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The artus C. difficile QS-RGQ MDx Kit is an in vitro polymerase chain reaction (PCR) assay for use on the QIAsymphony RGQ MDx system for the qualitative detection of toxigenic Clostridium difficile toxin A and toxin B genes in human liquid or soft stool specimens from patients suspected of having Clostridium difficile associated disease. The test is intended to be used directly on patient samples.

The artus C. difficile QS-RGQ MDx Kit is intended to be used to aid in diagnosis of Clostridium difficile infection.

The artus C. difficile QS-RGQ MDx Kit assay uses PCR to generate an amplified product from the tcdA and tedB/tedBv genes of toxigenic C. difficile DNA in clinical specimens. Samples are extracted and prepared using the Q1Asymphony SP instrument with the QIAsymphony DSP Virus/Pathogen Mini Kit, followed by assay setup on the OIAsymphony AS. Amplification and detection are carried out using the artus C. difficile OS-RGQ MDx Kit with the Rotor-Gene Q MDx (RGQ MDx) and Rotor-Gene AssayManager software. The presence of a toxigenic C. difficile target sequence is indicated by the fluorescent signal generated through the use of fluorescently labeled oligonucleotide probes. The probes do not generate a signal unless they are specifically bound to the amplified product. The amplification cycle at which fluorescent signal is detected by the RGQ MDx is inversely proportional to the toxigenic C. difficile DNA target concentration present in the original specimen. A bacterial species unrelated to toxigenic C. difficile is introduced into each specimen during sample preparation to serve as an internal control. The internal control bacteria are lysed simultaneously with toxigenic C. difficile in the specimen. and amplified in the same reaction as the C. difficile targets using PCR, and serve to demonstrate that the entire assay process has proceeded correctly for each specimen.

Here's a summary of the acceptance criteria and study details for the QIAGEN artus® C. difficile QS-RGQ MDx Kit, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria (e.g., "Sensitivity must be >X%", "Specificity must be >Y%"). Instead, it reports the device's performance against a comparative method (enriched toxigenic culture and direct toxigenic culture) for the purpose of demonstrating substantial equivalence to a predicate device.

However, based on the provided clinical performance tables, we can present the reported performance:

2. Sample Size and Data Provenance for the Test Set

• Sample Size (for clinical evaluation):
  • Initially, 759 liquid or soft stool specimens were collected.
  • 10 specimens were withdrawn due to missing results.
  • 16 specimens reported an invalid result with the artus kit (8 became valid upon retesting as negative, 8 remained invalid).
  • The final dataset for performance analysis included 741 specimens (for comparison against enriched culture).
  • For comparison against direct culture, 699 specimens were available.
• Data Provenance: The specimens were collected from 5 geographically diverse locations within the United States in 2013. The study was prospective as it involved collecting specimens from patients suspected of having Clostridium difficile-associated disease for concurrent testing.

3. Number of Experts and Qualifications for Ground Truth

The document does not mention the use of "experts" in the sense of clinicians or radiologists establishing ground truth. The "ground truth" for the clinical study was established by laboratory methods: enriched toxigenic culture and direct toxigenic culture. For discordant results, alternative PCR followed by bi-directional sequencing was used to resolve discrepancies. The qualifications of the personnel performing these laboratory tests are not specified, but it can be inferred they were trained laboratory technicians.

4. Adjudication Method for the Test Set

For discordant results in the clinical comparison studies:

• Discordant Analysis: An "alternative PCR followed by bi-directional sequencing" was used.
• Enriched Culture Comparison:
  • For 17 specimens that were artus Positive/Enriched Culture Negative, 12 were found positive by alternative PCR, agreeing with artus.
  • For 12 specimens that were artus Negative/Enriched Culture Positive, 10 were found negative by alternative PCR, agreeing with artus. One specimen was unavailable for testing.
• Direct Culture Comparison:
  • For 19 specimens that were artus Positive/Direct Culture Negative, 14 were found positive by alternative PCR, agreeing with artus. Two specimens were unavailable for testing.
  • The 1 specimen that was artus Negative/Direct Culture Positive was unavailable for testing.

This method resembles a third-party arbitration/adjudication (2+1 or similar logic) where an additional, more definitive test (alternative PCR + sequencing) was used to resolve disagreements between the index test (artus kit) and the primary comparator (culture).

