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The Great Basin Toxigenic C. difficile Direct Test, performed on the Great Basin PA500 Analyzer, is a qualitative in vitro diagnostic test for the detection of toxigenic Clostridioides difficile in unformed (liquid or soft) stool samples collected from patients suspected of having C. difficile infection (CDI). The automated assay utilizes polymerase chain reaction (PCR) to detect a conserved region of the toxin gene (tcdB) associated with toxin-producing C. difficile.

The Toxigenic C. difficile Direct Test is intended for use as an aid in the diagnosis of CDI in conjunction with clinical and epidemiological risk factors.

The Great Basin Toxigenic C. difficile Direct Test (CDF2) performed on the PA500 Analyzer utilizes automated, hot-start PCR amplification technology to amplify specific nucleic acid sequences that are then detected using hybridization probes immobilized on a modified silicon chip surface, in a single-use, self-contained test cartridge.

A swab volume of the specimen (raw stool) is first processed using the Sample Preparation Device (SPD). During processing through the SPD the specimen is infused with a synthetic bacterial sample processing control (SPC). An aliquot (250 µL) of the eluate obtained from the SPD, containing diluted specimen mixed with SPC, is loaded into the sample port of the CDF2 Test Cartridge.

Genomic DNA is extracted from microbial cells and diluted to reduce potential inhibitors of PCR. During the PCR process, biotin-labeled primers direct the amplification of specific nucleic acid sequences within a conserved region of the C. difficile Toxin B (tcdB) gene.

Following PCR, biotin-labeled, amplified target DNA sequences are hybridized to sequence specific probes immobilized on the silicon chip surface and incubated with antibody conjugated to the horseradish peroxidase enzyme (HRP). The unbound conjugate is washed away, and then tetramethylbenzidine (TMB) is added to produce a colored precipitate at the location of the probe/target sequence complex.

The resulting signal is detected by the automated PA500 Optical Reader within the PA500 Analyzer System. The SPC undergoes the same extraction, and detection steps as the sample in order to monitor for inhibitory substances, as well as process inefficiency due to instrument or reagent failure. No operator intervention is required once the sample is loaded into the sample port and the Toxigenic C. difficile Direct Test cartridge is loaded into the PA500 Analyzer.

The Great Basin System is a fully automated in vitro diagnostic system that includes: the PA500 Analyzer, single-use SPDs, single-use Toxigenic C. difficile Direct Test Cartridges, and the PA500 Data Analysis Software Program. The PA500 Analyzer is designed to perform automated sample preparation, target amplification via PCR, chip-based (optical) target detection, and integrated data analysis in less than two hours.

The Great Basin Toxigenic C. difficile Direct Test (CDF2) is a qualitative in vitro diagnostic test designed to detect toxigenic Clostridioides difficile in unformed stool samples from patients suspected of CDI. The device utilizes PCR to detect a conserved region of the toxin B gene (tcdB).

The study that proves the device meets the acceptance criteria is a prospective multi-center method comparison study (section H. Performance Data - Clinical Studies, page 12).

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical targets in the provided text. However, the study aims to demonstrate "acceptable performance" and states that the "information submitted...supports substantial equivalence." Based on the clinical performance, the implicit acceptance criteria would involve high positive and negative percent agreements with an FDA-cleared molecular reference.

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

• Sample Size (Clinical Test Set): A total of 829 specimens were included in the final dataset (page 12).
• Data Provenance: The study was conducted at three geographically diverse U.S. clinical study sites (Midwest, West). The data is prospective, as specimens were collected from symptomatic individuals suspected of CDI between June 2022 and February 2023 (page 12). The specimens were "excess remnants of unpreserved stool specimens...processed according to routine standard of care testing, and would have otherwise been discarded" (page 12).

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications

The ground truth for the clinical test set was established using an FDA-cleared molecular reference (page 12), not human experts. Discrepant results were investigated by testing on a third molecular test (page 14). Therefore, no human experts were directly involved in establishing the primary ground truth for the clinical samples.

4. Adjudication Method for the Test Set

The adjudication method for discrepant results was comparison to a third FDA-cleared molecular C. difficile test (page 14). If the CDF2 test result differed from the initial molecular comparator, the specimen was re-tested using a third molecular test to resolve the discrepancy.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done

No, an MRMC comparative effectiveness study was not done. The study compares the device performance against a molecular reference, not human readers.

6. If a Standalone Study (algorithm only without human-in-the-loop performance) was done

Yes, this was a standalone study. The device is an automated in vitro diagnostic test where "No operator intervention is required once the sample is loaded into the sample port and the Toxigenic C. difficile Direct Test cartridge is loaded into the PA500 Analyzer" (page 4). The performance metrics (PPA, NPA) directly reflect the device's accuracy against a molecular comparator without human interpretation of the results.

7. The Type of Ground Truth Used

The primary ground truth for the clinical study was an FDA-cleared molecular reference (page 12). For discrepant samples, a third FDA-cleared molecular C. difficile test was used for resolution (page 14).

8. The Sample Size for the Training Set

The document does not explicitly state a separate training set or its size for the algorithm itself. The studies described are primarily analytical (LoD, inclusivity, exclusivity, interference, reproducibility) and a clinical validation study. These types of in vitro diagnostic device submissions typically focus on analytical and clinical performance rather than a distinct "training set" for an AI algorithm in the same sense as image recognition or similar machine learning applications. The device's "automated data analysis software program" (page 4) is part of its design, and its performance is evaluated through the described analytical and clinical studies.

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

As no specific "training set" is described for an AI algorithm, the method for establishing its ground truth is not detailed. However, the performance is established through rigorous analytical studies using characterized microbial strains and spiked samples (e.g., cell cultures with known CFU/mL) and clinical specimens compared to a molecular reference.

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The cobas® Cdiff Nucleic acid test for use on the cobas® Liat® System is an automated, qualitative in vitro diagnostic test, that uses real-time polymerase chain reaction (PCR), for the detection of the toxin B (tcdB) gene of toxigenic Clostridioides difficile (C.difficile) in unformed (liquid or soft) stool specimens obtained from patients suspected of having C. difficile Infection (CDI). The cobas® Cdiff Nucleic acid test for use on the cobas® Liat® System is intended for use as an aid in the diagnosis of CDI in humans in conjunction with clinical and epidemiological risk factors.

