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The eSensor® Warfarin Sensitivity Saliva Test is an in vitro diagnostic for the detection and genotyping of the *2 and *3 alleles of the cytochrome P450 (CYP450) 2C9 gene locus and the Vitamin K epoxide reductase C1 (VKORC1) gene promoter polymorphism (-1639G>A) from genomic DNA extracted from human saliva samples collected using the Oragene® Dx and ORAcollect® Dx devices, as an aid in the identification of patients at risk for increased warfarin sensitivity.

The eSensor® XT-8 instrument is an in vitro diagnostic device intended for genotyping multiple mutations or polymorphisms in an amplified DNA sample utilizing electrochemical detection technology.

The kit consists of the eSensor® Warfarin Sensitivity Saliva Test cartridge, the eSensor® Warfarin Sensitivity Saliva Test amplification reagents (including PCR mix and DNA polymerase), the eSensor® Warfarin Sensitivity Saliva Test detection reagents (including exonuclease, probes and hybridization buffer ingredients) and the eSensor® XT-8 System. One eSensor® Warfarin Sensitivity Saliva Test Kit has sufficient materials for 24 tests.

The provided document, a 510(k) summary for the eSensor® Warfarin Sensitivity Saliva Test, details performance data primarily focused on a new specimen collection kit (ORAcollect®·Dx Device) and its impact on the existing device's performance. The study aims to demonstrate that incorporating this new collection kit does not compromise the accuracy or reliability of the Warfarin Sensitivity Saliva Test.

Here's an analysis of the acceptance criteria and study findings:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state 'acceptance criteria' in terms of specific numerical thresholds for accuracy, reproducibility, or call rates. However, the studies consistently aim for 100% agreement with the ground truth (bi-directional sequencing), and 100% correct calls with 0% incorrect calls. The "Method Comparison" section indicates an aspiration for high concordance and call rate.

2. Sample Sizes and Data Provenance

• Reproducibility (Sample-to-Sample, Lot-to-Lot, Day-to-Day, Operator-to-Operator):

  • Test set sample size: 10 donors, with 3 samples each (total 30 samples collected). These were processed by 3 operators, with genotyping data evaluated for each operator for each of the 3 SNPs. This implies 20 tests per SNP per operator (based on the "20" under "Samples Tested" for each SNP for each operator), totaling 60 tests per SNP across all operators, or 120 calls per SNP when considering all samples and operators for the "Summary of Results by Sample and Genotype" table.
  • Data Provenance: Not explicitly stated, but likely prospective and from a controlled lab environment.

• Multi-center Reproducibility:

  • Test set sample size: 30 donors. Multiple saliva samples collected from each.
  • Data Provenance: Saliva samples were collected from 3 sites. Two sites were described as "professional setting" with "supervised collections," and the third site had "unsupervised collections." One sample from each donor was transported to three independent sites for extraction. All eSensor Warfarin Sensitivity Saliva testing was conducted at Site 1. This suggests a prospective data collection design, with samples from multiple (unspecified) locations. No country of origin is mentioned.

• Method Comparison:

  • Test set sample size: 156 saliva samples.
  • Data Provenance: Not explicitly stated, but implies a prospective or retrospectively collected set of human saliva samples. No country of origin is mentioned.

• Interfering Substances (Endogenous):

  • Test set sample size: 14 donors, each providing 4 saliva samples.
  • Data Provenance: Not explicitly stated, but likely prospective, controlled lab study.

• Interfering Substances (Exogenous):

  • Test set sample size: Varied per activity, ranging from 5 to 9 donors per activity group. Each donor provided samples at two time-points (immediate and 30 minutes post-activity).
  • Data Provenance: Not explicitly stated, but likely prospective, controlled lab study.

3. Number of Experts and Qualifications for Ground Truth

The ground truth for all studies was established by bi-directional DNA sequencing. This is a laboratory-based method, not typically requiring "experts" in the sense of clinical specialists. The interpretation of sequencing results is a standard molecular biology technique. No specific number of experts or their qualifications (e.g., geneticists, molecular biologists) are mentioned for establishing the ground truth, as it's assumed to be a direct, objective measurement.

4. Adjudication Method for the Test Set

The studies used bi-directional DNA sequencing as the gold standard, not a human expert adjudication process. The agreement was calculated directly between the device's genotypes and the sequencing results. If there were discrepancies in the initial device results (e.g., initial miscalls or no-calls in the method comparison), retests were performed. For instance, in the method comparison, two miscalls were attributed to "operator error (sample mix-up) occurring during the first XT8 testing" and one remaining no-call to "an operator error at the purification step." This suggests an internal investigation and re-testing process rather than an external adjudication panel.

