescent signal increases as additional templates are amplified and more probes are hydrolyzed.

JBAIDS Software analyzes the fluorescence amplification curves and reports results as positive, negative, uncertain or inhibited. A failure of the Positive or Negative Control will result in the entire run being called invalid. Retesting is required to resolve uncertain, invalid or inhibited results. The Target 2 assay is used as a supplementary test only after a positive result is obtained with the Target 1 assay.

This document describes the validation of the JBAIDS Plague Detection Kit, specifically the modification for use with the IT 1-2-3™ Platinum Path Sample Purification Kit Accessory. The study aims to demonstrate that the new purification method provides equivalent performance to previously validated methods.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the "equivalence" study design, where the performance of the new extraction method (Platinum Path) is compared to the previously validated methods (QFLOWdna for whole blood, VIBE for sputum). The goal is to show that the Platinum Path method performs equivalently to the existing methods. For the clinical performance, the reported metrics are Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA). For Limit of Detection (LoD), the acceptance criterion is the confirmation of the previously established LoD. For reproducibility, the criteria are defined by the agreement with expected results and consistency across sites.

2. Sample Sizes used for the Test Set and Data Provenance

• Clinical Performance (Whole Blood):
  • Test Set Sample Size: 100 surrogate whole blood samples (50 spiked with inactivated Y. pestis, 50 unspiked).
  • Data Provenance: Prospectively collected specimens from febrile volunteers in the USA (November 2012 - April 2013). This is surrogate data, not from actual plague patients.
• Clinical Performance (Sputum):
  • Test Set Sample Size: 100 surrogate sputum samples (50 spiked with inactivated Y. pestis, 50 unspiked).
  • Data Provenance: Residual frozen sputum specimens (presumably from the USA). This is surrogate data.
• Limit of Detection:
  • Whole Blood LoD Confirmation: 20 independent whole blood specimens.
  • Sputum LoD Confirmation: 20 independent sputum specimens.
• Reproducibility:
  • Whole Blood: A panel of 12 blood samples (4 medium positive, 4 low positive, 4 negative) tested twice a day for 4 days at 3 sites = 12 samples * 2 tests/day * 4 days * 3 sites = 288 individual tests for each target.
  • Sputum: A panel of 9 sputum samples (3 medium positive, 3 low positive, 3 negative) tested twice a day for 5 days at 3 sites = 9 samples * 2 tests/day * 5 days * 3 sites = 270 individual tests for each target.
• Detection of Direct Culture Samples: 10 Y. pestis colonies and 10 non-Y. pestis colonies.

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

The ground truth for the clinical performance and LoD studies was established by spiking samples with known quantities of inactivated Y. pestis. In the clinical performance comparison, the result obtained from the previously validated extraction method (QFLOWdna for blood, VIBE for sputum) was considered the "correct result" to which the new method (Platinum Path) was compared.
For the reproducibility study, the samples were prepared with known spike levels, making the expected outcome clear.
For the direct culture detection, the ground truth was the known identity of the bacterial colonies (Y. pestis vs. non-Y. pestis).

This is a molecular diagnostic test, so there isn't an "expert" interpreting images or clinical signs to establish ground truth. The ground truth is determined by the controlled experimental design (spiking, known bacterial cultures) and the performance of the predicate device.

4. Adjudication Method for the Test Set

Not applicable in the traditional sense for a molecular diagnostic device measuring defined targets in spiked samples or known cultures. The "adjudication" in the clinical equivalency studies was implicitly done by comparing the new method's results to those of the previously validated predicate method. JBAIDS operators were blinded to the analyte content of the samples.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This is a molecular diagnostic test, not an AI-powered diagnostic imaging device requiring human interpretation of results. The device provides a qualitative "positive," "negative," "uncertain," or "inhibited" result.

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

Yes, the device operates autonomously to detect target DNA sequences and report results (positive, negative, uncertain, or inhibited) based on its pre-programmed algorithms. The performance data presented (PPA, NPA, LoD confirmation, reproducibility, direct culture detection) are all standalone performance metrics of the device with the new extraction method. Human operators perform the sample preparation and initiate the test, but the interpretation of the PCR amplification curves and the final result determination are automated by the JBAIDS software.

