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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 2009 H1, Influenza B, Parainfluenza Virus 1, Parainfluenza Virus 2, Parainfluenza Virus 3, Parainfluenza Virus 4, 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 pouch contains freeze-dried reagents to perform nucleic acid purification, reverse transcription, and nested, multiplex PCR with DNA melt analysis. The Respiratory Panel (RP) pouch identifies 20 common and emerging viral respiratory pathogens (see Table 1). 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, Idaho Technology). 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.

Acceptance Criteria and Device Performance Study for FilmArray® Respiratory Panel (RP)

This document describes the acceptance criteria and supporting studies for the FilmArray® Respiratory Panel (RP) device with added assays for Coronavirus OC43, Coronavirus 229E, Bordetella pertussis, Mycoplasma pneumoniae, and Chlamydophila pneumoniae.

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 >90%"). Instead, the clinical performance is presented as observed Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) with 95% confidence intervals. The reproducibility study shows percent agreement with expected results at various concentrations. For clarity, we will present the key performance metrics observed in the clinical and archived specimen studies as "reported device performance."

(N/A - Not Applicable, LoD - Limit of Detection)

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

The evaluation for the newly added assays was conducted through a combination of prospective clinical studies, retrospective testing of archived clinical specimens, and contrived specimens.

• Prospective Clinical Study:

  • Sample Size: 1117 subjects (initially 1144 enrolled, 27 withdrawn or omitted).
  • Data Provenance: 3 U.S. clinical sites.
  • Retrospective or Prospective: Prospective. The study spanned two respiratory seasons (December 2009 - May 2010 and September 2010 - January 2011).

• Archived Specimens Study (for B. pertussis, Coronavirus 229E, Coronavirus OC43, or M. pneumoniae):

  • Sample Size: 305 total specimens.
  • Data Provenance: Not explicitly stated but implied to be from various sources, likely within the U.S., as they were "preselected archived samples."
  • Retrospective or Prospective: Retrospective.

• Contrived C. pneumoniae Specimens Study:

  • Sample Size: 100 specimens (50 spiked, 50 unspiked).
  • Data Provenance: Residual specimens from the prospective clinical study, spiked with C. pneumoniae.
  • Retrospective or Prospective: Contrived/Spiked.

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

The document describes the reference/comparator methods used to establish the ground truth, rather than directly mentioning "experts" in the context of adjudication for individual test results.

• Method: For Coronavirus 229E, Coronavirus OC43, B. pertussis, C. pneumoniae, and M. pneumoniae, the ground truth was established by composite comparator methods consisting of two analytically validated PCR assays followed by bi-directional sequencing.
  • "True" positives were defined as samples with bi-directional sequencing data meeting pre-defined quality acceptance criteria and matching NCBI GenBank database sequences.
  • "True" negatives were defined as samples negative by both comparator PCR assays.
• Number of Experts: Not explicitly stated as a number of human experts adjudicating each case. The "experts" implied are the skilled laboratory personnel performing and interpreting the bi-directional sequencing, which is a highly technical molecular biology method. Their qualifications would implicitly be in molecular diagnostics and sequence analysis.

4. Adjudication Method for the Test Set

The adjudication method relies on the described composite comparator methods:

• Method: Two independent PCR assays targeting different sequences, followed by bi-directional sequencing for confirmation.
• Rule: "True" positives were confirmed by sequencing matching GenBank. "True" negatives were confirmed by negativity in both PCR assays. Discrepant results between the FilmArray RP and the initial comparator PCRs were further investigated using bi-directional sequencing (as seen in the footnotes for discrepancy investigations in Table 4).

This is a form of adjudicated ground truth based on a robust laboratory method rather than human consensus interpretation of device output.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done.

This device is an automated multiplex nucleic acid test. Its performance is evaluated against reference laboratory methods, not by comparing human reader performance with and without AI assistance. The readout is qualitative (presence/absence of target nucleic acid), and interpretation is automated by the device's software.

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

Yes, a standalone performance study was done.

The clinical performance data (PPA, NPA) presented in Tables 4, 8, and 9 reflects the performance of the FilmArray RP system (including the algorithm responsible for interpreting the raw data and providing a result) operating independently without human modification or interpretation of the final result. The system's software automatically interprets results based on melting curve analysis and internal controls.

