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The Genomadix Cube CYP2C19 System is a qualitative in vitro diagnostic test for the identification of a patient's CYP2C19 *2, *3, and *17 genotypes determined from genomic DNA obtained from a buccal swab sample.

The Genomadix Cube CYP2C19 System can be used to aid clinicians in determining therapeutic strategy for therapeutics that are metabolized by the cytochrome P450 2C19 gene product, specifically *2, *3, and *17 alleles. This test is not intended to be used to predict drug response or non-response.

The Genomadix Cube CYP2C19 Test Kit is indicated for use with the Genomadix Cube CYP2C19 Platform.

The Genomadix Cube CYP2C19 System is a sample-to-result DNA testing system with integrated DNA extraction and amplification. Genotypes are determined using Polymerase Chain Reaction (PCR) and fluorescent probe detection. The Genomadix Cube CYP2C19 System is comprised of the Genomadix Cube CYP2C19 Platform (Genomadix Cube, computer, and barcode scanner) and the Genomadix Cube CYP2C19 Test Kit (swabs and cartridges). The test is run on the Genomadix Cube CYP2C19 Platform.

The Genomadix Cube is a thermal cycling instrument that automatically integrates extraction of DNA from the buccal sample, PCR amplification, fluorescence-based detection of CYP2C19 alleles, and genotype calling.

Acceptance Criteria and Study Details for Genomadix Cube CYP2C19 System

The Genomadix Cube CYP2C19 System is a qualitative in vitro diagnostic test for the identification of a patient's CYP2C19 *2, *3, and *17 genotypes from genomic DNA obtained from a buccal swab sample.

The acceptance criteria for the device performance are not explicitly stated as distinct pass/fail thresholds in the provided text. However, the study results demonstrate the device's accuracy and reproducibility, implying that the reported performance metrics serve as the de facto acceptance criteria. The primary performance metric appears to be the "correct call rate."

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample Sizes and Data Provenance

Reproducibility Study:

• Test Set Sample Size: 8 individuals (buccal samples) across 3 sites. A total of 960 tests were performed across the 3 sites (8 subjects x 2 operators x 2 sessions x 2 replicates x 5 days).
• Data Provenance: Not explicitly stated, but the study was conducted at 3 sites, implying a multi-center study likely within the country of the applicant (Genomadix Inc.). The study involved prospective sample collection from individuals for the purpose of the study.

Analytical Specificity/Interference Study:

• Test Set Sample Size: 16 samples for each of the 14 potential interfering substances, totaling 224 samples. These were buccal swab samples from individuals with specific genotypes (4 replicates of each genotype tested).
• Data Provenance: Not explicitly stated, but likely prospective collection for the study.

Detection Limit Study:

• Test Set Sample Size:
  • Swabbing conditions (LLoD, IFU, ULoD): A total of 208 tests in the first pass across various swabbing conditions.
  • Expected DNA concentration: 140 samples for low concentration (20 replicates from 7 individuals) and 21 samples for high concentration (3 replicates from 7 individuals).
• Data Provenance: Not explicitly stated, but likely prospective collection for the study.

Carry-Over Study:

• Test Set Sample Size: 122 samples (61 *1/*1 genotypes alternated with 61 non-*1/*1 genotypes).
• Data Provenance: Not explicitly stated.

Method Comparison Study:

• Test Set Sample Size: 444 unique patient samples initially collected. 11 samples were excluded for low quality, resulting in 433 samples included in the final analysis.
• Data Provenance: Not explicitly stated, but samples were collected from unique patients for this study, implying prospective collection. The multi-site nature (3 sites) suggests a broader data collection if applicable.

3. Number of Experts for Ground Truth and Qualifications

For Reproducibility, Analytical Specificity/Interference, Detection Limit, and Method Comparison Studies:

• Number of Experts: Not explicitly stated in terms of "experts establishing ground truth."
• Qualifications of Experts: The ground truth for these studies was established by bi-directional sequencing. This is a highly accurate molecular method and itself serves as the "gold standard" for genotype confirmation. The performance of the sequencing would be overseen by qualified laboratory personnel, though details on their specific qualifications (e.g., molecular geneticists, clinical laboratory directors) are not provided.

4. Adjudication Method for the Test Set

The adjudication method used throughout the performance studies (reproducibility, interference, detection limit, method comparison) involved a "second pass" testing for inconclusive results:

• "If an inconclusive result was obtained on the first set of samples, the second set of samples from the same patient were used for a second pass test."
• This indicates a repeat testing adjudication for inconclusive results. There is no mention of a formal expert consensus (e.g., 2+1, 3+1) for resolving discrepancies between the device and the ground truth. The ground truth (bi-directional sequencing) is considered definitive.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not explicitly described or performed. The device is an automated genotyping system, so the concept of human readers "improving with AI vs. without AI assistance" does not directly apply in the traditional sense of image interpretation or complex diagnostic decision-making. The study focuses on the device's accuracy against a molecular gold standard.

6. Standalone Performance Study

Yes, the studies described (Reproducibility, Analytical Specificity/Interference, Detection Limit, Carry-Over, and Method Comparison) represent standalone performance of the algorithm/device. The device processes samples and generates genotype calls without direct human intervention in the interpretation of raw signal data. The "correct call rate" is a measure of the algorithm's performance alone against the established ground truth.

7. Type of Ground Truth Used

The primary type of ground truth used across all reported studies (reproducibility, interference, detection limit, and method comparison) was bi-directional sequencing. This is a gold standard molecular technique for confirming DNA sequences and, consequently, genotypes.