7. The Type of Ground Truth Used

• Spiking studies (Clinical Performance, LoD, Reproducibility): Ground truth was established by spiking clinically relevant matrices (whole blood, sputum) with known quantities of inactivated Y. pestis. For the clinical performance comparison, the results from the previously cleared extraction methods served as the comparator "ground truth" to determine equivalency.
• Direct Culture Detection: Ground truth was established by using known bacterial colonies (Y. pestis vs. non-Y. pestis).

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of developing the JBAIDS Plague Detection Kit or its modification. This is a PCR-based assay, not a machine learning algorithm that typically requires a large training dataset. The device utilizes pre-defined molecular targets and amplification curves for detection. Any 'training' would refer to the initial development and optimization of the PCR primers/probes and reaction conditions, rather than a data-driven machine learning training set described here.

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

As noted above, a "training set" in the machine learning sense is not applicable here. The development of the JBAIDS Plague Detection Kit and its components (like the PCR assays and sample purification methods) would involve:

• Design and optimization: Identifying specific DNA targets for Y. pestis.
• Analytical validation: Testing the assay with characterized strains of Y. pestis and related/unrelated organisms at various concentrations.
• Limit of Detection (LoD) determination: Empirically determining the lowest concentration consistently detected.
• Specificity and Sensitivity testing: Challenging the assay with known positive and negative samples.

These processes would utilize known samples and cultures where the presence/absence and concentration of Y. pestis are precisely controlled.

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The Joint Biological Agent Identification and Diagnostic System (JBAIDS) Tularemia Detection Kit is a real-time polymerase chain reaction (PCR) test kit intended for the qualitative in vitro diagnostic (IVD) detection of target DNA sequences of Francisella tularensis. The system can be used to test human whole blood collected in sodium citrate or sputum collected aseptically from individuals greater than 18 years of age suspected of having tularemia. In addition, positive blood cultures and colonies may be tested. This assay is intended to aid in the diagnosis of individual presenting with signs and symptoms of pneumonic or typhoidal tularemia. It is not intended to aid in the diagnosis of glandular, ulceroglandular, oculoglandular, or oropharyngeal tularemia.

The JBAIDS Tularemia Detection Kit is run on the JBAIDS instrument using the Diagnostic Wizard. Results are for the presumptive identification of F. tularensis in conjunction with culture and other laboratory tests. The definitive identification of F. tularensis from colony growth. liguid blood culture growth, blood specimens, or sputum specimens requires additional testing and confirmation procedures in consultation with public health or other authorities for whom reports are required.

The diagnosis of tularemia must be made based on history, signs, symptoms, exposure likelihood, and other laboratory evidence in addition to the identification of the target either from colonies, blood culture whole blood or sputum specimens.

The JBAIDS Tularemia Detection Kit is intended for use by trained clinical laboratory personnel who have received specific training on the use of the JBAIDS Tularemia Detection Kit. The level of F. tularensis that would be present in blood or sputum from individuals with early systemic or pneumonic infection is unknown. Due to the difficulty in obtaining clinical specimens, this assay was not evaluated with blood or sputum from individuals presenting with signs and symptoms of tularemia who have subsequently developed pneumonic or typhoidal tularemia pneumonic or typhoidal tularemia.

The Joint Biological Agent Identification and Diagnostic System (JBAIDS) Tularemia Detection System is a fully integrated IVD system composed of the portable JBAIDS instrument, laptop computer and software and the JBAIDS Tularemia Detection Kit with one freeze-dried PCR assay for detection of Francisella tularensis DNA. The system has been validated using four different sample preparation kits for isolating DNA from whole blood (IT /-2-3TM Platinum Path and QFLOWana Sample Purification Kits), sputum (IT I-2-3TM Platinum Path and IT 1-2-3TM VIBE Sample Purification Kits), positive blood cultures (IT 1-2-3 TM SWIPE Sample Purification Kit), and plate cultures (IT /-2-3TM Platinum Path and IT 1-2-3TM SWIPE Sample Purification Kits). Use of the JBAIDS DNA Extraction Control Kit is also recommended.

