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The eSensor® Thrombophila Risk Test is an in vitro diagnostic for the detection and genotyping of Factor II (Prothrombin) G20210A, Factor V (Factor V Leiden) G1691A and MTHFR (human 5, 10 methylenetetrahydrofolate reductase gene) C677T and A1298C mutations with suspected thrombophilia from isolated genomic DNA obtained from whole blood samples. The test is intended to be used on the eSensor® XT-8 System.

The eSensor® FII-FV Genotyping Test is an in vitro diagnostic for detection and genotyping of Factor II (Prothrombin) G20210A and Factor V (Factor V Leiden) G1691A mutations in patients with suspected thrombophilia from isolated genomic DNA obtained from whole blood samples. The test is intended to be used on the eSensor® XT-8 System.

The eSensor® FV Genotyping Test is an in vitro diagnostic for the detection and genotyping of a single point mutation (G to A at position 1691; also known as Factor V Leiden) of the human Factor V gene (FV; Coagulation Factor V gene) in patients with suspected thrombophilia from isolated genomic DNA obtained from whole blood samples. The test is intended to be used on the eSensor® XT-8 System.

The eSensor® FII Genotyping Test is an in vitro diagnostic for the detection and genotyping of a single point mutation (G to A at position 20210 of the human Factor II gene (FII; prothrombin gene) in patients with suspected thrombophilia, from isolated genomic DNA obtained from whole blood samples. The test is intended to be used on the eSensor® XT-8 System.

The eSensor® MTHFR Genotyping Test is an in vitro diagnostic for the detection and genotyping of point mutations (C to T at position 677) and (A to C at position 1298) of the human 5, 10 methylenetetrahydrofolate reductase gene (MTHFR) in patients with suspected thrombophilia, from isolated genomic DNA obtained from whole blood samples. The test is intended to be used on the eSensor® XT-8 System.

The eSensor® Thrombophila Risk Tests on the eSensor® XT-8 System are in vitro diagnostic devices for performing hybridization and genotyping of multiple mutations and/or polymorphisms in an amplified DNA sample. A single-use, disposable test carridge is used to perform hybridization and genotyping. The cartridge contains an EEPROM chip which transmits the cartridge lot number, expiration date and protocol identity to the XT-8 instrument.

The analysis process for each sample consists of three steps: 1) Genomic DNA isolated from whole blood obtained using EDTA as anti-coagulant is combined with PCR Mix and Taq polymerase enzyme and is subjected to amplification of target sequences by PCR using a thermal cycler. 2) Amplified DNA is treated with exonuclease enzyme to generate single-stranded target DNA. 3) Single-stranded, amplified target DNA is mixed with hybridization and genotyping reagents and transferred to an eSensor® Test cartidge, and the cartridge is inserted in the eSensor® XT-8 Instrument. The instrument controls the circulation of the cartridge to allow hybridization at a controlled temperature and then detects and genotypes the sample by voltammetry.

Genotyping of the test panel polymorphisms is achieved by a sandwich assay principle: 1) Each pair of electrodes contains a different synthetic oligonucleotide capture probe which is complementary to one of the target DNA fragments. 2) The hybridization reagents contain pairs of ferrocene-labeled synthetic oligonucleotide signal probes; one member of each pair is complementary to the major allele sequence of the target polymorphism, while the second member of the pair is complementary to the minor allele sequence. Each member of the probe pair has a ferrocene label with a different oxidation potential for each allele. 3) Single-stranded, amplified target DNA hybridizes to its specific capture probe, and in turn hybridizes to the allele-specific, ferrocene-labeled signal probe. 4) Each electrode of the array is analyzed by voltammetry; the target polymorphism is determined by the location of the electrode containing the capture probe, and the genotype is identified by the ratio of signals from the allele-specific ferrocene labels. The array also includes positive controls to confirm the hybridization reaction and detect non-specific signals.

Upon completion of the test, the EEPROM chip on the cartridge contains information that prevents its re-use with a new sample. The eSensor® XT-8 instrument analyzes the results and provides a report of the test results.

Here's a summary of the acceptance criteria and study details for the eSensor® Thrombophila Risk Test, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The 510(k) summary does not explicitly state "acceptance criteria" with numerical thresholds prior to presenting the results. However, the performance characteristics, particularly the "Method Comparison" results, implicitly serve as the primary demonstration of meeting performance expectations against a gold standard. For the reproducibility studies, "100% agreement" strongly implies this as an implicit acceptance criterion for internal consistency.