The cobas® Cdiff Nucleic Acid Test for use on the cobas® Liat® System (cobas® Cdiff) is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of C. difficile DNA in human stool specimens. The cobas® Liat® is for in vitro diagnostic use. The system is designed to identify and/or measure presence of genetic material in a biological sample. The system automates all nucleic acid amplification test (NAAT) processes, including reagent preparation, target enrichment, inhibitor removal, nucleic acid extraction, amplification, real-time detection, and result interpretation in a rapid manner. The cobas® Cdiff test uses silica magnetic particle-based nucleic acid extraction and TaqMan probe-based real-time PCR amplification and detection. The cobas® Liat® Analyzer automates and integrates sample purification, nucleic acid amplification and detection of the target sequence in biological samples. Other than adding the sample to the cobas® Cdiff assay tube, no reagent preparation or additional steps are required. The cobas® Cdiff assay tube that holds all of the sample purification and PCR reagents and hosts the sample preparation and PCR process specific for the Cdiff analyte. The test uses the assay tube as both the sample and reaction vessel. The assay tube comprises flexible tubing containing all required unit dose reagents pre-packed in tube segments, separated by pressure-sensitive seals, in the order of reagent use. During the testing process, multiple sample processing actuators of the analyzer compress the cobas® Cdiff assay tube to selectively release reagents from tube segments, move the sample from one segment to another, and control reaction conditions such as reaction volume, temperature, pressure, and incubation time. Precise control of all these parameters provides optimal conditions for assay reactions, allowing the test to achieve high performance similar to or better than that of currently available molecular assays. The cobas® Liat® Analyzer software controls and coordinated these actions to perform all required assay processes, including sample preparation, nucleic acid extraction, target enrichment, inhibitor removal, nucleic acid elution, and real-time PCR. All assay steps are performed within the closed and self-contained cobas® Cdiff assay tube, thereby eliminating the potential for cross-contamination between samples. The collected data are automatically analyzed and the result is displayed in the assay report on the integrated LCD touch screen of the cobas® Liat® Analyzer.

The document provided does not contain the level of detail required to answer all aspects of your request. Specifically, it is a 510(k) summary for a change in shelf life for an existing device, the cobas® Cdiff Nucleic Acid Test. Therefore, it focuses on demonstrating that this change does not negatively impact performance, rather than providing all the original study details for the device's initial clearance.

Here's an analysis of the provided text in relation to your questions:

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

The document does not explicitly state specific numerical acceptance criteria for the initial device performance. It focuses on demonstrating that the performance of the device with the new shelf life is equivalent to the currently cleared device.

However, it does mention a new stability study was performed with "modified stability testing approach and acceptance criteria." It then states the result:

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

The document mentions a "new stability study" was performed to verify the shelf life. It does not provide:

• Sample size: No explicit number of samples or runs for this stability study is provided.
• Data Provenance: Not mentioned (e.g., country of origin).
• Retrospective/Prospective: Implied to be prospective for the shelf-life stability study, as it's a "new stability study." However, for the original clearance of the device itself, this information is not provided.

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 device is an in vitro diagnostic (IVD) test for detecting a bacterial gene (Clostridioides difficile toxin B gene). The "ground truth" for such a test would typically be established by:

• Reference methods: E.g., bacterial culture, toxigenic culture, or a highly sensitive and specific laboratory reference PCR assay.
• Clinical diagnosis: Based on patient symptoms, other lab tests, and clinical assessment.

This document does not mention the use of human experts (like radiologists) for ground truth establishment. For an IVD, the "experts" are the laboratory and clinical staff following established protocols to provide the comparator data. The document does not specify details about these "experts" or their qualifications.

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

Not applicable or not mentioned. Adjudication methods like 2+1 or 3+1 are typically used in image analysis studies where human readers interpret images. For an IVD, the comparison is usually against a pre-defined "gold standard" or reference method.

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 is an IVD test, not an AI-powered diagnostic imaging device that assists human readers.

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

Yes, by its nature, an IVD test like the cobas® Cdiff Nucleic Acid Test on the cobas® Liat® System is a standalone device. The "algorithm" here refers to the pre-programmed steps of nucleic acid extraction, amplification, and real-time detection performed by the automated system, leading to a qualitative result (positive/negative). The document states: "The cobas® Liat® Analyzer automates and integrates sample purification, nucleic acid amplification and detection of the target sequence in biological samples... The collected data are automatically analyzed and the result is displayed in the assay report on the integrated LCD touch screen of the cobas® Liat® Analyzer." This indicates standalone performance.

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

The document implies the ground truth for establishing initial performance would have been comparison to a reference method, likely a combination of toxigenic C. difficile culture and a highly reliable molecular method, or clinical diagnosis supported by confirmatory lab tests in the original clearance (K171770). For the current shelf-life stability study, the ground truth appears to be the expectation that the device continues to perform according to its established analytical specifications when tested at different time points after manufacturing. It refers to "assay performance and claims."

8. The sample size for the training set.

Not applicable/Not mentioned. As an IVD test, there isn't a "training set" in the machine learning sense. The device's performance is established through analytical and clinical validation studies with defined sample sizes. The document doesn't provide these sizes for the original device, nor for any "training" in the context of this specific 510(k) which is for a shelf-life change.

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

Not applicable/Not mentioned for the same reasons as #8. For an IVD, the "ground truth" for validation studies (analogous to a test set in ML) would be established by reference methods or clinical diagnosis.

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The cobas® Cdiff Nucleic acid test for use on the cobas® Liat® System is an automated, qualitative in vitro diagnostic test that uses real-time polymerase chain reaction (PCR) for the detection of the toxin B (tcdB) gene of toxigenic Clostridioides difficile (C.difficile) in unformed (liquid or soft) stool specimens obtained from patients suspected of having C. difficile infection (CDI). The cobas® Cdiff Nucleic acid test for use on the cobas® Liat® System is intended for use as an aid in the diagnosis of CDI in humans in conjunction with clinical and epidemiological risk factors.

