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The Influenza A/B Typing Kit contains reagents and controls of the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument that has been FDA-cleared for use with this kit in conjunction with clinical and epidemiological information:
· For qualitative detection of influenza virus type A or B viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NPS], throat swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture;
· To provide epidemiologic information for surveillance of circulating influenza viruses.

The Influenza A Subtyping Kit contains reagents and controls of the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument that has been FDA-cleared for use with this kit in conjunction with clinical and epidemiological information:
· For determination of the subtype of seasonal human influenza A viruses as seasonal A(H3), and/or A(H1)pdm09 from viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NS], throat swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and or from viral culture;
· To provide epidemiologic information for surveillance of circulating influenza viruses.

The Influenza B Lineage Genotyping Kit contains reagents and controls of the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR ) assays on an in vitro diagnostic realtime PCR instrument that has been FDA-cleared for use with this kit in conjunction with clinical and epidemiological information:
· For the determination of the genetic lineage of human influenza B viruses as B/Victoria or B/Yamagata lineage from viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NS], throat swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) from human patients with signs and symptoms of respiratory infection and/or from viral culture;
· To provide epidemiologic information for surveillance of circulating influenza viruses.

The Influenza A/H5 Subtyping Kit contains reagents and controls of the CDC Human Influenza Virus RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR ) assays on an in vitro diagnostic real-time PCR instrument that has been FDA-cleared for use with this kit in conjunction with clinical and epidemiological information:
· For the 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 of circulating influenza viruses.

The CDC Human Influenza Real-Time RT-PCR Diagnostic Panel is used in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR system. The panel is configured in four separate kits. Each kit consists of oligonucleotide primers, fluorescently labeled hydrolysis probes, and controls which are used in rRT-PCR assays for the in vitro qualitative detection and characterization of influenza virus RNA in respiratory specimens from patients presenting with influenza-like illness (ILI). Oligonucleotide primers and probes for detection of influenza A, influenza B, and 2009 influenza A (swine origin) were selected from highly conserved regions of the matrix (M), non-structural (NS), and nucleoprotein (NP) genes, respectively. Oligonucleotide primers and probes for characterization and differentiation of influenza A(H3) and A(H1)pdm(9 viruses and genetic lineages of influenza B were selected from highly conserved regions of their HA genes. Oligonucleotide primers and probes to detect the human RNase P gene (RP) in control samples and clinical specimens is also included in the panel.

Here's a breakdown of the acceptance criteria and study details based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance:

The document focuses on demonstrating substantial equivalence of the modified device (with new PCR instruments) to a predicate device. The key acceptance criteria are related to analytical sensitivity (Limit of Detection or LOD) and reproducibility, and clinical agreement.

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

• Analytical Sensitivity (LOD):

  • For each virus type and dilution: Triplicate samples were tested. The testing involved multiple influenza viruses (e.g., A/H3N2, A/H1N1pdm09, B/Victoria, B/Yamagata, A/H5N8) and two enzyme systems (SuperScript and qScript) across the original instrument and the two new instruments. It's difficult to give a single "sample size" number but it involved a substantial number of replicates across various conditions to establish LOD.
  • Data Provenance: The samples were "characterized influenza viruses of known egg infectious dose 50% titer," diluted in BPL-treated A549 cells in viral transport medium (VTM). This indicates laboratory-prepared, controlled samples.

• Analytical Precision (Reproducibility):

  • Sample Size: A blinded panel of 5 contrived samples (moderate positive A/H3N2, moderate positive B/Victoria, negative, low positive A/H3N2, low positive B/Victoria). Each sample was tested by two analysts at each of three sites, over five different days. This means for each contrived sample, there were $3 \text{ sites} \times 2 \text{ analysts} \times 5 \text{ days} = 30$ results. Across the 5 samples this totals $5 \text{ samples} \times 30 \text{ tests/sample} = 150$ tests for the QSDx and 150 for the QMDx.
  • Data Provenance: Contrived samples (BPL-treated A549 cells in VTM, spiked with BPL-treated influenza A(H3N2) or B/Victoria virus).

• Carryover and Cross-contamination:

  • Sample Size: An alternating pattern of high positive (HP) and negative (N) contrived samples. There were 5 high positive samples and 5 negative samples tested across 5 runs. The tables show 5 sets of HP samples and 5 sets of N samples for each assay (InfA, H5a, H5b, RP). For each assay, this means $5 \text{ HP samples} \times 5 \text{ runs} = 25$ tests and $5 \text{ N samples} \times 5 \text{ runs} = 25$ tests.
  • Data Provenance: Contrived samples (BPL-inactivated influenza A/gyrfalcon/41088-6/2014 (H5N8) in A549 cells).

