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The Prodesse® Pro hMPV®+ Assay is a Real-Time PCR (RT-PCR) in vitro diagnostic test for the qualitative detection of human Metapneumovirus (hMPV) nucleic acid isolated and purified from nasopharyngeal swab (NP) specimens obtained from individuals exhibiting signs and symptoms of acute respiratory infection. This Assay targets a highly conserved region of the Nucleocapsid gene of hMPV. The detection of hMPV nucleic acid from symptomatic patients aids in the diagnosis of human respiratory hMPV infection if used in conjunction with other clinical and laboratory findings. This test is not intended to differentiate the four genetic sub-lineages of hMPV.

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

The Pro hMPV+ Assay enables detection of human Metapneumovirus and internal control nucleic acid. Nasopharyngeal swab specimens are collected from patients with signs and symptoms of a respiratory infection using a polyester, rayon or nylon tipped swab and placed into viral transport medium.

A Universal Internal Control (UIC) is added to each sample prior to nucleic acid isolation to monitor for inhibitors present in the specimens. The isolation and purification of the nucleic acids is performed using either a MagNA Pure LC Instrument (Roche) and the MagNA Pure Total Nucleic Acid Isolation Kit (Roche) or a NucliSENS® easyMAG™ System (bioMérieux) and the Automated Magnetic Extraction Reagents (bioMérieux).

The purified nucleic acids are added to Pro hMPV+ Supermix along with enzymes included in the Pro hMPV+ Assay Kit. The Pro hMPV+ Supermix contains oligonucleotide primers complementary to a highly conserved region of the Nucleocapsid gene of hMPV and a targetspecific oligonucleotide probe dual-labeled with a reporter dye attached to the 5'-end and a quencher dve attached to nucleotide #7 from the 5 end.

Reverse transcription of the RNA in the sample into complementary DNA (cDNA) and subsequent amplification of DNA is performed in a Cepheid SmartCycler® II instrument. In this process, the probe anneals specifically to the template followed by primer extension and amplification. The Pro hMPV+ Assay is based on Taqman chemistry, which utilizes the 5' - 3' exonuclease activity of the Taq polymerase to cleave the probe thus separating the reporter dye from the quencher. This generates an increase in fluorescent signal upon excitation from a light source. With each cycle, additional reporter dye molecules are cleaved from their respective probes, further increasing fluorescent signal. The amount of fluorescence at any given cycle is dependent on the amount of amplification products present at that time. Fluorescent intensity is monitored during each PCR cycle by the SmartCyclerII instrument.

Here's a breakdown of the acceptance criteria and study information for the Prodesse® Pro hMPV®+ Assay, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state numerical acceptance criteria in terms of sensitivity, specificity, or predictive values. Instead, the "Verification/Validation Result" column of the "SUBSTANTIAL EQUIVALENCE" table functions as the reported performance, indicating that the modified device continues to meet the performance claims of the predicate device.

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

The document mentions a "retrospective clinical comparison study" (page 2), but does not specify the sample size used for this study. It also does not explicitly state the country of origin. The term "retrospective" indicates that the data was collected prior to the study being designed.

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

The document does not provide information on the number of experts used or their qualifications for establishing ground truth in the clinical comparison study.

4. Adjudication Method for the Test Set

The document does not specify any adjudication method for the test set used in the clinical comparison study.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and the Effect Size of Human Readers Improve with AI vs. Without AI Assistance

This question is not applicable to this device. The Prodesse® Pro hMPV®+ Assay is an in vitro diagnostic test (Real-Time PCR) for qualitative detection of nucleic acid, not an AI-powered diagnostic imaging or interpretation device that would involve human readers or MRMC studies.

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

Yes, the studies described (analytical sensitivity, IC interference, extractor equivalency, and sample stability) and the clinical comparison study effectively demonstrate the standalone performance of the assay as an in vitro diagnostic test. The "algorithm" here is the assay's chemical and enzymatic process, and its performance is evaluated in isolation.

7. The Type of Ground Truth Used

Based on the nature of the device (a diagnostic test for a pathogen), the ground truth for human Metapneumovirus (hMPV) infection would likely be based on clinical diagnosis in conjunction with other laboratory findings, as suggested by the intended use statement: "The detection of hMPV nucleic acid from symptomatic patients aids in the diagnosis of human respiratory hMPV infection if used in conjunction with other clinical and laboratory findings."
For the analytical studies (LOD, interference, etc.), the ground truth would be established by controlled experiments with known concentrations of the target analyte (hMPV nucleic acid) and known interfering substances.

