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510(k) Data Aggregation
(91 days)
The Cepheid Xpert® Xpress Flu Assay, performed on the GeneXpert® Instrument Systems, is an automated, multiplex real-time, reverse transcriptase polymerase chain reaction (RT-PCR) assay intended for the in vitro qualitative detection and differentiation of influenza A and influenza B viral RNA. The Xpert Xpress Flu Assay uses nasopharyngeal (NP) swab and nasal swab (NS) specimens collected from patients with signs and symptoms of respiratory infection. The Xpert Xpress Flu Assay is intended as an aid in the diagnosis of influenza infections in conjunction with clinical and epidemiological risk factors.
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 2015-2016 influenza season for NP swab specimens and the 2016-2017 influenza season for NS specimens. When other novel 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 departments 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 Xpress Flu Assay is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A (Flu A) and influenza B (Flu B) viral RNA directly from nasopharyngeal (NP) swab and nasal swab (NS) specimens. The assay is performed on the Cepheid GeneXpert® Instrument Systems.
The Xpert Xpress Flu Assay includes reagents for the detection and differentiation of influenza A and influenza B viral RNA directly from NP swab and NS specimens from patients with signs and symptoms of respiratory tract infection. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are internal controls utilized by the GeneXpert Instrument System platform. The SPC is present to control for an adequate extraction and processing of the target sequences and to monitor for the presence of inhibitor in the PCR reaction. The PCC verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.
The specimens are collected in viral transport medium and transported to the GeneXpert area. The specimen is prepared according to package insert instructions and transferred to the sample chamber (large opening) of the Xpert Xpress Flu Assay cartridge. The GeneXpert cartridge is loaded onto the GeneXpert Xpress System platform, which performs hands-off automated sample processing and real-time RT-PCR for detection of Flu viral RNA. Summary and detailed test results are obtained in approximately 30 minutes or less. The results are automatically generated at the end of the process in a report that can be viewed and printed.
Here's a detailed breakdown of the acceptance criteria and study findings for the Cepheid Xpert® Xpress Flu Assay:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are generally established by regulatory bodies through guidance documents and are demonstrated through the clinical performance relative to a comparator device (often an FDA-cleared molecular assay). The reported performance is presented as Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA). While explicit "acceptance criteria" are not listed in a numerical form in this document, the clinical study results are implicitly compared against regulatory expectations for substantial equivalence.
| Metric | Target (Implicit Acceptance Criteria - high agreement with comparator) | Reported Device Performance (Xpert Xpress Flu Assay) |
|---|---|---|
| NP Swab Specimens (Clinical Comparison) | ||
| Influenza A PPA (Combined) | High (e.g., >90%) | 98.1% (93.3 - 99.5% CI) |
| Influenza A NPA (Combined) | High (e.g., >95%) | 98.8% (98.2 - 99.2% CI) |
| Influenza B PPA (Combined) | High (e.g., >90%) | 100.0% (95.3 - 100.0% CI) |
| Influenza B NPA (Combined) | High (e.g., >95%) | 99.1% (98.6 - 99.5% CI) |
| NS Specimens (Clinical Comparison) | ||
| Influenza A PPA | High (e.g., >90%) | 98.9% (96.2 - 99.7% CI) |
| Influenza A NPA | High (e.g., >95%) | 97.6% (96.6 - 98.3% CI) |
| Influenza B PPA | High (e.g., >90%) | 98.4% (91.7 - 99.7% CI) |
| Influenza B NPA | High (e.g., >95%) | 99.3% (98.7 - 99.6% CI) |
| Analytical Sensitivity (LoD) | Reproducibly distinguishable from negative with 95% confidence (19/20 positive) | Values range from 0.006 TCID50/mL to 0.750 TCID50/mL depending on strain and specimen type. All met LoD definition. |
| Analytical Specificity | 100% (No false positives with tested organisms) | 100% |
| Analytical Reactivity | All Flu strains tested positive in 3 replicates (or 2/3 at 0.1 TCID50/mL for one strain) | Met criteria (one strain tested positive in 2/3 replicates at 0.1 TCID50/mL, others 3/3) |
| Interfering Substances | No interference observed | None of the tested substances caused interference. |
| Carry-Over Contamination | No carry-over contamination with negative samples preceded by high positive samples | All 20 positive samples and 21 negative samples correctly reported. |
| Fresh vs. Frozen Sample Equivalency | No statistically significant effect | No statistically significant effect. All positive/negative replicates correctly identified. |
| Competitive Interference | Expect no/minimal inhibitory effects (with caveats) | Observed competitive inhibitory effects on targets when high concentrations of competing strains were present (addressed in limitations). Otherwise no effects. |
| Assay Success Rate | High (implicitly >95%) | 99.3% |
| Indeterminate Rate | Low (implicitly 90% for low positive, 100% for moderate positive & negative) | Range from 93.6% (Flu A Low Pos) to 100% (Negative, Flu A Mod Pos, Flu B Mod Pos). Flu B Low Pos: 95.1%. |
| Reproducibility (Ct value variability) | Low coefficient of variation (CV) for SD components | All CVs for between-site, lot, day, operator, and within-assay were low (max 4.2%). |
2. Sample Size Used for the Test Set and Data Provenance
- Clinical Comparison Study (Test Set):
- NP Swab Specimens: 2051 total specimens.
