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The ARIES® Flu A/B & RSV Assay is a polymerase chain reaction (PCR) based qualitative in vitro diagnostic test for the direct detection and differentiation of influenza A virus, influenza B virus, and respiratory syncytial virus (RSV) nucleic acid in nasopharyngeal swab (NPS) specimens from patients with signs and symptoms of respiratory tract infection in conjunction with clinical and laboratory findings. The test is intended for use as an aid in the differential diagnosis of Influenza A, Influenza B, and RSV in humans and is not intended to detect Influenza C.

Negative results do not preclude influenza virus or RSV infection and should not be used as the sole basis for diagnosis, treatment or other management decisions. Conversely, positive results do not rule-out bacterial infection or co-infection with other viruses. The agent detected may not be the definite cause of disease. The use of additional laboratory testing (e.g. bacterial culture, immunofluorescence, X-ray findings) and clinical presentation must be taken into consideration in order to obtain the final diagnosis of respiratory viral infection.

Performance characteristics for influenza A were established during the 2015-2016 influenza seasons when influenza A/H3N2 and A/H1N1 pandemic were the predominant influenza A viruses in circulation. When other Influenza A viruses are emerging, performance characteristics may vary.

If infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to state or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

The ARIES® Flu A/B & RSV Assay is indicated for use with the ARIES® Systems.

The ARIES® Flu A/B & RSV Assay is a polymerase chain reaction (PCR)-based qualitative in vitro diagnostic test system that will consist of an ARIES® System with its included software, an assay-specific cassette, and an assay-specific protocol file. The ARIES® Flu A/B & RSV Assay cassette is a disposable, single-use cassette containing nucleic acid purification reagents, internal sample process control (SPC), and an assay-specific master mix capable of performing the designated assay on one sample. The ARIES® Flu A/B & RSV Assay cassette directly detects and differentiates influenza A virus, influenza B virus, and respiratory syncytial virus (RSV) nucleic acid in nasopharyngeal swabs (NPS) specimens from patients with signs and symptoms of respiratory tract infection in conjunction with clinical and laboratory findings. Specifically, the ARIES® Flu A/B & RSV Assay cassette detects the matrix protein genes of influenza A and influenza B viruses, and the fusion gene of RSV and a RNA Sample Processing Control.

The specimen is lysed and nucleic acid is extracted using an ARIES® System. An extractable sample processing control (SPC) target is present in the ARIES® Flu A/B & RSV assay cassette and is processed with the specimen. The SPC controls for specimen lysis, for recovery of extracted nucleic acid, for inhibitory substances and for PCR reagent and instrument integrity. The Ct value of the SPC is designed to verify proper specimen lysis and nucleic acid extraction, to identify PCR inhibition, if any, and verify proper function of the extraction system and real-time instrument. The Tm value of the SPC is used as a reference for determining the target Tm.

The extracted nucleic acid and SPC are transferred via magnetic beads through the cassette to the ARIES® Flu A/B & RSV Assay lyophilized PCR reagents in the PCR tube that contain primer pairs specific to influenza A, influenza B, RSV, and the SPC sequence. The specific primer pairs are labeled with distinct fluorophore labels. PCR amplification is performed and assay fluorescence is monitored on an ARIES® System. Incorporation of the quencherlabeled nucleotide causes a decrease in assay fluorescence. Following amplification, the reaction is slowly heated and fluorescence is monitored. The strands of the amplification products will separate at a specific melting temperature (Tm) that is determined by an increase in fluorescence as the strands are separated. The instrument fluorescence output is analyzed and test results are determined using the ARIES® Flu A/B & RSV Assay protocol file. A printed results report is generated.

Here's a breakdown of the acceptance criteria and study information for the ARIES® Flu A/B & RSV Assay, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

Clinical Performance Acceptance Criteria:

Reported Device Performance (Clinical Study):

Additional Influenza B Performance (Supplemented Study):

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

• Sample Size for Prospective Clinical Study: 2479 eligible unique nasopharyngeal swab (NPS) specimens.
• Sample Size for Supplemented Influenza B Study: 40 pre-selected Influenza B positive specimens + 40 unique negative clinical specimens (total 80).
• Data Provenance: Retrospective and prospective.
  • Prospective Data: Specimens collected during the 2014/2015 (Jan 18, 2015 to Mar 20, 2015) and 2015/2016 (Nov 02, 2015 to Feb 29, 2016) flu seasons.
  • Geographical Origin: Collected at 3 clinical sites (2014/2015) and 4 clinical sites (2015/2016) in the United States and Canada.
  • Retrospective/Pre-selected Data: 40 banked (pre-selected) Influenza B positive specimens collected at a single clinical laboratory (collection site) in Canada for the supplemental study.

