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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 Cepheid® Xpert Flu Assay is an automated, multiplex real-time RT-PCR assay intended for the in vitro qualitative detection and differentiation of influenza B and 2009 H1N1 influenza viral RNA. The Xpert Flu Assay uses nasal aspirates/washes and nasopharyngeal swab specimens collected from patients with signs and symptoms of respiratory infection in conjunction with clinical and epidemiological risk factors. The Xpert Flu Assay is intended as an aid in the diagnosis of influenza.

Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other patient management decisions.

Performance characteristics for influenza A were established during the 2009-2010 influenza season when 2009 H1N1 influenza was the predominant influenza A virus 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.

The Xpert Flu Assay is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A, influenza B and influenza A, subtype 2009 HINI. The assay is performed on the Cepheid GeneXpert Instrument Systems. The GeneXpert Instrument Systems automate and integrate sample purification, nucleic acid amplification, and detection of the target sequence in simple or complex samples using real-time PCR and RT-PCR assays. The systems require the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained and specimens never come into contact with working parts of the instrument modules, cross-contamination between samples is eliminated.

The Xpert Flu Assay includes reagents for the detection and differentiation of influenza A, influenza B and influenza A, subtype 2009 H1N1 directly from nasal aspirates/washes (NA/W) and nasopharyngeal (NP) swab specimens from patients with signs and symptoms of respiratory infection. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included. The SPC is present to control for adequate processing of the target viruses and to monitor the presence of inhibitors in the PCR reaction. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity and dye stability.

The liquid specimen (NA/W) or swab specimen (NP) is collected according to the institution's standard procedures and placed into Universal Transport Medium (3mL UTM tubes). Following a brief mixing by inverting the UTM tube five times, the eluted material and one single-use reagent (Reagent 1), that is provided with the assay, are transferred to different, uniquely-labeled chambers of the disposable fluidic cartridge (the Xpert Flu cartridge). The user initiates a test from the system user interface and places the cartridge into the GeneXpert instrument platform, which performs hands-off reverse transcription and real-time, multiplex polymerase chain reaction (PCR) for detection of DNA. In this platform, additional sample preparation, amplification, and real-time detection are all fully-automated and completely integrated.

The single-use, multi-chambered fluidic cartridges are designed to complete sample preparation and real-time RT-PCR for detection and differentiation of influenza A, influenza B and influenza A, subtype 2009 H1N1 in 75 minutes. The GeneXpert Instrument Systems have 1 to 48 randomly accessible modules that are each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and detection.

Acceptance Criteria and Device Performance Study for Xpert Flu Assay

This report details the acceptance criteria and the study proving the Cepheid Xpert Flu Assay meets these criteria, based on the provided 510(k) summary (K103766).

1. Table of Acceptance Criteria and Reported Device Performance

The 510(k) summary does not explicitly state pre-defined quantitative acceptance criteria for sensitivity and specificity. Instead, the clinical study results are presented as the "performance characteristics" and are compared against a reference method. It's implied that achieving high agreement with the reference method across various influenza types and specimen types constitutes acceptable performance for substantial equivalence.

Based on the clinical performance study, the device performance is reported as follows:

Clinical Performance on Prospective Nasal Aspirates/Washes (NA/W)

Clinical Performance on Prospective Nasopharyngeal (NP) Swabs

Clinical Performance on Archived NA/W Specimens (vs. FDA Cleared Molecular Comparator)

Clinical Performance on Archived NP Swabs (vs. Viral Culture + DFA)

Clinical Performance on Archived NP Swabs (vs. FDA Cleared Molecular Comparator)

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

Prospective Specimens:

• NA/W specimens: 342
• NP swab specimens: 297

Archived Specimens:

• NA/W specimens: 425
• NP swab specimens: 150 (compared to viral culture + DFA), 177 (compared to FDA cleared molecular assay)

Data Provenance: The clinical study was conducted at six institutions in the U.S. and Australia. The study included both prospective and archived 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 of experts or their specific qualifications (e.g., radiologist with X years of experience) used to establish the ground truth. However, the ground truth for "viral culture followed by direct fluorescent assay (DFA)" is a standard laboratory method, implying trained laboratory personnel perform these tests, which typically require specific certifications and experience. Sequencing results for influenza A positive specimens were also used as part of the ground truth.

