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The Xpert Xpress CoV-2 plus test, performed on the GeneXpert Xpress System, is a rapid real-time RT-PCR test intended for the qualitative detection of SARS-CoV-2 RNA in nasopharyngeal and anterior nasal swab specimens collected from individuals with signs and symptoms of respiratory tract infection.

The Xpert Xpress CoV-2 plus test is intended for use as an aid in the diagnosis of COVID-19 if used in conjunction with other clinical, epidemiologic, and laboratory findings. Positive results are indicative of the presence of SARS-CoV-2 RNA. Positive results do not rule out bacterial infection or co-infection with other pathogens.

Negative results do not preclude SARS-CoV-2 infection. The results of this test should not be used as for diagnosis and patient management decisions.

The Xpert Xpress CoV-2 plus test is a rapid, automated in vitro diagnostic test for the qualitative detection of viral RNA from SARS-CoV-2 in nasopharyngeal swab (NPS) and anterior nasal swab (NS) specimens collected from individuals with signs and symptoms of respiratory tract infection.

The Xpert Xpress CoV-2 plus test is performed on GeneXpert Xpress System, which consist of a GeneXpert IV instrument that executes sample preparation, nucleic acid amplification and real-time fluorescent signal detection for the tests, and a GeneXpert Hub with preloaded GeneXpert Xpress software for running the tests and viewing the test results. The GeneXpert Hub accessory integrates the computer, touchscreen monitor and barcode scanner. Each of the GeneXpert modules in the GeneXpert IV instrument can perform independent sample preparation and testing. The GeneXpert Xpress System requires the use of single-use disposable cartridges that hold the RT-PCR reagents and host sample purification, nucleic acid amplification, and detection of the target sequences. Because the cartridges are selfcontained, cross-contamination between samples is minimized.

The Xpert Xpress CoV-2 plus test includes reagents for the detection of viral RNA from SARS-CoV-2 in NPS and NS specimens. The primers and probes in the Xpert Xpress CoV-2 plus test are designed to amplify and detect unique sequences in the genes that encode the following SARS-CoV-2 proteins: nucleocapsid (N2), envelope (E), and RNA-dependent RNA polymerase (RdRP). A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge serving as internal controls. The SPC is present to control for adequate processing of the sample and to monitor for the presence of potential inhibitor(s) in the RT-PCR reaction. The SPC also ensures that the RT-PCR reaction conditions (temperature and time) are appropriate for the amplification reaction and that the RT-PCR reagents are functional. The PCC verifies reagent rehydration, PCR tube filling, and confirms that all reaction components are present in the cartridge including monitoring for probe integrity and dye stability.

The Xpert Xpress CoV-2 plus test is designed for use with NPS or NS specimen collected with nylon flocked swabs and placed into viral transport medium (VTM), Universal Transport Medium (UTM) or eNAT®.

Acceptance Criteria and Study for Xpert Xpress CoV-2 plus

The Xpert Xpress CoV-2 plus test is a rapid real-time RT-PCR test for the qualitative detection of SARS-CoV-2 RNA in nasopharyngeal and anterior nasal swab specimens. The study aims to demonstrate substantial equivalence to a predicate device (K230440) by evaluating its analytical and clinical performance.

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample Sizes and Data Provenance

• Test Set (Clinical Performance):

  • Total specimens: 1783
    • NPS (Nasopharyngeal Swab): 883
    • NS (Anterior Nasal Swab): 900
  • Data Provenance: Prospective clinical specimens collected from individuals showing signs and symptoms of respiratory infection in the United States (22 geographically diverse CLIA-waived sites). Data was collected in 2022.