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 (IVD) assay that provides a quantitative or qualitative result, not an image-based diagnostic read by human observers. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable here.

6. Standalone Performance

Yes, the studies reported demonstrate the standalone performance of the algorithm (the artus C. difficile QS-RGQ MDx Kit). The clinical performance tables compare the kit's results directly against culture methods, without human interpretation for the artus kit's output.

7. Type of Ground Truth Used

The primary ground truth for the clinical studies was laboratory culture results, specifically:

• Enriched Toxigenic Culture
• Direct Toxigenic Culture
• For discordant cases, a more definitive molecular method, alternative PCR followed by bi-directional sequencing, was used as a confirmatory "reference standard" to resolve discrepancies.

8. Sample Size for the Training Set

The document does not specify the sample size used for any training set. This information is typically proprietary to the manufacturer's algorithm development process and is not always disclosed in 510(k) summaries for IVD devices. The studies described are performance validation studies, not algorithm training studies.

9. How Ground Truth for the Training Set Was Established

As the sample size for a training set is not provided, the method for establishing its ground truth is also not described.

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The Rotor-Gene Q MDx instrument with Rotor-Gene Q software version 2.1.0 or higher is a real-time nucleic acid amplification and detection system which measures nucleic acid signals from amplified DNA using fluorescent detection.

The Rotor-Gene Q MDx instrument is intended for in vitro diagnostic use with FDA cleared or approved nucleic acid tests in clinical laboratories.

The Rotor-Gene® Q MDx is a real-time PCR analyzer designed for rapid thermal cycling and real-time detection of PCR assays. The Rotor-Gene Q MDx uses a centrifugal rotary design for thermal cycling where each tube spins in a chamber of moving air, keeping all samples at a uniform temperature. Detection is performed as each tube aligns with the detection optics, where the sample is illuminated and the fluorescent signal is rapidly collected from a single, short optical pathway.

The QIAGEN GmbH Rotor-Gene® Q MDx is a real-time PCR analyzer intended for in vitro diagnostic use with FDA cleared or approved nucleic acid tests in clinical laboratories. As an instrument, its performance is assessed in conjunction with specific assays. The provided summary focuses on the instrument itself and refers to a separate submission for the assay's performance.

Here's an analysis of the provided information based on your request:

1. A table of acceptance criteria and the reported device performance

The provided document describes the device, its intended use, and notes that the analytical and clinical performance of the Rotor-Gene Q MDx instrument is assessed for each assay to be run on this system. It explicitly states that the artus® Infl A/B RG RT-PCR assay is being submitted separately and refers to that submission for detailed performance data.

Therefore, specific acceptance criteria and reported device performance for the Rotor-Gene Q MDx instrument in isolation (e.g., regarding thermal cycling uniformity or detection sensitivity as inherent characteristics of the instrument) are not detailed in this document. The performance metrics listed are for the assay that runs on the instrument.

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

The document refers to the artus® Infl A/B RG RT-PCR assay 510(k) submission for full testing details, which includes "Testing of prospectively collected and banked specimens."

• Sample Size for Test Set: Not specified in this document. It would be in the assay's submission.
• Data Provenance: "prospectively collected and banked specimens." Country of origin is not specified.

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)

This information is not provided in the given document. It would typically be detailed in the specific assay's submission.

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

This information is not provided in the given document. It would typically be detailed in the specific assay's submission.

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

The Rotor-Gene Q MDx is a real-time PCR instrument, not an AI software or imaging device used by 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 Rotor-Gene Q MDx is an instrument that performs real-time PCR. Its performance is inherent to its functionality (thermal cycling, fluorescence detection) when used with an assay. The concept of "standalone algorithm performance" without human intervention, as typically understood in AI-based devices, does not directly apply here in the same way. The instrument itself operates independently once a user initiates a run.

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

For the associated artus® Infl A/B RG RT-PCR assay, the document indicates "Testing of prospectively collected and banked specimens." While the specific "ground truth" method (e.g., culture, another FDA-approved PCR test, clinical diagnosis) is not detailed in this document, it implies clinical samples with a reference standard.