8. Sample Size for the Training Set

The document does not provide details on the sample size used for the training set. This is common for this type of medical device submission, as the focus is on the analytical validation of the finished device. The underlying algorithms for PCR-based fluorescent probe detection are based on well-established biochemical principles rather than statistical machine learning models that require explicit training sets.

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

As no explicit "training set" and associated ground truth establishment is described for a machine learning model, this information is not applicable in the context of the provided document. The device's operation relies on established principles of molecular diagnostics (PCR, fluorescent probe detection) and programmed thresholds for signal analysis, rather than an trained artificial intelligence model in the contemporary sense.

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The provided document is an FDA 510(k) clearance letter for a medical device called "xTAG CYP2D6 Kit V3". This type of document does not contain the detailed technical information about acceptance criteria, study methodologies, or performance data that would be necessary to answer your request.

The letter confirms that the FDA has reviewed the premarket notification and determined the device is substantially equivalent to a legally marketed predicate device. It informs the manufacturer about regulatory obligations but does not include the specifics of the performance studies.

To get the information you are looking for (acceptance criteria, study details, sample sizes, ground truth establishment, expert qualifications, etc.), you would typically need to refer to documents like:

• The 510(k) summary or 510(k) Traditional submission itself, which is often publicly available through the FDA's database.
• The device's Instruction for Use (IFU) or Product Insert, which usually contains performance data.
• Scientific publications if the study results were published in peer-reviewed journals.

Therefore, based solely on the provided document, I cannot fulfill your request for: a table of acceptance criteria, sample sizes, expert details, adjudication methods, MRMC study results, standalone performance, ground truth types, or training set details.

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The xTAG® CYP2C19 Kit v3 is an in vitro diagnostic test used to simultaneously detect and identify a panel of nucleotide variants found within the highly polymorphic CYP450 2C19 gene, located on chromosome 10q24, from genomic DNA extracted from EDTA or citrate anticoagulated whole blood samples. The xTAG CYP2C19 Kit v3 is a qualitative genotyping assay which can be used as an aid to clinicians in determining therapeutic strategy for the therapeutics that are metabolized by the CYP2C19 gene product, specifically *2, *3 and *17. The kit is not indicated for stand-alone diagnostic purposes. This test is not intended to be used to predict drug response or non-response.

The xTAG® CYP2C19 Kit v3 is indicated for use with the Luminex® 100/200™ instrument or MAPGIX® with xPONENT® software systems.

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The provided text describes the 510(k) clearance for the xTAG® CYP2C19 Kit v3. While it lists the device name, regulation details, and indications for use, it does not contain any information about acceptance criteria, device performance from a study, sample sizes, expert qualifications, or ground truth establishment.

Therefore, I cannot provide the requested table and study details from the given input. The document is essentially the FDA's clearance letter and the "Indications for Use" statement, not a performance study report.

To answer your request, I would need a different document that details the device's validation study, including:

• Methods and results of performance testing.
• Specific acceptance criteria used for the study.
• The breakdown of data provenance and sample sizes.
• Details on how ground truth was established and by whom.
• Information on MRMC studies or standalone performance.

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The Spartan RX CYP2C19 System is a qualitative in vitro diagnostic test for the identification of a patient's CYP2C19 *2, *3 and *17 genotype determined from genomic DNA obtained from a buccal swab sample. For prescription use only.

Spartan RX CYP2C19 Assay - The Spartan RX CYP2C19 System is indicated for use as an aid to clinicians in determining therapeutic strategies for therapeutics that are metabolized by the Cytochrome P450 2C19 gene product, and that are specifically affected by the *2, *3, and *17 alleles. The Spartan RX CYP2C19 Assay will be run on the Spartan RX CYP2C19 Platform from the buccal sample collected with a buccal swab. The Spartan RX CYP2C19 Assay is not indicated to be used to predict drug response or non-response.

Spartan RX CYP2C19 Platform - The Spartan RX CYP2C19 System is indicated for use as an aid to clinicians in determining therapeutic strategies for therapeutics that are metabolized by the Cytochrome P450 2C19 gene product, and that are specifically affected by the *2, *3, and *17 alleles. The Spartan RX CYP2C19 Platform will be used to run the Spartan RX CYP2C19 Assay.

The Spartan RX CYP2C19 System is a sample-to-result DNA testing system that uses proprietary technology to integrate DNA extraction and amplification. Genotypes are determined using PCR and fluorescent probe detection. The Spartan RX CYP2C19 System is comprised of the Spartan RX liadrooom prable a and Spartan RX CYP2C19 Assays. The Spartan RX CYP2C19 Assays are run on the Spartan RX CYP2C19 Platform.

The Spartan RX CYP2C19 System is based on the following processes:

• Buccal swab collection i.
• ii. DNA extraction
• PCR-based amplification of the target gene lii.
• Detection of the *2, *3, and *17 alleles using fluorescent-probes iv.
• Fluorescent signal detection and analysis V.
• Genotype determination vi.

The Spartan RX CYP2C19 System integrates and automates steps ii to vi. Results are presented to the end user as genotype calls. The system also has integrated controls that monitor performance of a run and automatically inform the user of any anomalies in the instrument or reagents.

The system detects the CYP2C19 *2, *3, and *17 genotypes in separate reagent tubes. The operator collects buccal swab samples from a patient; inserts each sample into a reagent tube; and then inserts the reagent tubes into a Spartan RX Analyzer instrument.

The Spartan RX CYP2C19 System is a qualitative in vitro diagnostic test for the identification of a patient's CYP2C19 *2, *3, and *17 genotype from buccal swab samples. The system comprises the Spartan RX Platform (instrumentation) and Spartan RX CYP2C19 Assays (consumables). It integrates DNA extraction, PCR-based amplification, fluorescent probe detection, and genotype determination.