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

The document does not explicitly state the number or qualifications of "experts" used to establish ground truth in the traditional sense (e.g., radiologists interpreting images).

Instead, the ground truth for the clinical study was established using:

• An FDA-cleared molecular comparator assay (primary reference standard).
• Bi-directional sequencing for discordant results.

This approach means the "ground truth" relies on the performance of another validated diagnostic device and a molecular sequencing technique, rather than human expert consensus on clinical presentation or imaging.

4. Adjudication Method for the Test Set

• Primary Comparison: All 2479 eligible clinical specimens were initially tested by an FDA-cleared molecular comparator and the ARIES® Flu A/B & RSV Assay.
• Discordant Analysis: For specimens where the ARIES® Flu A/B & RSV Assay results differed from the comparator assay result, they were further assessed by bi-directional sequencing using analytically validated primers that targeted genomic regions distinct from the ARIES® Flu A/B & RSV Assay.
• Reporting: Results from discordant testing analysis were not included in the initial calculation of Positive Percent Agreement and Negative Percent Agreement for each target. These discordant results were noted as footnotes in the performance evaluation tables (e.g., "False Negative by bi-directional sequencing").

This indicates a form of secondary adjudication using an independent, highly specific molecular method to resolve discrepancies between the new device and the predicate.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, this was not a Multi-Reader Multi-Case (MRMC) comparative effectiveness study involving human readers. This study evaluated the standalone performance of a molecular diagnostic assay against a comparator assay and sequencing, not the improvement of human readers with AI assistance.

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

Yes, a standalone performance study was conducted. The ARIES® Flu A/B & RSV Assay is an automated molecular diagnostic test system. The clinical performance evaluation directly tested the device's output against a molecular comparator and sequencing, without human interpretation of the assay's raw output determining the final diagnostic call. The assay itself provides a qualitative "Positive" or "Negative" result.

7. The Type of Ground Truth Used

The ground truth for the test set was an combination of:

• Molecular Comparator Assay Results: An FDA-cleared molecular test used as the primary reference standard.
• Bi-directional Sequencing: Used as a confirmatory "tie-breaker" or definitive reference for specimens yielding discordant results between the ARIES® assay and the primary comparator.

8. The Sample Size for the Training Set

The document does not directly specify a "training set" sample size in the context of machine learning model development. For in vitro diagnostic devices like the ARIES® Flu A/B & RSV Assay, "training" typically refers to the process of developing and optimizing the assay's chemical reagents, amplification protocols, and the algorithms for interpreting raw signal (e.g., Ct values, Tm values) into a qualitative result. This development process uses numerous laboratory experiments with contrived samples and potentially some early clinical samples, but these are generally not referred to as a "training set" in the same way as in AI/ML literature.

The document describes extensive analytical performance studies (e.g., Limit of Detection, Inclusivity, Specificity, Precision, Stability) that are crucial for defining the assay's operating characteristics and establishing the cut-offs and parameters that lead to accurate results. These analytical studies utilize:

• Precision/Reproducibility: 675 replicates (initial precision) and 1260 replicates (site-to-site reproducibility) using contrived samples (viral cultures at specific concentrations diluted in simulated nasal matrix).
• Limit of Detection: At least 20 replicates for each of 7 viral strains.
• Inclusivity: Triplicate testing for each of 34 different viral strains (some required additional testing).
• Interfering Substances: Triplicate testing for viral targets with 18 different interfering substances.
• Cross-Reactivity: Triplicate testing for 32 microorganisms (some required additional testing).
• Microbial Interference/Co-infection: Triplicate testing for various pathogen combinations.

These extensive studies with known concentrations and types of pathogens and interferents essentially "train" and validate the design and interpretation rules of the assay.

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

Again, the concept of a "training set" with ground truth in the AI/ML sense is not explicitly detailed. However, for the analytical studies (which inform the assay's design and operating parameters), the "ground truth" was established based on:

• Known Concentrations of Characterized Viral Stocks/Strains: Viral cultures were quantified and diluted to precise concentrations (e.g., TCID50/mL) to create samples with a known positive status and concentration.
• Known Negative Samples: Simulated nasal matrix (SNM) or Universal Transport Medium (UTM) were used as known negative samples.
• Known Interfering/Cross-Reactive Agents: Specific microorganisms or substances were added at defined concentrations to evaluate their impact.

Essentially, the ground truth for these analytical studies was derived from laboratory-controlled conditions where the presence, identity, and concentration of analytes were precisely known.

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