8. The sample size for the training set

This information is not provided in the given document. For a PCR instrument, the concept of a "training set" in the context of machine learning (AI) is generally not applicable. Instead, the instrument's design and calibration are based on engineering principles and verified through analytical studies. For the assay run on the instrument, there would be analytical validation data (e.g., sensitivity, specificity, LOD) established using various samples, but these are not typically referred to as a "training set."

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

As noted in point 8, the concept of a "training set" and associated "ground truth" as typically used for AI devices is not directly applicable to this PCR instrument. Any "ground truth" would be related to the analytical and clinical validation of the assays running on the instrument, and those details are referred to a separate submission.

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The artus® Infl A/B RG RT-PCR Kit is a multiplex real time PCR in vitro diagnostic test for the qualitative detection and identification of Influenza A and Influenza B virus RNA in nasopharyngeal swab specimens using the Rotor-Gene® Q MDx instrument. The test is intended for use as an aid in the differential diagnosis of Influenza A and Influenza B viral infections in patients symptomatic for respiratory tract infection in conjunction with clinical and epidemiological risk factors. It is not intended to detect Influenza C virus.

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

Performance characteristics for Influenza A were established during the 2009/2010 and 2010/2011 flu seasons when Influenza A (H3N2) and Influenza A/2009 (H1N1) were the predominant Influenza A viruses in circulation. When other Influenza A viruses emerge, 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 artus Infl A/B RG RT-PCR Kit contains reagents and instructions for the detection and differentiation of Influenza A and Influenza B viral RNA in nasopharyngeal swabs of symptomatic patients.

The assay utilizes the EZ1 Advanced XL instrument with the EZ1 Advanced XL DSP Virus Card v. 1.0. and the EZ1 DSP Virus Kit (QIAGEN) for viral nucleic acid extraction. The Rotor-Gene Q MDx instrument with the artus Influenza Assay Software Package (QIAGEN) is used for amplification and detection.

Pathogen detection by the reverse transcription polymerase chain reaction (RT-PCR) is based on the reverse transcription of the RNA into complementary DNA (cDNA) and subsequent amplification of specific regions of the pathogen genome. In real-time PCR the amplified product is detected via fluorescent dyes. These are linked to oligonucleotides that bind specifically to the amplified product. Monitoring the fluorescence intensities during the PCR run (i.e., in real time) allows the detection of the accumulating product without having to re-open the reaction tubes after the PCR run.

The Influenza A/B Master contains primers, probes, enzymes, and other reaction components (except Mg solution) needed for the specific amplification of a 141 bp region of the Influenza A virus genome and a 95 bp region of the influenza virus B genome, and for the direct detection of the specific amplicons in two fluorescence channels of the Rotor-Gene O MDx instrument. The primers are complementary to highly conserved regions of the Matrix gene locus within the influenza B virus genome. The probes are dual-labeled with a reporter dye attached to the 5'-end and a quencher dye attached to the 3'-end. Detection is performed on the Rotor-Gene O MDx instrument at wavelengths listed in Table 5.1.

In addition, the Master contains a second heterologous primer/probe set to detect the Influenza A/B Internal Control (IC). The IC result identifies possible failure of RNA extraction or the presence of PCR inhibition. The Internal Control is detected in a third fluorescence channel.

An Influenza A Control and an Influenza B Control comprised of in vitro transcripts representing the amplified regions of the Influenza A virus genome and the Influenza B virus genome, respectively, are provided. PCR grade water is provided as a negative (notemplate) control.

The procedure consists of four consecutive steps:

1. Sample collection: Collect nasopharyngeal swab specimens from symptomatic patients using a polyester, nylon, or rayon swab and place it into virus transport medium.
2. Nucleic acid extraction: Add the Influenza IC to the carrier RNA before starting the extraction procedure. Extract viral RNA using the EZ1 DSP Virus Kit in combination with the EZ1 Advanced XL instrument.
3. Real-time RT-PCR: Add the extracted RNA and positive and negative control material to Influenza A/B Master mix. Perform real-time RT-PCR using the Rotor-Gene O MDx instrument.
4. Result interpretation: The Influenza Assay Package evaluates the results of the positive and negative controls to determine if the run is valid. If the run is valid, the internal control and target-specific results of each specimen are evaluated.