Acceptance Criteria and Reported Device Performance

Note: The acceptance criteria are implicitly inferred from the reported performance results, which consistently show very high percentages of correct calls and agreement. A lower limit of detection study indicates an acceptable first pass correct call rate of 84.6% at input levels lower than 0.1 swabs per test.

Study Details

1. Sample sizes used for the test set and data provenance:

   • Limit of Detection (LOD):
     • Part 1: 100 individual buccal swabs collected from 40 different individuals.
     • Part 2: 52 samples were tested per condition (5 conditions, total 260 tests), collected from *1/*1, *2/*17, *17/*17, and *2/*3 individuals.
     • Data Provenance: Not explicitly stated, but implies clinical samples possibly from Canada where the submitter is located. Retrospective or prospective is not explicitly mentioned for sample collection, but the samples were analyzed as part of a validation study.
   • Method Comparison: 327 samples tested, with 325 included in the analysis.
     • Data Provenance: Not explicitly stated, but implies clinical samples. Samples were de-identified.
   • Inter-Laboratory Reproducibility: 960 tests performed (8 individuals * 2 operators * 2 sessions * 5 days * 3 sites).
     • Data Provenance: Not explicitly stated, but implies clinical samples or samples with confirmed genotypes.
   • Reagent Lot-to-Lot Reproducibility: 107 samples (Lot 1), 106 samples (Lot 2), 107 samples (Lot 3) in the first pass testing.
     • Data Provenance: Not explicitly stated.
   • Exogenous and Endogenous Interfering Substances: 16 samples tested for each of 14 substances (total 224 tests).
     • Data Provenance: Buccal swab samples collected from *1/*1, *2/*17, *17/*17, and *2/*3 individuals where genotypes were confirmed.

2. Number of experts used to establish the ground truth for the test set and their qualifications:

   • The ground truth for all studies was established by bi-directional sequencing. This is a molecular biology technique, not a human expert interpretation. Geneticists or molecular biologists would be involved in performing and interpreting the sequencing results, but specific numbers and qualifications are not mentioned.

3. Adjudication method for the test set:

   • The study design employed a "second pass" re-test for samples that initially yielded "No calls." For the Method Comparison and Inter-Laboratory Reproducibility studies, if a first pass resulted in a "No call," the sample was re-tested. This serves as an internal adjudication or re-evaluation mechanism. No explicit "2+1" or "3+1" expert adjudication is described, as the ground truth is objective sequencing data.

4. Multi-reader multi-case (MRMC) comparative effectiveness study:

   • No MRMC comparative effectiveness study was done. The device is a diagnostic test that provides a genotype call, not an imaging device or aid to human interpretation that would typically involve human readers.

5. Standalone (i.e., algorithm only without human-in-the-loop performance) study:

   • Yes, the performance studies (Limit of Detection, Method Comparison, Inter-Laboratory Reproducibility, Reagent Lot-to-Lot Reproducibility, Exogenous and Endogenous Interfering Substances) represent standalone performance of the Spartan RX CYP2C19 System. The system integrates and automates the DNA testing process, and results are presented as genotype calls directly, indicating an algorithm-only performance assessment against sequencing-derived ground truth.

6. Type of ground truth used:

   • Bi-directional sequencing was used as the ground truth for all performance studies. This is a highly accurate and widely accepted method for confirming DNA sequences and, thus, genotypes.

7. Sample size for the training set:

   • The document does not explicitly mention a separate training set or its sample size. The reported studies primarily describe validation/test set performance. For molecular diagnostic devices, the development often involves internal optimization and algorithm tuning using various samples, but these are not typically referred to as a "training set" in the same way as machine learning models.

8. How the ground truth for the training set was established:

   • Since a distinct "training set" is not explicitly defined or discussed in the document for performance evaluation, the method for establishing its ground truth is also not detailed. However, it can be inferred that any samples used during the development and optimization phases would also likely have been characterized using highly accurate methods like bi-directional sequencing, similar to the test sets.

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The xTAG® CYP2D6 Kit v3 is a device used to simultaneously detect and identify a panel of nucleotide variants found within the highly polymorphic CYP2D6 gene located on chromosome 22 from genomic DNA extracted from an EDTA or citrate anticoagulated whole blood sample. This kit can also identify gene rearrangements associated with the deletion (*5) and duplication genotypes. The xTAG® CYP2D6 Kit v3 is a qualitative genotyping assay which can be used as an aid to clinicians in determining therapeutic strategy for therapeutics that are metabolized by the CYP2D6 gene product. This kit is not indicated for stand- alone diagnostic purposes. This test is not intended to be used to predict drug response or non-response.

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This document is a 510(k) clearance letter for a medical device called the xTAG® CYP2D6 Kit v3. It indicates the device is substantially equivalent to legally marketed predicate devices. However, it does NOT contain the detailed information required to answer your specific questions about acceptance criteria and the study that proves the device meets them.

The letter primarily covers the regulatory approval of the device and its intended use. It does not include:

• A table of acceptance criteria and reported device performance: This sort of data would typically be found in the 510(k) summary or the pivotal study report, not in the clearance letter itself.
• Sample sizes used for the test set and data provenance: Again, this detailed study information is not part of the clearance letter.
• Number of experts and their qualifications for ground truth: This pertains to the study design, not the FDA's regulatory decision letter.
• Adjudication method for the test set: Study design detail absent from this document.
• MRMC comparative effectiveness study details (effect size): This device is a genotyping kit, not an AI-assisted diagnostic imaging device for human readers, so an MRMC study with human readers would not be relevant or performed.
• Standalone algorithm performance: This is a lab kit, not an "algorithm" in the sense of AI software. Its performance is evaluated biochemically/molecularly.
• Type of ground truth used: While the ground truth for genetic testing is typically highly reliable reference methods (e.g., Sanger sequencing, alternative validated genotyping assays), the clearance letter doesn't specify this for this particular study.
• Sample size for the training set: Not applicable as this is not an AI/ML device that requires a training set in that context.
• How ground truth for the training set was established: Not applicable.

