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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 INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin is an in vitro diagnostic test for the detection and genotyping of the *2 and *3 CYP4502C9 genetic variants and the VKORC1 3673 (-1639) intronic variant in genomic deoxyribonucleic acid (DNA) obtained from EDTA-anticoagulated whole blood samples. The INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin is a qualitative assay for use in clinical laboratories upon prescription by the attending physician.
The INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin is indicated for use to identify individuals at risk for sensitivity to warfarin.

The INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin 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 2C92, 2C93, and VKORC1 3673 (-1639) mutations from EDTA-anticoagulated whole blood samples.

The INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin is comprised of the BioFilmChip™ Microarray, the Intellipac Reagent Module and the PCR Amplification Mix. The INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin 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 to eight reservoirs that house the test reagents and has an integrated memory chip. Information on the reagent such as lot number, expiration date and volume usage, are archived in the memory.

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

The INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin 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 [determination of the 2C92, 2C93 and VKORC1 3673 (-1639) genotypes]
Steps (c) through (f) are automated by the INFINITI Analyzer.

The INFINITI Analyzer automates the 2C9 and VKORC1 assays and integrates all the discrete processes of sample (PCR amplicon) handling, reagent management, hybridization, detection, and results analysis. The assays are processed automatically and read by the built-in confocal microscope. Results are analyzed and presented as genotype calls.

Here's an analysis of the acceptance criteria and study details for the INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin, based on the provided text:

Acceptance Criteria and Device Performance

The document describes the performance characteristics without explicitly stating pre-defined "acceptance criteria" as pass/fail thresholds. Instead, it presents the "reported device performance" and implies that these results demonstrate the device's suitability. For the purpose of this analysis, I will synthesize the reported performance values as the de facto "acceptance criteria" that the device met.

1. Table of Acceptance Criteria and Reported Device Performance

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

Sample Size for Test Set:

• Agreement with Bi-directional Sequencing:
  • 150 patient samples tested in the initial comparison (first run data for 2C9*2, 2C9*3, VKORC1).
  • Table 2b "by Sample Type" also shows 150 samples, implying these are the same samples analyzed by genotype.
• Inter-Laboratory Reproducibility:
  • 7 genomic DNA samples and 5 whole blood samples (total 12 unique samples).
  • Each unique sample was run in duplicate per day/operator for six days at each of 3 sites.
  • Total tests: 12 samples * 2 replicates/day * 6 days * 3 sites = 432 tests per site, for a total of 1296 tests across all sites for the "first time run" and "final result".

Data Provenance:

• Agreement with Bi-directional Sequencing:
  • Origin: Not explicitly stated, but "patient samples" were used. Given the FDA submission context, it's highly likely these were de-identified samples from the United States.
  • Nature: The description "Each site tested its own patient samples" and that they were "from patients using or have used warfarin" suggests these were retrospective samples, collected from a patient population relevant to the intended use.
• Inter-Laboratory Reproducibility:
  • Origin: Not explicitly stated, but likely from the United States given the submission.
  • Nature: Controlled study using "seven genomic DNA samples and five whole blood samples." These would be prospective in the sense that they were specifically prepared and distributed for this reproducibility study, though the original source of the genetic material might have been retrospective.

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

The document does not mention the use of experts to establish ground truth.

For the Agreement with Bi-directional Sequencing study, the ground truth was established by:

• Bi-directional DNA sequencing. This is a recognized laboratory method for determining genetic sequences and is considered the gold standard for many genetic variants. Thus, the ground truth was established by laboratory method, not expert consensus.
• The document implies that the sequencing results were accepted as the definitive truth without the need for expert adjudication or review.

For the Inter-Laboratory Reproducibility study, the ground truth for the 7 genomic DNA samples and 5 whole blood samples was their known genotypes, which would have been previously determined, presumably also by a method like bi-directional sequencing.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method involving multiple human reviewers for the test set.

• In the "Agreement with Bi-directional Sequencing" study, "bi-directional sequencing" served as the comparator/ground truth. The device results were directly compared to these sequencing results.
• For the inter-laboratory reproducibility study, device results from different sites and operators were compared to the known genotype of the samples.

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

No MRMC comparative effectiveness study was done. This study assesses the improvement of human readers with AI assistance versus without AI assistance. The INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin is an in vitro diagnostic device for genotype detection, not an imaging or diagnostic support tool that assists human readers. Its output is a genotype call, not an interpretation that radiologists or other human experts would then refine or improve upon.

6. Standalone Performance Study (Algorithm Only)

Yes, a standalone performance study was done. The entire submission details the performance of the "INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin" as a standalone device. The device automates key steps and provides genotype calls:

• "Steps (c) through (f) are automated by the INFINITI Analyzer."
• "The INFINITI Analyzer automates the 2C9 and VKORC1 assays and integrates all the discrete processes of sample (PCR amplicon) handling, reagent management, hybridization, detection, and results analysis. The assays are processed automatically and read by the built-in confocal microscope. Results are analyzed and presented as genotype calls."
• The performance metrics (agreement with sequencing, reproducibility, LOD, specificity, etc.) are all measures of the algorithm's direct output.

There is no human-in-the-loop component described for its routine operation or performance evaluation.

7. Type of Ground Truth Used

The primary ground truth used for the performance studies was established laboratory method results, specifically bi-directional DNA sequencing. This method is considered highly accurate for determining DNA sequences and genetic variants.

8. Sample Size for the Training Set

The document does not specify a sample size for a training set. This is typical for in vitro diagnostic devices based on established molecular biology principles (PCR, hybridization, genotyping microarrays) where the design is more mechanistic and less dependent on machine learning models requiring extensive "training data" in the conventional sense. The "development" of the assay mentioned for analytical specificity would involve testing various known samples, but these are generally considered part of the assay development and validation rather than a distinct "training set" for an algorithm in the AI context.

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

Since no explicit training set is detailed, the method for establishing its ground truth is also not described. If one were to consider the samples used during "assay development" as a form of training/optimization, their ground truth would also have been established by known genomic samples (e.g., cell lines with characterized genotypes, or samples sequenced by a gold-standard method).

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