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

No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was done. This device is a diagnostic test for genotyping, not an imaging device or a system requiring human interpretation with or without AI assistance. Therefore, the concept of "readers improving with AI vs. without AI" is not applicable here. The device itself performs the genotyping.

6. Standalone Performance Study

Yes, a standalone performance study was done. All the performance data described (reproducibility across operators/sites, method comparison with sequencing, and interfering substances studies) directly assesses the performance of the eSensor® Warfarin Sensitivity Saliva Test (algorithm/device only, without human-in-the-loop performance influencing the genotyping call itself, though human operators are involved in sample preparation and running the test). The percentage agreement and call rates reflect the direct output of the device compared to the ground truth.

7. Type of Ground Truth Used

The primary ground truth used for all studies was bi-directional DNA sequencing. This is a highly accurate molecular method for determining genetic sequences and polymorphisms (genotypes).

8. Sample Size for the Training Set

The document is a 510(k) summary for a labeling modification (addition of a new specimen collection kit) to an already cleared device. It primarily presents validation data for the continued performance of the device with the new collection kit. It does not mention a "training set" for the eSensor® Warfarin Sensitivity Saliva Test itself, as this device likely relies on established molecular biology principles and probes designed against known genetic targets, rather than machine learning algorithms that require extensive training data. It's a deterministic diagnostic test, not an AI model that learns from data in the way a computer vision algorithm would.

9. How Ground Truth for the Training Set Was Established

As noted above, the concept of a "training set" doesn't directly apply in the context of this device. The device's design is based on known genetic sequences and electrochemical detection rather than a machine learning model. The validation studies verify its performance against the established ground truth of bi-directional DNA sequencing.

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The eSensor® Warfarin Sensitivity Saliva Test is an in vitro diagnostic test for the detection and genotyping of the *2 and *3 alleles of the cytochrome P450 (CYP450) 2C9 gene locus and the Vitamin K epoxide reductase C1 (VKORC1) gene promoter polymorphism (-1639G>A) from genomic DNA of human saliva samples collected using the Oragene® Dx Device, as an aid in the identification of patients at risk for increased warfarin sensitivity.

The eSensor® Warfarin Sensitivity Saliva Test is a multiplex microarray-based genotyping test system. It is based on the principles of competitive DNA hybridization using a sandwich assay format, wherein a single-stranded target binds concurrently to sequence-specific solution-phase signal probe and solid-phase electrode-bound capture probe. The test employs polymerase chain reaction amplification, exonuclease digestion and hybridization of target DNA. In the process, the double stranded PCR amplicons are digested with exonuclease to generate single stranded DNA suitable for hybridization. Hybridization occurs in the eSensor XT-8 Cartridge (described below) where the singlestranded target DNA is mixed with a hybridization solution containing labeled signal probes.

During hybridization, the target DNA binds to a complementary, single-stranded capture probe immobilized on the working electrode surface. Single-stranded signal probes (labeled with electrochemically active ferrocenes) bind to the target adjacent to the capture probe. When inserted into the eSensor XT-8 instrument (described below), simultaneous hybridization of target to signal probes and capture probe is detected by alternating current voltammetry (ACV). Each pair of working electrodes on the array contains a different capture probe, and sequential analysis of each electrode allows genotyping of multiple mutations or polymorphisms.

The Assay Cartridge (eSensor XT-8 Cartridge): The eSensor XT-8 cartridge device consists of a printed circuit board (PCB) with a multi-layer laminate and a plastic cover that forms a hybridization chamber has a volume of approximately 140 µl. The cartridge consists of a diaphragm pump and check valves (microfluidic components) that circulate the hybridization solution in the hybridization chamber when inserted into the eSensor XT-8 instrument. The PCB chip consists of an array of 72 gold-plated working electrodes, a silver/silver chloride reference electrode, and two gold-plated auxiliary electrodes. Each working electrode has a connector contact pad on the opposite side of the chip for electrical connection to the eSensor XT-8 instrument. Each electrode is modified with a multicomponent, self-assembled monolayer that includes presvnthesized oligonucleotide capture probes specific for each polymorphic site on the test panel and insulator molecules. The cartridge also contains an electrically erasable programmable read-only memory component (EEPROM) that stores information related to the cartridge (e.g., assay identifier, cartridge lot number, and expiration date).