Note on "Implicit Acceptance Criteria": The document consistently reports 100% (final) agreement with DNA sequencing across all categories in the Method Comparison and 100% correct calls for reproducibility studies. This suggests that achieving perfect or near-perfect agreement with the gold standard (DNA sequencing) and internal consistency was the unstated "acceptance criterion" for these performance studies. The 95% LCB (Lower Confidence Bound) values provided in the method comparison table suggest that the statistical power was sufficient to be confident in these high agreement rates, even with sometimes smaller sample sizes for specific mutation types.

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

• Test Set Sample Size:
  • Method Comparison: 219 gDNA samples.
  • Reproducibility (Inter-laboratory, Inter-operator): 5 gDNA samples run in duplicate each day by each of 6 operators (2 operators per site across 3 sites) over 5 days = 5 x 2 x 3 x 5 = 150 test runs. The table states "Samples Tested: 50" per operator, totaling 300 tests. This implies a set of 5 gDNA samples were tested multiple times.
  • Genomic DNA Extraction Reproducibility: 6 whole blood samples tested with 3 different extraction methods = 18 tests.
  • Lot to Lot Reproducibility: 5 genomic DNA samples tested in duplicates using 3 different kit lots = 30 tests.
  • Limit of Detection: 2 genomic DNA samples, each tested 20 times at 5 different concentrations = 2 x 20 x 5 = 200 tests.
• Data Provenance: Not explicitly stated (e.g., country of origin). The document mentions "3 different sites and 1 internal site" for the reproducibility study, indicating multi-site testing within an unspecified geographic region. The "Method Comparison" study uses "gDNA samples extracted from whole blood," but the origin of these samples is not detailed. All data appears to be prospective in the sense of being generated specifically for these performance studies.

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

• Number of Experts: Not applicable in the traditional sense, as the ground truth was established by DNA sequencing, which is a laboratory method, not human expert consensus.
• Qualifications of Experts: Not applicable. DNA sequencing is a technical standard.

4. Adjudication Method for the Test Set

• Adjudication Method: Not applicable. The ground truth (DNA sequencing) is considered the definitive standard. Any discrepancies between the eSensor® test and DNA sequencing would be considered an error by the eSensor® test, not a disagreement among experts requiring adjudication. The document mentions "Final Results" after "additional run for a single no-call" in the Lot to Lot study, suggesting a re-run policy for initial "no-calls" rather than adjudication. Similarly, in the method comparison, "Final Results" reflect cases where initial "no-calls" were resolved, making the "Final Agreement" 100%.

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

• No, an MRMC comparative effectiveness study was not done. This device is a molecular diagnostic test for genotyping, not an imaging diagnostic requiring interpretation by human readers. Therefore, the concept of human readers improving with AI assistance does not apply here.

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

• Yes, a standalone performance study was done. This entire submission focuses on the performance of the eSensor® system (instrument + assay kits) as a standalone diagnostic device. The results are compared directly against DNA sequencing (the gold standard), and the system provides results without real-time human interpretation for genotype determination. Human intervention is limited to sample preparation, loading, and reviewing the automatically generated report.

7. The Type of Ground Truth Used

• The type of ground truth used was DNA sequencing. This is explicitly stated across various sections, most notably under "Genomic DNA Extraction Reproducibility," "Lot to Lot Reproducibility," and "Method Comparison" where "All samples gave 100% correct calls when compared with DNA sequencing."

8. The Sample Size for the Training Set

• The document does not explicitly state a separate "training set" or its sample size. Diagnostic kits like this, especially those based on hybridization and electrochemical detection principles for known mutations, are typically developed and optimized during an R&D phase, and then validated with the performance studies presented. There isn't typically a distinct "training set" in the same way machine learning algorithms have. The pre-market submission focuses on the validation of the finalized device.

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

• Since a separate "training set" is not explicitly mentioned or detailed, the method for establishing ground truth for such a set is also not described. If an internal training or optimization phase utilized samples, it can be inferred that DNA sequencing would have been the likely method for establishing their ground truth, consistent with the validation studies.

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The eSensor® CF Genotyping Test is an in vitro diagnostic device used to simultaneously detect and identify a panel of mutations and variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in genomic DNA samples isolated from human peripheral whole blood specimens. The panel includes mutations and variants recommended by the 2004 American College of Medical Genetics (ACMG). The eSensor® CF Genotyping Test is a qualitative genotyping test that provides information intended to be used for cystic fibrosis carrier screening as recommended by ACMG and the 2005 American College of Obstetricians and Gynecologists (ACOG) for adults of reproductive age, as an aid in newborn screening for cystic fibrosis, and in confirmatory diagnostic testing for cystic fibrosis in newborns and children. The test is not indicated for use in fetal diagnostic or pre-implantation testing. This test is also not indicated for stand-alone diagnostic purposes and results should be used in conjunction with other available laboratory and clinical information.