8. The Sample Size for the Training Set

The document does not mention a training set sample size. This is common for predicate-based 510(k) submissions where the device "continues to meet the performance claims" of an already approved device, rather than being a de novo artificial intelligence or machine learning device that requires explicit training data. The development of the original predicate device would have involved internal optimization and validation, but these details are not provided for this submission.

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

As no explicit "training set" is mentioned in the context of this 510(k) submission (due to it being a modification of an existing device), the method for establishing ground truth for a training set (if one were used in the original development) is not described. For the development and optimization of the original assay, ground truth would have been established through methods similar to those described in point 7, involving known positive and negative controls, spiked samples, and potentially clinical samples with confirmed hMPV status.

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The Pro hMPV™+ Assay is a Real-Time PCR (RT-PCR) in vitro diagnostic test for the qualitative detection of human Metapneumovirus (hMPV) nucleic acid isolated and purified from nasopharyngeal swab (NP) specimens obtained from individuals exhibiting signs and symptoms of acute respiratory infection. This assay targets a highly conserved region of the Nucleocapsid gene of hMPV. The detection of hMPVnucleic acid from symptomatic patients aids in the diagnosis of human respiratory hMPV infection if used in conjunction with other clinical and laboratory findings. This test is not intended to differentiate the four genetic sub-lineages of hMPV.

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

The Pro hMPV+ Assay enables detection human Metapneumovirus and Internal Control nucleic acid. Nasopharyngeal swab specimens are collected from patients with signs and symptoms of a respiratory infection using a polyester, rayon or nylon tipped swab and placed into viral transport medium.

An Internal Control (IC) is added to each sample prior to nucleic acid isolation to monitor for inhibitors present in the specimens. The isolation and purification of the nucleic acids is performed using either a MagNA Pure LC Instrument (Roche) and the MagNA Pure Total Nucleic Acid Isolation Kit (Roche) or a NucliSENS easyMAGTM System (bioMérieux) and the Automated Magnetic Extraction Reagents (bioMérieux).

The purified nucleic acids are added to Pro hMPV+ Supermix along with enzymes included in the Pro hMPV+ Assay Kit. The Pro hMPV+ Supermix contains oligonucleotide primers and target-specific oligonucleotide probes. The primers are complementary to highly conserved regions of genetic sequences for these respiratory viruses. The probes are dual-labeled with a reporter dye attached to the 51-end and a quencher dye attached to the 3'-end.

Reverse transcription of the RNA in the sample into complementary DNA (cDNA) and subsequent amplification of DNA is performed in a Cepheid SmartCycler® II instrument. In this process, the probe anneals specifically to the template followed by primer extension and amplification. The Pro hMPV+ Assay is based on Taqman chemistry, which utilizes the 5' - 3' exonuclease activity of the Taq polymerase to cleave the probe thus separating the reporter dye from the quencher. This generates an increase in fluorescent signal upon excitation from a light source. additional reporter dye molecules are cleaved from their respective probes, further increasing fluorescent signal. The amount of fluorescence at any given cycle is dependent on the amount of amplification products present at that time, Fluorescent intensity is monitored during each PCR cycle by the SmartCyclerII instrument.

Here's an analysis of the provided information, structured according to your request:

1. Table of Acceptance Criteria and Reported Device Performance

The document compares the "New Pro hMPV+ Assay" (reformulated) to the "Current Pro hMPV+ Assay" (predicate device). The acceptance criteria are implied by the "Percent Positive Agreement" and "Percent Negative Agreement" with confidence intervals. While specific numerical acceptance criteria (e.g., "must be >90%") are not explicitly stated, the reported performance is presented as demonstrating substantial equivalence.

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

• Sample Size (Clinical Comparison): 183 nasopharyngeal swab samples (one sample was excluded from the final analysis, resulting in 182).
• Data Provenance: Retrospective, collected during 2011-2012 from two sites: Milwaukee, WI, and Chicago, IL, USA.

