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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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The 23andMe PGS Carrier Screening Test for Bloom Syndrome is indicated for the detection of the BLMAsh variant in the BLM gene from saliva collected using an FDA cleared collection device (Oragene DX model OGD-500.001). This test can be used to determine carrier status for Bloom syndrome in adults of reproductive age, but cannot determine if a person has two copies of the BLM140 variant. The test is most relevant for people of Ashkenazi Jewish descent.

The 23andMe Personal Genome Service (PGS) Carrier Screening Test for Bloom Syndrome (hereafter the "PGS") is a non-invasive genetic information service that combines qualitative genotyping data for an individual. The PGS is indicated for use for the detection of the BLM4sh variant in the BLM gene from saliva collected using the Oragene•Dx Saliva Collection Device (Oragene Dx model OGD-500.01). The core components of the PGS consist of the saliva collection kit: custom genotyping chip: laboratory procedures, equipment and analysis; and result reporting software.

Here's a breakdown of the acceptance criteria and the study details for the 23andMe Personal Genome Service Carrier Screening Test for Bloom Syndrome, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document sometimes mixes "acceptance criteria" for the studies themselves with broader regulatory criteria. This table focuses on the performance metrics explicitly stated as needing to be met within the studies.

Study Details

2. Sample Size and Data Provenance for Test Set

• Human Cell Line Precision Study (Test Set):

  • Sample Size: 6 DNA samples from cell lines (4 BLM homozygous common ("DD"), 1 BLMAsh heterozygous ("DI"), 1 BLMAsh homozygous rare ("II")). These samples were replicated extensively: "DD" samples had 360 replicates each (total 1440), "DI" and "II" samples had 720 replicates each (total 1440). Grand total of 2,880 replicates.
  • Data Provenance: Not explicitly stated, but implies laboratory-prepared cell lines, not patient-derived samples from a specific country. This is retrospective in the sense of using pre-existing cell lines.

• Saliva Sample Reproducibility Study (Test Set):

  • Sample Size: 105 BLMAsh homozygous common ("DD") saliva samples.
  • Data Provenance: Obtained from individuals using the 23andMe Saliva Collection kit (Oragene-DX, OGD500.001). Implies prospective collection by users for 23andMe's biobank but used retrospectively for this study. Country of origin not specified.

• Limit of Detection Study (LoD) (Test Set):

  • Sample Size: DNA samples from cell lines: BLMAsh (homozygous wild type, DD) - 4 samples/4 replicates per sample; BLMAsh (heterozygous variant, DI) - 1 sample/8 replicates per sample; BLMAsh (homozygous variant, II) - 1 sample/8 replicates per sample. Each DNA sample tested at 3 concentrations (5, 15, 50 ng/uL).
  • Data Provenance: Cell lines (retrospective, laboratory-prepared).

• Interference Studies (Test Set):

  • Endogenous Interference: 10 individuals (homozygous common "DD") with saliva samples.
  • Exogenous Interference: 5 individuals with saliva samples, tested under 5 conditions (eating beef, eating non-beef, drinking, chewing gum, mouthwash) at 3 time points, in triplicate. Total 225 replicates.
  • Smoking Interference: 5 donors with saliva samples, tested under 1 condition (smoking) at 3 time points, in triplicate. Total 45 replicates.
  • Microbial Interference: 6 DNA samples from cell lines (4 "DD", 1 "DI", 1 "II") with 3 replicates each, spiked with 5 microbial DNAs. Total 90 replicates (6 samples x 5 microbes x 3 reps; plus controls).
  • Data Provenance: Saliva from individuals for endogenous/exogenous/smoking (likely retrospective from 23andMe's biobank, country unspecified); cell lines for microbial interference (retrospective, laboratory-prepared).

• Accuracy/Method Comparison Study (Test Set):

  • Sample Size: 65 saliva samples (25 DD and 22 DI at Site 1; 18 DI at Site 2). Also, 6 human cell line samples (4 DD, 1 DI, 1 II) at both sites. Totaling 71 unique samples, but with some samples counted across sites (e.g., 22 DI at Site 1 + 18 DI at Site 2 = 40 DI unique saliva samples tested across sites).
  • Data Provenance: Saliva samples randomly selected from the 23andMe Biobank (retrospective, country unspecified). Human cell line samples (retrospective, laboratory-prepared).