The eSensor XT-8 Instrument (Same as cleared under K073720): The eSensor XT-8 is a clinical multiplex instrument that has a modular design consisting of a base module and one, two, or three cartridge-processing towers containing 8, 16, or 24 cartridge slots, respectively. The cartridge slots operate independently of each other. Any number of cartridges can be loaded at one time, and the remaining slots are available for use while the instrument is running. The base module controls each processing tower, provides power, and stores and analyzes data. The base module includes the user interface, and a 15-in. portrait-orientation display and touch panel. The instrument is designed to be operated solely with the touch screen interface. Entering patient accession numbers and reagent lot codes can be performed by the bar code scanner, the touch screen, or uploading a text file from a USB memory stick. Each processing tower consists of eight cartridge modules, each containing a cartridge connector, a precision-controlled heater, an air pump, and electronics. The air pumps drive the diaphragm pump and valve system in the cartridge, eliminating fluid contact between the instrument and the cartridge. The pneumatic pumping enables recirculation of the hybridization solution allowing the target DNA and the signal probes to hybridize with the complementary capture probes on the electrodes. The diaphragm pump in the cartridge is connected to a pneumatic source from the eSensor XT-8 instrument and provides unidirectional pumping of the hybridization mixture through the microfluidic channel during hybridization. Using microfluidic technology to circulate the hybridization solution minimizes the unstirred boundary layer at the electrode surface and continuously replenishes the volume above the electrode that has been depleted of complementary targets and signal probes. The XT-8 instrument provides electrochemical detection of bound signal probes by ACV and subsequent data analysis and test report generating functions. All hybridization, ACV scanning and analysis parameters are defined by a scanning protocol loaded into the XT-8 Software, and then specified for use by the EEPROM on each cartridge.

The Assay Kit: The Warfarin Sensitivity Saliva Test consists of the test cartridge and the following components: 1) PCR REAGENTS consisting of: PCR Mix [PCR buffer containing primers and dNTP mixture (dCTP, dGTP, dATP, and dUTP)], MgCl2 thermostable DNA polymerase (Taq Polymerase ); and 2 GENOTYPING REAGENTS consisting of: lambda exonuclease, signal probes and hybridization buffer ingredients (Buffer-1 and Buffer-2).

Here's a breakdown of the acceptance criteria and the study details for the eSensor® Warfarin Sensitivity Saliva Test, based on the provided document:

Acceptance Criteria and Device Performance

The acceptance criteria are implied by the comparison to DNA sequencing, which is considered the gold standard for genotyping. The device performance is reported as agreement percentages with DNA sequencing.

Note: The document implies acceptance criteria by comparing the device's performance to DNA sequencing, which is implicitly considered the standard for accuracy. Specific numeric thresholds for "acceptance" are not explicitly stated, but the high agreement percentages (mostly 100%) and the lower bounds of the 95% confidence intervals (LCB) suggest a requirement for high concordance.

Study Information

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

• Sample Size: A total of 316 gDNA samples were extracted from saliva specimens for the method comparison study.
• Data Provenance: The document does not explicitly state the country of origin or if the data was retrospective or prospective. It uses "saliva specimen" without further context on donor recruitment or source.

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

• Experts: Not applicable. The "ground truth" for the genotyping results was established by DNA sequencing, not by human experts.
• Qualifications: Not applicable.

4. Adjudication Method for the Test Set:

• Adjudication Method: Not applicable in the traditional sense of human consensus. The reference method (ground truth) was DNA sequencing. The study reports "No-Calls" and "Miscalls" by the eSensor® device when compared to DNA sequencing. The "After Retest" results suggest that initial "No-Calls" were re-evaluated and resolved, leading to higher agreement.

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:

• MRMC Study: No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is an in-vitro diagnostic (IVD) for genotyping, which is an automated process, not an imaging device requiring human interpretation alongside AI.

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

• Standalone Performance: Yes, the performance reported is essentially a standalone (algorithm only) performance. The eSensor® Warfarin Sensitivity Saliva Test is an automated system that generates results which are then compared to DNA sequencing, without human-in-the-loop interpretation being part of the primary performance evaluation.

7. The Type of Ground Truth Used:

• Ground Truth Type: DNA sequencing (referred to as "bidirectional DNA sequencing" or "DNA Sequencing Result"). This is considered a gold standard for genetic polymorphism detection.

8. The Sample Size for the Training Set:

• Training Set Sample Size: The document does not specify a separate training set. For IVD devices, especially those based on established molecular biology principles, the "training" (development) often involves optimizing reagents and protocols, rather than machine learning algorithm training with distinct datasets. The method comparison study appears to be the primary validation of the device's performance against a reference method.

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

• Training Set Ground Truth: As no explicit training set is mentioned in the context of machine learning, this question is not directly applicable. For the performance validation, as stated above, DNA sequencing was used as the ground truth.

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