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

The document does not mention the use of experts to establish the ground truth for the clinical comparison study. Instead, the "ground truth" was established by:

• "True" hMPV positives: Defined as any sample that tested positive by the original Pro hMPV+ Assay.
• "True" hMPV negatives: Defined as any sample that tested negative by the original Pro hMPV+ Assay.
• Discrepant Analysis: For samples where the new and original assays disagreed, RT-PCR with hMPV specific primers targeting the hMPV phosphoprotein gene followed by bi-directional genetic sequencing was performed. The document does not specify who performed this analysis or their qualifications, but this would be a laboratory-based method.

4. Adjudication Method for the Test Set

The primary comparison was against the predicate device's results. For discrepancies, a molecular method (RT-PCR followed by bi-directional genetic sequencing) was used to resolve disagreements. This acts as a form of "adjudication" based on a more definitive molecular test, rather than human expert consensus.

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 reported. This study evaluates human reader performance, with or without AI assistance. The described study is a comparison of two in vitro diagnostic (IVD) assays.

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

Yes, the described clinical comparison study is a standalone assessment of the new IVD assay's performance against the predicate IVD assay. There is no human-in-the-loop component mentioned; it evaluates the assay's ability to detect hMPV directly from samples.

7. The Type of Ground Truth Used

The ground truth for the clinical comparison study was multi-faceted:

• Reference standard (initial): The results of the predicate device (original Pro hMPV+ Assay).
• Adjudication/Confirmatory method: For discrepant results, RT-PCR with hMPV specific primers targeting the hMPV phosphoprotein gene followed by bi-directional genetic sequencing was used, which can be considered a more definitive molecular ground truth.

8. The Sample Size for the Training Set

The document does not specify a separate training set. The study describes the re-formulation of an existing assay and its performance evaluation. Diagnostic assays like this typically undergo development and optimization phases (which might involve various "training" or optimization samples), but the clinical comparison details the final performance validation using a test set.

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

As no specific training set is outlined in this document, the method for establishing its ground truth is not provided. The information focuses on the validation of the reformulated assay.

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The Pro hMPV+ Assay is a Real Time RT-PCR in vitro diagnostic test for the qualitative detection of human Metapneumovirus (hMPV) nucleic acid isolated and purified from nasopharyngeal swab (NP) specimens obtained from individuals exhibiting signs and symptoms of acute respiratory infection. This assay targets a highly conserved region of the Nucleocapsid gene of hMPV. The detection of hMPV nucleic acid from symptomatic patients aids in the diagnosis of human respiratory hMPV infection if used in conjunction with other clinical and laboratory findings. This test is not intended to differentiate the four genetic sub-lineages of hMPV.

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

The Pro hMPV+ Assay enables detection human Metapneumovirus and Internal Control nucleic acid. Nasopharyngeal swab specimens are collected from patients with signs and symptoms of a respiratory infection using a polyester, rayon or nylon tipped swab and placed into viral transport medium.

An Internal Control (IC) is added to each sample prior to nucleic acid isolation to monitor for inhibitors present in the specimens. The isolation and purification of the nucleic acids is performed using either a MagNA Pure LC Instrument (Roche) and the MagNA Pure Total Nucleic Acid Isolation Kit (Roche) or a NucliSENS® easyMAG™ System (bioMérieux) and the Automated Magnetic Extraction Reagents (bioMérieux).

The purified nucleic acids are added to Pro hMPV+ Supermix along with enzymes included in the Pro hMPV+ Assay Kit. The Pro hMPV+ Supermix contains oligonucleotide primers and target-specific oligonucleotide probes. The primers are complementary to highly conserved regions of genetic sequences for these respiratory viruses. The probes are dual-labeled with a reporter dye attached to the 5'-end and a quencher dye attached to the 3'-end.

Reverse transcription of the RNA in the sample into complementary DNA (cDNA) and subsequent amplification of DNA is performed in a Cepheid SmartCycler® II instrument. In this process, the probe anneals specifically to the template followed by primer extension and amplification. The Pro hMPV+ Assay is based on Taqman chemistry, which utilizes the 5' - 3' exonuclease activity of the Taq polymerase to cleave the probe thus separating the reporter dye from the quencher. This generates an increase in fluorescent signal upon excitation from a light source. With each cycle, additional reporter dye molecules are cleaved from their respective probes, further increasing fluorescent signal. The amount of fluorescence at any given cycle is dependent on the amount of amplification products present at that time. Fluorescent intensity is monitored during each PCR cycle by the SmartCyclerII instrument.

