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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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(164 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 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. 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 specimens. The assay is performed on the Cepheid GeneXpert® Instrument Systems.
The Xpert Xpress Flu Assay includes reagents for the simultaneous detection and differentiation of the target viruses. The primers and probes in the Xpert Xpress Flu Assay detect the presence of nucleic acid sequences for Flu A and Flu B directly from NP swab specimens collected from patients with signs and symptoms of respiratory 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 in every assay to control for adequate processing of the target viruses and to monitor for the presence of inhibitor(s) in the PCR assay to avoid false-negative results. The PCC verifies reagent rehydration, real-time 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 Instrument 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.
The provided document describes the Cepheid Xpert Xpress Flu Assay, an automated, multiplex real-time, reverse transcriptase polymerase chain reaction (RT-PCR) assay for the qualitative detection and differentiation of influenza A and influenza B viral RNA. The study referenced aims to demonstrate the substantial equivalence of this device to a legally marketed predicate device, the Xpert Flu/RSV XC Assay (K142045).
Here's a breakdown of the requested information based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria in terms of specific thresholds for PPA (Positive Percent Agreement) and NPA (Negative Percent Agreement) that the device must meet. However, the reported performance is compared to an FDA-cleared molecular comparator assay to demonstrate substantial equivalence. The reported performance can be interpreted as implicitly meeting the expectation for substantial equivalence.
| Metric (Target) | Acceptance Criteria (Implicit) | Reported Device Performance (Combined Dataset) |
|---|---|---|
| PPA (Influenza A) | Performance comparable to FDA-cleared molecular comparator assay | 98.1% (CI: 93.4-99.5) |
| NPA (Influenza A) | Performance comparable to FDA-cleared molecular comparator assay | 98.4% (CI: 97.7-98.8) |
| PPA (Influenza B) | Performance comparable to FDA-cleared molecular comparator assay | 100.0% (CI: 95.3-100.0) |
| NPA (Influenza B) | Performance comparable to FDA-cleared molecular comparator assay | 98.7% (CI: 98.1-99.1) |
| Analytical Specificity | 100% (No cross-reactivity with common respiratory pathogens) | 100% |
| Analytical Reactivity (Inclusivity) | All tested influenza strains to be detected | Positive in all three replicates for all but one strain (which was 2/3 at 0.1 TCID50/mL) |
| Carry-Over Contamination | No contamination of negative samples | 100% correct reporting for all negative samples (Flu A NEGATIVE; Flu B NEGATIVE) |
| Fresh vs. Frozen Sample Equivalency | No difference in performance between fresh and freeze-thaw samples | No difference; all positive and negative replicates correctly identified |
| Competitive Interference | Identification of potential inhibitory effects | Competitive inhibitory effects observed under specific conditions |
2. Sample Size Used for the Test Set and Data Provenance
-
Sample Size (Clinical Comparison Study - NP Swab Specimens):
- Total: 2065 NP swab specimens
- Fresh, prospectively collected: 1142 specimens
- Consistently collected, frozen: 923 specimens
- Pre-selected frozen NP swab specimens (analyzed separately): 102 specimens
-
Data Provenance: The study was conducted at eleven institutions in the U.S. during the 2015-2016 influenza season. The data includes both prospectively collected fresh specimens and retrospectively (consecutively) collected frozen specimens.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not specify the number or qualifications of experts used to establish the ground truth for the clinical test set. The ground truth for the clinical comparison study was established by an "FDA-cleared molecular comparator assay."
4. Adjudication Method for the Test Set
- For discordant results between the Xpert Xpress Flu Assay and the comparator assay, bi-directional sequencing was performed. The text states this was "for informational purposes only," implying it was used to investigate discrepancies rather than for primary adjudication that would re-classify initial ground truth results.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, a multi-reader multi-case (MRMC) comparative effectiveness study was not conducted as described in the document. This study focuses on the performance of the assay itself compared to a reference method, not on human reader performance with or without AI assistance.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
- Yes, the clinical comparison study directly evaluates the standalone performance of the Xpert Xpress Flu Assay (the algorithm/device) against an FDA-cleared molecular comparator assay. The results provided in Table 8-9 (PPA, NPA) are for the device alone.
