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The BioFire® FilmArray® Pneumonia Panel plus (BioFire Pneumonia Panel plus) is a multiplexed nucleic acid test intended for use with BioFire® FilmArray® 2.0 (BioFire® FilmArray® Torch (BioFire Torch) systems for the simultaneous detection and identification of nucleic acids from Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL or mini-BAL) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.

Testing with BioFire Pneumonia Panel plus should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspected MERS-CoV specimens. This includes: clinical signs and symptoms associated with MERS-CoV infection, contact with a probable or confirmed MERS-CoV case, history of travel to geographic locations where MERS-CoV cases were detected, or other epidemiological links for which MERS-CoV testing may be indicated.

The following bacteria are reported semi-quantitatively with bins representing approximately 10^4, 10^5, or ≥10^7 genomic copies of bacterial nucleic acid per milliliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL

• · Acinetobacter calcoaceticus-baumannii complex
• · Enterobacter cloacae complex
• · Escherichia coli
• · Haemophilus influenza
• · Klebsiella aerogenes
• · Klebsiella oxytoca
• · Klebsiella pneumoniae group
• · Moraxella catarrhalis
• · Proteus spp.
• · Pseudomonas aeruginosa
• · Serratia marcescens
• · Staphylococcus aureus
• · Streptococcus agalactiae
• · Streptococcus pneumoniae
• · Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:

Atypical Bacteria

• · Chlamydia pneumoniae
• · Legionella pneumophila
• · Mycoplasma pneumoniae

Viruses
· Middle East respiratory syndrome coronavirus (MERS-CoV)

• · Adenovirus
• · Coronavirus
• · Human metapneumovirus
• · Human rhinovirus/enterovirus
• · Influenza A virus
• · Influenza B virus
• · Parainfluenza virus
• · Respiratory syncytial virus

Antimicrobial Resistance Genes

• · CTX-M
• · IMP
• · КРС
• · NDM
• · OXA-48-like
• · VIM
• · mecA/C and MREJ (MRSA)

The detection and identification of specific viral and bacterial nucleic acids from MERS-CoV and other respiratory pathogens, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from individuals meeting MERS-CoV clinical and/or epidemiological criteria aids in the differential diagnosis of MERS-CoV infection, if used in conjunction with other clinical and epidemiological information in accordance with the guidelines provided by the appropriate public health authorities.

BioFire Pneumonia Panel plus MERS-CoV positive results are for the identification of MERS-CoV. The definitive identification of MERS-CoV requires additional testing and confirmation procedures in consultation with the appropriate public health authorities (e.g., local or state public health departments, etc.) for whom reporting is necessary. The diagnosis of MERS-CoV infection must be made based on history, signs, symptoms, exposure likelihood, and other laboratory evidence in addition to the identification of MERS-CoV.

BioFire Pneumonia Panel plus MERS-CoV negative results, even in the context of a BioFire Pneumonia Panel plus positive result for one or more of the common respiratory pathogens, do not preclude MERS-CoV infection and should not be used as the sole basis for patient management decisions. The levels of MERS-CoV that would be present in sputum-like or BAL-like specimens from individuals with early infection and from asymptomatic MERS-CoV cariers are not well understood. A negative BioFire Pneumonia Panel plus MERS-CoV result in an asymptomatic individual does not rule out the possibility of future illness and does not demonstrate that the individual is not infectious.

Viral culture should not be attempted on specimens with positive BioFire Pneumonia Panel plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.

Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 10^4 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the BioFire Pneumonia Panel plus 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 lower respiratory tract infection.

Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative Bin (copies/mL) results generated by the BioFire Pneumonia Panel plus are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFU/ mL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative Bin (copies/mL) for clinical management.

The antimicrobial resistance gene detected may or may not be associated with the agent(s) responsible for disease. Negative results for these antimicrobial resistance gene assays do not indicate susceptibility to corresponding classes of antimicrobials, as multiple mechanisms of antimicrobial resistance exist.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and BioFire Pneumonia Panel plus results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance.

Due to the genetic similarity between human rhinovirus and enterovirus, the test cannot reliably differentiate them. A positive Rhinovirus/Enterovirus result should be followed up using an alternate method (e.g., cell culture or sequence analysis) if differentiation is required.

Culture is required to identify pathogens not detected by the BioFire Pneumonia Panel plus, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 10°4 copies/mL bin if desired, and for antimicrobial susceptibility testing.

The FilmArray Pneumonia Panel plus is designed to simultaneously identify MERS-CoV and 26 potential pathogens of lower respiratory tract infection (LRTI) and associated antimicrobial resistance (AMR) genes from a sputum-like (induced and expectorated sputum as well as endotracheal aspirate, ETA) or bronchoalveolar lavage (BAL)-like (BAL and mini-BAL) specimens obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria in a time (~1 hour). The FilmArray Pneumonia Panel plus is compatible with BioFire Diagnostics' (BioFire) PCR-based in vitro diagnostic BioFire FilmArray 2.0 (K143178) and BioFire FilmArray Torch (K160068) systems for infectious disease testing. A specific software module (i.e., FilmArray Pneumonia Panel plus pouch module) is used to perform FilmArray Pneumonia Panel plus testing on these systems.