Prior to testing, specimens are processed using BioFire Diagnostic's IT I-2-3 Sample Purification Kits. The resulting purified sample is added to Unknown and Inhibition Control vials, along with reconstitution buffer. Positive Control and Negative Control vials are prepared using reconstitution buffer and water. When F. tularensis DNA is present, a fragment of F. tularensis DNA is amplified. The amplicon is detected by fluorescence using a specific hydrolysis probe. Each probe is labeled on one end with a fluorescent reporter moiety (6-carboxyfluorescein (6-FAM)) and elsewhere with a quencher moiety (carboxy tetramethyIrhodamine (TAMRA)). When the probe is intact, the quencher absorbs the light emitted by the reporter moiety. During PCR, the probe hybridizes to the target sequence before the exonuclease activity of Taq polymerase hydrolyzes the probe, separating the fluorophore from the quencher and permitting detection of the fluorescent signal generated by the reporter. The fluorescent signal increases as additional templates are amplified and more probes are hydrolyzed.

JBAIDS Software analyzes the fluorescence amplification curves and reports results as positive, negative, uncertain or inhibited. A failure of the Positive or Negative Control will result in the entire run being called invalid. Retesting is required to resolve uncertain, invalid or inhibited results.

Here's a breakdown of the acceptance criteria and study information for the JBAIDS Tularemia Detection Kit, based on the provided text:

Acceptance Criteria and Device Performance

The study aimed to demonstrate that the modified JBAIDS Tularemia Detection Kit, when used with the IT 1-2-3™ Platinum Path Sample Purification Kit, performs equivalently to the predicate device (JBAIDS Tularemia Detection Kit) using its established sample purification methods. The acceptance criteria are implicitly defined by achieving high agreement (PPA and NPA) with the results obtained from the predicate methods for surrogate clinical specimens and confirming Limit of Detection (LoD).

Study Details

1. Sample Size and Data Provenance for Test Set:

   • Whole Blood Surrogate Specimens (Clinical Performance): 100 specimens (50 spiked with inactivated F. tularensis, 50 unspiked).
     • Data Provenance: Prospectively collected from febrile volunteers from November 2012 to April 2013. The country of origin is not specified, but the submission is to the U.S. FDA.
   • Sputum Surrogate Specimens (Clinical Performance): 100 specimens (50 spiked with inactivated F. tularensis, 50 unspiked).
     • Data Provenance: Frozen residual sputum specimens. The country of origin is not specified.
   • Limit of Detection (LoD) - Whole Blood: 20 independent whole blood specimens.
   • Limit of Detection (LoD) - Sputum: 20 independent sputum specimens.
   • Reproducibility (Whole Blood): A panel of 12 distinct samples, tested twice a day for 4 days at 3 sites (total 96 observations per category for positive/negative conclusions). Effectively, 4 medium positive, 4 low positive, and 4 negative samples were used.
   • Reproducibility (Sputum): A panel of 9 distinct samples, tested twice a day for 5 days at 3 sites (total 90 observations per category for positive/negative conclusions). Effectively, 3 medium positive, 3 low positive, and 3 negative samples were used.
   • Direct Culture Detection: 10 F. tularensis colonies and 10 non-F. tularensis colonies.

2. Number of Experts and Qualifications for Ground Truth:
   The document does not mention the use of human experts to establish ground truth for the test sets in the typical sense of clinical expert review. For the "clinical performance" studies, the ground truth was established by:

   • Spiking: Preparing specimens by spiking with inactivated F. tularensis at known concentrations (for positive samples) or leaving them unspiked (for negative samples).
   • Comparison to Predicate: The results from the existing, cleared sample purification methods (QFLOWdna for whole blood, VIBE for sputum) were considered the "correct result" a comparative effectiveness study, implying these methods served as the de facto reference standard for comparison with the new Platinum Path method.

3. Adjudication Method for Test Set:
   No formal adjudication method (e.g., 2+1, 3+1) is described for resolving discrepancies, as the "ground truth" was largely established by the known spiked status of the samples or by the result from the predicate device's processing method. The JBAIDS system itself reports "uncertain" results, which require retesting by the trained laboratory personnel.

4. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
   No MRMC comparative effectiveness study was done to assess how human readers improve with AI vs. without AI assistance. This device is an in vitro diagnostic (IVD) PCR test kit, not an AI-assisted diagnostic imaging or interpretative technology for human readers. However, a multicenter reproducibility study was performed with JBAIDS operators, effectively involving multiple readers/sites, but not in the context of comparing human performance with and without AI.

5. Standalone Performance (Algorithm Only):
   Yes, this study primarily assesses the standalone performance of the JBAIDS Tularemia Detection Kit (the algorithm/assay) when used with the new Platinum Path sample purification kit. The "JBAIDS operators were blinded to the analyte content of the samples," indicating a focus on the assay's performance independent of operator knowledge of the expected outcome. The device's software provides the final interpretation (positive, negative, uncertain, or inhibited).

6. Type of Ground Truth Used:

   • Surrogate Clinical Specimens: Ground truth was established by spiking known concentrations of inactivated F. tularensis into prospectively collected or residual human specimens. For comparative purposes, the results from the predicate device's purification method were also used as a reference for "correctness."
   • Limit of Detection (LoD): Ground truth was based on the known, spiked concentrations of F. tularensis.
   • Reproducibility: Ground truth was based on the known, spiked concentrations (medium positive, low positive) or unspiked status (negative).
   • Direct Culture Samples: Ground truth was based on the known identity of the colonies (F. tularensis or non-F. tularensis).

7. Sample Size for Training Set:
   The document does not specify a separate "training set" sample size. As this is a modification to an existing, cleared diagnostic kit (K072547), the current study focuses on validation of the modification (addition of a new sample purification kit). The development and initial validation of the JBAIDS Tularemia Detection Kit itself would have involved training data, but that information is not part of this 510(k) summary for the modification.

8. How Ground Truth for Training Set Was Established:
   Since no training set details are provided in this document, the method for establishing ground truth for any potential training set for the original device is not described here. Typically, for IVD assays, training data would involve well-characterized samples (e.g., clinical samples confirmed by culture or other gold-standard methods, or contrived samples with known analyte concentrations).

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The FilmArray Blood Culture Identification (BCID) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with the FilmArray Instrument. The FilmArray BCID Panel is capable of simultaneous detection and identification of multiple bacterial and yeast nucleic acids and select genetic determinants of antimicrobial resistance. The BCID assay is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system that demonstrates the presence of organisms as determined by Gram stain.

The following gram-positive bacteria, gram-negative bacteria, and yeast are identified using the FilmArray BCID Panel: Enterococci, Listeria monocytogenes, commonly encountered Staphylococci (including specific differentiation of Staphylococcus aureus), commonly encountered Streptococci (with specific differentiation of Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes), Acinetobacter baumannii, commonly encountered Enterobacteriaceae (including specific differentiation of the Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus, and Serratia marcescens), Haemophilus influenzae, Neisseria meningitidis (encapsulated), Pseudomonas aeruginosa, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, and Candida tropicalis.

The FilmArray BCID Panel also contains assays for the detection of genetic determinants of resistance to methicillin (mecA), vancomycin (vanA and vanB), and carbapenems (blaKPC) to aid in the identification of potentially antimicrobial resistant organisms in positive blood culture samples. The antimicrobial resistance gene detected may or may not be associated with the agent responsible for disease. Negative results for these select antimicrobial resistance gene assays do not indicate susceptibility, as multiple mechanisms of resistance to methicillin, vancomycin, and carbapenems exist.

FilmArray BCID is indicated as an aid in the diagnosis of specific agents of bacteremia and fungemia and results should be used in conjunction with other clinical and laboratory findings. Positive FilmArray results do not rule out co-infection with organisms not included in the FilmArray BCID Panel. FilmArray BCID is not intended to monitor treatment for bacteremia or fungemia.

Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing and epidemiological typing, to identify organisms in the blood culture that are not detected by the FilmArray BCID Panel, and for species determination of some Staphylococci, Enterococci, Streptococci, and Enterobacteriaceae that are not specifically identified by the FilmArray BCID Panel assays.