In summary, the provided document does not contain the information requested in your prompt regarding acceptance criteria and study details. To find this information, you would typically need to consult the 510(k) summary submitted by the manufacturer to the FDA, which often contains a more detailed description of the performance studies.

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The Verigene® CYP2C19 Nucleic Acid Test (CYP2C19 Test), performed using the sample-to-result Verigene System, is a qualitative multiplexed in vitro diagnostic test for the simultaneous detection and identification of an individual's CYP450 2C19 genotype in genomic deoxyribonucleic acid (DNA) obtained from EDTA-anticoagulated whole blood samples. The Verigene CYP2C19 Nucleic Acid Test (CYP2C19 Test) is indicated for use in clinical laboratories upon prescription by the attending physician as an aid to clinicians in determining therapeutic strategy for therapeutics that are metabolized by the CYP450 2C19 gene product, specifically *2, *3, and *17. The Verigene CYP2C19 Nucleic Acid Test (CYP2C19 Test) is not indicated to be used to predict drug response or non-response.

The Verigene® System is comprised of test consumables and shared instrumentation. All Verigene tests are formatted in self-contained test-specific Verigene Test Cartridges which serve to analyze a nucleic acid sample that is presented to them. Nucleic acids are prepared directly from a whole blood specimen using magnetic glass particles and input automatically into a Test Cartridge inside the Verigene Processor SP. Test progress is tracked and directed by the Verigene Reader instrument, which serves as a central control unit for each Verigene System. Genomic DNA is extracted from the white blood cells in a whole blood specimen, fragmented and denatured. This fragmented, single-stranded genomic DNA hybridizes to complementary sequence-specific DNA oligonucleotides, known as capture oligonucleotides, arrayed on the surface of a substrate (glass slide). A second DNA oligonucleotide is then hybridized to the captured genomic DNA that was captured initially. This oligonucleotide is known as a mediator oligonucleotide containing two sequence domain is complementary to the genomic DNA target and a second domain is complementary to a common oligonucleotide attached to a signal generating gold nanoparticle probe. After washing away any DNA not affixed to the captures, the probe is exposed to the captured mediator/target compound where it hybridizes to any captured mediators. Presence of the gold nanoparticle probes at a particular location on the substrate is assessed optically. The Verigene CYP2C19 Nucleic Acid Test is designed to detect and genotype the CYP450 2C19 *2, *3 and *17 alleles. The test report lists the alleles and provides which genotype was detected in the specimen. The CYP2C19 Test algorithm automatically calculates each of the allele results using a preset normalized ratio of the signal of wild type capture locations on the microarray to the mutant capture locations on the microarray.

This submission focuses on the analytical and clinical performance of the Verigene® CYP2C19 Nucleic Acid Test. Here's a breakdown based on your request:

1. Table of Acceptance Criteria and Reported Device Performance

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

The document describes several test sets used for different studies:

• Analytical Sensitivity / LOD: 7 individual whole blood samples, each with a different genotype. Tested in replicates of 40 (total 280 tests). The data provenance is not specified, but it refers to "individual whole blood samples," suggesting clinical samples. The study appears to be prospective in nature, designed specifically for this validation.
• Interference Testing: 5 individual whole blood samples, each with a different genotype. Tested in 30 replicates per specimen for each interfering substance (total 150 tests per substance, with 5 substances and a control, leading to 900 measurements in Table 2). Data provenance is not specified, but it refers to "EDTA-anticoagulated whole blood samples," suggesting clinical samples. This study appears to be prospective.
• Specimen Stability Study: 35 EDTA whole blood samples. Tested once at 5, 10, 12, and 15 day time points (total 140 tests). Data provenance is not specified (e.g., "freshly-collected whole blood samples"). This study appears to be prospective.
• Carry-over / Cross-contamination: Whole blood specimens containing different genotypes. Tested sequentially on ten Verigene instruments, repeated in triplicate (total number of samples not explicitly stated, but includes "*1/*2, followed by *1/*1, then *1/*17, then *1/*1" repeated in triplicate). Data provenance is not specified. This study appears to be prospective.
• Precision Study: 8 unique whole blood specimens. Each tested in duplicate twice daily by two operators over 12 non-consecutive days at one site (48 replicates per specimen, total 384 data points). Data provenance is not specified. This study appears to be prospective.
• Reproducibility Study: The same 8-member panel of specimens as the Precision Study. Tested in duplicate twice daily by two operators over 5 non-consecutive days at three sites (60 replicates per specimen, total 480 data points). Data provenance is not specified. This study appears to be prospective.
• Method Comparison Study: 670 unique human whole blood samples, collected in EDTA. Data provenance is not specified, but the samples are "human whole blood samples," implying clinical origin. The study appears to be prospective, specifically for method comparison.

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

The ground truth for all performance studies (Analytical Sensitivity, Interference, Precision, Reproducibility, Method Comparison) was established by bi-directional sequencing (BDS). This is a laboratory method, not reliant on human experts for interpretation in the same way imaging studies might be. Therefore, the concept of "number of experts" and their "qualifications" for ground truth establishment is not applicable here.

