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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 for the purpose of reporting and interpreting genetic health risks, including the 23andMe PGS Genetic Health Risk Report for Hereditary Prostate Cancer (HOXB13-Related). The 23andMe PGS Genetic Health Risk Report for Hereditary Prostate Cancer (HOXB13- Related) is indicated for reporting of the G84E variant in the HOXB13 gene. The report describes if a person has the G84E variant and if a male is at increased risk for prostate cancer. The variant included in this report is most common in people of European descent. 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 for diagnosis, to determine any treatments or medical interventions.

The 23andMe Personal Genome Service (PGS) is an over-the-counter (direct-to-consumer), DNA testing service that provides information and tools for consumers to learn about and explore their DNA.

The 23andMe Personal Genome Service (PGS) is a currently marketed, non-invasive genetic information 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 home use, over-thecounter (direct-to-consumer) DNA testing service intended to provide information and tools for consumers to learn about and explore their DNA.

Customer saliva is self-collected using the Oragene-Dx® Device manufactured by DNA Genotek, Inc. (previously cleared for carrier screening indications under K141410, and the same collection kit used to generate performance data for DEN140044, DEN160026, DEN170046, K182784, DEN180028, and K193492, which consists of a sealable collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to one of our 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, and off the shelf 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 indications proposed herein.

Raw data is generated using Illumina GenomeStudio software, and then sent to 23andMe. The data is then analyzed using 23andMe's proprietary Coregen software, where a genotype is determined for each tested SNP. The results for certain of these SNPs are used to generate personalized reports for the customer that provide information about the detected genotype.

Personalized reports are generated for each user that provide results of the testing performed. These reports tell the user which genetic health risk variant(s) have been detected in their sample and provide information about the 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 any appropriate actions that may be taken based on their results.

The modified components of the Personal Genome Service included in this 510(k) submission are new labeling to include (a) one new variant to be reported, and (b) the qualitative reporting of one's Genetic Health Risk for Hereditary Prostate Cancer (HOXB13-Related).

Engineering drawings, schematics, etc. of Genetic Health Risk Report for Hereditary Prostate Cancer (HOXB13-Related) are not applicable to this device.

The provided document describes the acceptance criteria and study proving the device meets these criteria for the 23andMe PGS Genetic Risk Report for Hereditary Prostate Cancer (HOXB13-Related).

Here's the breakdown of the information requested:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Accuracy/Method Comparison Study:
  • Sample Size: Not explicitly stated as a number, but "Saliva samples were selected from the 23andMe customer biobank, based on their predetermined genotype and minimum volume required for testing." This implies a varied sample size based on the availability of specific genotypes.
  • Data Provenance: From the "23andMe customer biobank" and "approved contract laboratory sites." The origin of the customers is not specified beyond "23andMe customer" which is a US-based company, suggesting primarily US data. The study was retrospective, using pre-existing samples from the biobank.
• Precision Study:
  • Sample Size: "DNA samples were selected based on their confirmed genotypes, and were obtained from the 23andMe biobank." Not an explicit number.
  • Data Provenance: From the "23andMe biobank." Implies primarily US data, retrospective.
• DNA Input Study:
  • Sample Size: "DNA samples were obtained from the 23andMe biobank based on their listed genotypes." Not an explicit number.
  • Data Provenance: From the "23andMe biobank." Implies primarily US data, retrospective.
• Interfering Substance Study (referenced from DEN140044):
  • Sample Size: Over 35,000 sample replicates.
  • Data Provenance: Not explicitly stated for this particular study, but given it's for a US regulatory submission by a US company, it's highly likely to be US data, retrospective.
• Labeling Comprehension Study (referenced from DEN160026):
  • Sample Size: Not explicitly stated.
  • Data Provenance: Not explicitly stated, but also likely US data.

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

• Ground Truth Method: For the analytical studies (Method Comparison, Precision, DNA Input), the ground truth for genotyping was established by bi-directional Sanger sequencing.
• Number/Qualifications of Experts: The document does not specify the number or qualifications of experts involved in performing or interpreting the Sanger sequencing results to establish the "truth." It only states that sequencing was performed "by an approved supplier" and that the sequencing results were "considered to be 'truth.'"

4. Adjudication Method for the Test Set (e.g., 2+1, 3+1, none)

• The document does not describe any human adjudication method for establishing the ground truth from Sanger sequencing. It implies that the sequencing results themselves were directly taken as ground truth without further expert consensus or 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 MRMC or comparative effectiveness study involving human readers (e.g., radiologists) with or without AI assistance was performed or described. This device is a direct-to-consumer genetic test, not an imaging-based AI diagnostic tool.
• The closest concept is the "Labeling Comprehension" study, which assesses how well consumers understand the report. It indicates that the report and educational materials were effective in communicating relevant concepts for safe use. This is a measure of user comprehension, not human reader improvement with AI assistance.

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

• Yes, the performance studies (Accuracy, Precision, DNA Input, Interfering Substance) represent a standalone evaluation of the genotyping assay, which is essentially the "algorithm" or technical process of the device. The accuracy and precision figures are "algorithm only" performance metrics, as they compare the device's genotype calls directly against Sanger sequencing as the ground truth.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

• For the analytical performance studies (Accuracy, Precision, DNA Input), the ground truth for specific genetic variants (genotype) was established by bi-directional Sanger sequencing.
• For the clinical performance, the document refers to "published studies of variant frequencies in various populations and the results of analytical studies" and "allele frequencies in the 23andMe customer database." This relies on established scientific literature and aggregated anonymized real-world data rather than individual outcomes or pathology reports.

8. The Sample Size for the Training Set

• The document primarily describes validation studies (test sets) for the analytical performance of the device. It does not provide information about a separate "training set" sample size for developing the genotyping assay or the underlying "Coregen software." The genotyping method described relies on physical beadchip arrays and established principles of DNA analysis, not on a machine learning model that would typically have a distinct training phase with a dedicated dataset.
• The "Customer biobank" is used for selecting samples for the performance studies, which may implicitly reflect data used in the development or refinement of their overall genotyping process, but it's not explicitly defined as a separate 'training set' for an AI model.

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

• As mentioned above, the document does not elaborate on a distinct "training set" with established ground truth in the context of an AI/ML model for this genetic test. The "Coregen software" analyzes raw data from the beadchip, and its accuracy is validated against Sanger sequencing. The development process of this proprietary software, and any data used to "train" it (if it involves statistical modeling beyond simple rule-based interpretation of genotyping signals), is not detailed in terms of ground truth establishment.

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