A test is initiated by loading Hydration Solution into one port of the FilmArrav pouch and a soutumlike or BAL-like sample mixed with the provided Sample Buffer into the port of the FilmArray Pneumonia Panel plus pouch and placing it in a FilmArray instrument. The pouch contains all the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and Sample/Buffer Mix rehydrates the reagents. After the pouch is prepared, the FilmArray Software quides 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 lvsis 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 Plus, BioFire Diagnostics). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the end of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the 2nd stage PCR captures fluorescent images of the PCR reactions and software interprets the data.

The 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 is a summary of a Special 510(k) submission for the BioFire FilmArray Pneumonia Panel plus. The purpose of this submission is solely to modify the labeling of the device to include new limitations regarding the Adenovirus2 assay's performance closer to its expiration date.

Therefore, the document does not describe a new study to prove device performance against acceptance criteria. Instead, it refers to a problem identified through stability studies and a voluntary recall. The premise of this 510(k) submission is that because there are no changes to the actual device, its fundamental scientific technology, performance, and risk are unchanged from the legally marketed predicate device (K181324).

The acceptance criteria table below is inferred from the identified issue and the proposed label modifications, not from a performance study demonstrating device capabilities.

Acceptance Criteria and Reported Device Performance

Study Details (Based on the information provided)

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

   • The document does not explicitly state the sample size of the test set used in the stability study that identified the Adenovirus C issue.
   • The data provenance is from stability studies conducted by BioFire Diagnostics, LLC. It is retrospective in the sense that the issue was discovered after initial marketing and through ongoing stability monitoring of manufactured product.

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

   • This information is not provided as the document describes a stability study related to device shelf-life rather than a diagnostic performance study against a clinical ground truth. The "ground truth" here would have been the presence/absence and concentration of adenovirus species C in the stability samples, likely confirmed by a reference method in a laboratory setting. Details on experts or their qualifications are not given.

3. Adjudication method for the test set:

   • This information is not provided. Given it's a stability study on a diagnostic assay, adjudication in the context of expert consensus on clinical cases is not directly applicable. The determination of "false negative" would have been based on comparison to expected results or a reference method.

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

   • No, an MRMC comparative effectiveness study was not done. This device is a multiplexed nucleic acid test (an in vitro diagnostic device), not an imaging AI device that involves human readers.

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

   • The FilmArray Pneumonia Panel plus is an automated diagnostic assay. Its performance (detection of nucleic acids) is inherently "standalone" in the sense that the instrument and software interpret the results without human interpretation of raw data. The stability study assessed this standalone performance.

6. The type of ground truth used:

   • For the stability studies that identified the issue, the ground truth was likely analytical truth (known presence, absence, and concentration of specific analytes like Adenovirus species C) in manufactured control samples or spiked specimens. This is standard for stability testing of IVD assays.

7. The sample size for the training set:

   • This document describes a modification to labeling based on post-market stability findings, not a de novo development or training of an algorithm. Therefore, information about a "training set" is not applicable and not provided.

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

   • As there is no mention of a training set for an algorithm, this information is not applicable.

Ask a specific question about this device

The FilmArray® Pneumonia Panel is a multiplexed nucleic acid test intended for use with FilmArray® 2.0 or FilmArray® Torch systems for the simultaneous detection of multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL or mini-BAL) obtained from individuals suspected of lower respiratory tract infection.

The following bacteria are reported semi-quantitatively with bins representing approximately 10^4, 10^5 genomic copies of bacterial nucleic acid per milliliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL
-Acinetobacter calcoaceticus-baumannii complex

• -Enterobacter cloacae complex
• -Escherichia coli
• -Haemophilus influenzae
• -Klebsiella aerogenes
• -Klebsiella oxytoca
• -Klebsiella pneumoniae group
• -Moraxella catarrhalis
• -Proteus spp.
• -Pseudomonas aeruginosa
• -Serratia marcescens
• -Staphylococcus aureus
• -Streptococcus agalactiae
• -Streptococcus pneumoniae
• -Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively: Atypical Bacteria -Chlamydia pneumoniae -Legionella pneumophila

• -Mycoplasma pneumoniae
  Viruses -Adenovirus

• -Coronavirus

• -Human Metapneumovirus

• -Human Rhinovirus/Enterovirus

• -Influenza A

• -Influenza B

• -Parainfluenza Virus

• -Respiratory Syncytial Virus

Antimicrobial Resistance Genes -CTX-M -IMP -KPC -NDM -OXA-48-like -VIM -mecA/C and MREJ

The detection and identification of specific viral and bacterial nucleic acids, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from individuals exhibiting signs and/or symptoms of a respiratory infection, aids in the diagnosis of lower respiratory infection with other clinical and epidemiological information. The results of this test should not be used as for diagnosis, treatment, or other patient 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, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 10^4 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the FilmArray Pneumonia Panel 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 lower respiratory tract infection.

Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative Bin (copies/mL) results generated by the FilmArray Pneumonia Panel are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFUmL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative Bin (copies/mL) for clinical management.

The antimicrobial resistance gene detected may or may not be associated with the agent(s) responsible for disease. Negative results for these antimicrobial resistance gene assays do not indicate susceptibility to corresponding classes of antimicrobials, as multiple mechanisms of antimicrobial resistance exist.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and FilmArray Pneumonia Panel results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance.

Due to the genetic similarity between human rhinovirus and enterovirus, the test cannot reliably differentiate them. A positive Rhinovirus Enterovirus result should be followed up using an alternate method (e.g., cell culture or sequence analysis) if differentiation is required.

Culture is required to identify pathogens not detected by the FilmArray Pneumonia Panel, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 10^4 copies/mL bin if desired, and for antimicrobial susceptibility testing.

The FilmArray Pneumonia (PN) Panel is designed to simultaneously identify 26 potential pathogens of lower respiratory tract infection (LRTI) and associated antimicrobial resistance (AMR) genes from a sputum-like (induced and expectorated sputum as well as endotracheal aspirate, ETA) or bronchoalveolar lavage (BAL)-like (BAL and mini-BAL) specimens obtained from individuals with signs and/or symptoms of lower respiratory tract infection in a time (~1 hour) that allows the test results to be used in determining appropriate patient treatment and management. FilmArray PN Panel is compatible with BioFire Diagnostics' (BioFire) PCR-based in vitro diagnostic FilmArray 2.0 (K143178) and FilmArray Torch (K160068) systems for infectious disease testing. A specific software module (i.e. FilmArray PN Panel pouch module) is used to perform FilmArray PN Panel testing on these systems.

Bacteria - Quantitative Results: Acinetobacter calcoaceticus-baumannii complex, Enterobacter cloacae complex, Escherichia coli, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae group, Moraxella catarrhalis, Proteus spp., Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes
Bacteria (Atypical) - Qualitative Results: Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae
Antimicrobial Resistance Genes: blaCTX-M (Extended spectrum beta-lactamase (ESBL)), blaIMP (Carbapenem resistance), blaKPC (Carbapenem resistance), mecA/mecC and MREJ (Methicillin resistance), blaNDM (Carbapenem resistance), blaOXA48-like (Carbapenem resistance), blaVIM (Carbapenem resistance)
Viruses: Adenovirus, Coronavirus, Human Metapneumovirus, Human Rhinovirus/Enterovirus, Influenza A, Influenza B, Parainfluenza Virus, Respiratory Syncytial Virus

A test is initiated by loading Hydration Solution into one port of the FilmArray pouch and a sputum-like or BAL-like sample mixed with the provided Sample Buffer into the other port of the FilmArray PN Panel pouch and placing it in a 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 lysis 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® Plus, BioFire Diagnostics). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, is performed in single plex fashion in each well of the array. At the conclusion of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the 2nd stage PCR captures fluorescent images of the PCR reactions and software interprets the data.

The 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.

A feature of the FilmArray PN Panel is the reporting of organism abundance for common bacteria in discrete bins representing 10^4, 10^5, 10^6, and >10^7 genomic copies/mL. The panel accomplishes this by comparing the amplification of the bacterial assays with that of a Quantified Standard Material (QSM) present in the pouch.

Here's an analysis of the provided text regarding the FilmArray Pneumonia Panel, focusing on the acceptance criteria and study details. It's important to note that this document is a Special 510(k) Summary for a labeling modification related to a previously cleared device. Therefore, it primarily discusses the change and its impact on the device's labeling, rather than presenting a comprehensive de novo validation study.

Key takeaway: The document describes a labeling modification due to a stability issue with the Adenovirus2 assay (specifically for Adenovirus C) within 6 months of the pouch expiration date. It does not provide details of an initial, full validation study with acceptance criteria and reported performance for all analytes, as that would have been part of the original K180966 submission. The information below is extracted from what's available in this specific document regarding the impact of the noted issue.

1. Table of Acceptance Criteria and Reported Device Performance

This document does not present a table of general acceptance criteria and reported performance for all analytes of the FilmArray Pneumonia Panel since it's a labeling modification submission. The focus is specifically on the change in performance for Adenovirus C due to stability.

The "acceptance criteria" discussed here are essentially the observed degradation in sensitivity and the resulting limitation on the use of the device for Adenovirus C detection under specific conditions.

Note: The original acceptance criteria for the initial clearance (K180966) would have included specific sensitivity (Limit of Detection - LoD) and specificity targets, which are not detailed in this specific document.