7. The Type of Ground Truth Used

The primary type of ground truth used was expert-defined laboratory gold standard:

• Clinical and Archived Specimen Studies: Ground truth was established using composite comparator methods comprising two analytically validated PCR assays followed by bi-directional sequencing. This is a highly robust and specific laboratory reference method.
• Contrived C. pneumoniae Specimens: Ground truth was established by spiking known concentrations of the pathogen into clinical matrix, and also by using unspiked controls.

8. The Sample Size for the Training Set

The document does not explicitly state the sample size for the training set used to develop the FilmArray RP algorithms for the newly added assays. Regulatory submissions typically focus on the performance of the final, locked algorithm on independent test sets (as described in this document), rather than detailing the internal development and training processes.

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

As the document does not provide details on a specific "training set," it also does not describe how the ground truth for any training set was established. It's common for diagnostic device development to use well-characterized positive and negative specimens, often confirmed by highly sensitive and specific laboratory methods (similar to the comparator methods described for the test set), for initial algorithm development and optimization.

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The Trinity Biotech Captia™ Mycoplasma IgG ELISA kit is an Enzyme-Linked Immunosorbent Assay (ELISA) for semi-quantitative or qualitative determination of IgG antibodies in human serum to Mycoplasma pneumoniae for the determination of immunological experience. The Mycoplasma IgG ELISA kit may be used to evaluate paired sera for seroconversions and the presence of a significant increase in specific IgG as and aid in the diagnosis of Mycoplasma pneumoniae infection in the adult population.

The Mycoplasma IgG ELISA kit is an Enzyme-Linked Immunosorbent Assay (ELISA) for semi-quantitative or qualitative determination of IgG antibodies in human serum to Mycoplasma pneumoniae for the determination of immunological experience. The Mycoplasma IgG ELISA kit may be used to evaluate paired sera for the presence of seroconversions and a significant increase in specific IgG as an aid in the diagnosis of Mycoplasma pneumoniae infection in the adult population. For In Vitro Diagnostic Use Only.

The Mycoplasma IgG ELISA test is an enzyme linked immunosorbent assay to detect IgG antibodies to Mycoplasma pneumoniae. Purified Mycoplasma pneumoniae antigen is attached to a solid phase microtiter well. Diluted test sera are added to each well. If the antibodies are present that recognize the antigen, they will bind to the antigen in the well. After incubation, the wells are washed to remove unbound antibody. An enzyme labeled anti-human IgG is added to each well. After incubation, the wells are washed to remove unbound conjugate. A substrate solution is added to each well. If enzyme is present, the substrate will undergo a color change. After an incubation period the reaction is stopped and the color intensity is measured photometrically, producing and indirect measurement of specific antibody in the patient specimen.

Here's an analysis of the provided text, focusing on the acceptance criteria and the study proving the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

Note on Acceptance Criteria: The document primarily presents performance characteristics and compares them to a predicate device or implied standards (e.g., "With appropriate technique the user should obtain precision of < 15% CV"). Explicit, pre-defined numerical acceptance criteria are not always stated, but the reported values demonstrate the device's performance in relation to the predicate or common laboratory standards. For precision, the text itself suggests "< 15% CV" as an expected outcome with appropriate technique.

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

• Agreement with Predicate Device (IFA):
  • Study 1: 187 frozen retrospective sera.
    • Provenance: Normal individuals of various ages, gender, from Lyme disease endemic and non-endemic areas. (Country of origin not specified, but commercial companies were located in Maryland and New York, affiliated with the manufacturer).
  • Study 2: 176 frozen retrospective sera.
    • Provenance: Randomly selected sera from normal individuals of various ages, gender, and geographical location. (Country of origin not specified, but commercial companies were located in Maryland and New York, affiliated with the manufacturer).
• Precision:
  • 7 sera, each assayed 10 times on 3 different assays at 2 different sites. This means 7 * 10 * 3 * 2 = 420 individual tests for sera, plus controls.
  • Provenance: Not explicitly stated for the sera samples themselves, but the testing was done at R&D laboratories at commercial companies affiliated with the manufacturer (Maryland and New York).
• Linearity (Simulated Paired Sera):
  • 20 positive sera, serially two-fold diluted. The number of dilutions is not specified, but at least 4-5 dilutions per serum would be typical (Neat, 1:2, 1:4, 1:8, 1:16 as shown in the graph).
  • 56 paired sera (for % agreement positive detection of four-fold increase).
  • Provenance: Not specified for individual sera or paired sera.
• Complement Fixation Paired Serum Study:
  • 11 serum pairs, with 7 ultimately used for analysis.
  • Provenance: From patients suspected of having acute Mycoplasma pneumoniae infection, tested by CF. (Country of origin not specified).
• Reproducibility Study:
  • 50 different sera.
  • Provenance: Assayed at three different sites: two R&D labs at commercial companies (Maryland and New York) and one large clinical laboratory (Pennsylvania).