The FilmArray Blood Culture Identification (BCID) Panel is a multiplex nucleic acid test designed to be used with the FilmArray Instrument. The FilmArray BCID pouch contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex PCR with DNA melt analysis. The FilmArray Blood Culture Identification (BCID) Panel simultaneously tests a single positive blood culture sample to provide results for 24 different organisms and organism groups that cause bloodstream infections and three genetic markers that are known to confer antimicrobial resistance (see Table 1).

A test is initiated by loading Hydration Solution and a positive blood culture sample mixed with the provided Sample Buffer into the FilmArray BCID pouch. 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 lysis and standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, the FilmArray performs a nested multiplex PCR that is exceuted in two stages. During the first stage, the FilmArray performs a single, large volume, highly multiplexed PCR reaction which includes all primers of the outer primer sets. 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 200 stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 2" 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 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 and antimicrobial resistance gene on the panel.

Here's a breakdown of the acceptance criteria and study information for the FilmArray Blood Culture Identification (BCID) Panel, based on the provided text:

FilmArray Blood Culture Identification (BCID) Panel

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state quantitative acceptance criteria in a dedicated section. However, the "Clinical Performance" and "Reproducibility" sections present performance metrics (sensitivity, specificity, positive percent agreement, negative percent agreement, and percent agreement with expected results) that act as the de facto acceptance criteria. I'll present the overall clinical performance from Tables 6, 7, 8, 9, and 10 and the overall reproducibility from Tables 59 and 60.

Overall Clinical Performance (Aggregated from Prospective and Seeded Arms)

Overall Reproducibility (All Sites, Across All Analytes Tested)

2. Sample Sizes and Data Provenance for the Test Set:

• Total Test Set Sample Size: 2207 blood cultures
  • Prospective Arm: 1568 specimens
    • 67 specimens excluded (e.g., >8 hours past positivity, incomplete reference data, previous specimen from same subject).
    • Tested either fresh (821 specimens) or frozen (747 specimens).
  • Seeded Arm: 639 specimens
    • 77 cultures excluded (e.g., >8 hours past positivity, not positive by automated blood culture, contaminated).
    • Tested either fresh (419 specimens) or frozen (220 specimens).
• Data Provenance: The study was a "two-armed clinical study" conducted at eight U.S. clinical sites. This indicates the data is prospective for the clinical arm and retrospective/contrived for the seeded arm (as isolates were seeded into blood culture bottles).

3. Number of Experts and Qualifications for Ground Truth - Test Set:

The document does not explicitly state the number of experts used to establish the ground truth for the test set, nor their specific qualifications (e.g., "radiologist with 10 years of experience").

Instead, the ground truth for organism detection was established using "Standard manual and automated microbiological/biochemical identification methods." For Acinetobacter baumannii, this was supplemented with "16S PCR with bi-directional sequencing."

For antimicrobial resistance genes, the ground truth involved "PCR with bi-directional sequencing for specific resistance gene - direct from blood culture" or "PCR with bi-directional sequencing for specific resistance gene from - appropriate cultured isolates." Additionally, "Standard manual and automated phenotypic antimicrobial susceptibility testing of appropriate cultured isolates" was performed for informational purposes.

While these are standard laboratory methods typically performed by trained microbiologists or laboratory technicians, the number and specific qualifications of the experts overseeing or performing these reference methods are not detailed.

4. Adjudication Method for the Test Set:

The document does not explicitly describe an adjudication method (like 2+1 or 3+1) for discrepant results in the test set.

However, the detailed tables of results often include footnotes explaining discrepancies. For instance, for Acinetobacter baumannii, isolates misidentified by phenotypic methods were subjected to 16S PCR and bi-directional sequencing for definitive characterization. Similarly, for other organisms and resistance genes, bidirectional sequencing was used to investigate false positive and false negative results. This implies an investigative process to reconcile differences, rather than a formal, predefined expert adjudication panel for every case.

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

A Multi-Reader Multi-Case (MRMC) comparative effectiveness study was NOT done for this device. The study evaluated the standalone performance of the FilmArray BCID Panel against reference laboratory methods, not its impact on human reader performance or diagnostic accuracy with AI assistance.

6. Standalone Performance Study:

Yes, a standalone study was performed. The entire "Clinical Performance" section (Tables 6-10) reports the performance of the FilmArray BCID Panel as a standalone diagnostic device. The results (sensitivity, specificity, PPA, NPA) are presented for the algorithm/device only, without human-in-the-loop interaction, compared against established laboratory reference methods. The "Reproducibility" section also evaluates the device's technical consistency in a standalone capacity.