7. Type of Ground Truth Used
- Clinical Comparison Study: The ground truth for the clinical comparison study was established using an FDA-cleared molecular comparator assay. For discordant results, bi-directional sequencing was used for informational purposes.
- Analytical Studies (LoD, Specificity, Reactivity, Interference): Ground truth was established by known concentrations of purified viruses or bacterial/yeast strains in simulated matrices.
8. Sample Size for the Training Set
- The document describes a submission for a medical device (assay) and its performance evaluation. It does not refer to an "AI algorithm" in the common sense of machine learning that would have a separate "training set" of data. The assay's design and optimization would have involved internal development and validation, but this is not presented as a distinct "training set" in the context of typical AI device submissions. The analytical and clinical studies describe the test set used to validate the final device.
9. How the Ground Truth for the Training Set Was Established
- As mentioned above, the concept of a "training set" in the context of an AI algorithm is not explicitly applicable here. The device is a molecular diagnostic assay. Its "training" (development and optimization) would involve standard laboratory methods, reagent formulation, and protocol refinement to achieve optimal detection and differentiation of target nucleic acid sequences. The ground truth for this development phase would be established through controlled experiments using known positive and negative controls, spiked samples, and characterized clinical samples, as outlined in the non-clinical studies (e.g., LoD, inclusivity, specificity studies).
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(174 days)
The Cepheid Xpert® Xpress Flu/RSV Assay, performed on the GeneXpert® Instrument Systems, is an automated, multiplex real-time, reverse transcriptase chain reaction (RT-PCR) assay intended for the in vitro qualitative detection and differentiation of influenza B. and respiratory syncytial virus (RSV) viral RNA. The Xpert Xpress Flu/ RSV Assay uses nasopharyngeal (NP) swab specimens with signs and symptoms of respiratory infection. The Xpert Xpress Flu/RSV Assav is intended as an aid in the diagnosis of influenza and respiratory syncytial virus infections in conjunction with clinical and epidemiological risk factors.
Negative results do not preclude influenza virus or RSV 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. 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.
Ancillary Collection Kit Indications for Use:
The Xpert® Nasopharyngeal Sample Collection Kit is designed to collect, preserve, and transport nasopharyngeal swab specimens and to preserve and transport nasal aspirate/wash specimens containing viruses from patients with signs and symptoms of respiratory infection prior to analysis with the Xpert Flu Assay or the Xpert Flu/RSV XC Assay.
The Xpert® Nasopharyngeal Sample Collection Kit is designed to collect, preserve, and transport nasopharyngeal swab specimens containing viruses from patients with signs and symptoms of respiratory infection prior to analysis with the Xpert Flu+RSV Xpress Assay or the Xpert Xpress Flu/RSV Assay.
The Xpert Xpress Flu/RSV Assay is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A (Flu A), influenza B (Flu B), and respiratory syncytial virus (RSV) viral RNA directly from nasopharyngeal (NP) swab specimens. The assay is performed on the Cepheid GeneXpert® Instrument Systems.
The Xpert Xpress Flu/RSV Assay includes reagents for the simultaneous detection and differentiation of the target viruses. The primers and probes in the Xpert Xpress Flu/RSV Assay detect the presence of nucleic acid sequences for Flu A, Flu B, and RSV directly from NP swab specimens collected from patients with signs and symptoms of respiratory 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 in every assay to control for adequate processing of the target viruses and to monitor for the presence of inhibitor(s) in the PCR assay to avoid false-negative results. The PCC verifies reagent rehydration, real-time 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/RSV Assay cartridge. The GeneXpert cartridge is loaded onto the GeneXpert Instrument System platform, which performs hands-off automated sample processing and real-time RT-PCR for detection of Flu and RSV 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.