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

• No "experts" per se were used to establish ground truth in the traditional sense for the primary agreement studies.
• The ground truth for the agreement studies (Studies 1 and 2) was the Mycoplasma IFA (1:32) kit, which is the predicate device. This is a comparative study against an existing, legally marketed device, not a comparison to a clinical diagnosis established by experts.
• For the Complement Fixation Paired Serum Study, the ground truth for "significant rise in antibody" was established by the CF method.
• The "expected results" for the Reproducibility Study were derived from "previous Trinity Biotech ELISA testing of the samples."

4. Adjudication Method for the Test Set

• For the primary agreement studies (Studies 1 and 2), the comparison was directly between the new Trinity Biotech Mycoplasma IgG ELISA and the commercial IFA kit. There was no mention of an adjudication process between different readers or methods beyond the direct comparison.
• In cases where the Trinity Biotech ELISA and the IFA kit disagreed, all 20 sera in Study 1 and 20 sera in Study 2 that were positive by IFA but negative by the Trinity Biotech ELISA were further tested by "an alternate ELISA" to confirm their positive status. This serves as a form of secondary evaluation or tie-breaking for discordant results.
• For the reproducibility study, "expected results were derived from previous Trinity Biotech ELISA testing." This suggests a pre-defined reference, not an adjudication of new readings.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size

• No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done.
• This device is an in vitro diagnostic (ELISA test kit), not an imaging or interpretation device that would typically involve multiple human readers interpreting results with and without AI assistance. The performance studies focus on the analytical and clinical agreement of the assay itself with a predicate device and its internal consistency (precision, linearity, reproducibility).

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

• Yes, the studies presented are all standalone performance evaluations of the Mycoplasma IgG ELISA kit.
• The ELISA kit is a laboratory test where the "algorithm" is the biochemical reaction and photometric measurement, yielding a quantitative or semi-quantitative result. There is no human-in-the-loop variable being tested in terms of interpreting algorithmic output. The performance metrics (agreement, precision, linearity, reproducibility) represent the intrinsic performance of the device on its own.

7. The Type of Ground Truth Used

• Primary Ground Truth for Agreement Studies: The predicate device (commercial IFA kit) was used as the comparator for determining "% Agreement Positive" and "% Agreement Negative." This is a comparator or reference method ground truth.
• Secondary Ground Truth for Discordant Results: An "alternate ELISA" was used to confirm positive status for samples where the predicate IFA was positive but the study device was negative.
• Paired Sera Studies: The "significant rise in antibody" was determined by either the calculated % rise in ISR value within the Trinity Biotech ELISA or by the Complement Fixation (CF) method as a reference.
• Reproducibility Study: "Expected results" were derived from "previous Trinity Biotech ELISA testing".

8. The Sample Size for the Training Set

• No explicit training set is mentioned in the description.
• ELISA kits, particularly for a 510(k) submission, are typically validated through analytical and clinical performance studies, not by training a machine learning algorithm. The "development" or "optimization" would involve chemical and biological engineering, not data training in the AI sense.
• The provided studies evaluate the final product's performance, not the iterative development process that might involve a 'training set' for an AI model.

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

• As no explicit training set for an AI/algorithm was described, the concept of establishing ground truth for a training set does not apply directly to this device's validation as presented in the summary.
• The 'ground truth' pertinent to the evaluation was established by either a predicate device (IFA), an alternate ELISA, or a CF method as described in section 7.

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