The cobas® Cdiff Nucleic Acid Test for use on the cobas® Liat® System (cobas® Cdiff) is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of C. difficile DNA in human stool specimens. The cobas® Liat® is for in vitro diagnostic use. The system is designed to identify and/or measure presence of genetic material in a biological sample. The system automates all nucleic acid amplification test (NAAT) processes, including reagent preparation, target enrichment, inhibitor removal, nucleic acid extraction, amplification, real-time detection, and result interpretation in a rapid manner. The cobas® Cdiff test uses silica magnetic particle-based nucleic acid extraction and TaqMan probe-based real-time PCR amplification and detection. The cobas® Liat® Analyzer automates and integrates sample purification, nucleic acid amplification and detection of the target sequence in biological samples. Other than adding the sample to the cobas® Cdiff assay tube, no reagent preparation or additional steps are required. The cobas® Cdiff assay tube that holds all of the sample purification and PCR reagents and hosts the sample preparation and PCR process specific for the Cdiff analyte. The test uses the assay tube as both the sample and reaction vessel. The assay tube comprises flexible tubing containing all required unit dose reagents pre-packed in tube segments, separated by pressure-sensitive seals, in the order of reagent use. During the testing process, multiple sample processing actuators of the analyzer compress the cobas® Cdiff assay tube to selectively release reagents from tube segments, move the sample from one segment to another, and control reaction conditions such as reaction volume, temperature, pressure, and incubation time. Precise control of all these parameters provides optimal conditions for assay reactions, allowing the test to achieve high performance similar to or better than that of currently available molecular assays. The cobas® Liat® Analyzer software controls and coordinates these actions to perform all required assay processes, including sample preparation, nucleic acid extraction, target enrichment, inhibitor removal, nucleic acid elution, and real-time PCR. All assay steps are performed within the closed and self-contained cobas® Cdiff assay tube, thereby eliminating the potential for cross-contamination between samples. The collected data are automatically analyzed and the result is displayed in the assay report on the integrated LCD touch screen of the cobas® Liat® Analyzer.

The provided text is a 510(k) summary for the cobas® Cdiff Nucleic Acid Test for use on the cobas® Liat® System. The purpose of this submission is to demonstrate substantial equivalence to a previously cleared device (K171770), specifically addressing a software update (Liat® Analyzer Software 3.3).

Therefore, the primary study discussed is a performance evaluation to demonstrate that the software update does not negatively impact the device's performance, thereby maintaining substantial equivalence to the predicate device.

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 present a table of "acceptance criteria" with numerically reported performance metrics for sensitivity, specificity, accuracy, etc., as typically seen in initial device clearance studies. Instead, it states that the performance of the modified device was evaluated and that the overall cobas® Cdiff assay performance and claims were not impacted by the software changes. This implies that the acceptance criterion was essentially "no significant change in performance" compared to the predicate device, which had already met its own performance criteria.

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

The document does not provide details on the sample size or data provenance (e.g., country of origin, retrospective/prospective) for the performance evaluation related to the software update. It only discusses the evaluation of the software's impact on the assay. The original predicate device clearance (K171770) would contain this information for the initial performance claims.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

This information is not provided in the context of this software update evaluation. The ground truth for the test set of the original device was likely established during its initial clearance (K171770), and this document focuses on confirming that the software change doesn't alter that established performance.

4. Adjudication Method for the Test Set

This information is not provided in this document.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done

No, an MRMC comparative effectiveness study is not applicable here. This device is an automated in vitro diagnostic test (nucleic acid amplification test), not an imaging device or a system that involves human readers interpreting results in a comparative effectiveness study setting. The device is designed to provide a qualitative result (detection of the toxin B gene).

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

Yes, implicitly. The evaluation focuses on the performance of the cobas® Cdiff assay with the updated software on the cobas® Liat® System. This is a standalone performance assessment of the automated diagnostic device (algorithm and hardware combined) without human interpretation impacting the primary result itself. The result is "automatically analyzed and...displayed" (page 5).

7. The Type of Ground Truth Used

The document does not explicitly state the type of ground truth used for this specific software update evaluation. For the initial clearance of a diagnostic test like this, ground truth for clinical performance studies would typically involve:

• Culture confirmation (e.g., toxigenic C. difficile culture)
• An FDA-cleared reference method or composite reference method (CRM) utilizing multiple tests and/or expert clinical judgment.

This document assumes that the established ground truth methodology for the predicate device remains valid and that the software update does not affect the device's ability to correlate with that ground truth.

8. The Sample Size for the Training Set

The document does not provide information on the sample size for the training set for the software (algorithm) itself. Given that this is a software update for an already cleared diagnostic system, "training set" in the context of machine learning (if applicable for some internal functions) is not detailed. The test uses established PCR principles and validated oligonucleotide sequences.

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

This information is not provided and is likely not relevant as this is an update to an analytical testing platform rather than a de novo AI/ML algorithm requiring a specific "training set" with ground truth in the traditional sense. The assay's core principles (oligonucleotide sequences, PCR) are described as unchanged from the predicate, which would have undergone its own rigorous analytical and clinical validation.

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The GenePOC CDiff assay performed on the revogene instrument is a qualitative in vitro diagnostic test that utilizes automated sample processing and real-time polymerase chain reaction (PCR) to detect the toxin B (tcdB) gene of toxigenic Clostridium difficile( C. difficile) in unformed (liquid or soft) stool specimens obtained from patients suspected of having C. difficile infection (CDI). The GenePOC CDiff assay is intended to aid in the diagnosis of CDI.

The GenePOC™ CDiff assay is a single-use test for the qualitative detection of the toxin B (tcdB) gene of toxigenic Clostridium difficile (C. difficile) in unformed (liquid or soft) stool specimens. The GenePOC™ CDiff assay kit is comprised of the disposable CDiff microfluidic cartridges (PIE), Disposable Transfer Loops (DTL), Sample Buffer Tubes (SBT), and Disposable Transfer Tools (DTT; pipette). These components are used to suspend the sample, extract, amplify, and detect C. difficile nucleic acid. A Process Control (PrC) is also incorporated into each PIE to verify sample processing and amplification steps. The PrC allows for the verification of potential inhibitor substances as well as microfluidic, instrument or reagent failure. The GenePOC™ CDiff assay is designed to be used on the revogene™. The revogene™ is an instrument that automates sample homogenization, sample dilution, cells lysis, DNA amplification and detection of the amplified PCR products.

Each GenePOC™ CDiff assay kit provides components for 24 tests. User intervention is required for sample preparation, transferring the stool specimen with the DTL into the SBT, using the DTT to transfer the sample into the PIE, and loading/unloading the PIE into the revogene™ carousel. Each PIE is a completely integrated closed device in which a sample is dispensed and processed through different microfluidic chambers and channels that allow for the sample processing and subsequent real-time PCR steps.