4. Adjudication Method for the Test Set

Not applicable for this type of laboratory test. The ground truth (bi-directional sequencing) is considered definitive. When the device produced "No Calls" initially, these samples were re-tested, and if successful, contributed to the "Final Call Rate." In the Reproducibility study, the two final "No Call" results were considered discordant. For the Method Comparison study, one sample with an initial and final no-call on the Verigene test had a BDS result of *1/*2, indicating this was a definite discrepancy.

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

No, an MRMC comparative effectiveness study was not conducted. This device is a molecular diagnostic test that provides a genotype result, not an imaging device requiring human reader interpretation.

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

Yes, the performance studies detailed (Analytical Sensitivity, Interference, Stability, Carry-over, Precision, Reproducibility, Method Comparison) represent the standalone performance of the Verigene® CYP2C19 Nucleic Acid Test. The system is described as "sample-to-result" with "automated DNA extraction" and the "Test algorithm automatically calculates each of the allele results." This indicates minimal human intervention in the final result generation once the sample is loaded.

7. The Type of Ground Truth Used

The primary ground truth used for all performance evaluations was bi-directional sequencing (BDS). This is a highly accurate molecular method for determining specific DNA sequences, considered the gold standard for genotyping.

8. The Sample Size for the Training Set

The document does not specify a separate training set or its sample size. This is common for diagnostic tests like this, especially when the underlying technology (genotyping microarray and algorithm) is based on established scientific principles rather than a machine learning model that requires explicit training data in the context of regulatory submissions. The algorithm's parameters are likely "preset" based on scientific design and internal development/optimization rather than a distinct, large-scale training dataset as seen with AI/ML systems.

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

Since no explicit "training set" is described in the context of this 510(k) summary, the method for establishing its ground truth is also not provided. The device's "preset normalized ratio of the signal of wild type capture locations on the microarray to the mutant capture locations on the microarray" implies that the underlying genetic science and expected signal profiles for specific alleles dictate the algorithm's basis, rather than being "trained" on a dataset in the AI/ML sense.

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The INFINITI CYP2C19 Assay is an in vitro diagnostic test for the identification of a patient's CYP450 2C19 genotype in genomic deoxyribonucleic acid (DNA) obtained from EDTA-anticoagulated whole blood samples. The INFINITI CYP2C19 Assay is a qualitative assay for use in clinical laboratories upon prescription by the attending physician.

The INFINITI CYP2C19 Assay is indicated for use as an aid to clinicians in determining therapeutic strategy for therapeutics that are metabolized by the CYP450 2C19 gene product, specifically *2, *3, *17.

The INFINITI CYP2C19 Assay is not indicated to be used to predict drug response or non-response.

The INFINITI CYP2C19 Assay is an in vitro diagnostic device which utilizes proprietary film-based microarray technology combined with process automation, reagent management, and software technology for the detection and genotyping of the 2C19 *2, *3, and *17 mutations in genomic deoxyribonucleic acid (DNA) obtained from EDTA-anticoagulated whole blood samples.

The INFINITI CYP2C19 Assay is comprised of the BioFilmChipTM Microarray, the Intellipac Reagent Module and the PCR Amplification Mix. The INFINITI CYP2C19 Assay should be run using the AutoGenomics INFINITI Analyzer.

The BioFilmChip Microarray consists of a polyester film coated with proprietary multi-layer components designed for DNA analysis. The layers have been designed to provide a versatile surface to enhance test performance. There can be up to 240 spots per microarray with each spot representing a different allele. The microarrays are designed to be assay specific.

The Intellipac Reagent Module contains up four reservoirs that house the test reagents and has an integrated memory chip. Information on the reagent such as lot number, expiration date and remaining tests, are archived in the memory.

The PCR Amplification Mix consists of the reagents needed for the PCR amplification step of the assay.

The INFINITI CYP2C19 Assay is based on the following processes: (a) DNA extraction (b) PCR amplification of purified DNA from human genomic DNA (c) Labeling of the amplified product (allele specific primer extension) (d) Hybridization of the labeled amplified product to a microarray by signature Tag/Capture probe hybridization under isothermal conditions. (e) Scanning of the microarray (f) Signal detection and analysis Steps (c) through (f) are automated by the INFINITI Analyzer. The INFINITI Analyzer automates the 2C19 assay and integrates all the discrete processes of sample (PCR amplicon) handling, reagent management, hybridization, and results The assays are processed automatically and read by the built-in confocal analysis. microscope. Results are analyzed and presented as genotype calls.

Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:

Acceptance Criteria and Device Performance for INFINITI CYP2C19 Assay

The document focuses on the analytical performance of the device rather than clinical efficacy for patient outcomes or human reader improvement, as it is an in vitro diagnostic device for genotyping. Therefore, some of the requested information, such as effect size of human readers with AI assistance, is not applicable.

1. Table of Acceptance Criteria and Reported Device Performance

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

• Limit of Detection (LOD) Test Set:

  • Sample Size: A total of 1,560 individual tests were completed across various DNA input levels and sample genotypes.
  • Data Provenance: The document implies these were internally generated samples used for development and characterization of the assay. The genotypes (*1/*1, *1/*17, *2/*2, *2/*17) were determined by bi-directional sequencing. The text refers to "whole blood samples," suggesting human samples, but the country of origin is not specified. It is likely retrospective as these are characterized samples used for method validation.

• Percent Agreement vs. Bi-directional Sequencing (Test Set):

  • Sample Size: 317 patient samples.
  • Data Provenance: The samples were "patient samples" tested at "Three sites." They were "de-identified to protect patient's identity." Country of origin is not specified but generally implies samples obtained where the sites are located, likely within the US given the FDA submission. The nature of these being "patient samples" suggests they are clinical samples, used retrospectively for assay validation.