The eSensor® CF Genotyping Test is intended for use on the eSensor® XT-8 System.

The eSensor® CF Genotyping Test on the eSensor® XT-8 System is an in vitro diagnostic device for performing hybridization and genotyping of multiple mutations and/or polymorphisms in an amplified DNA sample. A single-use, disposable test cartridge is used to perform hybridization and genotyping. The cartridge contains an EEPROM chip which transmits the cartridge lot number, expiration date and protocol identity to the XT-8 instrument.

The analysis process for each sample consists of three steps: 1) Genomic DNA isolated from whole blood obtained using EDTA as anti-coagulant is combined with PCR Mix and Taq polymerase enzyme and is subjected to amplification of target sequences by PCR using a thermal cycler. 2) Amplified DNA is treated with exomuclease enzyme to generate single-stranded target DNA. 3) Single-stranded, amplified target DNA is mixed with hybridization and genotyping reagents and transferred to an eSensor® CF Genotyping Tet cartinge, and the cartridge is inserted in the eSensor® XT-8 Instrument controls the circulation of the sample inside the cartridge to allow hybridization at a controlled temperature and then detects and genotypes the sample by voltammetry.

Genotyping of the test panel polymorphisms is achieved by a sandwich assay principle: 1) Each pair of electrodes contains a different synthetic oligonucleotide capture probe which is complementary to one of the target DNA fragments. 2) The hybridization reagents contain pairs of ferrocenc-labeled synthetic oligonucleotide signal probes; one member of each pair is complementary to the major allele sequence of the target polymorphism, while the second member of the pair is complementary to the minor allele sequence. Each member of the probe pair has a ferrocene label with a different oxidation potential for each allele. 3) Single-stranded, amplificd target DNA hybridizes to its specific capture probe, and in turn hybridizes to the allele-specific, ferrocenc-labeled signal probe. 4) Each electrode of the array is analyzed by voltammetry; the target polymorphism is determined by the location of the electrode containing the capture probe, and the genotype is identified by the ratio of signals from the allclespecific ferrocene labels. The array also includes positive and negative confirm the hybridization reaction and detect non-specific signals.

Upon completion of the test, the EEPROM chip on the cartridge contains information that prevents its re-use with a new sample. The eSensor® XT-8 instrument analyzes the results and provides a report of the test results.

The eSensor® CF Genotyping Test on the XT-8 System is an in vitro diagnostic device intended for genotyping multiple mutations or polymorphisms in an amplified DNA sample utilizing electrochemical detection technology.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied through the successful demonstration of 100% agreement with DNA sequencing after repeat testing for initial no-calls across various studies. The primary performance metric is the agreement with the gold standard (DNA sequencing).

2. Sample Sizes and Data Provenance

• Test Set Sample Sizes:
  • Reproducibility Study: 22 gDNA samples containing positive calls for all ACOG/ACMG panel mutations and the 5/7/9T polymorphism. Each sample was run in duplicate, generating 1320 total replicates across multiple sites and operators.
  • Lot-to-Lot Reproducibility: 21 genomic DNA samples covering all possible genotypes.
  • Genomic DNA Extraction Reproducibility: 20 whole blood samples of different genotypes.
  • Method Comparison: 112 gDNA samples extracted from whole blood.
• Data Provenance: The document does not explicitly state the country of origin for the data or whether it was retrospective or prospective. Given the nature of a 510(k) submission for a diagnostic test, it is highly likely that samples were collected prospectively or obtained from biobanks with appropriate ethical approvals, and the studies were conducted in a controlled, prospective manner to validate device performance. The reproducibility study involved an "Internal Site" and "External Sites," suggesting multi-center data collection, likely within the USA where the manufacturer is located.

3. Number of Experts and Qualifications for Ground Truth Establishment

The document does not explicitly state the number of experts or their qualifications for establishing the ground truth. However, the ground truth was established using DNA sequencing, which is a widely accepted gold standard in genetic testing. The interpretation of DNA sequencing results for CFTR mutations is a specialized task typically performed by molecular geneticists or clinical laboratory directors with expertise in sequencing analysis.

