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The LIAISON PLEX Respiratory Flex (RSP Flex) Assay is a multiplexed qualitative test for the simultaneous in vitro detection and identification of multiple bacterial and viral nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals with clinical signs and symptoms of respiratory tract infection, including SARS-CoV-2. The test is performed on the automated LIAISON PLEX System utilizing reverse transcription (RT), polymerase chain reaction (PCR), and array hybridization to detect specific nucleic acid gene sequences of the following organism types and subtypes:

Viruses: Adenovirus Human Coronavirus (HKU1, NL63, OC43, and 229E not differentiated) Human Enterovirus/Rhinovirus (not differentiated) Human Metapneumovirus, Influenza A Influenza A (subtype H1) Influenza A (subtype H3) Influenza B Parainfluenza 1 Parainfluenza 2 Parainfluenza 3 Parainfluenza 4 Respiratory Syncytial Virus Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2)

Bacteria: Bordetella holmesii Bordetella parapertussis Bordetella pertussis Chlamydia pneumoniae Mycoplasma pneumoniae

Nucleic acids from the bacterial and viral organisms identified by this test are generally detectable in NPS specimens during the acute phase of infection. Detecting and identifying specific bacterial and viral nucleic acids from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory infection, if used in conjunction with other clinical, epidemiological, and laboratory findings. The results of this test should not be used as the sole basis for diagnosis, treatment, or patient management decisions.

Negative results in the presence of a respiratory illness may be due to infection with pathogens that are not detected by this test or due to lower respiratory that is not detected by an NPS specimen. Conversely, positive results do not rule out infection or co-infection with organisms not detected by the LIAISON PLEX Respiratory Flex (RSP Flex) Assay. The agent(s) detected may not be the definite cause of disease.

The use of 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 LIAISON PLEX® Respiratory Flex Assay is a multiplexed nucleic acid test system composed of the LIAISON PLEX Instrument, the LIAISON PLEX® System Software (preinstalled on the LIAISON PLEX Instrument), the LIAISON PLEX® Respiratory Flex Assay cartridge, and the LIAISON PLEX® Respiratory Flex Assay File. The LIAISON PLEX® Respiratory Flex Assay cartridge contains the reagents to perform nucleic acid extraction and purification, reverse transcription, PCR, and array hybridization. Specifically, the LIAISON PLEX® Respiratory Flex Assay detects bacteria and viruses from nasopharyngeal swab (NPS) specimens collected from individuals with signs and symptoms of respiratory infection.

The LIAISON PLEX System consists of a touchscreen user interface that includes the software for running and analyzing assay results, one to six processing/imaging LIAISON PLEX modules, and a handheld barcode reader. Each LIAISON PLEX module processes one sample at a time under the control of the LIAISON PLEX System software.

LIAISON PLEX® automates the sample processing through analysis within a single cartridge. Processing steps include 1.) Sample Preparation: Nucleic acid extraction from organisms by chemical and mechanical means and isolation of nucleic acid on magnetic beads 2.) Target Amplification: Multiplex PCR and RT-PCR based amplification of extracted nucleic acid to generate target specific amplicons 3.) Hybridization: Amplicons hybridize with their target specific DNA probe arranged in a microarray format and that are attached to mediator and gold nanoparticles 4.) Analysis: Gold nanoparticles specifically bound to target amplicons are silver enhanced and the light scatter from microarray spot is measured and analyzed to confirm presence (Detected) or absence (not Detected) of a target.

The LIAISON PLEX Respiratory Flex Assay has the option of creating and processing results for custom panels using Flex® Software. Flex Software allows users to randomly select and group targets in tiers for result processing. Up to 7 targets may be selected for the initial test tier. After the first tier, each additional tier requires a specific number of credits. Flex™ credits allow the end-user to create custom panels and pay for a smaller subset of results tailored to the individual patient's clinical presentation. Alternatively, a laboratory may choose the fixed price option where all target results are processed at the same time.

The LIAISON PLEX Respiratory Flex Assay is a multiplexed qualitative test for the simultaneous in vitro detection and identification of multiple bacterial and viral nucleic acids in nasopharyngeal swabs (NPS) from individuals with clinical signs and symptoms of respiratory tract infection, including SARS-CoV-2.

Here's an analysis of the acceptance criteria and study proving its performance:

1. Table of Acceptance Criteria and Reported Device Performance

The provided document doesn't explicitly state "acceptance criteria" with numerical thresholds for performance metrics. However, regulatory bodies like the FDA typically expect high sensitivity (Positive Percent Agreement - PPA) and specificity (Negative Percent Agreement - NPA) for diagnostic assays. Based on the clinical performance summary, we can infer the achieved performance.