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

The document does not specify a "test set" in the context of a de novo validation study. Instead, it refers to a stability study where the issue with Adenovirus2 assay's performance was discovered.

• Sample Size for Test Set: Not explicitly stated as a separate test set. The issue was identified during a stability study of the device pouches.
• Data Provenance: The issue was identified through internal stability study results conducted by BioFire Diagnostics, LLC. No country of origin for clinical samples is mentioned, as the data appears to be from analytical testing (stability of laboratory-manufactured pouches). The study type is retrospective in the sense that previously manufactured pouches were being tested for stability over time.

3. Number of Experts Used to Establish Ground Truth and Qualifications

Not applicable. This document does not describe a study involving expert consensus to establish ground truth for clinical cases. The issue identified was an analytical performance degradation discovered during internal stability testing.

4. Adjudication Method

Not applicable. This document is not describing a study that required adjudication of complex clinical cases or image interpretations. The "adjudication" was the internal assessment of stability study results and the determination that the performance characteristic (LoD for Adenovirus C) had degraded under specific conditions.

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

Not applicable. The device is an in vitro diagnostic (IVD) based on molecular detection, not one requiring human interpretation of results. Therefore, an MRMC study is not relevant to this type of device.

6. Standalone (Algorithm Only) Performance

Yes, the information presented relates to standalone performance of the device. The reported impairment in LoD for Adenovirus C was determined through analytical testing of the device itself (the assay in the pouch) under specific storage conditions. There is no human-in-the-loop component in the detection process of the FilmArray Pneumonia Panel.

7. Type of Ground Truth Used

The ground truth used for identifying this issue was analytical performance data (stability study results) and the degradation of the Limit of Detection (LoD) for Adenovirus C, which represents a quantifiable measure of the assay's sensitivity. This is akin to a "spike-in" experiment or testing known positive controls at various concentrations across the shelf-life of the product.

8. Sample Size for the Training Set

Not applicable. This document describes a stability issue with an already-cleared device and a subsequent labeling modification. It does not refer to a "training set" in the context of an algorithm or AI development. The device pre-dates common AI/ML nomenclature in medical device submissions for IVDs.

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

Not applicable, as there is no "training set" described in this document.

Ask a specific question about this device

The FilmArray® Pneumonia Panel plus is a multiplexed nucleic acid test intended for use with FilmArray® 2.0, or FilmArray® Torch systems for the simultaneous detection of nucleic acids from Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes. in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.

Testing with FilmArray Pneumonia Panel plus should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspecimens. This includes: clinical signs and symptoms associated with MERS-CoV infection, contact with a probable or confirmed MERS-CoV case, history of travel to geographic locations where MERS-CoV cases were detected, or other epidemiological links for which MERS-CoV testing may be indicated.

The following bacteria are reported semi-quantitatively with bins representing approximately 10^4, 10^5, 10^6, or ≥10^7 genomic copies of bacterial nucleic acid per milliliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL

• Acinetobacter calcoaceticus-baumannii complex
• Enterobacter cloacae complex
• · Escherichia coli
• · Haemophilus influenza
• Klebsiella aerogenes
• · Klebsiella oxytoca
• · Klebsiella pneumoniae group
• Moraxella catarrhalis
• · Proteus spp.
• Pseudomonas aeruginosa
• · Serratia marcescens
• Staphylococcus aureus
• Streptococcus agalactiae
• Streptococcus pneumoniae
• · Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:

Atypical Bacteria

• Chlamydia pneumoniae
• · Legionella pneumophila
• Mycoplasma pneumoniae

Viruses

• · Adenovirus
• · Coronavirus
• Human Metapneumovirus
• · Human Rhinovirus/Enterovirus
• · Influenza A
• · Influenza B
• · Parainfluenza Virus
• · Respiratory Syncytial Virus

Antimicrobial Resistance Genes

• · CTX-M
• IMP
• КРС
• NDM
• OXA-48-like
• VIM
• · mecA/C and MREJ

The detection and identification of specific viral and bacterial nucleic acids from MERS-CoV and other respiratory pathogens, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from individuals meeting MERS-CoV clinical and/or epidemiological criteria aids in the differential diagnosis of MERS-CoV infection, if used in conjunction with other clinical and epidemiological information in accordance with the guidelines provided by the appropriate public health authorities.

FilmArray Pneumonia Panel plus MERS-CoV positive results are for the presumptive identification of MERS-CoV. The definitive identification of MERS-CoV requires additional testing and confirmation procedures in consultation with the appropriate public health authorities (e.g., local or state public health departments, etc.) for whom reporting is necessary. The diagnosis of MERS-CoV infection must be made based on history, signs, symptoms, exposure likelihood, and other laboratory evidence in addition to the identification of MERS-CoV.