The Cepheid Xpert® Xpress Flu/RSV Assay 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, influenza B, and respiratory syncytial virus (RSV) viral RNA from nasopharyngeal (NP) swab specimens. It is designed to aid in the diagnosis of influenza and respiratory syncytial virus infections.
Here's an analysis of the acceptance criteria and the studies performed:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" in a table format with performance targets, but rather presents the results of clinical and analytical studies to demonstrate substantial equivalence to a predicate device. Based on the clinical comparison study, the implicit acceptance criteria would be high Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to an FDA-cleared molecular comparator assay.
| Metric (vs. Comparator Assay) | Target (Implicit) | Reported Device Performance (Combined Dataset, N=2065 NP swabs) |
|---|---|---|
| Influenza A | PPA: High (e.g., >95%) | 98.1% (95% CI: 93.4-99.5) |
| NPA: High (e.g., >95%) | 98.4% (95% CI: 97.7-98.8) | |
| Influenza B | PPA: High (e.g., >95%) | 100.0% (95% CI: 95.3-100.0) |
| NPA: High (e.g., >95%) | 98.7% (95% CI: 98.1-99.1) | |
| RSV | PPA: High (e.g., >95%) | 98.5% (95% CI: 91.8-99.7) |
| NPA: High (e.g., >95%) | 98.8% (95% CI: 98.2-99.2) | |
| Analytical Specificity (Exclusivity) | 100% | 100% |
| Reproducibility (Total Agreement) | High (e.g., >90%) | Negative: 100%; Flu A-Low Pos: 93.7%; Flu A-Mod Pos: 100%; Flu B-Low Pos: 95.1%; Flu B-Mod Pos: 98.6%; RSV-Low Pos: 94.4%; RSV-Mod Pos: 100% |
| Limit of Detection (LoD) | Lowest concentration for 95% confidence | Ranges from 0.01 to 2.30 TCID50/mL depending on the viral strain. |
2. Sample Size for the Test Set and Data Provenance:
- Sample Size for Clinical Comparison Test Set: A total of 2065 NP swab specimens were used.
- 1142 were fresh, prospectively collected.
- 923 were consecutively collected, frozen specimens (to supplement for low prevalence and difficulty in obtaining fresh positive samples).
- Additionally, 102 pre-selected frozen NP swab specimens were tested and analyzed separately.
- Data Provenance: The specimens were collected from individuals exhibiting signs and symptoms of respiratory infection. The study was a multi-center clinical study conducted at eleven institutions in the U.S. during the 2015-2016 influenza season.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Their Qualifications:
The document indicates that the Xpert Xpress Flu/RSV Assay performance was compared to an FDA-cleared molecular comparator assay. This comparator assay served as the primary method for establishing ground truth.
For discordant results between the Xpert Xpress Flu/RSV Assay and the comparator assay, bi-directional sequencing was performed. The document does not specify the number or qualifications of experts involved in interpreting the results of the comparator assay or the bi-directional sequencing for ground truth establishment. It implies that these are standard laboratory procedures that yield definitive results for the presence or absence of viral RNA.
4. Adjudication Method for the Test Set:
Discordant results between the Xpert Xpress Flu/RSV Assay and the FDA-cleared molecular comparator assay were analyzed by bi-directional sequencing using primers different from those used in the Xpert Xpress Flu/RSV Assay. This sequencing served as a tie-breaker or confirmatory test for discrepancies. The report states that this sequencing data was "provided for informational purposes only" in relation to the primary comparison with the predicate, suggesting the comparator assay was the direct reference. However, the interpretation of the "true" positive/negative status for performance calculation likely involved considering the sequencing results.
5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study:
No MRMC comparative effectiveness study was performed as this is a diagnostic assay for viral RNA detection, not an imaging device requiring human reader interpretation. The device itself performs the detection and differentiation.
6. Standalone Performance:
Yes, the studies reported are for the standalone performance of the Xpert Xpress Flu/RSV Assay. The clinical comparison study directly evaluates the device's accuracy (PPA and NPA) against a comparator assay without human-in-the-loop assistance for interpretation of the assay's results.