• Assay Inter-Laboratory Reproducibility (Test Sets):

  • Study 1 Sample Size: 12 whole blood samples, resulting in 430 tests.
  • Study 2 Sample Size: 6 genomic whole blood samples, resulting in 255 tests.
  • Combined Sample Size: Across all reproducibility studies, 18 samples were tested, totaling 685 individual replicates/tests.
  • Data Provenance: The samples were "identical samples comprised of whole blood samples." The sites were blinded to sample identity. Like the previous studies, these imply human samples, but the country of origin is not specified. These are clinical samples likely used retrospectively for method validation.

• Interference Test Set:

  • Sample Size: 8 whole blood samples.
  • Data Provenance: Not explicitly stated, but consistent with other studies, likely human whole blood samples used retrospectively for assay validation.

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

For the genetic assays described, the "ground truth" is established through bi-directional sequencing.

• Number of Experts: The document does not specify the number of individuals involved in performing or interpreting the bi-directional sequencing, nor their explicit qualifications (e.g., molecular geneticists, laboratory technologists). However, bi-directional sequencing is a standard molecular biology technique and its interpretation falls under the expertise of qualified laboratory professionals familiar with genetic sequence analysis.
• Qualifications: "Bi-directional sequencing" itself is the gold standard for defining genetic sequences. Thus, the qualification is implied through the choice of this highly accurate method for ground truth determination.

4. Adjudication Method for the Test Set

• Adjudication Method: The document does not describe an explicit "adjudication method" in the typical sense of multiple expert reviewers resolving discrepancies. Instead, the ground truth was established by bi-directional sequencing. For the "no calls" that occurred with the INFINITI assay, the samples were repeated, and the "repeat test gave the correct call." This indicates an internal re-testing protocol for initial "no calls" rather than a formal expert adjudication of differing results between the device and the ground truth. When an "incorrect call" (1 instance) occurred, the root cause was "not definitively determined," suggesting internal review rather than a formal, pre-defined expert adjudication panel.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

• This question is not applicable to the INFINITI CYP2C19 Assay. This is an in vitro diagnostic (IVD) device directly measuring genetic material, not an imaging or diagnostic support system where a human "reader" (e.g., radiologist) would interact with AI. The device provides genotype calls directly, without human interpretation in the analytical performance step.

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

• Yes, the performance studies described are essentially standalone (algorithm only). The INFINITI Analyzer automates the entire process from hybridization to signal detection and analysis, presenting "genotype calls." The "Percent Agreement vs. Bi-directional Sequencing" and "Inter-Laboratory Reproducibility" studies specifically evaluate the accuracy and consistency of these automated genotype calls against the gold standard (bi-directional sequencing) and across different operational conditions, respectively. Human involvement is in sample preparation, loading, and interpreting the final report, but the "genotype call" generation is automated.

7. The Type of Ground Truth Used

• The primary ground truth used for all performance validation studies (Limit of Detection, Percent Agreement, Reproducibility) was bi-directional sequencing.

8. The Sample Size for the Training Set

• The document does not specify a separate "training set" size for the device's development. This is typical for in vitro diagnostic devices that rely on molecular biology principles and analytical performance rather than machine learning algorithms trained on large datasets. The device's design is based on known genetic sequences and established assay chemistry (PCR, hybridization). The "studies related to specificity were conducted during assay development" (Analytical Specificity section) implies iterative testing and optimization, but not necessarily a distinct, quantified "training set" like in AI/ML applications.

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

• As a formal "training set" is not explicitly mentioned or quantified, this question is largely not applicable in the context of this traditional IVD device.
• For the initial development and optimization of the assay (analogous to internal "training" or development data), the ground truth for samples used would have been established by bi-directional sequencing or other established genotyping methods, as indicated for the LOD studies and as the comparator method for all validation. The "known genomic samples" used for ASP primer specificity determination would also have had their ground truth established by such highly accurate molecular methods.

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The xTAG® CYP2D6 Kit v3 is a device used to simultaneously detect and identify a panel of nucleotide variants found within the highly polymorphic CYP2D6 gene located on chromosome 22 from genomic DNA extracted from EDTA and citrate anticoagulated whole blood samples. This kit can also identify gene rearrangements associated with the deletion (*5) and duplication genotypes. The xTAG® CYP2D6 Kit v3 is a qualitative genotyping assay which can be used as an aid to clinicians in determining therapeutics that are metabolized by the CYP2D6 gene product. This kit is not indicated for stand-alone diagnostic purposes. This test is not intended to be used to predict drug response or nonresponse.

The xTAG CYP2D6 Kit v3 includes the following components:

• xTAG® 2D6 v3 PCR Primer Mix A
• xTAG® 2D6 v3 PCR Primer Mix B
• xTAG® 2D6 v3 ASPE Primer Mix
• xTAG® 2D6 v3 Bead Mix
• xTAG® 10x Buffer
• xTAG® Shrimp Alkaline Phosphatase
• xTAG® Exonuclease I
• xTAG® Streptavidin, R-Phycoerythrin Conjugate
• Platinum TI Exo(-) DNA Polymerase
• Platinum® Tfl Reaction Buffer, 5x
• Tfi 50mM MgCl3
• xTAG® Hot Start Taq (Long Acting)
• xTAG® 10x Tag Buffer (Long Acting)
• xTAG® Data Analysis Software (TDAS) CYP2D6

The provided document describes the xTAG® CYP2D6 Kit v3, a qualitative genotyping assay for detecting nucleotide variants and gene rearrangements in the CYP2D6 gene. The performance characteristics focus on accuracy, reproducibility, detection limit, analytical specificity, and matrix comparison, using bidirectional DNA sequencing as the comparator.

