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The 23andMe Personal Genome Service (PGS) uses qualitative genotyping to detect select clinically relevant variants in genomic DNA isolated from human saliva collected from individuals ≥18 years with the Oragene Dx model OGD500.001 for the purpose of reporting and interpreting genetic health risks, including the 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants). The 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) is indicated for reporting of the 185delAG and 5382insC variants in the BRCA1 gene and the 6174delT variant in the BRCA2 gene. The report describes if a woman is at increased risk of developing breast and ovarian cancer, and if a man is at increased risk of developing breast cancer or may be at increased risk of developing prostate cancer. The three variants included in this report are most common in people of Ashkenazi Jewish descent and do not represent the majority of the BRCA1/BRCA2 variants in the general population. The test report does not describe a person's overall risk of developing any type of cancer, and the absence of a variant tested does not rule out the presence of other variants that may be cancer-related. This test is not a substitute for visits to a healthcare provider for recommended screenings or appropriate follow-up and should not be used to determine any treatments.

The 23andMe PGS is a non-invasive DNA testing service that combines qualitative genotyping data covering genetic ancestry, traits, and certain heritable health conditions from a single multiplex assay with descriptive information derived from peer reviewed, published genetic research studies. It is a direct-to-consumer, over-the-counter, DNA genetic test intended to provide information and tools for individual users.

A user's saliva is self-collected using the Oragene Dx device manufactured by DNA Genotek. Inc. (previously cleared under K141410), which consists of a sealable collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to one of two Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories for testing.

DNA is isolated from the saliva and tested in a multiplex assay using a customized genotyping beadchip, reagents and instrumentation manufactured by Illumina. The multiplex assay simultaneously tests for more than 500,000 variants, including those for the previously authorized indications, as well as for the indication proposed herein.

The raw data is generated using Illumina GenomeStudio software, and then sent to 23andMe (the Manufacturer). The data are analyzed using the Manufacturer's proprietary Coregen software, and a genotype is determined for each tested variant. The results for certain of these variants, as noted in the indications for use, are used to generate personalized reports for users that provide information about the diseases associated with tested variants.

Personalized reports are generated for each user that provides results of the testing performed. These reports tell the user which variant(s) has/have been detected in their sample and provide information on the risk of disease associated with the variant(s). If no variant was detected, that information is also provided. The personalized reports are designed to present scientific concepts to users in an easy-to-understand format. The reports provide scientifically valid information about the risks associated with the presence of a particular variant. The reports are designed to help users understand the meaning of their results and inform conversations with their doctor or other healthcare professional. The 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) reports on three specific variants including the 185de1AG and 5382insC variants in the BRCA1 gene and the 6174delT variant in the BRCA2 gene. The variants included in this report are most common in people of Ashkenazi Jewish descent and do not represent the majority of BRCA2 variants in the general population. Therefore the absence of a variant tested does not rule out the presence of other genetic variants that may be disease-related.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

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

The document specifies acceptance criteria for analytical performance studies, particularly for accuracy.

• Site 1: 0.41% FQC for Homozygous Common, 2.53% FQC for Heterozygous.
• Site 2: 3.85% FQC for Homozygous Common, 8.00% FQC for Heterozygous.
  BRCA1 5382insC (i400378):
• Site 1: 0.41% FQC for Homozygous Common, 1.25% FQC for Heterozygous.
• Site 2: 3.85% FQC for Homozygous Common, 3.18% FQC for Heterozygous.
  BRCA2 6174delT (i400379):
• Site 1: 0.41% FQC for Homozygous Common, 0% FQC for Heterozygous.
• Site 2: 3.84% FQC for Homozygous Common, 2.53% FQC for Heterozygous.
  All valid calls were 100% correct across all conditions. |
  | Detection Limit (LoD) | At least 95% correct calls at the lowest concentration tested (5 ng/uL). | 100% correct calls per genotype for all samples across all reagent lots, at all sample concentrations tested (including 5 ng/uL). |
  | Accuracy (Comparison with Sanger Bidirectional Sequencing) | Minimum of 99% positive percent agreement (PPA) and negative percent agreement (NPA) for each genotype. Uncertainty of the point estimate within an acceptable range, presented using 95% confidence interval. | BRCA1 185delAG:
• Homozygous Common: 100% PPA, 100% NPA (95% CI: 96.6 - 100)
• Heterozygous: 100% PPA, 100% NPA (95% CI: 93.8 - 100)
  BRCA1 5382insC (referring to the first instance of this variant in Table 4 for combined entries):
• Homozygous Common: 100% PPA, 100% NPA (95% CI: 94.0 - 100)
• Heterozygous: 100% PPA, 100% NPA (95% CI: 83.9 - 100)
  BRCA2 6174delT (referring to the combined entries for this variant in Table 4):
• Homozygous Common: 100% PPA, 100% NPA (95% CI: 93.9 - 100)
• Heterozygous: 100% PPA, 100% NPA (95% CI: 92.1 - 100)
  All reported agreements are 100% for correct calls, with some samples failing QC ("No Call" or "FQC") which are accounted for separately. The CIs met the acceptance criteria. |
  | User Comprehension | Minimum of a 90% or greater overall comprehension rate for each comprehension concept, with justification from physician/genetic counselor identifying relevant concepts. | Specific user comprehension studies were not performed for this specific BRCA1/BRCA2 report. Instead, the document refers to studies from DEN160026. The general acceptance criteria for user comprehension studies from the special controls are listed (90% comprehension rate). |