7. Type of Ground Truth Used:
The primary ground truth used was an FDA-cleared molecular comparator assay. For discrepant results, bi-directional sequencing provided additional confirmatory evidence. This falls under the category of expert consensus (implied by FDA-cleared and sequencing interpretation) and laboratory/molecular pathology findings.
8. Sample Size for the Training Set:
The document does not explicitly state the size of a training set for the Xpert Xpress Flu/RSV Assay. As this is a molecular diagnostic assay using RT-PCR, its design and optimization (e.g., primer/probe selection, assay conditions) are based on known viral sequences and extensive analytical validation rather than a "training set" in the machine learning sense. The clinical studies (1142 fresh, 923 frozen, and 102 pre-selected frozen specimens) serve as a validation set to demonstrate clinical performance.
9. How the Ground Truth for the Training Set Was Established:
Since a distinct "training set" in the machine learning context is not described, the concept of establishing ground truth for it is not applicable here. The assay development likely involved internal analytical studies to optimize reagents and parameters, where the ground truth would be precisely characterized laboratory samples with known viral presence and concentration.
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(227 days)
- The cobas® Influenza A/B & RSV Nucleic Acid Test for Use on the cobas® Liat System (cobas® Liat Influenza A/B & RSV) is an automated multiplex real-time RT-PCR assay for the rapid in vitro qualitative detection and discrimination of influenza A virus, influenza B virus and respiratory syncytial virus (RSV) RNA in nasopharyngeal swab specimens from patients with signs and symptoms of respiratory infection in conjunction with clinical and epidemiological risk factors. The test is intended for use as an aid in the diagnosis and differentiation of influenza B, and RSV in humans and is not intended to detect influenza C.
Negative results do not preclude influenza virus or RSV infection and should not be used as the sole basis for treatment or other patient management decisions. Conversely, positive results do not ruleout bacterial infection or co-infection with other viruses. The agent detected may not be the definite cause of disease.
Performance characteristics for influenza A were established during the 2013-2014 and the 2014-2015 influenza seasons when influenza A/H3 and A/H1N1 pandemic were the predominant influenza A viruses in circulation. When other 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 department for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.
- The cobas® Influenza A/B & RSV Quality Control Kit contains External Controls for use with the cobas® Liat Influenza A/B & RSV assay. External Controls are run during the Add cobas® Liat Influenza A/B & RSV Tube Lot procedure. Additional External Controls should be tested in accordance with local, state, federal and/or accrediting organization requirements as applicable.
The cobas Liat Influenza A/B & RSV Nucleic Acid Test for Use on the cobas Liat System ("cobas" Liat Influenza A/B & RSV assay") is a rapid, automated in vitro diagnostic test for the qualitative detection of influenza A, influenza B, and RSV RNA in nasopharyngeal swab (NPS) specimens eluted in viral transport media.
The assay targets a well-conserved region of the matrix gene of influenza A (Inf A target), the non-structural protein gene of influenza B (Inf B target), and the matrix gene of RSV (RSV target). An Internal Process Control (IPC) is also included. The IPC is present to control for adequate processing of the target viruses and to monitor the presence of inhibitors in the sample preparation and RT-PCR.
The assay utilizes a single-use disposable cobas® Liat Tube that holds the sample purification and PCR reagents, and hosts the sample preparation and PCR processes. The cobas Liat Tube uses a flexible tube as a sample vessel. It contains all required unit dose reagents pre-packed in tube segments, separated by peelable seals, in the order of reagent use.
The cobas "Liat System automates and integrates sample purification, nucleic acid amplification, and detection of the target sequence in biological samples. The cobas Liat System performs all assay steps from clinical sample and reports assay result automatically. During the testing process. multiple sample processing actuators of the cobas " Liat System compress the cobas" Liat Tube to selectively release reagents from tube segments, move the sample from one segment to another, and control reaction volume, temperature, and time to conduct sample preparation, nucleic acid extraction, target enrichment, inhibitor removal, nucleic acid elution and real-time PCR. An embedded microprocessor controls and coordinates the actions of these sample processors to perform all required assay processes within the closed cobas Liat Tube.
