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1. The cobas® Influenza A/B & RSV Nucleic Acid Test for Use on the cobas® Liat System (cobas® Liat Influenza A/B & RSV) is an automated multiplex real-time RT-PCR assay for the rapid in vitro qualitative detection and discrimination of influenza A virus, influenza B virus and respiratory syncytial virus (RSV) RNA in nasopharyngeal swab specimens from patients with signs and symptoms of respiratory infection in conjunction with clinical and epidemiological risk factors. The test is intended for use as an aid in the diagnosis and differentiation of 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 treatment or other patient management decisions. Conversely, positive results do not ruleout bacterial infection or co-infection with other viruses. The agent detected may not be the definite cause of disease.

Performance characteristics for influenza A were established during the 2013-2014 and the 2014-2015 influenza seasons when influenza A/H3 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 department for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

2. The cobas® Influenza A/B & RSV Quality Control Kit contains External Controls for use with the cobas® Liat Influenza A/B & RSV assay. External Controls are run during the Add cobas® Liat Influenza A/B & RSV Tube Lot procedure. Additional External Controls should be tested in accordance with local, state, federal and/or accrediting organization requirements as applicable.

The cobas Liat Influenza A/B & RSV Nucleic Acid Test for Use on the cobas Liat System ("cobas" Liat Influenza A/B & RSV assay") is a rapid, automated in vitro diagnostic test for the qualitative detection of influenza A, influenza B, and RSV RNA in nasopharyngeal swab (NPS) specimens eluted in viral transport media.

The assay targets a well-conserved region of the matrix gene of influenza A (Inf A target), the non-structural protein gene of influenza B (Inf B target), and the matrix gene of RSV (RSV target). An Internal Process Control (IPC) is also included. The IPC is present to control for adequate processing of the target viruses and to monitor the presence of inhibitors in the sample preparation and RT-PCR.

The assay utilizes a single-use disposable cobas® Liat Tube that holds the sample purification and PCR reagents, and hosts the sample preparation and PCR processes. The cobas Liat Tube uses a flexible tube as a sample vessel. It contains all required unit dose reagents pre-packed in tube segments, separated by peelable seals, in the order of reagent use.

The cobas "Liat System automates and integrates sample purification, nucleic acid amplification, and detection of the target sequence in biological samples. The cobas Liat System performs all assay steps from clinical sample and reports assay result automatically. During the testing process. multiple sample processing actuators of the cobas " Liat System compress the cobas" Liat Tube to selectively release reagents from tube segments, move the sample from one segment to another, and control reaction volume, temperature, and time to conduct sample preparation, nucleic acid extraction, target enrichment, inhibitor removal, nucleic acid elution and real-time PCR. An embedded microprocessor controls and coordinates the actions of these sample processors to perform all required assay processes within the closed cobas Liat Tube.

Positive and negative controls are provided in the cobas® Influenza A/B & RSV Quality Control Kit. The positive control comprises inactivated Influenza B and RSV virus in a dried format. The negative control comprises Universal Transport Media (UTM).

To perform the cobas Liat Influenza A/B & RSV assay, an operator first collects a nasopharyngeal swab and places the swab into UTM. The operator transfers the sample into cobas " Liat Influenza A/B & RSV assay tube using a transfer pipette, and scans the tube barcode to identify the test and the sample barcode to code the sample ID with the assay run on the cobas® Liat System. The cobas® Liat Tube is then inserted into the cobas® Liat System. The system performs all the test steps and outputs interpreted results (e.g. Influenza A Detected, Influenza B Not Detected, RSV Not Detected) in ~20 minutes. A report of the interpreted results can be viewed on the cobas " Liat System's LCD screen, and printed directly through a USB or network connected printer. No reagent preparation or additional steps are required other than adding the sample to the cobas Liat Tube. Because all the reagents are contained within the cobas Liat Tube and no sample or reagent needs to be removed from the tube, crosscontamination between samples is minimized.

The results are interpreted by the cobas Liat System software from measured fluorescent signals and real time curve recognition algorithm. All possible final test results are described below.

Here's a breakdown of the acceptance criteria and study details for the cobas® Liat Influenza A/B & RSV Nucleic Acid Test, based on the provided document:

1. Table of Acceptance Criteria & Reported Device Performance

The document doesn't explicitly lay out "acceptance criteria" in a single, aggregated table with pass/fail marks. Instead, it presents performance data for various analytical and clinical studies. For the clinical studies, it provides percentage agreements and confidence intervals. The "acceptance criteria" can be inferred from the reported performance, implying that these values were considered acceptable by the FDA for substantial equivalence.

Here's a table summarizing the key performance metrics from the study. For acceptance criteria, we'll assume that the reported performance figures met the internal thresholds set by the manufacturer and deemed sufficient by the FDA for 510(k) clearance.

Inferred Acceptance Criteria / Reported Performance for cobas® Liat Influenza A/B & RSV Assay

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

• Clinical Test Set Sample Size:

  • Prospective Specimens: 1,350 nasopharyngeal swab (NPS) specimens.
  • Retrospective Specimens: 292 nasopharyngeal swab (NPS) specimens.
  • Total Clinical Samples: 1,642 specimens.