Upon completion of a run, the results are computed by the revogene™ from measured fluorescent signals and embedded calculation algorithms. The output results include positive, negative, indeterminate, and unresolved. Upon completion of a run, the user removes the used cartridges and disposes of them in normal biological waste. Results may be viewed, printed, transferred, and/or stored by the user.

The provided document describes the regulatory submission for the GenePOC CDiff assay, a diagnostic test for Clostridium difficile infection (CDI). The document focuses on the analytical and clinical performance of the device to demonstrate its substantial equivalence to a predicate device.

Here's a breakdown of the acceptance criteria and study details 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 a formal table. However, the performance characteristics sections imply the criteria for various analytical and clinical aspects. The reported performance is presented in the tables and text within the document.

Let's infer the acceptance criteria from the reported results, especially concerning agreement percentages and confidence intervals. Typically, for in vitro diagnostics, high sensitivity and specificity are desired, often above certain thresholds (e.g., 85% or 90% for sensitivity, and 95% or more for specificity). For reproducibility, high agreement is also expected (e.g., >95%).

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The cobas® Cdiff Nucleic acid test for use on the cobas® Liat® System is an automated, qualitative in vitro diagnostic test, that utilizes real-time polymerase chain reaction (PCR), for the detection of the toxin B (tcdB) gene of toxigenic Clostridium difficile in unformed (liquid or soft) stool specimens suspected of having C. difficile infection (CDI). The cobas® Cdiff Nucleic acid test for use on the cobas® Liat® System is intended for use as an aid in the diagnosis of CDI in humans in conjunction with clinical and epidemiological risk factors.

The cobas® Cdiff Nucleic acid test for use on the cobas® Liat® System (cobas® Cdiff ) is a rapid, automated in vitro diagnostic test for the qualitative detection of C. difficile DNA in human stool specimens. The cobas® Liat® System is for in vitro diagnostic use. The system is designed to identify and/or measure the presence of genetic material in a biological sample. The system automates all nucleic acid amplification test (NAAT) processes, including reagent preparation, target enrichment, inhibitor removal, nucleic acid extraction, amplification, real-time detection, and result interpretation in a rapid manner. The cobas® Cdiff test uses silica magnetic particle-based nucleic acid extraction and TaqMan probe-based real-time PCR amplification and detection. The cobas® Liat® Analyzer automates and integrates sample purification, nucleic acid amplification and detection of the target sequence in biological samples. Other than adding the sample to the cobas® Cdiff assay tube, no reagent preparation or additional steps are required. The cobas® Liat® System consists of an cobas® Liat® Analyzer with integrated software for running tests and analyzing the results, and a single-use disposable cobas® Cdiff assay tube that holds all of the sample purification and PCR reagents and hosts the sample preparation and PCR processes specific for the Cdiff analyte. The test uses the assay tube as both the sample and reaction vessel. The assay tube comprises flexible tubing containing all required unit dose reagents pre-packed in tube segments, separated by pressure-sensitive seals, in the order of reagent use. During the testing process, multiple sample processing actuators of the analyzer compress the cobas® Cdiff assay tube to selectively release reagents from tube segments, move the sample from one segment to another, and control reaction conditions such as reaction volume, temperature, pressure, and incubation time. Precise control of all these parameters provides optimal conditions for assay reactions, allowing the test to achieve high performance similar to or better than that of currently available molecular assays. The cobas® Liat® Analyzer software controls and coordinated these actions to perform all required assay processes, including sample preparation, nucleic acid extraction, target enrichment, inhibitor removal, nucleic acid elution, and real-time PCR. All assay steps are performed within the closed and self-contained cobas® Cdiff assay tube, thereby eliminating the potential for cross-contamination between samples. The collected data are automatically analyzed and the result is displayed in the assay report on the integrated LCD touch screen of the cobas® Liat® Analyzer.

Here's an analysis of the acceptance criteria and study details based on the provided text:

Acceptance Criteria and Device Performance for cobas® Cdiff Nucleic acid test for use on the cobas® Liat® System

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state formal "acceptance criteria" in a separate section with numerical targets like a typical clinical trial report for an AI device. Instead, the performance metrics are presented as the results of the studies conducted. I will infer the acceptance criteria from the reported performance, implying that the reported values met the internal standards set by the manufacturer for substantial equivalence.

2. Sample size used for the test set and the data provenance

• Analytical Sensitivity (LOD): Not specified as a per-sample-size, but replicates of each 5-member test panel were tested with 2 different lots of assay tubes. Additional replicates were tested for confirmation.
• Inclusivity: 3 replicates per strain (37 toxigenic strains) were tested.
• Analytical Specificity (Cross-reactivity): Not specified as a per-sample-size, but 149 non-toxigenic organisms/cells were tested.
• Interference: Not specified as a per-sample-size, but 38 commonly used medications, fecal fat, whole blood, and mucin were tested.
• Reproducibility: 818 total tests were performed, with 798 valid for analysis across 3 panel members (Negative, ~1xLOD, ~3xLOD). 3 replicates per panel member, run on 5 nonconsecutive days by 2 operators at 3 sites for 3 reagent lots.
• Clinical Performance: 1,013 evaluable fresh remnant stool specimens were prospectively collected.
  • Data Provenance:
    • Country of Origin: Not explicitly stated, but "Nine (9) study sites from geographically diverse locations participated in this study." This suggests a multi-center study, likely within a single country (such as the US, given the FDA submission) or potentially across a few countries, but a specific list is not provided.
    • Retrospective/Prospective: The clinical performance study was prospective. "Evaluable fresh remnant specimens were prospectively collected from 1,013 patients."

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

• Analytical (LOD, Inclusivity, Specificity, Interference): Not applicable for these studies as the "ground truth" is based on engineered samples (known concentrations of specific strains, or presence/absence of interfering substances).
• Reproducibility: Not applicable, as this assessed the consistency of the device's own results, not against an external ground truth.
• Clinical Performance:
  • Number of experts: Not explicitly stated.
  • Qualifications of experts: Not explicitly stated. The "ground truth" was established by "combined results of direct and enriched toxigenic culture using leftover, deidentified, unformed stool samples" performed at a "reference laboratory." The document mentions "Nineteen (19) operators distributed across these study sites performed testing with the cobas® Cdiff test," but these are operators, not necessarily the adjudicating experts for the ground truth. For microbiological culture, laboratory personnel with specific training in microbiology would establish the ground truth.