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

• Accuracy Study (Test Set):

  • Sample Size:
    • BRCA1 185delAG Homozygous Common: 109 samples
    • BRCA1 185delAG Heterozygous: 58 samples
    • BRCA1 5382insC Homozygous Common: 60 samples
    • BRCA1 5382insC Heterozygous: 22 samples
    • BRCA2 6174delT Homozygous Common (presumably the combined 59 samples from the table as the 6174delT is mistakenly written as 5382insC for its second entry in Table 4): 60 samples (including 1 FQC)
    • BRCA2 6174delT Heterozygous (presumably the combined 45 samples from the table as the 6174delT is mistakenly written as 5382insC for its second entry in Table 4): 46 samples (including 1 FQC)
  • Data Provenance: Saliva samples were selected from the 23andMe customer biobank. The document doesn't explicitly state the country of origin, but "customer biobank" implies they are from their existing customer base, likely primarily US. The study appears to be retrospective as samples were "selected... based on predetermined genotypes."

• Precision/Reproducibility Study:

  • Sample Size:
    • BRCA1 185delAG: 2 wildtype samples, 1 heterozygous sample. Each replicated multiple times (e.g., 242-321 replicates per site for specific genotypes, across multiple runs).
    • BRCA1 5382insC: 2 wildtype samples, 1 heterozygous sample. Each replicated multiple times (e.g., 321-402 replicates per site for specific genotypes).
    • BRCA2 6174delT: 2 wildtype samples, 1 heterozygous sample. Each replicated multiple times (e.g., 313-323 replicates per site for specific genotypes).
  • Data Provenance: DNA samples were procured and genotyped. No specific country of origin mentioned, likely internal to 23andMe's operations or commercial vendors.

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

The ground truth for the analytical validation (accuracy study) was established by Sanger bidirectional sequencing performed at an independent laboratory site. There is no mention of human experts defining the ground truth for the analytical studies. The "experts" in the context of user comprehension studies (which were not specifically performed for this report but referenced generally) would be physicians and genetic counselors to determine relevant concepts, but not for establishing a genetic variant ground truth.

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

No adjudication method for the genetic variant determination is mentioned. The ground truth was established directly by Sanger bidirectional sequencing. This is a direct comparison study, not a human reader study requiring adjudication.

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 such MRMC comparative effectiveness study was done. This device is a qualitative genetic test for detecting specific SNPs, not an imaging AI diagnostic aid for human readers.

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

Yes, the analytical performance studies (precision, LoD, and accuracy against Sanger sequencing) represent the standalone performance of the 23andMe PGS test, which is an algorithm interpreting genotyping data. The human element is in the initial sample acquisition and laboratory processing, but the "device" itself (the genotyping and data analysis system) operates in a standalone manner for assigning genotypes.

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

The primary ground truth for validating the device's accuracy in identifying genetic variants was Sanger bidirectional sequencing. For analytical studies, this is considered a highly reliable and established gold standard for DNA sequencing.

8. The sample size for the training set

The document describes performance studies on a "test set" (accuracy, precision, LoD), but does not provide details on the training set size for the underlying genotyping and analysis algorithms (e.g., Illumina's GenomeStudio or 23andMe's Coregen software). Genetic tests like this rely on established biochemical and computational methods for genotype calling, which are developed and validated using extensive, but typically not detailed in regulatory submissions in terms of a specific "training set" size in the same way an AI model's training set would be. The focus is on the analytical validation of the test system's performance for the specific variants.

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

As there's no explicit mention of a "training set" in the context of a machine learning model, the concept of ground truth establishment for it isn't directly addressed. For the underlying genotyping technology and software, ground truth is typically based on known genetic sequences, synthetic constructs, or samples previously characterized by highly accurate sequencing methods like Sanger.

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