4. Adjudication Method for the Test Set

The concept of an "adjudication method" (like 2+1, 3+1) is typically associated with studies where multiple human readers interpret results, and disagreement is resolved by an adjudicator. This is not directly applicable to a molecular diagnostic assay where results are objectively determined by instrumentation.

The document describes sequencing being performed for all influenza A positive specimens (identified by viral culture/DFA or the FDA cleared molecular assay) to differentiate subtypes. This acts as a confirmatory "adjudication" step for influenza A subtyping.

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 study is for a diagnostic assay, not an AI-assisted human reading task.

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

Yes, a standalone performance study was done. The Xpert Flu Assay is an automated, multiplex real-time RT-PCR assay intended for in vitro qualitative detection and differentiation of influenza viral RNA. The performance characteristics described in the "Clinical Performance Study" sections (Pgs. 14-21) are for the device (Xpert Flu Assay) operating independently, generating its own results. There is no human interpretation of imaging or other complex data involved in generating the primary test result from the assay itself.

7. The Type of Ground Truth Used

The ground truth used for the clinical performance study varied based on the specimen type and whether it was prospective or archived:

• Prospective specimens: Viral culture followed by direct fluorescent assay (DFA) was the primary comparator. This is a recognized laboratory standard.
• Archived specimens (where viral culture was not performed prior to freezing): An FDA cleared molecular assay was performed as the comparator assay.
• For all influenza A positive specimens (from both prospective and archived sets): Sequencing was used to differentiate influenza A subtypes (e.g., 2009 H1N1 from other influenza A). This can be considered as a highly specific confirmatory method.

8. The Sample Size for the Training Set

The document describes analytical and clinical performance studies but does not detail a separate "training set" or its size for an algorithm development since this is a molecular diagnostic assay, not a machine learning model in the typical sense. The assay is based on predefined biological reactions and detection thresholds, not trainable parameters derived from a large dataset. The analytical studies (Analytical Sensitivity, LoD, Analytical Specificity) and reproducibility studies define the assay's fundamental performance characteristics.

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

As noted above, there isn't a traditional "training set" as understood in machine learning. The assay's design and operating parameters would have been established through extensive laboratory work and optimization, including:

• Analytical Reactivity (Inclusivity): Testing against known influenza strains at specific concentrations (Table 5.2).
• Limit of Detection (LoD): Empirically determined as the lowest concentration (TCID50/mL) where 19/20 or 20/20 replicates were positive (Tables 5.3-5.6).
• Analytical Specificity (Exclusivity): Testing against potentially interfering viral, bacterial, and yeast strains at specified concentrations (Table 5.7).

These studies use well-defined, characterized strains and concentrations as their "ground truth" to ensure the assay performs as expected.

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The Human Influenza Virus Real-time RT-PCR Detection and Characterization Panel (rRT-PCR Flu Panel) is intended for use in Real-time RT-PCR assays on an AB1 7500 Fast Dx Real-time PCR instrument in conjunction with clinical and epidemiological information:

• for qualitative detection of influenza virus type A or B in symptomatic patients from viral RNA in nasopharyngeal and/or nasal swab specimens,
• for determination of the subtype of seasonal human influenza A virus, as seasonal A/H1 or A/H3, if present, from viral RNA in nasopharyngeal and/or nasal swab specimens,
• for presumptive identification of virus in patients who may be infected with influenza A subtype A/H5 (Asian lineage) from viral RNA in human respiratory specimens and viral culture in conjunction with clinical and epidemiological risk factors.
• to provide epidemiologic information for surveillance for influenza viruses.

The CDC Human Influenza Virus Real-time RT-PCR Detection and Characterization Panel (rRT-PCR Flu Panel) is a panel of oligonucleotide primers and dual-labeled hydrolysis (TagMan®) probes which may be used in real-time RT-PCR assays using the ABI 7500 Fast Dx Real-Time PCR instrument for the in vitro qualitative detection and characterization of human influenza viruses (RNA) in respiratory specimens from patients presenting with influenza-like illness (ILI). Detection of viral RNA not only aids in the diagnosis of illness caused by seasonal and novel influenza viruses in patients with ILI, but also provides epidemiologic information on influenza and aids in the presumptive laboratory identification of specific novel influenza A viruses.