4. Adjudication method for the test set

• Analytical, Reproducibility: Not applicable.
• Clinical Performance:
  • Initial Ground Truth: "Combined results of direct and enriched toxigenic culture" served as the primary comparative method.
  • Discrepant Analysis: "All evaluable discordant specimens and an equal number of randomly selected and representative concordant samples were used for discrepant testing by an FDA-cleared comparator NAAT. Testing was performed at an external lab that was preselected and qualified by RMS." This implies a form of 2-method consensus with a third method for discrepancies. If direct and enrichment culture disagreed, or if the cobas test disagreed with the combined culture, a third (comparator NAAT) test was used for "discrepant analysis." However, the final clinical performance tables still directly compare the cobas test to the combined culture results, with the discrepant analysis results discussed qualitatively ("Of the 23 specimens with false-negative cobas® Cdiff test results relative to combined direct culture and enrichment culture, 19 were negative. 3 were positive and 1 was invalid by the second NAAT method.").

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done

• No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) test, not an imaging AI device that relies on human-in-the-loop interpretation. The clinical study compares the device's output to laboratory culture results, not to human readers' interpretations with or without AI assistance.

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

• Yes, the performance presented is purely standalone (algorithm/device only). The cobas® Cdiff Nucleic acid test is an automated, qualitative in vitro diagnostic test. The device provides "result interpretation" directly on its integrated LCD touch screen (page 5). The clinical performance data reflects the device's ability to detect the target gene independently, compared against culture methods.

7. The type of ground truth used

• Analytical Studies (LOD, Inclusivity, Specificity, Interference): Lab-prepared spiked samples with known concentrations/compositions.
• Clinical Performance: Microbiological culture results. Specifically, "combined results of direct and enriched toxigenic culture." A "second NAAT method" was used for discrepant analysis.

8. The sample size for the training set

• Not applicable / Not explicitly stated. This is a molecular diagnostic test for Clostridium difficile, not a machine learning or AI algorithm in the typical sense that requires explicit "training data" for a model to learn from. The assay uses predefined primers and probes for real-time PCR detection (page 4). While the assay design and optimization would involve extensive internal development and testing, this is not characterized as a "training set" in the context of typical AI algorithm development.

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

• Not applicable / Not explicitly stated. As mentioned above, this is not an AI/ML device that uses a "training set" in the conventional sense. The "ground truth" for developing the test was based on well-characterized isolates of C. difficile and other microorganisms to design and validate the specificity and sensitivity of the primers and probes.

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The ARIES® C. difficile Assay is a real-time polymerase chain reaction (PCR) based qualitative in vitro diagnostic test for the direct detection of toxigenic Clostridium difficile (C. difficile) nucleic acid in unpreserved, unformed (liquid or soft) stool specimens obtained from patients suspected of having Clostridium difficile infection (CDI). The test targets the C. difficile toxin A gene (tcdA) and toxin B gene (tcdB) and is indicated for use as an aid in the diagnosis of C. difficile infection (CDI). The ARIES® C. difficile Assay is indicated for use with ARIES® Systems.

The ARIES® C. difficile Assay is a polymerase chain reaction (PCR)-based qualitative in vitro diagnostic test system which consists of the ARIES® System or the ARIES® M1 System with their included ARIES® Software, a stool resuspension kit, an assay-specific cassette, and an assay-specific protocol file. The ARIES® C. difficile Assay cassette is a disposable, single-use cassette containing nucleic acid purification reagents, internal sample process control (SPC), and an assay-specific master mix capable of performing the designated assay on one sample. The ARIES® C. difficile Assay cassette directly detects toxigenic Clostridium difficile (C. difficile) from unformed stool specimens obtained from patients suspected of having Clostridium difficile infection. Specifically, the ARIES® C. difficile Assay cassette detects the C. difficile toxin A gene (tcdA) and toxin B gene (tcdB) and a DNA Sample Processing Control. Unpreserved raw stool is processed using the ARIES® Stool Resuspension Kit. The ARIES® Stool Resuspension Kit includes a flocked swab, a tube containing preprocessing beads, and Stool Resuspension Buffer. The preprocessing method involves transfer of a swab of stool specimen into a tube containing preprocessing beads and Stool Resuspension Buffer. The swab is mixed in the tube by vortexing and then centrifuged. Finally, the preprocessed sample is added to the ARIES® C. difficile Assay cassette. The specimen is lysed and nucleic acid is extracted using an ARIES® instrument. An extractable sample processing control (SPC) target is also present in the ARIES® C. difficile Assay cassette and is processed with the specimen. The SPC controls for recovery of extracted nucleic acid, for inhibitory substances and for PCR reagent and instrument integrity. The Ct value of the SPC is designed to verify nucleic acid extraction, to identify PCR inhibition, if any, and verify proper function of the extraction system and real-time instrument. The Tm value of the SPC is used as a reference for determining the Tm of the tcdA and tcdB targets (if present). The extracted nucleic acid and SPC are transferred via magnetic beads through the cassette to the ARIES® C. difficile Assay lyophilized PCR reagents in the PCR tube that contain primer pairs specific to tcdA, tcdB, and the SPC sequence. Each of the primer pairs is labeled with a distinct fluorophore and detected in distinct channels of an ARIES® System. PCR amplification is performed and assay fluorescence is monitored. Incorporation of a quencher-labeled nucleotide results in a decrease in fluorescence for the associated primer pair. Following amplification, the reaction is slowly heated to separate the fluorescent-labeled strand from the quencher-labeled strand, a process that results in an increase in the fluorescence signal. The reaction fluorescence is measured during this process and the temperature at which the change in fluorescence is the maximum Tm of the amplicon. The strands of the amplicons will separate at a specific melting temperature (Tm) and an increase in fluorescence is observed. The instrument fluorescence output is analyzed and test results are determined using the ARIES® System software and the ARIES® C. difficile Assay protocol and run files. ARIES® C. difficile Assay results may be reported from the ARIES Software or from the optional SYNCT® Software.

Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided FDA 510(k) summary for the ARIES® C. difficile Assay:

1. Table of Acceptance Criteria and Reported Device Performance

The FDA 510(k) summary does not explicitly state pre-defined acceptance criteria values for clinical performance as a single table. Instead, it presents the assay's performance metrics against a reference method and implicitly indicates that these results were considered "acceptable" for substantial equivalence. Based on the clinical performance section, we can infer the key performance metrics reported.