7. Type of Ground Truth Used:

The ground truth primarily used was:

• Expert Consensus/Reference Laboratory Methods:
  • Standard manual and automated microbiological/biochemical identification methods for all organism detections.
  • 16S PCR with bi-directional sequencing for A. baumannii speciation.
  • PCR with bi-directional sequencing for antimicrobial resistance gene detection (from blood culture or cultured isolates).
• Pathology: Not explicitly mentioned as a primary ground truth for organism identification in this context, which focuses on molecular/microbial identification.
• Outcomes Data: Not used as ground truth for diagnostic accuracy in this study.

8. Sample Size for the Training Set:

The document does not explicitly specify a sample size for a "training set." The studies primarily focus on clinical validation (prospective and seeded arms) and analytical validation (inclusivity, exclusivity, reproducibility). While the device's algorithm undoubtedly relies on an underlying model, information regarding its specific training data and size is not provided in this regulatory submission summary. The inclusivity studies involve testing a "diverse collection of 303 isolates," which could be considered part of the data informing the assay's design and optimization, but it's not explicitly labeled as a "training set" in the context of a machine learning model.

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

As the document does not explicitly identify a "training set" in the context of a machine learning model with corresponding ground truth establishment, this information is not provided. The inclusivity and exclusivity studies, which evaluate the assay's breadth and specificity, likely contribute to the "training" or development of the assay's detection capabilities. The ground truth for these analytical studies was established by known characteristics of the isolates (e.g., ATCC strains, clinical isolates with confirmed identity), and confirmed through standard microbiological identification and sequencing methods.

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FilmArray® Respiratory Panel (RP) is a multiplexed nucleic acid test intended for use with the FilmArray Instrument for the simultaneous qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals suspected of respiratory tract infections. The following organism types and subtypes are identified using the FilmArray RP: Adenovirus, Coronavirus 229E, Coronavirus HKU1, Coronavirus NL63, Coronavirus OC43, Human Metapneumovirus, Influenza A, Influenza A subtype H1, Influenza A subtype H3, Influenza A subtype H1-2009, Influenza B, Parainfluenza Virus 1, Parainfluenza Virus 2, Parainfluenza Virus 3, Parainfluenza Virus 4, Human Rhinovirus/Enterovirus, Respiratory Syncytial Virus, Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. The detection and identification of specific viral and bacterial nucleic acids from individuals exhibiting signs and symptoms of a respiratory infection aids in the diagnosis of respiratory infection if used in conjunction with other clinical and epidemiological information. The results of this test should not be used as the sole basis for diagnosis, treatment, or other management decisions. Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test or, lower respiratory tract infection that is not detected by a nasopharyngeal swab specimen. Positive results do not rule out co-infection with other organisms: the agent(s) detected by the Film Array RP may not be the definite cause of disease. Additional laboratory testing (e.g. bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible respiratory tract infection.

The FilmArray RP System is a multiplex nucleic acid test system composed of the FilmArray instrument, the FilmArray software (preinstalled on a laptop computer) and the FilmArray RP pouch. The FilmArray RP reagent pouch contains freeze-dried reagents to perform nucleic acid purification, reverse transcription, and nested, multiplex PCR with DNA melt analysis. The RP identifies 20 respiratory pathogens as shown in the following table.

Organisms Detected by the FilmArray Respiratory Panel

A test is initiated by loading Hydration Solution and an unprocessed patient nasopharyngeal swab (NPS) specimen (i.e., specimen mixed with Sample Buffer) into the FilmArray RP pouch. The pouch contains all of the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and specimen/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 reverse transcription reactions, the PCR reactions, and the melting curve analysis.

Nucleic acid extraction occurs within the FilmArray pouch using mechanical lysis and 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®Plus, BioFire Diagnostics). This second master mix 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 second stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 200 stage PCR, the array is interrogated by melting curve analysis for the detection of signature amplicons denoting the presence of specific viral or bacterial targets. A digital camera placed in front of the second stage PCR captures fluorescent images of the PCR reactions in real time.

