(144 days)
The xTAG® Respiratory Viral Panel (RVP) is a qualitative nucleic acid multiplex test intended for the simultaneous detection and identification of multiple respiratory virus nucleic acids in nasopharyngeal swabs from individuals suspected of respiratory tract infections. The following virus types and subtypes are identified using RVP: Influenza B, Respiratory Syncytial Virus subtype A, Respiratory Syncytial Virus subtype B, Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus, Human Metapneumovirus, Rhinovirus, and Adenovirus. The detection and identification of specific viral nucleic acids from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection if used in conjunction with other clinical and laboratory findings.
xTAG RVP can also differentiate the hemagglutinin (HA) gene of some Influenza A subtypes H1 and H3 strains. Differentiation of Influenza A HA subtypes is based on both a positive result for the Influenza A matrix gene and an accompanying positive result for the Influenza A HA subtype H1 (circulating prior to the emergence of 2009 H1N1pdm) or Influenza A HA subtype H3. This device cannot differentiate the Influenza A HA subtype 2009 H1N1pdm by design, and may not be able to differentiate potential newly emerging Influenza A HA subtypes.
The modified RVP is a PCR-based test system for detecting the presence / absence of viral DNA / RNA in clinical specimens. The modified device is the same as the predicate device, except for a reformulation of the PCR primer mix.
The Luminex xTAG® Respiratory Viral Panel (RVP) is a qualitative nucleic acid multiplex test designed for the simultaneous detection and identification of multiple respiratory virus nucleic acids in nasopharyngeal swabs. The device was modified to improve reactivity to influenza A/H3 strains. The study referenced primarily focuses on demonstrating the substantial equivalence of the modified device to its predicate devices, especially concerning the improved detection of Influenza A H3.
1. A table of acceptance criteria and the reported device performance
The document does not explicitly state pre-defined acceptance criteria in terms of specific percentages for Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) to consider the device successful. However, the performance metrics observed in the clinical comparison study serve as the reported device performance, and the FDA's clearance implies these results were acceptable for demonstrating substantial equivalence. The key comparison is between the modified xTAG RVP and the original xTAG RVP, as well as against sequencing for Influenza A H3.
| Analyte | Reported PPA (Modified RVP vs. Original RVP) | Confidence Interval (PPA) | Reported NPA (Modified RVP vs. Original RVP) | Confidence Interval (NPA) | Additional Criteria/Performance (where available) |
|---|---|---|---|---|---|
| Influenza A | 98.09% (154/157) | 94.52%-99.60% | 99.06% (210/212) | 96.63%-99.89% | |
| Influenza A H1 | 100% (4/4) | 39.76%-100.00% | 100% (365/365) | 98.99%-100.00% | |
| Influenza A H3 | 100% (80/80) | 95.49%-100.00% | 85.47% (247/289) | 80.87%-89.32% | PPA for Modified RVP vs. Sequencing: 91.7% (121/132) CI: 87.82%-96.91% |
| Influenza B | 100% (30/30) | 88.43%-100.00% | 100% (339/339) | 98.92%-100.00% | |
| RSV A | 100% (23/23) | 85.18%-100.00% | 99.71% (345/346) | 98.40%-99.99% | |
| RSV B | 96.30% (26/27) | 81.03%-99.91% | 100% (342/342) | 98.93%-100.00% | |
| Parainfluenza 1 | 100% (6/6) | 54.07%-100.00% | 99.72% (362/363) | 98.47%-99.99% | |
| Parainfluenza 2 | 100% (8/8) | 63.06%-100.00% | 99.72% (360/361) | 98.47%-99.99% | |
| Parainfluenza 3 | 100% (24/24) | 85.75%-100.00% | 100% (345/345) | 98.94%-100.00% | |
| hMPV | 96.43% (27/28) | 81.65%-99.91% | 100% (341/341) | 98.92%-100.00% | |
| Rhinovirus | 92.16% (47/51) | 81.12%-97.82% | 99.69% (317/318) | 98.26%-99.99% | |
| Adenovirus | 100% (5/5) | 47.82%-100.00% | 100% (364/364) | 98.99%-100.00% |
2. Sample size used for the test set and the data provenance
- Test Set Sample Size: A total of 369 retrospectively collected left-over clinical samples (nasopharyngeal swabs) were used for the clinical comparison studies (accuracy).