FilmArray Pneumonia Panel plus MERS-CoV negative results, even in the context of a FilmArray Pneumonia Panel plus positive result for one or more of the common respiratory pathogens, do not preclude MERS-CoV infection and should not be used as the sole basis for patient management decisions. The levels of MERS-CoV that would be present in sputum-like or BAL-like specimens from individuals with early infection and from asymptomatic MERS-CoV carriers are not well understood. A negative FilmArray Pneumonia Panel plus MERS-CoV result in an asymptomatic individual does not rule out the possibility of future illness and does not demonstrate that the individual is not infectious.

Viral culture should not be attempted on specimens with positive FilmArray Pneumonia Panel plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.

Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 10^4 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the FilmArray Pneumonia Panel plus 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 lower respiratory tract infection.

Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative Bin (copies/mL) results generated by the FilmArray Pneumonia Panel plus are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFUmL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative Bin (copies/mL) for clinical management.

The antimicrobial resistance gene detected may or may not be associated with the agent(s) responsible for disease. Negative results for these antimicrobial resistance gene assays do not indicate susceptibility to corresponding classes of antimicrobials, as multiple mechanisms of antimicrobial resistance exist.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and FilmArray Pneumonia Panel plus results should be used in conjunction with culture results for deterial susceptibility or resistance.

Due to the genetic similarity between human rhinovirus and enterovirus, the test cannot reliably differentiate them. A positive Rhinovirus/Enterovirus result should be followed up using an alternate method (e.g., cell culture or sequence analysis) if differentiation is required.

Culture is required to identify pathogens not detected by the FilmArray Panel plus, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 10^4 copies/mL bin if desired, and for antimicrobial susceptibility testing.

The FilmArray Pneumonia Panel plus is designed to simultaneously identify Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and 26 other potential pathogens of lower respiratory tract infection (LRTI) and seven associated antimicrobial resistance (AMR) genes from a sputum-like (induced and expectorated sputum as well as endotracheal aspirate, ETA) or bronchoalveolar lavage (BAL)-like (BAL and mini-BAL) specimens obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria in a time (~1 hour) that allows the test results to be used in determining appropriate patient treatment and management.

The FilmArray Pneumonia Panel plus is compatible with BioFire's PCR-based in vitro diagnostic FilmArray, FilmArray 2.0, and FilmArray Torch systems for infectious disease testing. A specific software module (i.e. FilmArray Pneumonia Panel pouch module) is used to perform FilmArray Pneumonia Panel testing on these systems.

A test is initiated by loading Hydration Solution into one port of the FilmArray pouch and a sputum-like or BAL-like sample mixed with the provided Sample Buffer into the other port of the FilmArray Pneumonia Panel plus pouch and placing it in a 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 through the steps of placing the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.

The FilmArray instruments contain coordinated systems 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, electronicallycontrolled 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, 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). 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 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 on the panel.

A new feature of the FilmArray Pneumonia Panel plus is the reporting of organism abundance for common bacteria in discrete bins representing 10^4, 10^5, 10^6, and ≥10^7 genomic copies/mL. The panel accomplishes this by comparing the amplification of the bacterial assays with that of a Quantified Standard Material (QSM) present in the pouch.

The provided text describes the performance study for the FilmArray Pneumonia Panel plus, a multiplex nucleic acid test. Below is a structured summary addressing the requested points.

Acceptance Criteria and Device Performance Study

The acceptance criteria for the FilmArray Pneumonia Panel plus are indirectly demonstrated through the clinical and analytical performance studies, showing the device's ability to accurately detect a wide range of respiratory pathogens and antimicrobial resistance genes in specific clinical samples. The study proves the device meets these criteria through robust empirical testing and in silico analyses.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a go/no-go format for each analyte, but rather presents the performance (Sensitivity/PPA and Specificity/NPA) from the clinical study as evidence of meeting regulatory requirements. The implicit acceptance criteria would likely be high agreement percentages and confidence intervals.

Table 1: Summary of Reported Device Performance (Clinical Study - BAL Specimens)

Note: Performance for Sputum specimens presented in Table 5.
Note: PPA = Positive Percent Agreement (Sensitivity), NPA = Negative Percent Agreement (Specificity).
Note: '-' indicates TP/(TP+FN) or TN/(TN+FP) was 0/0, thus percentage and CI could not be calculated.

2. Sample Sizes and Data Provenance

• Test Set (Clinical Performance):
  • Sample Size: 846 BAL specimens (including mini-BAL) and 836 sputum specimens (including ETA).
  • Data Provenance: Multi-center study conducted at eight geographically distinct U.S. study sites. The study was prospective in nature, collecting specimens from October 2016 to July 2017. Additionally, archived retrospective specimens were used for low-prevalence analytes, including 8 BAL and 10 sputum specimens from a 2015 MERS-CoV outbreak in South Korea, and 171 archived specimens from external laboratories (139 BAL, 14 sputum, and negative controls). Contrived specimens were also used (1225 total, N=625 BAL, N=600 sputum for main contrived study; N=60 BAL, N=60 sputum for polymicrobial contrived study).