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

• Sample Size:

  • Clinical Study: 984 unique specimens were included in the data analysis. After exclusions and re-tests, 979 eligible specimens were used for performance calculations.
  • Analytical Precision/Reproducibility:
    • Within-Laboratory: 252 samples (36 for each of 7 panel members).
    • Reproducibility (3 sites x 5 days x 6 panel members x 3 replicates): 270 samples (90 for each of 7 panel members, assuming negative also had 90 replicates).
  • Limit of Detection (LoD): Not specified precisely, but implied to be multiple replicates at various dilutions.
  • Analytical Reactivity: 15 distinct strains of toxigenic C. difficile (in addition to those in LoD).
  • Analytical Specificity (Cross-Reactivity/Interference): 61 microorganisms/viruses + human DNA, each tested with three replicates of two C. difficile strains (BAA-1870 and BAA-1871) and three negative replicates.
  • Carry-Over/Cross-Contamination: 30 high positive and 30 negative samples.

• Data Provenance:

  • Clinical Study: Prospective. The specimens were collected from 31-October-2016 to 21-February-2017 at four geographically distinct clinical sites within the United States. The specimens consisted of excess leftover de-identified, unpreserved, unformed stool specimens from patients suspected of having Clostridium difficile infection (CDI).

3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications of Experts

The document does not explicitly state the "number of experts" or their specific "qualifications" for establishing the ground truth using the reference method.

• Ground Truth Method: The reference method for the clinical study was "direct and enriched toxigenic culture." This is a laboratory-based method.
• Location of Ground Truth Establishment: "Reference method testing was performed at a centralized testing facility." It is implied that qualified laboratory personnel perform these culture tests, but specific number or qualifications are not provided.

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method (like 2+1, 3+1, none) for discordant results between the ARIES® C. difficile Assay and the reference method.

However, for discordant cases, further characterization was performed:

• For specimens negative by direct toxigenic culture but positive by ARIES® C. difficile Assay (False Positives based on direct culture), enriched toxigenic culture was used, and for some, bi-directional sequencing with analytically validated primers was performed.
• For specimens positive by direct toxigenic culture but negative by ARIES® C. difficile Assay (False Negatives based on direct culture), bi-directional sequencing with analytically validated primers was used.
• Similar follow-up testing (bi-directional sequencing) was done for discords when comparing to "Direct and Enriched Toxigenic Culture."

This suggests a form of further characterization for discordant results rather than an adjudication panel of experts re-reading primary data.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, an MRMC comparative effectiveness study involving human readers with and without AI assistance was not done. This device is an in vitro diagnostic (IVD) assay, not an AI imaging or diagnostic algorithm designed to assist human readers. Its performance is evaluated stand-alone against a reference laboratory method.

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

Yes, the clinical performance study evaluated the ARIES® C. difficile Assay as a standalone algorithm/device. The assay generates a qualitative result (POSITIVE, NEGATIVE, or INVALID) based on its internal processing and software analysis, without human interpretation of raw data for diagnosis. The ARIES® System software automatically determines and reports results.

7. The Type of Ground Truth Used

The primary ground truth used for the clinical performance study was direct and enriched toxigenic culture.

• Direct Toxigenic Culture: This involves culturing the C. difficile from the stool sample directly to identify toxigenic strains.
• Enriched Toxigenic Culture: This involves an enrichment step before culturing to increase the yield of C. difficile, potentially improving sensitivity.

For discordant results, further analysis using bi-directional sequencing with analytically validated primers was employed.

8. The Sample Size for the Training Set

The document does not specify a distinct training set sample size. For IVD submissions like this one, it's common that assay parameters (like Ct cut-offs and Tm windows) are established during "internal optimization studies" and "internal verification studies." The document explicitly states:

• "Initial Assay Protocol File parameters were set during internal optimization studies."
• "The final Assay Protocol File parameters were then established during internal verification studies."

The sizes of these internal optimization and verification studies are not provided but would have involved various analytical samples (LoD, inclusivity, exclusivity, etc.) rather than a dedicated "training set" of clinical samples in the same way an AI model might be trained. The clinical trial data (979 samples) served as a test set for validation, not for training the assay's parameters.

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

Since no distinct "training set" of clinical samples is explicitly described for algorithm development in the AI sense, the ground truth establishment for the internal optimization and verification studies likely involved:

• Carefully characterized reference strains of C. difficile (toxigenic and non-toxigenic).
• Spiked stool matrixes with known concentrations of C. difficile to determine detection limits and reactivity.
• Potentially, a smaller set of pre-characterized clinical samples to refine initial assay parameters.

Again, these studies would rely on established microbiological and molecular biology techniques (culture, PCR, sequencing) to define the presence/absence and characteristics of C. difficile in the samples used for internal development.

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The Solana® C. difficile Assay is an in vitro diagnostic test for the direct, qualitative detection of the Clostridium difficile Toxin A gene (tcdA) in unformed stool specients of patients suspected of having Clostridium difficile-infection (CDI). The Solana C. difficile Assay is intended for use as an aid in diagnosis of CDI. The assay utilizes helicase-dependent amplification (HDA) for the amplification of a highly conserved fragment of the Toxin A gene sequence. The Solana C. difficile Assay is intended for use only with the Solana® instrument.

The Solana C. difficile Assay combines simple sample processing and Helicase-Dependent Amplification (HDA) performed in Solana for the detection of toxigenic Clostridium difficile directly from CDI-suspected diarrheal specimens.

A small amount of specimen is transferred to a Lysis Tube using a swab. The Lysis Tube is then subjected to heat-treatment at 95°C for 5 minutes. The heat-treated sample is added to a Dilution Tube, and then transferred to a Reaction Tube. The Reaction Tube contains lyophilized HDA reagents, dNTPs, primers and probes. Once rehydrated with the diluted sample, the Reaction Tube is placed in Solana for amplification and detection of target sequence. In Solana, the target sequence is amplified by specific primers and detected by a specific fluorescence probe included in the Reaction Tube. A competitive process control (PRC) is included in the Lysis Tube to monitor sample processing, inhibitory substances in clinical samples, reagent failure or device failure. The PRC is amplified by the target-specific primers and detected by a PRC specific fluorescence probe.

The target and PRC probes are labeled with a quencher on one end and a fluorophore on the other end. Upon annealing to target or PRC amplicons, the fluorescence signal increases due to physical separation of fluorophore from quencher. Solana measures and interprets the fluorescent signal, using on-board method-specific algorithms. Solana then report the test results to the user on its display screen, and it can print out the results via a printer.