4. Adjudication Method for the Test Set

The document does not describe a formal adjudication method (e.g., 2+1, 3+1). Instead, discrepancies (initial "no-calls") in the device's output were resolved by re-running the tests, leading to "Final Correct Calls." Miscalls were not observed.

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

No multi-reader multi-case (MRMC) comparative effectiveness study was done. This device is an automated genotyping test, not an imaging device that would typically involve human readers for interpretation. The comparison is between the automated device's output and the established DNA sequencing results, and not aimed at quantifying human reader improvement with AI assistance.

6. Standalone Performance

Yes, standalone performance (algorithm only without human-in-the-loop) was performed. The eSensor® CF Genotyping Test is an automated system that provides results via a software program on the eSensor® XT-8 instrument. The performance data presented (reproducibility, method comparison, limit of detection, interfering substances) all reflect the standalone analytical performance of the device without explicit human intervention in the result interpretation process (beyond standard laboratory procedures for running the test and reviewing the final report).

7. Type of Ground Truth Used

The type of ground truth used was DNA sequencing. This is explicitly stated as the reference method for comparison throughout the performance characteristics section (e.g., "All samples gave 100% correct calls when compared with DNA sequencing," and "All samples gave 100% agreement with DNA sequencing").

8. Sample Size for the Training Set

The document does not specify a separate training set size for the device's development or algorithm. This is common for predicate-based 510(k) submissions of in vitro diagnostic devices where the focus is on analytical and clinical validation of the final product, rather than the development process of a machine learning algorithm that typically requires a distinct training phase. The device uses established electrochemical detection technology and a predefined panel of mutations, not a learning algorithm that would necessitate a large training dataset as seen in modern AI/ML submissions.

9. How Ground Truth for the Training Set Was Established

As no separate training set is explicitly mentioned or seems applicable in the context of this device's technology, the method for establishing ground truth for a training set is not provided. The development of the device likely relied on established scientific knowledge of CFTR mutations and electrochemical detection principles, rather than an iterative machine learning training process. The validation studies (using DNA sequencing as ground truth) confirm the performance of the final device.

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The eSensor® Warfarin Sensitivity 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 fresh whole blood samples preserved with EDTA, as an aid in the identification of patients at risk for increased warfarin sensitivity. The eSensor® Warfarin Sensitivity Test is for Rx only professional use within the confines of a licensed laboratory, as defined by the Clinical Laboratory Improvement Amendments (CLIA) of 1988.
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 eSensor® XT-8 System is an in vitro diagnostic device for performing hybridization and genotyping of multiple mutations and/or polymorphisms in an amplified DNA sample. The XT-8 Instrument is configured with one to three processing towers which perform up to 8 simultaneous tests per tower. The XT-8 System uses a single-use, disposable test cartridge to perform hybridization and genotyping in approximately 30 minutes per sample. The cartridge contains an EEPROM chip which transmits the cartridge lot number, expiration date and protocol identity to the instrument.
The analysis process for each sample consists of three steps: 1) Genomic DNA isolated from whole blood obtained using EDTA as anti-coagulant is combined with PCR Mix and Taq polymerase enzyme and is subjected to amplification of target sequences by PCR using a thermal cycler. 2) Amplified DNA is treated with exonuclease enzyme to generate single-stranded target DNA. 3) Single-stranded, amplified target DNA is mixed with hybridization and genotyping reagents and transferred to an eSensor® Warfarin Sensitivity Test cartridge, and the cartridge is inserted in the eSensor® XT-8 Instrument. The instrument controls the circulation of the sample inside the cartridge containing to allow hybridization at a controlled temperature, and then detects and genotypes the sample by voltammetry.
Genotyping of the test panel polymorphisms is achieved by a sandwich assay principle: 1) Each pair of electrodes contains a different synthetic oligonucleotide capture probe which is complementary to one of the target DNA fragments. 2) The hybridization reagents contain pairs of ferrocene-labeled synthetic oligonucleotide signal probes; one member of each pair is complementary to the major allele sequence of the target polymorphism, while the second member of the pair is complementary to the minor allele sequence. Each member of the probe pair has a ferrocene label with a different oxidation potential for each allele. 3) Single-stranded, amplified target DNA hybridizes to its specific capture probe, and in turn hybridizes to the allele-specific, ferrocene-labeled signal probe. 4) Each electrode of the array is analyzed by voltammetry; the target polymorphism is determined by the location of the electrode containing the capture probe, and the genotype is identified by the ratio of signals from the allele-specific ferrocene labels. The array also includes positive and negative controls to confirm the hybridization reaction and detect non-specific signals.
Upon completion of the test, the EEPROM chip on the cartridge contains information that prevents its re-use with a new sample. The instrument analyzes the results and provides a report of the test results. The operator removes the used cartridge from the slot of the XT-8 Instrument, and that slot is ready to accept a new test.