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the exact number and qualifications of experts establishing the ground truth for the test set. Instead, it details the reference methods used for ground truth:

• Bacterial Analytes: Quantitative reference culture (qRefCx) with a threshold of ≥ 3162 (10^3.5) CFU/mL. Discrepancies were further investigated using single PCR assays followed by quantitative molecular assay including sequencing (qMol), and additional molecular assays followed by sequence analysis where needed.
• Atypical Bacteria and Viruses: Two conventional PCR assays followed by bidirectional sequencing. A specimen was considered positive if bidirectional sequencing data met predefined quality acceptance criteria and matched organism-specific sequences in the NCBI GenBank database.
• AMR Genes: Single PCR assay followed by sequencing (qMol) from the specimen, combined with phenotypic AST (antimicrobial susceptibility testing) via qRefCx performed in conjunction with current CLSI guidelines for correlation.
• MERS-CoV: For clinical specimens, it was assumed they were negative as the virus was not circulating in the US during enrollment. For archived specimens, previous laboratory results (from South Korea during the 2015 outbreak) served as ground truth.

4. Adjudication Method for the Test Set

The adjudication method for discrepant results between the FilmArray Pneumonia Panel plus and the primary comparator method varied:

• For bacterial analytes, discrepancies were first examined to see if the qRefCx or FilmArray observed the analyte but below the detection threshold. If unresolved, qMol testing results were considered. If still unresolved, multiple additional molecular assays followed by sequence analysis were used.
• For other analytes (atypical bacteria, viruses, AMR genes), molecular comparator results (two conventional PCR assays followed by bidirectional sequencing) were used. If the two assays agreed, that was the ground truth. If they disagreed, additional molecular assays followed by sequence analysis were performed. The results of "SOC testing" (Standard of Care) were also considered.

This suggests an algorithm-mediated adjudication with expert review for difficult cases (discrepancies), rather than a fixed "2+1" or "3+1" expert consensus model initially. The ground truth itself often involved molecular methods, which are considered highly accurate for nucleic acid detection.

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

There is no MRMC comparative effectiveness study described in the provided text. The study focuses on comparing the device's performance against reference laboratory methods (molecular and culture-based) for direct detection, not on evaluating how human readers' performance might improve with or without AI assistance. The device is an in vitro diagnostic (IVD) test, not an AI-assisted diagnostic imaging tool.

6. Standalone (Algorithm Only) Performance

The entire performance study described is essentially a standalone (algorithm only without human-in-the-loop) performance evaluation for the FilmArray Pneumonia Panel plus. The results for sensitivity/PPA and specificity/NPA directly report the device's accuracy in detecting various pathogens and AMR genes compared to established reference methods.

7. Type of Ground Truth Used

The ground truth used varied by analyte:

• Bacterial Analytes: Quantitative Reference Culture (qRefCx) for primary evaluation. Discrepancies were resolved using quantitative molecular assays (qMol) and subsequent sequencing/additional molecular assays.
• Atypical Bacteria, Viruses (excluding MERS-CoV in US clinical samples): Two conventional PCR assays followed by bidirectional sequencing. Discrepancies resolved with additional molecular assays and sequencing.
• MERS-CoV (archived specimens): Previous laboratory results (implicitly molecular/viral culture confirmation) from the outbreak.
• Antimicrobial Resistance Genes: Single PCR assay followed by sequencing (qMol) directly from the specimen, and correlation with phenotypic AST from cultured isolates.

Therefore, the ground truth is a combination of expert-interpreted molecular data (PCR/sequencing), quantitative culture, and phenotypic AST, with further discrepancy resolution protocols.

8. Sample Size for the Training Set

The document focuses solely on the performance evaluation of the FilmArray Pneumonia Panel plus device. It states that the device is "designed to simultaneously identify Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and 26 other potential pathogens of lower respiratory tract infection (LRTI) and seven associated antimicrobial resistance (AMR) genes." It describes analytical and clinical validation studies but does not provide information on a "training set" sample size for an AI/ML model, as this is a molecular diagnostic device not explicitly using an AI/ML component in its core diagnostic algorithm. The phrase "FilmArray Software automatically interprets the results" implies a deterministic algorithm, not a trainable machine learning model.

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

Since no training set for an AI/ML model is mentioned, there is no information provided on how its ground truth was established. The document describes the validation/test set ground truth as outlined in point 7.

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The FilmArray® Pneumonia Panel is a multiplexed nucleic acid test intended for use with FilmArray® 2.0, or FilmArray® Torch systems for the simultaneous detection of multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL or mini-BAL) obtained from individuals suspected of lower respiratory tract infection.