The FilmArray software automatically interprets the results of each DNA melting 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.

Here's a summary of the acceptance criteria and the study details for the FilmArray® Respiratory Panel (RP) device, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance (Focusing on Adenovirus, as this is a modification)

The primary acceptance criteria for the modification appear to be improved detection of Adenovirus and equivalent performance for other analytes. Since specific numerical targets for "acceptance criteria" are not explicitly stated in percentages for agreement, the reported performance metrics (PPA and NPA) from the clinical comparison serve as the de facto demonstration of meeting the required performance for regulatory clearance.

2. Sample Size and Data Provenance for the Test Set

• Test Set Sample Size:

  • Clinical Comparison (Archived Specimens): 222 de-identified archived nasopharyngeal swab (NPS) specimens.
  • Contrived Clinical Specimens: 44 specimens (10 AdVC2, 10 AdVC6, 10 C. pneumoniae, and 14 M. pneumoniae).
  • Analytical Sensitivity (LoD): 20 replicates for each of four Adenovirus serotypes (AdVC1, AdVC2, AdVE4, AdVC6) at the estimated LoD.
  • Analytical Reactivity (Inclusivity): 22 Adenovirus serotypes (various species) were tested.
  • Analytical Specificity (Cross-reactivity/Exclusivity): High concentrations of 20 RP organisms and an exclusivity panel of 26 bacteria, 6 viruses, and 1 yeast.
  • Competitive Interference: 5 different virus combinations (co-infections), each tested with two viral components at varying concentrations.

• Data Provenance:

  • Archived Specimens: Retrospective, collected between 2008 and 2011 throughout the United States (at least 8 geographically distinct locations) and Scotland (at least 1 location).
  • Contrived Clinical Specimens: Spiked NPS specimens.
  • Analytical Studies (LoD, Reactivity, Specificity, Interference): Laboratory-generated data using quantified cultures and spiked samples.

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

The document does not specify the number or qualifications of experts used to establish the ground truth for the test set.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method for the test set results. The comparison is directly between the original FilmArray RP and the modified FilmArray RP. For discrepant results (e.g., in the archived specimen study), bidirectional sequence analysis was used for confirmation, which serves as a form of "ground truth" establishment for those specific cases, but not a general adjudication process between human readers.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted. This study focuses on "algorithm only" or "device only" performance in comparison to a previous version of the device, not on human reader performance with or without AI assistance.

6. Standalone (Algorithm Only) Performance Study

Yes, a standalone performance study was done. The entire submission details the performance of the modified FilmArray RP (an algorithm-driven diagnostic device) itself, comparing its output to that of the original FilmArray RP and, in discrepant cases or for analytical metrics, to direct molecular confirmation (e.g., sequencing) or known spiked concentrations. There is no human-in-the-loop component described in the performance evaluation.

7. Type of Ground Truth Used

The ground truth for the test samples was established using a combination of methods:

• Original FilmArray RP Results: Performance of the modified device was primarily compared against the results of the previously cleared original FilmArray RP.
• Bidirectional Sequence Analysis: Used to confirm discrepant Adenovirus detections in archived specimens and contrived specimens. Also used to categorize Adenovirus serotypes. This is a highly specific molecular method.
• Known Spiked Concentrations: For contrived specimens and analytical studies (Limit of Detection, Analytical Reactivity, Analytical Specificity, Competitive Interference), the ground truth was the known presence and concentration of the spiked organisms.

8. Sample Size for the Training Set

The document does not specify a sample size for a training set. This is typical for in-vitro diagnostic devices where validation might focus more on analytical performance and clinical concordance rather than a separate "training" of a machine learning algorithm in the same sense as an AI/ML product for image analysis, for example. The "training" of such a system would likely involve extensive internal development and optimization based on known strains and clinical samples, but these are not typically referred to as a "training set" in the context of regulatory submissions unless they are explicitly for an adaptive AI algorithm.

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

As no specific "training set" is mentioned in the context of the regulatory submission, the method for establishing its ground truth is not described. The device's underlying technology relies on primer design and DNA melt analysis, which are developed and optimized through laboratory experiments rather than a distinct "training set" in the AI/ML sense.

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