Acceptance Criteria and Device Performance for CDC Human Influenza Virus Real-time RT-PCR Detection and Characterization Panel

1. Table of Acceptance Criteria and Reported Device Performance

Study Details:

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

• Clinical Performance (Seasonal Influenza - InfA, InfB, H1, H3):
  • Sample Size: 415 total prospective specimens.
  • Data Provenance: Prospective collection from US state public health laboratories during the 2006-2007 respiratory virus season (February-April).
  • Specimen Type: Nasal and nasopharyngeal swabs.
• Clinical Performance (Influenza A/H5N1):
  • Clinical Specimens: 24 retrospective A/H5 influenza samples.
  • Data Provenance: Retrospective from suspect positive cases received at CDC, "diverse geographic locations."
  • Cultured Specimens: Not explicitly stated sample size, but also used for H5 detection with 100% agreement.
  • Prospective Clinical Specimens (for negative agreement): Implied to be part of the 415 prospective seasonal specimens, where no H5 was detected.

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

• No specific number or qualifications of experts are explicitly mentioned for establishing ground truth.
• The reference method for prospective seasonal influenza samples was "rapid culture (shell vial) followed by direct fluorescent antibody screening and identification." This implies laboratory personnel with expertise in virology and cell culture.
• Influenza A/H5 and discrepant prospective seasonal influenza samples were "further analyzed by bidirectional sequencing," suggesting molecular biology experts.

4. Adjudication Method for the Test Set:

• No formal adjudication method (e.g., 2+1, 3+1) is explicitly described.
• The ground truth for prospective seasonal influenza was based on rapid culture (shell vial) followed by direct fluorescent antibody screening and identification.
• Discrepant prospective seasonal influenza samples and influenza A/H5 samples were further analyzed by bidirectional sequencing. This serves as an additional, higher-resolution method for resolving discrepancies or confirming difficult cases.

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

• No, an MRMC comparative effectiveness study was not done. This device is a diagnostic assay (RT-PCR panel) for detecting and characterizing influenza viruses, not an imaging device or a device that requires human interpretation in the same way an AI-powered image analysis tool would. Therefore, the concept of "human readers improve with AI vs. without AI assistance" does not apply here.

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

• Yes, the performance presented for the rRT-PCR Flu Panel is standalone (algorithm only, without human-in-the-loop performance). This device is a molecular diagnostic kit, and its performance metrics (sensitivity, specificity, LoD, etc.) reflect the intrinsic analytical and clinical capabilities of the assay itself when executed according to protocol. Human involvement is in sample preparation, running the assay, and interpreting the raw output (e.g., Ct values), but the "diagnosis" of the presence and type of virus is determined by the output of the PCR reaction.

7. The Type of Ground Truth Used:

• Expert Consensus and "Gold Standard" Laboratory Methods:
  • For prospective seasonal influenza, the ground truth was established by gold standard virus culture testing (rapid culture (shell vial) followed by direct fluorescent antibody screening and identification).
  • For influenza A/H5 and discrepant prospective seasonal influenza samples, the ground truth was further analyzed and confirmed by bidirectional sequencing. This suggests a form of expert-validated, highly accurate laboratory confirmation.

8. The Sample Size for the Training Set:

• Not Applicable / Not Explicitly Stated for a "training set" as understood in machine learning. This device is a molecular diagnostic panel based on designed primers and probes, not a machine learning model that undergoes explicit training. The "development" and "optimization" would have involved testing various primer/probe combinations against known virus strains, but this isn't analogous to a "training set" for an AI algorithm.
• However, for Analytical Specificity (Inclusivity), the document mentions initial testing with "ten (10) influenza virus strains of A/H/N1, A/H3N2, and influenza B" and "24 influenza A/H5N1 clinical samples tested retrospectively" to demonstrate the panel's ability to detect different strains. This could be considered akin to an internal validation set during development.

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

• As above, the concept of a "training set" for this type of medical device (RT-PCR panel) is not directly applicable in the same way it would be for an AI algorithm.
• The "ground truth" for the various influenza virus strains and non-influenza pathogens used in analytical studies would have been primarily established through known viral cultures, characterized bacterial/yeast cultures, and molecular sequencing (e.g., 16S ribosomal RNA bi-directional sequencing for bacteria, bi-directional sequencing for non-influenza respiratory viruses), all validated by standard laboratory practices.

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