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The Quidel Molecular RSV + hMPV Assay is a multiplex Real-Time PCR (RT-PCR) assay for the qualitative detection and identification of respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) ribonucleic acid (RNA) extracted from nasal and nasopharyngeal swab specimens from patients with signs and symptoms of respiratory infection. This in vitro diagnostic test is intended to aid in the differential diagnosis of RSV and hMPV infections in humans in conjunction with clinical and epidemiological risk factors. This test is not intended to differentiate the two subtypes of RSV or the four genetic sub-lineages of hMPV.

Negative results do not preclude RSV infection and/or hMPV infection and should not be used as the sole basis for diagnosis, treatment or other patient 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 and clinical presentation must be considered in order to obtain the final diagnosis of respiratory viral infection.

The Quidel Molecular RSV + hMPV Assay can be performed using either the Life Technologies QuantStudio™ Dx RT-PCR Instrument, the Applied Biosystems® 7500 Fast Dx RT-PCR Instrument, or the Cepheid SmartCycler® II System.

The Quidel Molecular RSV + hMPV Assay detects viral nucleic acids that have been extracted from a patient sample using the bioMérieux 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 the Cepheid SmartCycler II, the Applied Biosystems 7500 Fast Dx. or the Life Technologies QuantStudio Dx. Identification of RSV, hMPV, and the process control (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.

Acceptance Criteria and Study for Quidel Molecular RSV + hMPV Assay

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state pre-defined acceptance criteria (e.g., minimum PPA/NPA percentages or specific LoD values that must be met for approval). However, it implicitly demonstrates acceptable performance by comparing the device to FDA-cleared predicate devices and presenting the results of analytical and clinical studies. We can infer the "reported device performance" from the "Combined Clinical Site Data" table.

Detailed Reproducibility Results (RSV):

Detailed Reproducibility Results (hMPV):

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

• Test Set Sample Size:
  • RSV: 700 nasal or nasopharyngeal swab specimens (after removing 13 invalid specimens from an initial 713).
  • hMPV: 707 nasal or nasopharyngeal swab specimens (after removing 6 invalid specimens from an initial 713).
• Data Provenance: Prospective study conducted during the 2013 respiratory virus season (January to March 2013) at three sites across the United States.

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

The ground truth for the clinical performance study was established by two FDA-cleared RT-PCR assays (Prodesse ProFlu+ and Pro hMPV+), rather than human experts. Thus, information about the number and qualifications of experts is not applicable to this study design.

4. Adjudication Method for the Test Set

The ground truth was established by two FDA-cleared predicate RT-PCR assays. The document does not describe an explicit adjudication method between these predicate devices or between the predicate devices and an independent reference standard. For each virus (RSV and hMPV) separately, the results of the Quidel Molecular assay were compared directly against the respective predicate device's results.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not done. This study compares the performance of a molecular diagnostic assay against other molecular diagnostic assays, not the performance of human readers with and without AI assistance.

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

Yes, the study describes the "standalone" performance of the Quidel Molecular RSV + hMPV Assay. It is a molecular diagnostic test that produces a qualitative result (positive/negative) based on the detection of viral nucleic acids through RT-PCR, without human interpretation of complex images or data that would typically involve a "human-in-the-loop" decision process. The output is directly generated by the instrument based on the fluorescent signal.

7. The Type of Ground Truth Used

The ground truth for the clinical performance study was established using comparison to FDA-cleared RT-PCR predicate devices. Specifically:

• For RSV, the predicate device was Prodesse ProFlu+.
• For hMPV, the predicate device was Prodesse Pro hMPV+.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" for the purpose of algorithm development or machine learning in the conventional sense. This is a molecular diagnostic assay where primers and probes are designed to target specific viral genes. The "development" of the assay involves optimizing reaction conditions, not training a machine learning model. Therefore, providing a sample size for a training set in this context is not applicable.

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

As noted above, the concept of a "training set" for this type of molecular diagnostic assay is not directly applicable. The "ground truth" for developing the analytical performance characteristics (like LoD, inclusivity, specificity) would have been established through controlled laboratory experiments using known quantities and strains of viruses, and known negative samples. These are standard methods in the development of PCR-based diagnostics.

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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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