Positive and negative controls are provided in the cobas® Influenza A/B & RSV Quality Control Kit. The positive control comprises inactivated Influenza B and RSV virus in a dried format. The negative control comprises Universal Transport Media (UTM).
To perform the cobas Liat Influenza A/B & RSV assay, an operator first collects a nasopharyngeal swab and places the swab into UTM. The operator transfers the sample into cobas " Liat Influenza A/B & RSV assay tube using a transfer pipette, and scans the tube barcode to identify the test and the sample barcode to code the sample ID with the assay run on the cobas® Liat System. The cobas® Liat Tube is then inserted into the cobas® Liat System. The system performs all the test steps and outputs interpreted results (e.g. Influenza A Detected, Influenza B Not Detected, RSV Not Detected) in ~20 minutes. A report of the interpreted results can be viewed on the cobas " Liat System's LCD screen, and printed directly through a USB or network connected printer. No reagent preparation or additional steps are required other than adding the sample to the cobas Liat Tube. Because all the reagents are contained within the cobas Liat Tube and no sample or reagent needs to be removed from the tube, crosscontamination between samples is minimized.
The results are interpreted by the cobas Liat System software from measured fluorescent signals and real time curve recognition algorithm. All possible final test results are described below.
Here's a breakdown of the acceptance criteria and study details for the cobas® Liat Influenza A/B & RSV Nucleic Acid Test, based on the provided document:
1. Table of Acceptance Criteria & Reported Device Performance
The document doesn't explicitly lay out "acceptance criteria" in a single, aggregated table with pass/fail marks. Instead, it presents performance data for various analytical and clinical studies. For the clinical studies, it provides percentage agreements and confidence intervals. The "acceptance criteria" can be inferred from the reported performance, implying that these values were considered acceptable by the FDA for substantial equivalence.
Here's a table summarizing the key performance metrics from the study. For acceptance criteria, we'll assume that the reported performance figures met the internal thresholds set by the manufacturer and deemed sufficient by the FDA for 510(k) clearance.
Inferred Acceptance Criteria / Reported Performance for cobas® Liat Influenza A/B & RSV Assay
| Category / Metric | Inferred Acceptance Criteria (e.g., "≥ X%") | Reported Device Performance (with 95% CI where available) |
|---|---|---|
| Analytical Performance | ||
| Reproducibility | ||
| Influenza A - Agreement w/ expected result (Negative) | Highly Accurate (e.g., 100%) | 91/91 (100.0%) [96.0% - 100.0%] |
| Influenza A - Agreement w/ expected result (High Negative) | Highly Accurate (e.g., ≥95%) | 88/90 (97.8%) [92.3% - 99.4%] |
| Influenza A - Agreement w/ expected result (Low Positive) | Highly Accurate (e.g., 100%) | 90/90 (100.0%) [95.9% - 100.0%] |
| Influenza A - Agreement w/ expected result (Moderate Positive) | Highly Accurate (e.g., 100%) | 90/90 (100.0%) [95.9% - 100.0%] |
| Influenza A - Total Agreement | Highly Accurate (e.g., ≥99%) | 900/902 (99.8%) [99.2% - 99.9%] |