The following bacteria are reported semi-quantitatively with bins representing approximately 10°4 10°5, 10°6, or ≥10°7 genomic copies of bacterial nucleic acid per milliliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:

Bacteria reported with bins of 10^4 10^5, 10^6, or ≥10^7 copies/mL

• Acinetobacter calcoaceticus-baumannii complex
• Enterobacter cloacae complex
• · Escherichia coli
• Haemophilus influenzae
• Klebsiella aerogenes
• Klebsiella oxytoca
• Klebsiella pneumoniae group
• Moraxella catarrhalis
• · Proteus spp.
• Pseudomonas aeruginosa
• Serratia marcescens
• Staphylococcus aureus
• Streptococcus agalactiae
• Streptococcus pneumoniae
• Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:

Atypical Bacteria

• Chlamydia pneumoniae
• Legionella pneumophila
• Mycoplasma pneumoniae

Viruses

• Adenovirus
• Coronavirus
• Human Metapneumovirus
• · Human Rhinovirus/Enterovirus
• · Influenza A
• · Influenza B
• Parainfluenza Virus
• Respiratory Syncytial Virus

Antimicrobial Resistance Genes

• CTX-M
• IMP
• КРС
• NDM
• · OXA-48-like
• VIM
• · mecA/C and MREJ

The detection and identification of specific viral and bacterial nucleic acids, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from individuals exhibiting signs and/or symptoms of a respiratory infection, aids in the diagnosis of lower respiratory infection if used in conjunction with other clinical and epidemiological information. The results of this test should not be used as for diagnosis, treatment, or other patient 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, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 10°4 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms: the agent(s) detected by the Film Array Pneumonia Panel 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 lower respiratory tract infection.

Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative bin (copies/mL) results generated by the FilmArray Pneumonia Panel are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFU/mL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative bin (copies/mL) for clinical management.

The antimicrobial resistance gene detected may or may not be associated with the agent(s) responsible for disease. Negative results for these antimicrobial resistance gene assays do not indicate susceptibility to corresponding classes of antimicrobials, as multiple mechanisms of antimicrobial resistance exist.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and FilmArray Pneumonia Panel results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance.

Due to the genetic similarity between human rhinovirus and enterovirus, the test cannot reliably differentiate them. A positive Rhinovirus/Enterovirus result should be followed up using an alternate method (e.g., cell culture or sequence analysis) if differentiation is required.

Culture is required to identify pathogens not detected by the FilmArray Pneumonia Panel, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 10°4 copies/mL bin if desired, and for antimicrobial susceptibility testing.

The FilmArray Pneumonia Panel is designed to simultaneously identify 26 potential pathogens of lower respiratory tract infection (LRTI) and associated antimicrobial resistance (AMR) genes from a sputumlike (induced and expectorated sputum as well as endotracheal aspirate, ETA) or bronchoalveolar lavage (BAL)-like (BAL and mini-BAL) specimens obtained from individuals with signs and/or symptoms of lower respiratory tract infection in a time (~1 hour) that allows the test results to be used in determining appropriate patient treatment and management. FilmArray Pneumonia Panel is compatible with BioFire Diagnostics' (BioFire) PCR-based in vitro diagnostic FilmArray 2.0, and FilmArray Torch systems for infectious disease testing. A specific software module (i.e. FilmArray Pneumonia Panel pouch module) is used to perform FilmArray Pneumonia Panel testing on these systems.

A test is initiated by loading Hydration Solution into one port of the FilmArray pouch and a sputum-like or BAL-like sample mixed with the provided Sample Buffer into the other port of the FilmArray Pneumonia Panel pouch and placing it in a 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 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 lysis 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 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). 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 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 on the panel.

Acceptance Criteria and Device Performance for BioFire FilmArray Pneumonia Panel (K180966)

The BioFire FilmArray Pneumonia Panel is a multiplexed nucleic acid test intended for the simultaneous detection of multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in respiratory specimens to aid in the diagnosis of lower respiratory tract infection.

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state pre-defined acceptance criteria (e.g., "sensitivity must be >X%"). Instead, the performance is reported as the observed sensitivity/PPA and specificity/NPA from clinical and analytical studies, which are then used to demonstrate substantial equivalence to the predicate device.

Below is a summary of the reported performance for key analytes in the clinical study for BAL specimens, which served as a primary evaluation for the device's effectiveness. A similar detailed table for sputum is also available in the source document.

Summary of FilmArray Pneumonia Panel Clinical Performance (BAL Specimens)

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

Clinical Study (Test Set):

• Total specimens acquired: 904 residual BAL (821 BAL and 83 mini-BAL) and 925 residual sputum (478 sputum and 447 ETA).
• Final data set for analysis: 846 BAL and 836 sputum specimens after exclusions.
• Data provenance: Multi-center study conducted at eight geographically distinct U.S. study sites from October 2016 to July 2017. The study was prospective as it involved collecting specimens for testing.

Archived Specimens (Supplemental Test Set):

• Total specimens: 171 frozen archived specimens (13 BAL and 5 sputum negatives; 139 BAL and 14 sputum positives).
• Final data set for analysis: 18 negative and 149 positive specimens (containing 173 analytes).
• Data provenance: Retrospective, preselected archived specimens from external laboratories.