- 1139 fresh, prospectively collected.
- 912 consecutively collected, frozen specimens.
- NS Specimens: 1598 total specimens.
- Provenance: Collected at eleven institutions in the U.S. (2015-2016 influenza season for NP swabs) and fourteen institutions in the U.S. (2016-2017 influenza season for NS specimens). This indicates a multi-center, prospective (for fresh samples) and retrospective (for frozen samples) study within the U.S.
- NP Swab Specimens: 2051 total specimens.
- Analytical Sensitivity (LoD): Not specified for specific numbers of specimens, but "replicates of 20 per concentration of virus in each matrix."
- Analytical Specificity: 44 cultures (16 viral, 26 bacterial, 2 yeast strains), each tested in triplicate.
- Analytical Reactivity: 48 strains (35 influenza A, 13 Influenza B), each tested in triplicate.
- Interfering Substances: 8 negative samples tested per substance, 8 positive samples tested per substance (with 6 influenza strains).
- Carry-Over Contamination: 20 positive followed by 20 negative samples.
- Fresh vs. Frozen Sample Equivalency Study: Not explicitly stated, but replicates of 20 were tested for each specimen type and concentration (low, moderate, high positive, and negative) across fresh, one freeze-thaw, and two freeze-thaw cycles for two influenza strains.
- Competitive Interference Study: Replicates of 20 for each target strain and each competitive strain combination.
- Reproducibility Study: 5-member specimen panel tested across 3 sites, 2 operators per site, 6 days, 2 testing days per lot, duplicate testing twice per day. This means each panel member was tested approximately 144 times (3 sites * 2 operators * ~24 tests/operator).
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 comparison study was established primarily using an FDA-cleared molecular comparator assay. For discrepant results between the Xpert Xpress Flu Assay and the comparator assay, bi-directional sequencing was performed. The document does not specify the number of experts or their qualifications for interpreting the sequencing results or for judging the "clinical and epidemiological risk factors" mentioned in the intended use. However, the use of an FDA-cleared molecular assay and sequencing provides a strong, objective ground truth.
4. Adjudication Method for the Test Set
The primary comparison was against an FDA-cleared molecular comparator assay.
For samples where the Xpert Xpress Flu Assay and the comparator assay produced discrepant results, bi-directional sequencing was used as an adjudication method. The sequencing results were "provided for informational purposes only," suggesting that while they informed the understanding of discrepancies, the primary performance metrics (PPA/NPA) were against the comparator.
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 device, the Xpert Xpress Flu Assay, is an automated, multiplex real-time RT-PCR assay. It is a standalone diagnostic test for qualitative detection and differentiation of viral RNA. It does not involve human interpretation of images or other subjective data that would necessitate a multi-reader multi-case (MRMC) study or human assistance with AI. Therefore, this section is not applicable. The results are automatically generated as "POSITIVE" or "NEGATIVE" for Influenza A and Influenza B.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was Done
Yes, a standalone performance evaluation was done. The entire clinical comparison study (for NP and NS specimens) and all non-clinical analytical studies (sensitivity, specificity, reactivity, interference, carry-over, fresh vs. frozen, competitive interference) as well as the reproducibility study evaluate the performance of the Xpert Xpress Flu Assay directly, without human interpretation of the assay's primary output (the detection of viral RNA). The GeneXpert Instrument Systems automatically perform sample processing and real-time RT-PCR, generating quantitative results (Ct values) which are then interpreted by the system's definition file to provide a qualitative POSITIVE/NEGATIVE result.
7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)
- Clinical Comparison Study: The primary ground truth was an FDA-cleared molecular comparator assay. For discrepant results, bi-directional sequencing was used.
- Analytical Studies (LoD, specificity, reactivity, interference, carry-over, fresh vs. frozen, competitive interference): Ground truth was established by known concentrations of purified or cultured viruses/organisms and/or negative controls.
8. The Sample Size for the Training Set
This document does not explicitly mention a separate "training set" for the Xpert Xpress Flu Assay itself in the context of machine learning. As a molecular diagnostic assay, its "training" or development would typically involve optimization of primers, probes, and reaction conditions based on known viral sequences and biological principles, rather than a data-driven machine learning training set in the conventional sense. The "clinical study" described serves as the validation/test set to demonstrate performance.
9. How the Ground Truth for the Training Set Was Established
As noted above, a traditional "training set" with ground truth in the machine learning context is not directly applicable here. The development of such molecular assays relies on extensive scientific and laboratory work to design and optimize the assay components (primers, probes) to specifically target the desired viral RNA sequences and to establish robust reaction conditions. This involves:
- Known viral strains: Using characterized strains of influenza A and B.
- Nucleic acid sequencing: Detailed knowledge of viral genomic sequences to design specific and sensitive PCR targets.
- Controlled experiments: Iterative testing and optimization of assay parameters using spiked samples with known concentrations.
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