• Analytical Performance Test Sets:

  • Limit of Detection (LoD):
    • NPS-UTM/VTM: At least 40 replicates (2 reagent lots x 20 replicates)
    • NPS-eNAT: At least 40 replicates (2 reagent lots x 20 replicates)
    • NS-UTM/VTM: At least 40 replicates (2 reagent lots x 20 replicates)
    • WHO First International Standard (NS-UTM/VTM): 20 replicates
  • Analytical Reactivity (Wet-testing): 61 SARS-CoV-2 strains, 3 replicates per strain (total 183 tests).
  • Analytical Specificity (Wet-testing): 62 microorganisms, 3 replicates per organism (total 186 tests).
  • Microbial Interference: 18 commensal microorganisms, 8 replicates per strain (total 144 tests) with SARS-CoV-2.
  • Potentially Interfering Substances: 23 substances, 8 replicates for negative samples and 8 replicates for positive samples (total up to 368 tests, plus re-tests).
  • Carryover Contamination: 40 positive samples, 42 negative samples.
  • Reproducibility: 3 panel members (Negative, Low Pos, Mod Pos), 90 observations per panel member (3 Sites x 3 Operators x 1 Lot x 5 Days x 1 Run x 2 Replicates = 90). Total 270 observations.

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

The document does not explicitly state the number of experts used to establish the ground truth for the clinical test set or their specific qualifications (e.g., radiologist with 10 years of experience). However, the ground truth was established by a "U.S. FDA-cleared molecular respiratory panel that included SARS-CoV-2," indicating an established and validated laboratory method. Discrepant results were investigated using a "U.S FDA EUA SARS-CoV-2 molecular test," further relying on FDA-authorized assays as the reference standard.

4. Adjudication Method (Test Set)

The adjudication method used for the clinical test set was a discrepant analysis. "Discrepant results between Xpert Xpress CoV-2 plus and the comparator were investigated using a U.S FDA EUA SARS-CoV-2 molecular test." This implies that for any cases where the Xpert Xpress CoV-2 plus result differed from the initial FDA-cleared comparator panel, a third, independent FDA EUA molecular test was used to determine the true positive or negative status.

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

There is no MRMC comparative effectiveness study mentioned in the provided text. The study focuses on the standalone performance of the device against a comparator device, not on human reader performance with or without AI assistance.

6. Standalone Performance Study

Yes, a standalone performance study was done. The entire "Performance Studies" section (1.4) details the analytical and clinical performance of the device itself (algorithm only, without human-in-the-loop performance). The clinical performance evaluation directly compares the Xpert Xpress CoV-2 plus test results to those of an FDA-cleared molecular respiratory panel.

7. Type of Ground Truth Used

For the clinical performance study, the ground truth was established by an FDA-cleared molecular respiratory panel and, in cases of discrepancy, by a U.S. FDA EUA SARS-CoV-2 molecular test. This falls under the category of reference standard laboratory testing rather than expert consensus, pathology, or outcomes data.

For analytical performance studies, the ground truth was established by spiking known concentrations/quantities of inactivated SARS-CoV-2 virus, genomic RNA, or other microorganisms into negative matrices, or by using established international standards (e.g., WHO First International Standard).

8. Sample Size for the Training Set

The document does not mention the sample size for the training set. This is a premarket notification (510(k)) and focuses on the performance testing of the final device, not on the developmental or training phases of its underlying algorithm. As a PCR-based diagnostic, it's unlikely to have a "training set" in the same sense as an AI/ML-based device; its analytical performance is determined by the specific primers and probes and their chemical/biological interactions.

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

Since no "training set" is explicit for this PCR diagnostic, there is no information provided on how its ground truth might have been established. The development of PCR assays typically involves careful design and validation of primers and probes against known genomic sequences and wet-lab testing with characterized samples, rather than machine learning training on a dedicated dataset.

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The Xpert Xpress CoV-2 plus test, performed on the GeneXpert Infinity Systems, is a rapid real-time RT-PCR test intended for the qualitative detection of SARS-CoV-2 RNA in nasopharyngeal and anterior nasal swab specimens collected from individuals with signs and symptoms of respiratory tract infection.