• Clinical Performance Evaluation:

  • Sample Size: A total of 50 clinical specimens and 10 contrived samples with influenza A(H5) were used as positive samples (totaling 60 positive samples if the contrived A(H5) are counted separate from the 50 general clinical positives). And 50 negative specimens. So, a total of 100 retrospective samples (50 positive, 50 negative) were evaluated against the QSDx and QMDx independently.
  • Data Provenance:
    • Retrospective clinical specimens: Collected during the 2013-2014 influenza seasons. (Country of origin not specified, but given the CDC involvement, likely U.S.)
    • Contrived samples: The 10 A(H5) samples were "prepared with BPL-inactivated influenza A(H5) virus in a suspension of human A549 cells and virus transport medium."

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

The document does not explicitly mention the number of experts or their specific qualifications for establishing ground truth for the test set (clinical performance evaluation).

• For the analytical studies (LOD, reproducibility, carryover), the ground truth was established by the known characteristics of the prepared viral stocks and dilutions.
• For the clinical performance, the ground truth was established by the "previously determined" results using the FDA-cleared Applied Biosystems™ 7500 Fast Dx. This implies that the predicate device serves as the ground truth. It does not state that independent experts re-adjudicated these samples, but rather that the previously established results from a gold-standard method were used.

4. Adjudication Method for the Test Set:

No explicit adjudication method (e.g., 2+1, 3+1) is described for the clinical test set. The clinical samples were "previously determined to be positive using the Applied Biosystems™ 7500 Fast Dx." This implies the predicate device's results were considered the reference standard for comparison.

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

This device is an in-vitro diagnostic (IVD) RT-PCR kit, not an AI-assisted diagnostic imaging device that involves human "readers" or AI assistance to humans. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable and was not performed.

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

The entire study focuses on the standalone performance of the device (RT-PCR kit with its associated instruments). The device is an automated molecular diagnostic assay, not an AI algorithm. Its performance is evaluated objectively based on its ability to detect and characterize viral RNA. While human analysts perform the procedure and interpret the output, the core 'performance' refers to the analytical and clinical accuracy of the molecular reactions and instrument readings.

7. The Type of Ground Truth Used:

• Analytical Studies (LOD, Reproducibility, Carryover): The ground truth was based on known concentrations of characterized viral stocks (EID50/mL titer) and the specific composition of contrived samples (known to be positive or negative for certain influenza strains). This is a form of laboratory-established ground truth.
• Clinical Performance Evaluation: The ground truth for the clinical specimens was derived from results previously obtained using the FDA-cleared Applied Biosystems™ 7500 Fast Dx. This acts as a reference standard from a legally marketed and established device. For the A(H5) samples, it was based on the known composition of the contrived samples.

8. The Sample Size for the Training Set:

The document describes an evaluation study for substantial equivalence of a molecular diagnostic kit with new instrument platforms. It does not mention a "training set" in the context of machine learning. The "training" for such a molecular kit would involve the extensive R&D and optimization of the primer/probe sets and PCR conditions during the device's development, not a data-based training set for an AI algorithm.

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

As mentioned above, there is no explicit "training set" in the machine learning sense described in this document. The ground truth for the development and optimization of such a diagnostic panel typically involves:

• Known viral isolates/strains: Using cultured viruses with confirmed identity and titer.
• Sequencing data: To design highly specific and sensitive primers/probes targeting conserved regions of the viral genome.
• Clinical validation: Testing against a large panel of clinical samples, where the true infection status (ground truth) is established through gold-standard methods (e.g., viral culture, sequencing, or other highly sensitive and specific molecular tests) performed by expert laboratories.

The document briefly states: "Oligonucleotide primers and probes for detection of influenza A, influenza B, and 2009 influenza A (swine origin) were selected from highly conserved regions of the matrix (M), non-structural (NS), and nucleoprotein (NP) genes, respectively. Oligonucleotide primers and probes for characterization and differentiation of influenza A(H3) and A(H1)pdm(9 viruses and genetic lineages of influenza B were selected from highly conserved regions of their HA genes." This suggests an established ground truth based on genomic sequencing and bioinformatic analysis to design the assay.

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