| Influenza B - Agreement w/ expected result (Negative) | Highly Accurate (e.g., 100%) | 91/91 (100.0%) [96.0% - 100.0%] |
| Influenza B - Agreement w/ expected result (High Negative) | Highly Accurate (e.g., ≥95%) | 90/91 (98.9%) [94.0% - 99.8%] |
| Influenza B - Agreement w/ expected result (Low Positive) | Highly Accurate (e.g., 100%) | 89/89 (100.0%) [95.9% - 100.0%] |
| Influenza B - Agreement w/ expected result (Moderate Positive) | Highly Accurate (e.g., 100%) | 90/90 (100.0%) [95.9% - 100.0%] |
| Influenza B - Total Agreement | Highly Accurate (e.g., ≥99%) | 901/902 (99.9%) [99.4% - 100.0%] |
| RSV - Agreement w/ expected result (Negative) | Highly Accurate (e.g., 100%) | 91/91 (100.0%) [96.0% - 100.0%] |
| RSV - Agreement w/ expected result (High Negative) | Highly Accurate (e.g., 100%) | 90/90 (100.0%) [95.9% - 100.0%] |
| RSV - Agreement w/ expected result (Low Positive) | Highly Accurate (e.g., ≥95%) | 90/91 (98.9%) [94.0% - 99.8%] |
| RSV - Agreement w/ expected result (Moderate Positive) | Highly Accurate (e.g., 100%) | 90/90 (100.0%) [95.9% - 100.0%] |
| RSV - Total Agreement | Highly Accurate (e.g., ≥99%) | 901/902 (99.9%) [99.4% - 100.0%] |
| Limit of Detection (LOD) | Lowest detectable concentration ≥95% of time | Influenza A: 2.0 × 10^-2 - 2.0 × 10^-3 TCID50/mL |
| Influenza B: 2.0 × 10^-3 - 4.0 × 10^-3 TCID50/mL | ||
| RSV: 4.0 × 10^-1 TCID50/mL | ||
| Analytical Specificity (Reactivity) | 100% detection of tested strains | Detected all 28 Influenza A, 15 Influenza B, and 7 RSV strains tested. |
| Analytical Specificity (Cross-reactivity) | 0% cross-reactivity with non-target microorganisms | No cross-reactivity observed with 35 microorganisms and human genomic DNA. |
| Interference | No interference | No interference observed with tested microorganisms and substances at specified concentrations. |
| Carry-over/Cross-contamination | 0% contamination rate | 0% carry-over/cross-contamination observed. |
| Fresh vs. Frozen Samples | 100% agreement | 100% agreement with expected results. |
| Clinical Performance (vs. Comparator Test) | ||
| Prospective Specimens | ||
| Inf A - Positive Agreement | High (e.g., ≥95%) | 98.3% (95.1% - 99.4%) |
| Inf A - Negative Agreement | High (e.g., ≥95%) | 96.0% (94.7% - 97.0%) |
| Inf B - Positive Agreement | High (e.g., ≥90%) | 95.2% (84.2% - 98.7%) |
| Inf B - Negative Agreement | High (e.g., ≥98%) | 99.4% (98.8% - 99.7%) |
| RSV - Positive Agreement | High (e.g., ≥95%) | 97.0% (91.5% - 99.0%) |
| RSV - Negative Agreement | High (e.g., ≥98%) | 98.7% (97.9% - 99.2%) |
| Retrospective Specimens | ||
| Inf A - Positive Agreement | High (e.g., ≥95%) | 98.7% (93.0% - 99.8%) |
| Inf A - Negative Agreement | High (e.g., ≥98%) | 99.1% (96.7% - 99.7%) |
| Inf B - Positive Agreement | High (e.g., ≥95%) | 99.0% (94.4% - 99.8%) |
| Inf B - Negative Agreement | High (e.g., ≥98%) | 99.5% (97.1% - 99.9%) |
| RSV - Positive Agreement | High (e.g., ≥95%) | 98.8% (93.6% - 99.8%) |
| RSV - Negative Agreement | High (e.g., ≥95%) | 96.6% (93.2% - 98.4%) |
2. Sample Size Used for the Test Set and Data Provenance
-
Clinical Test Set Sample Size:
- Prospective Specimens: 1,350 nasopharyngeal swab (NPS) specimens.
- Retrospective Specimens: 292 nasopharyngeal swab (NPS) specimens.
- Total Clinical Samples: 1,642 specimens.