Here's a breakdown of the acceptance criteria and study details for the Solana C. difficile Assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" as a separate section with predefined thresholds. However, the "Performance in Comparison to Enhanced toxigenic bacterial culture" section for sensitivity and specificity can be considered as the primary clinical performance evaluation against a recognized gold standard. The "Performance in Comparison to FDA-cleared molecular device" provides comparative performance.

Given this, I will present the clinical performance metrics as the reported device performance against what would typically be considered implicit acceptance targets for diagnostic devices of this type.

Table 1: Reported Device Performance Against Ground Truth (Enhanced Toxigenic Culture)

Table 2: Reported Device Performance Compared to an FDA-Cleared Molecular Device

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

• Sample Size for Test Set: 854 raw specimens were collected. After removing 2 invalid specimens, 852 specimens were used for analysis.
• Data Provenance:
  • Country of Origin: United States. The study was conducted at "three distinct geographical sites across the United States."
  • Retrospective or Prospective: Prospective. The study documents state, "Performance characteristics of the Solana C. difficile Assay were established during a prospective study conducted November 2016 to February 2017."

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications

The document does not specify the number of experts or their qualifications for establishing the ground truth (enhanced toxigenic culture). It describes the methodology for the enhanced toxigenic culture, which is a laboratory-based process, rather than an expert human interpretation.

4. Adjudication Method for the Test Set

The document does not explicitly detail an adjudication method beyond the methodology for the enhanced toxigenic culture. It mentions, "Three (3) of the six (6) specimens were positive for C. difficile toxin gene DNA by an alternate FDA cleared molecular device, three (3) were negative." and "Six (6) of eight (8) specimens were found positive for C. difficile toxin gene DNA by an alternate FDA cleared molecular device., and two (2) were negative", which suggests some level of discordant analysis against a second method, but no formal expert adjudication process is described for the ground truth establishment itself.

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

No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic test that provides a qualitative result (positive/negative) directly from the instrument. It is not designed to be interpreted by human readers, nor does it assist human readers in making a diagnosis. Therefore, the concept of human readers improving with or without AI assistance does not apply here.

6. Standalone Performance Study

Yes, a standalone performance study was done. The entire clinical performance evaluation described compares the "Solana C. difficile Assay" (the algorithm/device) directly against the enhanced toxigenic culture (ground truth) and an FDA-cleared molecular device. The results reported are for the device's performance without human intervention in the interpretation of the C. difficile Toxin A gene (tcdA) detection.

7. Type of Ground Truth Used

The primary ground truth used for evaluating the Solana C. difficile Assay was enhanced toxigenic bacterial culture.

An "alternate FDA cleared molecular device" was also used for comparison in cases of discordance, but the initial sensitivity and specificity calculations used the enhanced toxigenic culture as the reference.

8. Sample Size for the Training Set

The document does not provide information regarding a specific training set size or methodology for the Solana C. difficile Assay. The information provided focuses on the analytical and clinical validation of the final product. For an IVD like this, the "training" may happen during internal development and optimization phases, which are not typically detailed in 510(k) summaries.

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

As no specific training set or its sample size is mentioned, the method for establishing ground truth for a training set (if one existed separately from analytical validation) is not described in the provided document. The ground truth for the clinical test set was established by enhanced toxigenic bacterial culture.

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Simplexa C. difficile Direct: The Focus Diagnostics Simplexa™ C. difficile Direct assay is intended for use on the Integrated Cycler instrument for the detection of Clostridium difficile toxin B gene (tcdB) present in liquid or unformed stool samples from individuals suspected of C. difficile infection (CDI). This test aids in the diagnosis of illness resulting from CDI. The assay is for professional and prescription use only.

Simplexa C. difficile Positive Control Pack: The Simplexa™ C. difficile Positive Control Pack is intended to be used as a control with the Simplexa™ C. difficile Direct kit. This control is not intended for use with other assays or systems.

The Simplexa™ C. difficile Direct assay system is a real-time PCR system that enables the direct amplification and detection of toxigenic C. difficile DNA from unprocessed liquid or unformed stool specimens that have not undergone nucleic acid extraction. The system consists of the Simplexa™ C. difficile Direct assay, the Integrated Cycler (with Integrated Cycler Studio Software), the Direct Amplification Disc and associated accessories. In the Simplexa™ C. difficile Direct assay, bi-functional fluorescent probe-primers are used together with corresponding reverse primers to amplify C. difficile and DNA internal control targets. The assay targets a sequence which is in a well conserved region of C. difficile toxin B gene (todB). A DNA internal control is used to detect PCR failure and/or inhibition

Acceptance Criteria and Device Performance for Simplexa C. difficile Direct

1. Table of Acceptance Criteria and Reported Device Performance

The provided document describes the performance of the Simplexa C. difficile Direct assay in comparison to various gold standards and other NAATs. The acceptance criteria are implicit in the presented tables.

Acceptance Criteria for Simplexa C. difficile Direct (versus Combined Culture + Toxin Assay):

Additional Performance (versus other FDA-cleared NAATs for reference):

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

The primary clinical performance study (method comparison) used 2351 samples prospectively collected.

• Data Provenance: Samples were prospectively collected from five (5) geographically diverse sites in the USA between December 3, 2015, and June 10, 2016.
• Evaluable Samples: 2330 samples were evaluable on Simplexa C. difficile Direct & the Direct Culture method, and 2336 were evaluable on Simplexa C. difficile Direct & the Combination of Direct/Enriched Culture methods.
• Invalid Rate: The initial invalid rate was 0.64% (15/2351), reduced to a final invalid rate of 0.13% (3/2351) after repeat testing.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

The document does not explicitly state the "number of experts" or their "qualifications" involved in establishing the ground truth for the clinical sample test set. However, the ground truth was based on Direct Culture + Toxin Assay and Combined Culture (Direct & Enriched) + Toxin Assay, with confirmatory testing using FDA cleared nucleic acid amplification test (NAAT) results for discrepant analysis. This implies that the ground truth was established by laboratory methods and not by individual expert interpretation.

4. Adjudication Method for the Test Set

For discrepant samples in the clinical study, discrepant analysis was performed using FDA cleared nucleic acid amplification test (NAAT) results provided by the sites.