1. Table of acceptance criteria and the reported device performance

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

• Sample Size for Accuracy Study (Test Set): 459 clinical samples.
• Data Provenance: The majority of samples were "left-over, anonymized, banked extracted DNA from EDTA or citrate anticoagulated whole-blood specimens." For rare alleles, the sample set was supplemented with "blended" samples where linearized plasmid DNA was quantitatively added to genomic DNA to mimic heterozygous samples. The country of origin is not explicitly stated, but the applicant is based in Toronto, Canada. Given the nature of banked specimens, it implies retrospective data.

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

The ground truth was established by bidirectional DNA sequencing, which is a laboratory method, not human expert interpretation in this context. Therefore, the concept of "number of experts" and their "qualifications" for ground truth establishment does not directly apply here. The sequencing results themselves are considered the gold standard.

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

There is no mention of an adjudication method used in this report. The comparison is directly between the device's results and the bidirectional DNA sequencing results. Discrepancies were "re-tested," but a formal adjudication process involving multiple readers/reviewers is not described.

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, a multi-reader, multi-case (MRMC) comparative effectiveness study was not done. This device is a qualitative genotyping assay, not an AI-assisted diagnostic tool that would involve human readers interpreting images or results with and without AI. The output is a qualitative genetic call.

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

Yes, the accuracy and reproducibility studies represent the standalone algorithm performance (referred to as "device performance"). The xTAG® CYP2D6 Kit v3, with its associated Data Analysis Software (TDAS), performs the genotyping and provides qualitative calls. While human operators are involved in the laboratory procedures, the final "call" or genotype determination is made by the system, as evidenced by the method comparison against sequencing. The intended use also states, "This kit is not indicated for stand-alone diagnostic purposes," referring to clinical diagnosis, not the algorithmic performance itself.

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

The type of ground truth used was bidirectional DNA sequencing. This is a molecular biology technique considered highly accurate for determining DNA sequences and identifying genetic variants, serving as the gold standard for genetic genotyping in this context.

8. The sample size for the training set

The document does not explicitly state a sample size for a training set. Given the nature of a laboratory assay, it's likely that internal validation and optimization were performed during development, but these are not reported as distinct "training sets" in the context of machine learning, which is where that term is most commonly applied. The "Performance Characteristics" section details validation studies (accuracy, reproducibility, etc.) which act as a test of the final product.

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

Since a distinct training set is not explicitly mentioned or characterized, the method for establishing its ground truth is not provided. If internal developmental samples were used for optimization, it is highly probable that similar gold standard methods, such as DNA sequencing, would have been employed.

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The Invader® UGTIA1 Molecular Assay is an in vitro diagnostic test for the detection and genotyping of the *1 (TA6) and *28 (TA7) alleles of the UDP glucuronosyltransferase 1A1 (UGTIA1) gene in genomic DNA from whole peripheral blood as an aid in the identification of patients with greater risk for decreased UDP-glucunorosyltransferase activity.

The Invader® UGTIA1 Molecular Assay is an in vitro diagnostic test which utilizes sequence specific Invader DNA probes, a structure-specific cleavage enzyme and a fluorescent resonance energy transfer (FRET) system combined with universal interpretative software and third party microtiter plate reader instrumentation. Invader® is the term used to generically refer to the patented chemistry on which the Invader® UGT A 1 Molecular Assay is based. The assay is designed to identify specific nucleic acid sequences and query for the presence of known sequence polymorphisms through the structurespecific cleavage of a series of probes that are specifically complementary to TA repeat sequences in in the "TATA Box" of of the UGT1A1 promoter region.

In the Invader® UGT1A1 Molecular Assay, two oligonucleotides (a discriminatory Primary Probe and an Invader® Oligo) hybridize in tandem to the target DNA to form an overlapping structure. The 5'-end of the Primary Probe includes a 5'-flap that does not hybridize to the target DNA. The 3'-nucleotide of the bound Invader® Oligo overlaps the Primary Probe, but need not hybridize to the target DNA. The Cleavase® enzyme recognizes this overlapping structure and cleaves off the unpaired 5'-flap of the Primary Probe, releasing it as a target-specific product. The Primary Probe is designed to have a melting temperature close to the reaction temperature. Therefore, under the isothermal assay conditions, Primary Probes, which are provided in excess, cycle on the target DNA. This allows for multiple rounds of Primary Probe cleavage for each target DNA, and amplification of the number of released 5'-flaps.

In the secondary reaction, each released 5'-flap can serve as an Invader® Oligo on a fluorescence resonance energy transfer (FRET) Cassette to create another overlapping structure that is recognized and cleaved by the Cleavase® enzyme. When the FRET Cassette is cleaved, the fluorophore and quencher are separated, generating detectable fluorescence signal. Similar to the initial reaction, the released 5'-flap and the FRET Cassette cycle, resulting in amplified fluorescence signal. The initial and secondary reactions run concurrently in the same well.

The biplex format of the Invader® UGT1A1 Molecular Assay enables simultaneous detection of two DNA sequences, a non-varying segment of the human alpha actin (ACTAI) gene and the TA repeat in the TATA box of the human UGTIA1 gene, in a single well. The biplex format uses two different discriminatory Primary Probes, each with a unique 5'-flap, and two different FRET Cassettes, each with a spectrally distinct fluorophore. By design, the released 5'-flaps will bind only to their respective FRET Cassettes to generate a target-specific signal.

The Invader® UGT1A1 Molecular Assay utilizes four independent wells per sample (one well for each of the TA Oligo mix reactions), to make a single genotype call. Each well contains a TATA box specific probe and an alpha actin probe. The alpha actin probe serves as an internal control to confirm the validity of a given result when a particular TATA box polymorphism is absent.