• User Comprehension Study (Test Set):

  • Sample Size: A total of 11 of 678 (1.6%) participants were excluded, meaning approximately 667 participants were included. Quota-based sampling targeting at least 100 subjects per 5 different representative test reports.
  • Data Provenance: Prospective collection for the study, conducted at 5 locations across the U.S.

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

• Analytical Validation Studies (Precision, LoD, Interference, Accuracy):

  • Ground Truth Providers: Performed by bi-directional Sanger Sequencing. The document does not specify a "number of experts" or their qualifications. Bidirectional Sanger sequencing is considered a gold standard for genetic variant confirmation, and its results are interpreted by trained laboratory personnel. The "experts" in this context are the established and validated sequencing protocol itself and the standard bioinformatics analysis of the sequencing data, rather than individual human experts adjudicating cases for complex image interpretation.

• User Comprehension Study:

  • Ground Truth Providers: The ground truth is the "correct answer" to comprehension questions, which would have been established by the study designers (likely geneticists, educators, regulatory affairs specialists) based on the intended meaning of the labeling. No external "experts" were used to establish ground truth for individual participant responses; the correctness of responses was evaluated against pre-defined correct answers.

4. Adjudication Method for the Test Set

• Analytical Validation Studies:

  • Adjudication Method: None, in the typical sense of expert review for ambiguous cases. The ground truth (bi-directional Sanger sequencing) is considered definitive. Discordant results between the device and sequencing would be thoroughly investigated, but not "adjudicated" by multiple human reviewers. The document states that "BeadChip genotypes were compared with sequenced genotypes to determine the rates of correct BeadChip genotype calls." For FQC (failed quality control) replicates, they were re-run as per laboratory SOPs.

• User Comprehension Study:

  • Adjudication Method: None. Participant responses were assessed against pre-defined correct answers established by the study design. There was no mention of multiple reviewers adjudicating ambiguous participant answers.

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

• No MRMC comparative effectiveness study was done. This device is a standalone genetic test for detecting a specific variant, not an AI-assisted diagnostic tool that aids human readers (e.g., radiologists interpreting images). Therefore, there is no "human readers improve with AI vs without AI assistance" effect size reported or relevant for this type of device.

6. Standalone Performance (Algorithm Only without Human-in-the-Loop)

• Yes, a standalone performance study was done. All the analytical performance studies (Precision/Reproducibility, LoD, Interference, Accuracy) directly assess the performance of the 23andMe PGS Carrier Screening Test (BeadChip, iScan, GenomeStudio, and Coregen software) in detecting the BLMAsh variant without human geneticists or counselors "in the loop" for the initial genotype calling. The test produces a genotype call ("DD", "DI", "II", or "no-call") directly. Human interaction comes in downstream for result interpretation and counseling (which the user comprehension study addresses).

7. Type of Ground Truth Used

• Analytical Performance Studies (Precision, LoD, Interference, Accuracy):

  • Ground Truth Type: Bi-directional Sanger Sequencing. This is a highly accurate molecular method considered the gold standard for confirming specific DNA sequences and variants.

• User Comprehension Study:

  • Ground Truth Type: Expert consensus for the correct answers to comprehension questions about the test report and genetic concepts. This was established by the designers of the study, based on scientific and educational principles.

8. Sample Size for the Training Set

• The document does not explicitly describe a training set sample size for the device's core genotyping algorithm. The methods described (Infinium BeadChip, Illumina iScan System, GenomeStudio, and Coregen software) are based on established genotyping technologies that typically involve pre-defined probe sets and analytical algorithms. While these systems require initial development and calibration (analogous to 'training'), the document focuses on the validation of the specific assay and workflow for the BLMAsh variant.
• However, the GenomeStudio software is mentioned to perform "primary data analyses, such as raw data normalization, clustering, and genotype calling." These steps often involve some form of algorithmic learning or optimization that could be considered "training" on reference data sets, but specific sizes or details are not provided here for the 23andMe application.

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

• Since a specific "training set" with independent ground truth is not explicitly described for the underlying genotyping algorithm (see point 8), the method for establishing its ground truth is also not detailed.
• Implied ground truth for algorithm development/calibration: For systems like GenomeStudio's genotype calling, ground truth datasets for clustering and calling would typically be laboratory-prepared reference samples with known genotypes (confirmed by orthogonal methods like Sanger sequencing) or large population datasets where genotypes are well-established for common variants. This process is part of the general development and validation of the Illumina platform itself, rather than a specific 'training set' for this particular Bloom Syndrome test beyond the analytical validation datasets.

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