• For the "Simplexa C. difficile Direct versus Direct Toxigenic Culture Method" table:
  • 116/163 discrepant Simplexa-positive/Culture-negative samples were positive, and 46/163 were indeterminate for C. difficile Toxin B gene DNA when tested using an FDA cleared molecular test.
  • 8/12 discrepant Simplexa-negative/Culture-positive samples were negative, and 4/12 were positive for C. difficile Toxin B gene DNA when tested using an FDA cleared molecular test.
• For the "Simplexa C. difficile Direct versus Combined Direct and Enriched Toxigenic Culture Methods" table:
  • 59/96 discrepant Simplexa-positive/Culture-negative samples were positive, and 37/96 were negative for C. difficile Toxin B gene DNA when tested using an FDA cleared molecular test.
  • 43/55 discrepant Simplexa-negative/Culture-positive samples were negative for C. difficile Toxin B gene DNA when tested using an FDA cleared molecular test.

This indicates an adjudication process involving a third, independent, FDA-cleared NAAT for resolving discrepancies between the investigational device and the culture methods.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not explicitly described in the provided text. The study focuses on the performance of the analytical device rather than human reader interpretation with or without AI assistance.

6. If a Standalone Study (Algorithm Only Without Human-in-the-loop Performance) Was Done

Yes, the studies presented are standalone performance evaluations of the Simplexa C. difficile Direct assay. The assay is an automated real-time PCR system designed for direct detection of C. difficile toxin B gene, meaning its performance is measured independently of human interpretation of its results, although trained lab personnel would operate the instrument.

7. The Type of Ground Truth Used

The ground truth for the clinical performance study was established using:

• Direct Culture + Toxin Assay
• Combined Culture (Direct & Enriched) + Toxin Assay
• FDA cleared molecular tests (NAATs) for discrepant analysis.

This represents a composite reference standard based on microbiological culture techniques and molecular detection for toxigenic C. difficile, with additional molecular confirmation for discordant results.

8. The Sample Size for the Training Set

The document does not specify a separate "training set" sample size. The studies described are performance evaluations of the device, implying that the device's development and internal optimization would have occurred prior to these validation studies. Therefore, information regarding a training set is not provided as this is a diagnostic assay, not a machine learning algorithm that requires a separate training and test set in the same way.

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

As no specific training set is mentioned for the device (which is a molecular diagnostic assay), the method for establishing ground truth for such a set is not applicable or described in this document. The focus is on the analytical and clinical validation of the completed product.

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The cobas® Cdiff Test on the cobas® 4800 system is an automated, qualitative in vitro diagnostic test, that utilizes realtime polymerase chain reaction (PCR), for the direct detection of the toxin B (tcdB) gene of toxigenic Clostridium difficile (C. difficile) in unformed (liquid or soft) stool specimens obtained from patients suspected of having C. difficile infection (CDI). The cobas® Cdiff Test is intended for use as an aid in the diagnosis of CDI in humans in conjunction with clinical and epidemiological risk factors.

The Roche Molecular Systems (RMS) cobas® Cdiff Test utilizes real-time polymerase chain reaction (PCR) for the detection of Clostridium difficile (C. difficile) DNA from unformed (liquid or soft) stool specimens to aid in the diagnosis of Clostridium difficile infections in humans. The cobas Cdiff Test contains two major processes: (1) automated sample preparation to extract nucleic acids from the unformed stool specimens; (2) PCR amplification of target DNA sequences using C. difficile specific primers, and real-time detection of cleaved fluorescentlabeled C. difficile specific oligonucleotide detection probes. An Internal Control (IC), containing unrelated randomized DNA sequence, is added to all samples prior to automated sample preparation and is amplified and detected simultaneously with each sample to monitor the entire process. The cobas® Cdiff Test utilizes six reagent kits and is used with the cobas® 4800 System, which includes the cobas x 480 Instrument for sample preparation and the cobas z 480 Analyzer for amplification and detection, controlled by the cobas® 4800 System Software.

Here's a summary of the acceptance criteria and study details for the cobas® Cdiff Test, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state quantitative acceptance criteria in a dedicated section. However, performance targets are implicitly demonstrated and met by the reported study results. The clinical performance section compares the cobas® Cdiff Test to a "combined direct and enrichment culture" which serves as the reference standard. The reported performance metrics are:

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

• Sample Size for Clinical Performance (Test Set): 682 specimens were included in the statistical analysis for comparison with combined direct and enrichment culture. 683 subjects were initially collected from.
• Data Provenance: Prospective, multi-site investigation across five geographically diverse sites in the US. The samples were "leftover, de-identified, unformed stool samples from subjects suspected of having CDI."

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document does not explicitly state the number or qualifications of experts used to establish the ground truth. However, the ground truth for the clinical study was based on toxigenic culture, which involved laboratory procedures conducted at a "single reference laboratory." This suggests trained laboratory personnel, but no specific professional qualifications (e.g., "radiologist with 10 years of experience") are provided.

4. Adjudication Method for the Test Set

The primary ground truth for the clinical performance was established by toxigenic culture (direct and enrichment culture followed by cytotoxicity testing). Discrepant analysis was performed on all samples with discordant results and a random subset of concordant results between the cobas® Cdiff Test and toxigenic culture using a second FDA-cleared nucleic acid amplification test (NAAT). This indicates an adjudication method involving a third, independent test to resolve discrepancies.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not reported. This study evaluates the impact of AI on human reader performance. The cobas® Cdiff Test is an automated diagnostic test that doesn't involve human interpretation of images or complex data in a way that an MRMC study would be applicable.

6. If a Standalone Study Was Done

Yes, a standalone study was done. The entire clinical performance evaluation directly assesses the performance of the cobas® Cdiff Test (the algorithm/device) against the established ground truth (toxigenic culture) without human intervention in the interpretation of the device's results.

7. The Type of Ground Truth Used

The ground truth used for the clinical performance evaluation was expert consensus informed by culture and cytotoxicity testing. Specifically, a specimen was considered positive for toxigenic C. difficile if C. difficile was recovered from stool by either direct or enriched toxigenic culture and if isolates recovered tested positive by cytotoxicity testing. Specimens were negative only if they tested negative by both direct, repeat direct, and enrichment culture. Additionally, a second FDA-cleared NAAT was used for discrepant analysis, further supporting the ground truth adjudication.

8. The Sample Size for the Training Set

The document does not provide information on the sample size for the training set. This K142422 submission focuses on the performance of a developed device, not on the details of its developmental training data.

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

The document does not provide information on how the ground truth for the training set was established. The submission focuses on the clinical validation of the device, not its initial development or training process.

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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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