• Analytical Test Set Sample Size (Reproducibility): Approximately 900 runs (10 panel members × 3 replicates × 2 operators × 5 days × 3 sites).

• Data Provenance:

  • Country of Origin: United States (US). Prospective specimens were collected during the 2013-2014 and 2014-2015 flu seasons.
  • Retrospective/Prospective: The study included both prospective and retrospective clinical specimens. Prospective specimens were collected from patients with signs and symptoms of respiratory infection and tested at 12 CLIA waived healthcare facilities. Retrospective specimens were obtained from two reference laboratories and distributed to 3 of the 12 CLIA waived sites for testing.

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

The document states that the cobas Liat Influenza A/B & RSV assay results were compared against an "FDA-cleared laboratory-based multiplexed real-time reverse transcriptase PCR (RT-PCR) test (comparator test)."

• Number of Experts: Not explicitly stated as "experts" for ground truth adjudication in the traditional sense, as it relies on a comparator laboratory test. However, the interpretation of the comparator PCR results would implicitly rely on qualified laboratory personnel.
• Qualifications of Experts: Not detailed. It's inferred that the personnel performing and interpreting the comparator FDA-cleared RT-PCR tests were qualified laboratory technologists/scientists. For discordant results in prospective samples, PCR/sequencing was used as a tie-breaker. This would also imply qualified laboratory personnel.

4. Adjudication Method for the Test Set

• For the primary comparison, the cobas Liat assay results were compared directly against the FDA-cleared laboratory-based multiplexed real-time RT-PCR test (comparator test).
• For discordant results between the cobas Liat and the comparator test in the prospective specimens (specifically, when Liat was positive and comparator negative), PCR/sequencing was used as a "tie-breaker" or confirmatory method. For Influenza A, 41 such specimens were tested, with 18 confirmed positive and 23 negative by PCR/sequencing. For Inf B, 6 such specimens were tested, with 5 confirmed positive and 1 negative. For RSV, 15 such specimens were tested, with 3 confirmed positive and 12 negative.
• For retrospective specimens with discordant results (Liat positive, comparator negative), a similar PCR/sequencing method was used, though with fewer details on the number of confirmed cases (e.g., 1 Inf A sample was negative by PCR/sequencing, all 6 RSV samples were positive).

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance

This document describes the performance of an in vitro diagnostic (IVD) nucleic acid amplification test (NAAT), not an AI-assisted imaging device or a decision support system with human readers. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable to this device.

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

The cobas® Liat system is an automated diagnostic system (sample-to-answer) that performs nucleic acid purification, amplification, and detection, and provides an automated interpretation of the results. The results are reported as "Detected" or "Not Detected" for each virus by the instrument's software. As such, the performance data presented (e.g., clinical sensitivity and specificity) intrinsically represent the "standalone" performance of the algorithm/system, as human interpretation of complex signals (like in radiology) is minimized or absent in the final result determination. The operators (nurses and technologists) are responsible for sample collection, loading, and initiating the test, but the interpretation is automated.

7. The Type of Ground Truth Used

The primary ground truth for the clinical validation was an FDA-cleared laboratory-based multiplexed real-time RT-PCR test (comparator test). For discordant results, PCR/sequencing was used as a confirmatory method to establish a more definitive ground truth.

8. The Sample Size for the Training Set

The document does not specify a separate "training set" in the context of machine learning or AI models. This device is a molecular diagnostic assay (RT-PCR) with predefined chemical reactions and detection logic. Its "development" would involve optimizing reagents, primer/probe design, and reaction conditions, rather than training an algorithm on a distinct dataset. The performance characteristics described are from validation studies, not from a "training" phase.

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

Given that this is an RT-PCR assay and not an AI/ML device that requires a "training set" with ground truth in the AI context, this question is not applicable. The "ground truth" for developing such an assay would come from extensive analytical characterization against known viral positive and negative samples, including quantified viral loads, verified by traditional virological methods (e.g., cell culture infectivity assays, reference PCR methods).

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The Quidel Molecular RSV + hMPV assay is a multiplex Real Time RT-PCR assay for the in vitro qualitative detection and identification of respiratory syncytial virus and human metapneumovirus viral RNA extracted from nasal and nasopharyngeal swabs specimens from patients with signs and symptoms of respiratory infection. This in vitro diagnostic test is intended to aid in the differential diagnosis of respiratory syncytial virus and human metapneumovirus infections. This test is not intended to differentiate the four genetic sub-lineages of hMPV.

Negative results do not preclude RSV or hMPV infection and should not be used as the sole basis for diagnosis, treatment or other patient management decisions.

The Quidel Molecular RSV + hMPV Assay detects viral nucleic acids that have been extracted from a patient sample using the NucliSENS® easyMAG® automated extraction platform. A multiplex RT-PCR reaction is carried out under optimized conditions in a single tube generating amplicons for each of the target viruses present in the sample. This reaction is performed utilizing either the Cepheid SmartCycler® II or the Applied Biosystems 7500 Fast DX. Identification of RSV and hMPV and the PRC occurs by the use of target-specific primers and fluorescent-labeled probes that hybridize to conserved regions in the genomes of RSV and hMPV and the PRC.