Contrived Specimens (Supplemental Test Set):

• Total specimens: 1125 contrived specimens (spiked using residual clinical samples).
• Data provenance: Generated in-house by BioFire (presumably in the US) using residual clinical samples that were pre-screened to be negative for the analytes of interest.

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

The document describes the reference methods used to establish ground truth for the clinical and archived test sets, rather than explicitly stating "experts" for ground truth.

• For bacterial analytes: Quantitative reference culture (qRefCx) performed at a central reference laboratory. The method was considered positive if the organism was recovered and enumerated at ≥10^3.5 CFU/mL. Molecular methods (single PCR followed by quantitative molecular assay and sequencing (qMol)) were also used in discrepancy resolution.
• For atypical bacteria and viruses: Two conventional PCR assays followed by bidirectional sequencing. A specimen was positive if bidirectional sequencing data matched organism-specific sequences in the NCBI GenBank database.
• For antimicrobial resistance genes: Single PCR assay followed by sequencing for specimens where an applicable bacterium was detected by FilmArray.

The document does not specify the number or qualifications of the individuals performing these reference methods. However, the involvement of a "central reference laboratory" for qRefCx and detailed molecular methods suggests that qualified laboratory personnel with expertise in microbiology and molecular diagnostics would have performed these tasks.

4. Adjudication method for the test set

• Discrepancy Investigation: For clinical study results, discrepancies between FilmArray Pneumonia Panel results and comparator method results were investigated.
  • For bacterial analytes and qRefCx discrepancies: investigated whether FilmArray or qRefCx reported "negative" or "Not Detected" due to being below detection threshold. If unresolved, qMol testing results were considered. If still unresolved, multiple additional molecular assays followed by sequence analysis were used. Standard of Care (SOC) testing results were also considered.
  • For atypical bacteria, viruses, and AMR genes (where molecular comparators were primary): The discrepancy investigation involved further molecular assays (e.g., additional molecular methods, retesting with FilmArray Pneumonia Panel, or sequencing).

The document details the steps taken for resolving discrepancies but doesn't explicitly refer to an "adjudication panel" or specific "X+Y" method with named experts. The process is a multi-step laboratory investigation rather than a formalized expert adjudication panel in the context of imaging.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done

No a multi-reader multi-case (MRMC) comparative effectiveness study was mentioned. The study focused on the standalone performance of the device against reference methods, rather than comparing human reader performance with and without AI assistance.

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

Yes, the studies described are standalone performance evaluations. The FilmArray Pneumonia Panel automates the process from nucleic acid extraction to result interpretation. The reported sensitivity, specificity, PPA, and NPA values represent the performance of the algorithm/device itself in detecting and identifying pathogens and resistance genes, without human interpretation influencing the final binary output (Detected/Not Detected) or semi-quantitative binning.

7. The type of ground truth used

The ground truth used in the studies included:

• Quantitative Reference Culture (qRefCx): For bacterial analytes in clinical specimens.
• PCR/Sequencing: For atypical bacteria, viruses, and antimicrobial resistance genes in clinical and archived specimens. This involved conventional PCR followed by bidirectional sequencing, matching results to NCBI GenBank.
• Known Composition of Contrived Specimens: For contrived specimens, the ground truth was the known presence and concentration of spiked organisms and AMR genes.
• Phenotypic AST methods (e.g., ESBL activity testing, carbapenem susceptibility testing, cefoxitin susceptibility testing): Used to assess correlation with AMR gene results on cultured isolates from clinical specimens.

8. The sample size for the training set

The document does not explicitly state a sample size for a "training set." The FilmArray Pneumonia Panel is a molecular diagnostic test that identifies specific nucleic acid sequences. Its development likely involves extensive analytical validation (e.g., inclusivity, exclusivity, LoD, precision), which informs the assay design and algorithm parameters. This process differs from machine learning algorithms that typically require large labeled training sets. The document focuses on performance testing rather than algorithm training.

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

As no specific "training set" is described in the context of machine learning, the establishment of "ground truth" for training purposes is not directly detailed. However, the analytical studies (e.g., inclusivity, exclusivity, LoD) serve to validate the design and performance characteristics of the assays within the panel. For these analytical studies, ground truth was established by:

• Known concentrations of organisms/nucleic acids: Pure cultures and nucleic acid extracts at defined concentrations.
• Genetically characterized isolates: Using a diverse collection of confirmed strains/isolates/serotypes for inclusivity testing, whose identity and gene presence were validated through standard microbiological and molecular methods (e.g., sequencing, typing).
• In silico analysis: Predicting reactivity based on publicly available genetic sequences.

This rigorous analytical validation process ensures that the fundamental components of the FilmArray Pneumonia Panel (primers, probes, thermal cycling conditions, melting curve analysis parameters) are robust and accurate for their intended targets across known genetic diversity.

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