The Xpert Xpress CoV-2 plus test is intended for use as an aid in the diagnosis of COVID-19 if used in conjunction with other clinical, epidemiologic, and laboratory findings. Positive results are indicative of the presence of SARS-CoV-2 RNA. Positive results do not rule out bacterial infection or co-infection with other pathogens.

Negative results do not preclude SARS-CoV-2 infection. The results of this test should not be used as for diagnosis and patient management decisions.

The Xpert Xpress CoV-2 plus test is a rapid, automated in vitro diagnostic test for the qualitative detection of viral RNA from SARS-CoV-2 in nasopharyngeal swab (NPS) and anterior nasal swab (NS) specimens obtained from individuals with signs and symptoms of respiratory tract infection.

The Xpert Xpress CoV-2 plus test is performed on the Cepheid GeneXpert® Instrument Systems (GeneXpert Dx, GeneXpert Infinity-48s and GeneXpert Infinity-80 systems), which consist of an instrument, computer and preloaded software for running tests and viewing the results. The GeneXpert Instrument Systems automate and integrate sample preparation, nucleic acid extraction and amplification, and detection of the target sequences in simple or complex samples using real-time reverse transcription (RT)-polymerase chain reaction (PCR) and PCR assays. Depending on the instrument, the GeneXpert Instrument Systems can have from 1 and up to 80 randomly accessible modules, each capable of performing separate sample preparation and real-time RT-PCR and PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time RT-PCR and PCR as well as detection. The systems require the use of single-use disposable cartridges that hold the RT-PCR reagents and host sample purification, nucleic acid amplification, and detection of the target sequences. Because the cartridges are selfcontained, cross-contamination between cartridges during the testing process is minimized.

The Xpert Xpress CoV-2 plus test includes reagents for the detection of viral RNA from SARS-CoV-2 in NPS and NS specimens. The primers and probes in the Xpert Xpress CoV-2 plus test are designed to amplify and detect sequences in the genes that encode the following SARS-CoV-2 proteins: nucleocapsid (N2), envelope (E), and RNA-dependent RNA polymerase (RdRP). A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge utilized by the GeneXpert instrument. The SPC is present to control for adequate processing of the sample and to monitor for the presence of potential inhibitor(s) in the RT-PCR reaction. The SPC also ensures that the RT-PCR reaction conditions (temperature and time) are appropriate for the amplification reaction and that the RT-PCR reagents are functional. The PCC verifies reagent rehydration. PCR tube filling, and confirms that all reaction components are present in the cartridge including monitoring for probe integrity and dve stability.

The Xpert Xpress CoV-2 plus test is designed for use with NPS or NS specimen collected with nylon flocked swabs and placed into a viral transport medium (VTM), Universal Transport Medium (UTM) or eNAT®.

Here's a breakdown of the acceptance criteria and the study details for the Cepheid Xpert Xpress CoV-2 plus, based on the provided document:

Acceptance Criteria and Device Performance

Note: The document explicitly states the "claimed LoD" which can be interpreted as an acceptance criterion for analytical sensitivity. For clinical performance, the reported PPA and NPA values serve as the acceptance criteria.

Study Details

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Clinical Performance Test Set:

  • Initial Specimens: 4047 specimens (2029 Nasopharyngeal Swab (NPS) and 2018 Anterior Nasal Swab (NS)).
  • Valid Specimens (after exclusions): 3750 specimens (1879 NPS and 1871 NS).
  • Data Provenance: United States (32 geographically diverse sites), prospectively collected, fresh (98.6%) and frozen (1.4%) clinical specimens collected in 2022.