Here's a summary of the acceptance criteria and study details for the Invader® UGT1A1 Molecular Assay, based on the provided text:

Acceptance Criteria and Reported Device Performance

Study Details:

1. Sample sizes used for the test set and the data provenance:

   • Limit of Detection (Lower): 3 genomic DNA samples (TA6/6, TA6/7, TA7/7) concentrated at 50, 100, 150 ng DNA/µL. Total genotype calls for calculation: 120 (40 at each concentration for 3 genotypes).
   • Limit of Detection (Upper): 3 genomic DNA samples (TA6/6, TA6/7, TA7/7) concentrated at 80 ng DNA/µL. Total genotype calls: 120.
   • Genotype Detection: 285 blood samples.
   • Repeat Rate (Initial): 285 blood samples.
   • Repeat Rate (External Study): 20 samples, tested in triplicate at 3 sites on 5 separate days (900 possible genotype calls).
   • Stability (Freeze-Thaw): 20 genomic DNA samples.
   • Stability (Storage): 3 genomic DNA samples.
   • Lot-to-Lot Reproducibility: 40 whole blood samples, analyzed with 3 different lots of reagents (120 data points).
   • Sample Preparation Equivalency: 60 human genomic DNA samples.
   • Reproducibility (Multi-site): 20 blood samples, tested across 3 sites (900 sample points generated).
   • Interference Studies: 16 whole blood samples (for bilirubin, lipids, EDTA); 16 whole blood samples (for hemoglobin, AW2 buffer).

   The data provenance is not explicitly stated as retrospective or prospective, nor is the country of origin mentioned for the samples. It is implied to be clinical samples, likely from a patient population relevant to UGT1A1 genotyping.

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

   • The ground truth for all performance studies (Limit of Detection, Genotype Detection, Stability, Lot-to-Lot Reproducibility, Sample Preparation Equivalency, Interference, Reproducibility) was established using bi-directional DNA sequence analysis.
   • The document does not specify the number or qualifications of experts who performed or interpreted the bi-directional DNA sequencing. It is presented as a gold standard laboratory method.

3. Adjudication method for the test set:

   • The document does not describe an adjudication method involving multiple human readers for discrepancies. The genotype calls from the Invader assay were directly compared to the results of bi-directional DNA sequencing.
   • For the reproducibility study, where "misidentified" samples occurred at one site, it states "Discrepancy resolution by resequencing of the template in the original Invader assay confirmed that the genotypes present in the assay wells were consistent with the reported genotypes of the assay." This suggests a re-analysis by the measurement method itself rather than a formal expert adjudication panel.

4. 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 an in vitro diagnostic molecular assay, not an AI-powered diagnostic imaging tool that would typically involve human readers. The performance is evaluated against a gold standard molecular method (bi-directional DNA sequencing), not against human interpretation of images.

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

   • Yes, this entire submission focuses on the standalone performance of the Invader® UGT1A1 Molecular Assay, which is an algorithm-driven automated test. The "algorithm" here refers to the sequence-specific Invader DNA probes, cleavage enzyme, FRET system, and universal interpretative software that automates genotype calling. There is no human-in-the-loop performance described beyond standard laboratory handling and setup. The assay signal results are interpreted by a software program and assigned a genotype.

6. The type of ground truth used:

   • The primary ground truth used for all performance evaluations was bi-directional DNA sequence analysis. This is a highly accurate molecular method for determining DNA sequences.

7. The sample size for the training set:

   • The document does not mention a separate training set or training data used to develop the assay. The focus is on the performance data from non-clinical studies (validation studies) comparing the Invader assay results to bi-directional DNA sequencing. This suggests the assay's underlying chemistry and interpretive software were already developed and are being validated, rather than being developed using a specific training dataset in the context of machine learning.

8. How the ground truth for the training set was established:

   • As no training set is explicitly described, the method for establishing its ground truth is not applicable or detailed in this document. The assay's fundamental design relies on established molecular biology principles and specific probe-target recognition, rather than learning from a large, pre-labeled training dataset in the way a machine learning algorithm would.

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The AmpliChip CYP450 test is intended to identify a patient's CYP2C19 genotype from genomic DNA extracted from a whole blood sample. Information about CYP2C19 genotype may be used as an aid to clinicians in determining therapeutic strategy and treatment dose for therapeutics that are metabolized by the CYP2C19 gene product.

The AmpliChip CYP450 Test is based on five major processes: PCR amplification of purified DNA: fragmentation and labeling of the amplified products; hybridization of the amplified products to a microarray and staining of the bound products; scanning of the microarray; and determination of the CYP450 genotype and predicted phenotype.

The AmpliChip CYP450 Test is designed to identify specific nucleic acid sequences and query for the presence of known sequence polymorphisms through analysis of the pattern of hybridization to a series of probes that are specifically complementary either to wildtype or mutant sequences. Microarrays of oligonucleotide probes synthesized on a glass substrate are utilized for the analysis.

The provided document describes the performance of the AmpliChip CYP450 Test for CYP2C19. Here's an analysis based on your request:

Acceptance Criteria and Device Performance

The document doesn't explicitly state "acceptance criteria" as a separate section with predefined thresholds. Instead, it presents performance data from non-clinical studies (Limit of Detection, Specificity, Genotype Detection, Whole System Failure, Cross Contamination, Reproducibility, Interference Studies) and implicitly demonstrates that the device meets the expected performance for a diagnostic tool of this nature. The "Percent Agreement" values (often ≥99%) and "Positivity Rate" (100% at relevant DNA concentrations) serve as de facto performance targets that the device achieved.

Here's a table summarizing the reported device performance, with implicit acceptance criteria derived from the presented results:

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