Here's a breakdown of the acceptance criteria and the study details for the eSensor® Warfarin Sensitivity Test and XT-8 System, based on the provided 510(k) summary:

Acceptance Criteria and Device Performance

Study Details

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

   • Reproducibility Study Test Set:

     • Samples: 5 genomic DNA samples covering all possible genotypes for the three alleles (CYP2C92, CYP2C93, VKORC1).
     • Total Tests: 200 tests for each allele (CYP2C92, CYP2C93, VKORC1), for a grand total of 600 allele tests in the final analysis (5 samples * 4 operators/sites * 5 days * 2 runs per day = 200 tests per allele for an operator who performed 2 runs a day).
     • Data Provenance: Three sites were used: one internal (likely Osmetech Molecular Diagnostics) and two external. The country of origin is not specified, but given the submission is to the FDA, it is likely US-based or recognized for regulatory purposes. The study appears prospective, as it involves controlled testing of specific samples under varied conditions.

   • Genomic DNA Extraction Reproducibility Test Set:

     • Samples: 7 whole blood samples of different genotypes.
     • Total Tests: 21 tests for each allele per site (7 samples * 3 replicates). With 3 sites, this totals 63 tests per allele, and 189 allele tests overall.
     • Data Provenance: Three different sites, using different commercially available extraction methods. Similar to the above, country of origin is not specified but likely US-based, and the study is prospective.

   • Method Comparison Test Set:

     • Samples: 157 samples.
     • Total Tests: 157 samples tested on the eSensor device; 157 samples tested by DNA sequencing. On a per-SNP basis, this represents 471 data points (157 samples * 3 SNPs).
     • Data Provenance: Not explicitly stated, but implies collected samples for method comparison. The nature (retrospective/prospective) isn't directly stated, but typically, method comparison studies utilize a representative set of existing or collected samples in a controlled manner, making them essentially prospective for the purpose of the comparison.

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 studies (reproducibility and method comparison) was established by DNA sequencing. The document does not specify the number of experts or their qualifications for interpreting the DNA sequencing results. DNA sequencing is generally considered a highly accurate gold standard for genotyping, and its interpretation often involves trained molecular biologists or geneticists, but no specific details are provided here.

3. Adjudication method for the test set:

   • No formal adjudication method (like 2+1, 3+1 consensus) is explicitly mentioned for the test set.
   • For the reproducibility study, "An additional run using the same kit lot and sample as for the first-pass test were performed for test that gave a no-call result." This implies a re-testing/re-run strategy for initial failures rather than human expert adjudication of output discrepancies. All no-calls were resolved to 100% agreement after additional runs.
   • For the method comparison and extraction reproducibility, there were no initial no-calls or incorrect calls, so no adjudication or re-testing was necessary beyond the initial DNA sequencing ground truth.

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 MRMC comparative effectiveness study was performed or described. This device is an in vitro diagnostic for genotyping, meaning it produces a direct genetic result, and there is no "human reader" analogue in the typical sense of interpreting imaging or complex clinical data where AI assistance would be measured. The output is a genotype, which is then used by medical professionals.

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

   • Yes, the performance studies (reproducibility, extraction reproducibility, and method comparison) represent the standalone performance of the eSensor® Warfarin Sensitivity Test and XT-8 System. The device analyzes DNA samples and outputs a genotype. While human operators perform PCR and load samples, the critical genotyping step and result interpretation are performed by the instrument's software ("Assay signal results are interpreted by a software program and are assigned a genotype that is presented to the end-user in a report format"). The 100% agreement with DNA sequencing demonstrates this algorithmic performance.

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

   • The ground truth used for all performance studies was bi-directional DNA sequencing. This is considered a highly reliable molecular diagnostic method.

7. The sample size for the training set:

   • The document does not specify a separate "training set" or its size. As an in vitro diagnostic device, particularly for genetic testing, the development process generally involves analytical validation (like the studies described) rather than a machine learning training phase analogous to image analysis AI. The device's underlying "algorithm" is based on biochemical reactions and electrochemical detection, not a learned model from a dataset.

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

   • Since no training set is explicitly mentioned in the context of machine learning, there's no ground truth establishment for such a set described. The "knowledge" or parameters for the device's operation would have been developed through biochemical and engineering principles, with validation done against known standards (DNA sequencing) as detailed in the performance studies.

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