• Analytical Performance Test Sets:

  • LoD (NPS & NS): Replicates of 20 per reagent lot (2 lots).
  • LoD (WHO Standard): 20 replicates.
  • Analytical Inclusivity (Wet Testing): 61 SARS-CoV-2 strains, 3 replicates each.
  • Analytical Exclusivity (Wet Testing): 62 microorganisms, 3 replicates each.
  • Microbial Interference: 18 commensal microorganisms, 8 replicates each with SARS-CoV-2.
  • Potentially Interfering Substances: 23 substances, 8 replicates each for negative and positive samples.
  • Carryover Contamination: 40 positive samples and 42 negative samples.
  • Reproducibility: 144 observations per panel member (3 sites x 2 operators x 3 lots x 2 days/lot x 2 runs x 2 replicates).
  • Single-Site Precision: 80 observations per panel member (1 site x 1 operator x 1 lot x 20 days x 2 runs x 2 replicates).
  • Data Provenance: Not explicitly stated for analytical studies, but typically performed in-house or by contracted labs. The substances and strains used are clearly defined.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

• The clinical performance study used a U.S. FDA-cleared molecular respiratory panel that includes SARS-CoV-2 as the comparator (reference method). This type of comparator assay is itself considered a "ground truth" established by its own regulatory clearance process, relying on its validated accuracy rather than individual expert adjudication for each case in this study.
• Qualifications of experts: Not applicable as ground truth was established by a cleared molecular diagnostic test.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

• Clinical Performance: The comparator was a U.S. FDA-cleared molecular respiratory panel. For discrepant results with this comparator, additional testing was performed using a U.S. FDA EUA SARS-CoV-2 molecular test. The text indicates that these discrepant test results were used to resolve the discrepancies (e.g., 7/9 SARS-CoV-2 negative; 8/28 SARS-CoV-2 positive from the specific footnotes), implying a third party or a consensus reference method was used for discordant samples. This suggests a form of discrepant analysis, where a third, highly accurate method or a re-test with a known method, is used to resolve differences between the investigational device and the primary 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

• Not applicable. This submission describes a molecular diagnostic test (in vitro diagnostic device), not an imaging-based AI diagnostic device requiring human reader interpretation in an MRMC study. The device provides a direct qualitative result (POSITIVE/NEGATIVE).

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

• Yes, this is a standalone device. The Xpert Xpress CoV-2 plus test is an automated, real-time RT-PCR test performed on GeneXpert Instrument Systems. Its output is a qualitative result (SARS-CoV-2 POSITIVE or NEGATIVE) based on the algorithm within the instrument, without human interpretation of raw data for diagnosis. Although human operators load samples and review results, the diagnostic determination itself is made by the system.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

• Clinical Performance: The ground truth for clinical performance was established by concordance with a U.S. FDA-cleared molecular respiratory panel and, for discrepant cases, a U.S. FDA EUA SARS-CoV-2 molecular test. This represents a highly accurate molecular diagnostic reference method.
• Analytical Performance: Ground truth for analytical studies was established using known concentrations of inactivated SARS-CoV-2 virus, WHO International Standard for SARS-CoV-2 RNA, genomic RNA/DNA of various microorganisms, and in silico analyses against sequence databases.

8. The sample size for the training set

• Not explicitly stated in terms of a "training set". For molecular diagnostic tests, "training" typically refers to the development and optimization of the primer and probe design, and algorithmic thresholds. This development process often involves internal studies and iterations rather than a distinct "training set" in the machine learning sense. The extensive analytical performance studies (LoD, inclusivity, exclusivity) serve to validate the developed algorithm's performance against diverse known samples. In silico analyses involved millions of SARS-CoV-2 sequences.

9. How the ground truth for the training set was established

• As noted above, a distinct "training set" in the machine learning context is not explicitly described. However, the ground truth for optimizing the assay's primers, probes, and detection thresholds would have been established through:
  • Known concentrations of synthetic SARS-CoV-2 genetic material or inactivated virus.
  • In silico analysis against extensive public sequence databases (e.g., GISAID, NCBI) to identify target regions and ensure inclusivity of variants while maintaining exclusivity against other pathogens.
  • Laboratory-prepared samples with known microbial content and concentrations used to optimize and validate analytical performance characteristics like sensitivity and specificity.

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