- Data Provenance:
- Country of Origin: The samples were collected from 14 clinical sites in the United States and Canada.
- Retrospective or Prospective: The samples were retrospectively collected (primarily from the 2010-2011 influenza season).
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 state the number or qualifications of experts used to establish the ground truth for the clinical comparison test set. The ground truth for direct comparisons between the original and modified RVP was the original RVP's result. For Influenza A H3 subtyping, bi-directional sequencing was used as the ground truth. This process typically involves laboratory personnel but does not necessarily imply "expert" adjudication in the clinical sense with specific qualifications mentioned in the document.
4. Adjudication method (e.g., 2+1, 3+1, none) for the test set
The document does not describe an adjudication method involving multiple human readers (e.g., 2+1, 3+1). The primary comparison in the clinical study was between the modified device and the original device, and for Influenza A H3, against sequencing results. This is a direct comparison of assay results, not a process of adjudicating differing human interpretations.
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, a multi-reader multi-case (MRMC) comparative effectiveness study was not conducted. This device is a molecular diagnostic test for detecting viral nucleic acids, not an AI-assisted diagnostic device that a human reader would interpret. Therefore, the concept of "human readers improving with AI vs without AI assistance" is not applicable.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the performance presented in the tables for both the modified and original xTAG RVP are standalone (algorithm only) performances. These are in vitro diagnostic tests, where the instrument and reagents provide a result (qualitative positive/negative), without human interpretive "reading" in the way an imaging study would be read. The comparison to sequencing for Influenza A H3 also represents a standalone assessment against a molecular gold standard.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
The ground truth used depends on the specific comparison:
- For demonstrating equivalence across most targets: The results from the original xTAG RVP assay served as the comparator (ground truth) for evaluating the modified xTAG RVP's performance.
- For Influenza A H3 subtyping: Bi-directional sequencing was used as the definitive ground truth.
8. The sample size for the training set
The document does not explicitly describe a training set sample size for the device itself. For molecular diagnostic tests, "training" often refers to internal development and optimization by the manufacturer using various known positive and negative controls and clinical samples, rather than a distinct, quantifiable "training set" in the context of machine learning. The focus of this submission is on the performance of a reformulated PCR primer mix and its equivalence to a predicate device, as demonstrated through analytical and clinical comparison studies.
9. How the ground truth for the training set was established
As there is no distinct "training set" explicitly identified or described in the context of machine learning or algorithm development for this molecular diagnostic device in this document, the method for establishing its ground truth is not detailed. The development process would have involved establishing the analytical accuracy of the primers against known viral strains, which would implicitly form the "ground truth" for ensuring the primer mix works as intended.
§ 866.3980 Respiratory viral panel multiplex nucleic acid assay.
(a)
Identification. A respiratory viral panel multiplex nucleic acid assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify multiple viral nucleic acids extracted from human respiratory specimens or viral culture. The detection and identification of a specific viral nucleic acid from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection when used in conjunction with other clinical and laboratory findings. The device is intended for detection and identification of a combination of the following viruses:(1) Influenza A and Influenza B;
(2) Influenza A subtype H1 and Influenza A subtype H3;
(3) Respiratory Syncytial Virus subtype A and Respiratory Syncytial Virus subtype B;
(4) Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus;
(5) Human Metapneumovirus;
(6) Rhinovirus; and
(7) Adenovirus.
(b)
Classification. Class II (special controls). The special controls are:(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Respiratory Viral Panel Multiplex Nucleic Acid Assay;”
(2) For a device that detects and identifies Human Metapneumovirus, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Human Metapneumovirus (hMPV) Using Nucleic Acid Assays;” and
(3) For a device that detects and differentiates Influenza A subtype H1 and subtype H3, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Detection and Differentiation of Influenza A Virus Subtypes Using Multiplex Nucleic Acid Assays.” See § 866.1(e) for the availability of these guidance documents.