Infered Acceptance Criteria and Reported Device Performance (Summary for Key Analytes):

Note: For analytes with 0/0 positive cases (Bordetella holmesii, Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae in the prospective study), performance is "Not Evaluable" (NE) but the NPA is 100%. These were supplemented with contrived specimens.

2. Sample Size and Data Provenance

Prospective Clinical Study:

• Sample Size (Test Set): 1843 unique clinical specimens initially enrolled, with 1832 specimens yielding valid results after retests.
• Data Provenance: Prospectively collected between October 2022 to April 2023 from six geographically diverse clinical sites within the United States. Specimens were remnant and de-identified, collected from pediatric and adult patients.

Archived Specimen Testing (Retrospective):

• Sample Size (Test Set): 256 pre-selected, left-over, frozen, de-identified specimens, all yielding valid results after retests.
• Data Provenance: Retrospectively collected from November 2013 through June 2023 from four sites/vendors in the United States.

Contrived Specimen Testing:

• Sample Size (Test Set): 300 contrived specimens, all yielding valid results after retests.
• Data Provenance: Artificially created samples to cover low prevalence targets. Tested at two US sites (details about origin of base matrix not specified beyond "simulated NPS matrix").

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the number of experts used and their exact qualifications (e.g., "radiologist with 10 years of experience") for establishing ground truth. Instead, it indicates that the ground truth was established by comparator methods, which are themselves FDA-cleared molecular panels or analytically validated assays. These methods inherently rely on expertise for their development and validation but do not require additional human expert adjudication for each case in this study.

4. Adjudication Method for the Test Set

Specimens that obtained discordant results between the LIAISON PLEX Respiratory Flex Assay and the comparator method underwent additional testing for investigation.

• For targets typically compared against FDA-cleared molecular respiratory panels, discordant samples were re-tested with an FDA-cleared molecular respiratory panel or PCR/BDS.
• For Bordetella holmesii, Bordetella parapertussis, Bordetella pertussis, comparator performance was based on "well-validated Fragment Analysis (FA) assays followed by PCR/Bi-Directional Sequencing (PCR/BDS) assays."

This implies an adjudication method involving a third, more definitive or confirmatory test (often a "tie-breaker" or "gold standard" method like PCR/BDS) for discordant results. This is a common practice in diagnostic device studies. The document does not specify a "2+1" or "3+1" structure as those typically refer to multiple human readers or interpretations.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This study evaluates the performance of a diagnostic assay itself for detecting nucleic acids, not the impact of AI assistance on human readers' interpretation of images or other data. Therefore, there is no effect size reported for how much human readers improve with AI vs. without AI assistance.

6. Standalone (Algorithm Only) Performance

Yes, a standalone performance was done. The entire clinical performance study (prospective, archived, and contrived) evaluates the LIAISON PLEX Respiratory Flex Assay as an algorithm-only or device-only diagnostic tool without human-in-the-loop interpretation being part of the primary evaluation. The results presented for PPA and NPA are based solely on the device's output compared to the ground truth.

7. Type of Ground Truth Used

The ground truth used was primarily established through comparator laboratory methods:

• FDA-cleared molecular respiratory panels for most viral and bacterial targets.
• FDA-cleared molecular SARS-CoV-2 assay for SARS-CoV-2.
• Analytically Validated Fragment Analysis (FA) assays followed by PCR/Bi-Directional Sequencing (PCR/BDS) assays for Bordetella species.
• For discordant results, additional testing with FDA-cleared molecular respiratory panels or PCR/BDS was performed for investigation.

This combination of highly sensitive and specific molecular diagnostic assays, with confirmatory testing for discordance, serves as the ground truth.

8. Sample Size for the Training Set

The document does not explicitly state the sample size for a separate "training set" for the LIAISON PLEX Respiratory Flex Assay. This is characteristic of molecular diagnostic assays which are typically developed and optimized through analytical studies (e.g., limit of detection, inclusivity, exclusivity) and then validated in clinical performance studies without a distinct "AI training set" in the common machine learning sense. The performance characteristics (analytical and clinical) presented are for the final, locked-down assay.

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

Since a distinct "training set" in the AI/machine learning context is not specified, the method for establishing its ground truth is not detailed. However, the development of such assays involves extensive analytical testing using characterized isolates, strains, and clinical samples to define reactivity, specificity, and sensitivity. The ground truth for this analytical development would typically be based on:

• Known concentrations of purified nucleic acids or organisms.
• Well-characterized reference materials and clinical specimens with confirmed presence/absence of targets via established methods (e.g., culture, sequencing, reference PCR).

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