Here's a summary of the acceptance criteria and study details for the Quidel Molecular RSV + hMPV Assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria provided in the document are primarily for analytical performance (LoD, Reproducibility, Inclusivity, Specificity) and clinical performance (Sensitivity and Specificity/Positive and Negative Percent Agreement). The clinical performance is reported compared to predicate devices or established methods.

Device: Quidel Molecular RSV + hMPV Assay

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

• Clinical Performance Test Set Samples:
  • Total samples collected: 1014 specimens (414 fresh, 600 frozen) for RSV comparison.
  • RSV testing (SmartCycler II): 1009 specimens after excluding contaminated cell cultures.
  • hMPV testing (SmartCycler II): 951 specimens after excluding invalid comparative device results.
  • RSV testing (7500 Fast Dx): 1007 specimens after excluding contaminated cell cultures and invalid subject method results.
  • hMPV testing (7500 Fast Dx): 946 specimens after excluding invalid comparative and subject method results.
• Data Provenance: The samples were collected prospectively during the 2012 respiratory virus season (January to March 2012) from symptomatic patients at four sites across the United States. The study specifically used "fresh (414) and frozen (600) swab specimens."

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

The document does not explicitly state the number or qualifications of experts used. However, the ground truth for RSV was established using "DSFA & Cell Culture w/DFA" (Direct Specimen Fluorescent Antibody and Cell Culture with DFA), which implies interpretation by trained laboratory personnel or specialists, although their specific qualifications or number are not detailed. For hMPV, the ground truth was established by comparing it to the "FDA Cleared hMPV molecular test" (Gen-Probe Prodesse Pro hMPV+, K082688), which is a molecular diagnostic method rather than expert interpretation of raw data.

4. Adjudication Method for the Test Set

• RSV Discrepant Results:
  • For the SmartCycler II, all 21 originally discordant specimens (QM RSV + hMPV positive, reference method negative) were positive for RSV by an FDA-cleared RT-PCR assay and by bi-directional sequence analysis.
  • For the 7500 Fast Dx, 25 of 28 originally discordant specimens were positive by an FDA-cleared RT-PCR assay, and 27 of 28 were positive by bi-directional sequence analysis.
• hMPV Discrepant Results:
  • For both the SmartCycler II and the 7500 Fast Dx, all originally discordant specimens (QM RSV + hMPV positive, reference method negative) were positive for hMPV by bi-directional sequence analysis.

This indicates a form of post-hoc adjudication or discrepancy resolution using additional, more definitive molecular methods (FDA-cleared RT-PCR and bi-directional sequencing) for cases where the subject device and the initial reference method disagreed.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

No, this was not an MRMC study. The device is an in vitro diagnostic (molecular assay) for direct detection of viral RNA, not an imaging device requiring human reader interpretation or AI assistance in interpretation. Therefore, a multi-reader multi-case comparative effectiveness study on human reader improvement with or without AI assistance is not applicable here.

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

Yes, the clinical performance study evaluates the standalone performance of the Quidel Molecular RSV + hMPV Assay. The results are presented as the device's agreement (sensitivity, specificity, positive/negative percent agreement) compared directly to the reference methods, without human interpretation of the assay results impacting the reported performance metrics. The assay itself provides a qualitative (positive/negative) result based on its internal thresholding (e.g., fluorescence achieved by 50 cycles on SmartCycler II or 35 cycles on ABI 7500 Fast Dx).

7. The Type of Ground Truth Used

• For RSV: The ground truth for clinical performance was established using Direct Specimen Fluorescent Antibody (DSFA) and Cell Culture with DFA.
• For hMPV: The ground truth for clinical performance was established using an FDA Cleared hMPV molecular test (Gen-Probe Prodesse Pro hMPV+).
• For discrepant results: Bi-directional sequence analysis and/or another FDA-cleared RT-PCR assay were used as definitive ground truth.

8. The Sample Size for the Training Set

The document does not explicitly state a sample size for a "training set" in the context of machine learning or algorithm development. For this type of molecular diagnostic assay, analytical studies (LoD, inclusivity, specificity) and clinical validation are performed. The LoD study involved replicates of serially diluted viral cultures, and inclusivity/specificity studies used panels of various strains/organisms. These analytical studies are analogous to "training" or "development" data in that they inform and validate the assay's operational parameters, but they are not framed as a classic machine learning training set.

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

Given that this is a molecular diagnostic assay, the "ground truth" for establishing analytical parameters (like LoD, inclusivity, and specificity) is based on:

• Quantified viral cultures (TCID50/mL): Used for LoD studies, where the exact concentration of virus is known.
• Known viral strains or bacterial/yeast cultures: Used for inclusivity (known to contain the target virus) and specificity (known to contain other organisms to test for cross-reactivity) studies. The identity and concentration of these cultures are established through standard microbiological and virological techniques.

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