Here's an analysis of the acceptance criteria and supporting studies for the artus® Infl A/B RG RT-PCR Kit, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria (e.g., "Sensitivity must be >90%"). Instead, it presents the "performance characteristics" observed in the clinical evaluations. The interpretation below assumes that achieving these reported performance levels was sufficient for acceptance.

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

• Prospective Clinical Evaluation:
  • Sample Size: 254 nasopharyngeal (NP) swab specimens.
  • Data Provenance: Prospective, collected at 3 clinical laboratories in the United States during the 2010-11 respiratory virus season.
• Retrospective Clinical Evaluation 1:
  • Sample Size: 212 specimens.
  • Data Provenance: Retrospective, collected from the 2009 and 2010 respiratory virus season. Country of origin not explicitly stated but implied to be US clinical laboratories where initial testing occurred.
• Prospectively Collected and Archived Clinical Evaluation (Retrospective Clinical 2):
  • Sample Size: 462 well-characterized, de-identified, residual specimens.
  • Data Provenance: Retrospective (archived), collected from August 2009 to May 2011 respiratory virus season. Country of origin not explicitly stated but implied to be US clinical settings.

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 of experts" or their "qualifications" for establishing the ground truth in the clinical studies.

• Prospective Clinical Evaluation: The reference method was "standard viral culture (shell vial) followed by direct fluorescent antibody (DFA) screening and identification." This typically involves trained laboratory personnel (e.g., microbiologists, lab technologists) rather than a panel of clinical experts for interpretation. Bidirectional sequencing was used to confirm some discrepant results.
• Retrospective Clinical Evaluation 1 & 2: The ground truth was established using "an FDA cleared molecular test" or "FDA cleared molecular tests for routine patient management." This implies reliance on the validated results from these predicate devices, not on a panel of human experts re-interpreting raw data.

4. Adjudication Method for the Test Set

The document does not describe a formal adjudication method (e.g., 2+1, 3+1) involving multiple experts for the test set.

• In the prospective study, discrepant results (artus positive, culture negative) were investigated using "bidirectional sequencing." This is a molecular confirmation, not an expert panel adjudication.
• In the retrospective studies, the "FDA cleared molecular tests" were used as the reference, suggesting agreement with those established results was the primary measure, not a separate adjudication process.

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, an MRMC comparative effectiveness study was not done. This device is a molecular diagnostic test (RT-PCR kit), not an imaging or AI-assisted diagnostic tool that would typically involve human "readers" or assess improvement with AI assistance. The performance is entirely based on the kit's analytical and clinical accuracy.

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

Yes, the performance reported for the artus® Infl A/B RG RT-PCR Kit is inherently standalone (algorithm only, without human-in-the-loop performance in the sense of interpretative assistance). The device outputs a qualitative positive/negative result for Influenza A and B. While human operators are involved in sample preparation and running the assay, the "results interpretation" step involves the "Influenza Assay Package evaluating the results of the positive and negative controls to determine if the run is valid" and then evaluating the "internal control and target-specific results of each specimen." This is an automated interpretation by the device's software package based on pre-defined thresholds.

7. The Type of Ground Truth Used

• Prospective Clinical Evaluation: The primary ground truth was standard viral culture (shell vial) followed by direct fluorescent antibody (DFA) screening and identification. For discrepant results, bidirectional sequencing was used as a confirmatory method.
• Retrospective Clinical Evaluation 1 & 2: An FDA cleared molecular test was used as the ground truth (reference method).

8. The Sample Size for the Training Set

The document does not specify a "training set" or its sample size. For molecular diagnostic kits like this, the "development" or "training" phase usually refers to the analytical studies (e.g., determining optimal primer/probe concentrations, establishing LoD, testing specificity and reactivity) and initial method validation, rather than a distinct 'training set' for an algorithm in the way it's used for AI/machine learning. The provided data focuses on the performance of the finalized device.

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

Since no specific "training set" is identified for the device in the context of an algorithm, the concept of establishing ground truth for it is not applicable here. The ground truth for the performance evaluation (test sets) was established as described in section 7. The analytical parameters of the assay (e.g., target genes, detection channels, controls) are designed and experimentally validated, not "trained" on a dataset with external ground truth in the AI sense.

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