-
Analytical Test Set Sample Size (Reproducibility): Approximately 900 runs (10 panel members × 3 replicates × 2 operators × 5 days × 3 sites).
-
Data Provenance:
- Country of Origin: United States (US). Prospective specimens were collected during the 2013-2014 and 2014-2015 flu seasons.
- Retrospective/Prospective: The study included both prospective and retrospective clinical specimens. Prospective specimens were collected from patients with signs and symptoms of respiratory infection and tested at 12 CLIA waived healthcare facilities. Retrospective specimens were obtained from two reference laboratories and distributed to 3 of the 12 CLIA waived sites for testing.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
The document states that the cobas Liat Influenza A/B & RSV assay results were compared against an "FDA-cleared laboratory-based multiplexed real-time reverse transcriptase PCR (RT-PCR) test (comparator test)."
- Number of Experts: Not explicitly stated as "experts" for ground truth adjudication in the traditional sense, as it relies on a comparator laboratory test. However, the interpretation of the comparator PCR results would implicitly rely on qualified laboratory personnel.
- Qualifications of Experts: Not detailed. It's inferred that the personnel performing and interpreting the comparator FDA-cleared RT-PCR tests were qualified laboratory technologists/scientists. For discordant results in prospective samples, PCR/sequencing was used as a tie-breaker. This would also imply qualified laboratory personnel.
4. Adjudication Method for the Test Set
- For the primary comparison, the cobas Liat assay results were compared directly against the FDA-cleared laboratory-based multiplexed real-time RT-PCR test (comparator test).
- For discordant results between the cobas Liat and the comparator test in the prospective specimens (specifically, when Liat was positive and comparator negative), PCR/sequencing was used as a "tie-breaker" or confirmatory method. For Influenza A, 41 such specimens were tested, with 18 confirmed positive and 23 negative by PCR/sequencing. For Inf B, 6 such specimens were tested, with 5 confirmed positive and 1 negative. For RSV, 15 such specimens were tested, with 3 confirmed positive and 12 negative.
- For retrospective specimens with discordant results (Liat positive, comparator negative), a similar PCR/sequencing method was used, though with fewer details on the number of confirmed cases (e.g., 1 Inf A sample was negative by PCR/sequencing, all 6 RSV samples were positive).
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 document describes the performance of an in vitro diagnostic (IVD) nucleic acid amplification test (NAAT), not an AI-assisted imaging device or a decision support system with human readers. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable to this device.
6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done
The cobas® Liat system is an automated diagnostic system (sample-to-answer) that performs nucleic acid purification, amplification, and detection, and provides an automated interpretation of the results. The results are reported as "Detected" or "Not Detected" for each virus by the instrument's software. As such, the performance data presented (e.g., clinical sensitivity and specificity) intrinsically represent the "standalone" performance of the algorithm/system, as human interpretation of complex signals (like in radiology) is minimized or absent in the final result determination. The operators (nurses and technologists) are responsible for sample collection, loading, and initiating the test, but the interpretation is automated.
7. The Type of Ground Truth Used
The primary ground truth for the clinical validation was an FDA-cleared laboratory-based multiplexed real-time RT-PCR test (comparator test). For discordant results, PCR/sequencing was used as a confirmatory method to establish a more definitive ground truth.
8. The Sample Size for the Training Set
The document does not specify a separate "training set" in the context of machine learning or AI models. This device is a molecular diagnostic assay (RT-PCR) with predefined chemical reactions and detection logic. Its "development" would involve optimizing reagents, primer/probe design, and reaction conditions, rather than training an algorithm on a distinct dataset. The performance characteristics described are from validation studies, not from a "training" phase.
9. How the Ground Truth for the Training Set Was Established
Given that this is an RT-PCR assay and not an AI/ML device that requires a "training set" with ground truth in the AI context, this question is not applicable. The "ground truth" for developing such an assay would come from extensive analytical characterization against known viral positive and negative samples, including quantified viral loads, verified by traditional virological methods (e.g., cell culture infectivity assays, reference PCR methods).
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