Here's an analysis of the acceptance criteria and study detailed in the provided 510(k) summary for the Pro hMPV+ Assay:

Acceptance Criteria and Device Performance for Pro hMPV+ Assay

This summary focuses on the clinical performance of the Pro hMPV+ Assay, which is a Real Time RT-PCR in vitro diagnostic test for the qualitative detection of human Metapneumovirus (hMPV).

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for the clinical performance metrics (Percent Positive Agreement, Percent Negative Agreement). However, the reported performance is presented with 95% Confidence Intervals, which allows for an assessment of the assay's accuracy. For the purpose of this analysis, we will infer the desired performance to be high agreement with the composite reference methods.

2. Sample Size and Data Provenance for the Test Set

• Sample Size: A total of 1275 eligible nasopharyngeal (NP) swab samples were tested and included in the analysis.
• Data Provenance: The study was a prospective study conducted at 4 U.S. clinical laboratories during the 2008 respiratory virus season (January - March). The specimens represented excess NP swab specimens proactively collected from symptomatic individuals suspected of respiratory infection.

3. Number of Experts and Qualifications for Ground Truth Establishment (Test Set)

The ground truth was established using composite reference methods, which involved molecular testing and genetic sequencing, rather than direct expert interpretation of test results. Therefore, the concept of "experts" in the traditional sense (e.g., radiologists) for establishing ground truth doesn't directly apply here.

However, the "experts" involved would be the laboratory personnel performing the molecular (RT-PCR) tests and subsequent genetic sequencing, and those interpreting the sequencing data against the NCBI GenBank database. While no explicit qualifications are given, it can be inferred that these individuals are qualified laboratory professionals experienced in molecular diagnostics and bioinformatics, as they are performing highly specialized and technical analyses for clinical diagnostic purposes.

4. Adjudication Method for the Test Set

The adjudication method for establishing the ground truth was a composite reference standard approach:

• Two independent molecular (RT-PCR) tests for two separate gene targets of hMPV.
• Followed by bidirectional genetic sequencing of those targets.

True hMPV RNA positives were defined as any sample with bidirectional sequencing data meeting pre-defined quality acceptance criteria for one or both gene targets that matched hMPV sequences in the NCBI GenBank database.
True hMPV RNA negatives were defined as any sample tested negative by both comparator methods.

This effectively acts as an internal adjudication process based on multiple, high-specificity molecular methods. There is no mention of a human expert adjudication committee in the traditional sense (e.g., 2+1, 3+1).

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted. This device is an in vitro diagnostic test, not an AI-assisted human reader interpretation tool. Therefore, the concept of measuring how much human readers improve with AI vs. without AI assistance is not applicable.

6. Standalone Performance (Algorithm Only Without Human-in-the-Loop)

Yes, a standalone (algorithm only) performance study was conducted. The "Pro hMPV+ Assay" itself is the algorithm (or diagnostic method) being evaluated. Its performance was assessed directly against the composite reference methods. There is no human-in-the-loop component in its reported diagnostic performance.

7. Type of Ground Truth Used

The type of ground truth used was a composite reference standard based on:

• Molecular diagnostic testing (two independent RT-PCR tests) for different hMPV gene targets.
• Bi-directional genetic sequencing of those targets.
• Comparison of sequencing data to the National Center for Biotechnology Information (NCBI) GenBank database.

This is a highly reliable and objective form of ground truth for viral detection.

8. Sample Size for the Training Set

The document does not provide information regarding a distinct "training set" sample size. For in vitro diagnostic assays like the Pro hMPV+ Assay, the development process typically involves internal validation and optimization studies (which might be analogous to "training"), but specific sample sizes for these internal activities are usually not detailed in 510(k) summaries, which focus on the clinical validation (test set).

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

As no specific "training set" and its sample size were described, the method for establishing its ground truth is also not provided in this document. During assay development, ground truth for optimization and development samples would typically be established using similar highly sensitive and specific methods (e.g., highly characterized positive and negative controls, sequencing, or alternative validated molecular methods).

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