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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 Personal Genome Service (PGS) Risk Report for BRCA1/BRCA2 (Selected Variants) is indicated for the reporting of the following 44 variants in the BRCA1 and BRCA2 genes.

BRCA1: c.68 69del, c.213-11T>G, c.427G>T, c.815 824dup, c.1556del, c.1687C>T, c.1961del, c.2681 2682del, c.2864C>A, c.3481 3491del, c.3598C>T, c.3627dup, c.3756 3759del, c.3770 3771del, c.4035del, c.4065 4068del.c.4327C>T.c.4357+1G>A.c.4964 4982del.c.4986+6T>G.c.5123C>A.c.5177 5180del.c.5266dup

BRCA2: c.658 659del, c.771 775del, c.2808 2811del, c.2957 2958insG, c.3170 3174del, c.3264dup, c.3545 3546del, c.3847 3848del, c.4471 4474del, c.5542del, c.5576 5579del, c.5682C>G, c.5946del, c.6037A>T, c.6275 6276del, c.7024C>T, c.7480C>T, c.7934del, c.8904del

The report describes if a person's genetic result is associated with an increased risk of developing breast cancer and ovarian cancer and may be associated with an increased risk for prostate cancer, and potentially other cancers. The variants included in this report do not represent the majority of the BRCA1/BRCA2 variants in people of most ethnicities. 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 report is for over-the-counter use by adults over the age of 18, and provides genetic information to inform discussions with a healthcare professional. 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.

Customer saliva specimens are self-collected using the Oragene-Dx® Device manufactured by DNA Genotek, Inc. cleared by FDA for use with the PGS device 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 raw data is generated using Illumina GenomeStudio software, and then sent to 23andMe for analysis and interpretation. The raw data received is 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 and clinically 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.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided FDA 510(k) summary for the 23andMe Personal Genome Service (PGS) Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants):

Acceptance Criteria and Device Performance

1. Table of Acceptance Criteria and Reported Device Performance

• Negative Percent Agreement (NPA) ≥ 99% for each SNP (variant) compared to bidirectional Sanger sequencing. | - Achieved: Greater than 99% agreement for both PPA and NPA across all 41 tested variants. The study concluded that the 23andMe assay is comparable to bidirectional Sanger sequencing. |
  | Precision (Reproducibility) | - Minimum of 99% correct genotype calls at each of two laboratory sites. | - Achieved: 100% correct genotype calls for all samples across multiple days, operator teams, instruments, and reagent lots at 2 independent laboratory sites.
• Greater than 99% reproducibility and greater than 99% repeatability. |
  | Minimum DNA Input (Sensitivity) | - At least 95% of samples yielding the correct call at the minimum DNA concentration. | - Achieved: 100% correct genotype calls for all samples and reagent lots tested at DNA concentrations of 5, 15, and 50 ng/µL.
• Valid for samples with a DNA concentration range of 5 ng/µL to 50 ng/µL (well within the SOP requirement of 15 ng/µL to 50 ng/µL). |

2. Sample Size and Data Provenance

• Test Set Sample Size: The exact number of individual samples used for the "Method Comparison" (Accuracy), "Precision" (Reproducibility), and "Minimum DNA Input" studies is not explicitly stated as a numerical count. However, the document mentions that samples were "randomly selected from the 23andMe customer database" and that "all 41 variants were included in this study" for each of these performance tests.
• Data Provenance: The document states that samples were identified from the "23andMe customer database." This implies real-world, likely retrospective, data from individuals who have used 23andMe's services. The country of origin is not explicitly stated for individual samples, but 23andMe is a US-based company, suggesting the data is primarily from the US.

3. Number of Experts and Qualifications for Ground Truth

• This device is a genetic test, and the ground truth for performance testing (accuracy) was established by bidirectional Sanger sequencing, which is a widely accepted and highly accurate method for DNA sequencing.
• The document does not mention the use of human experts (e.g., radiologists) in establishing the ground truth for the analytical validity studies. The "truth" in this context is the confirmed genetic sequence obtained through an orthogonal, highly accurate laboratory method (Sanger sequencing), not human interpretation of images or clinical outcomes.

4. Adjudication Method for the Test Set

• Adjudication methods (e.g., 2+1, 3+1) are typically used in studies involving human interpretation or subjective assessments. Since the performance studies for this genetic test rely on objective laboratory methods (genotyping by the device vs. Sanger sequencing as ground truth), no human adjudication method was needed or applied for the analytical performance tests. The comparison was directly between the device's genotype call and the Sanger sequencing result.

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

• No, an MRMC comparative effectiveness study was not done. MRMC studies are relevant for imaging devices or other medical technologies where human readers interpret output, and the goal is to assess how a device affects human performance. This is a direct-to-consumer genetic test (an in vitro diagnostic device) that directly provides genotype information, not an interpretation aid for human experts. Therefore, the concept of human readers improving with AI assistance is not applicable here.

6. Standalone (Algorithm Only) Performance

• Yes, standalone performance was done for the analytical validation. The performance criteria (PPA, NPA, correct genotype calls) were measured for the 23andMe PGS assay (the "algorithm only" in this context of a genetic test) against the ground truth established by Sanger sequencing. The results presented in the acceptance criteria table (e.g., ">99% agreement," "100% correct calls") represent the standalone performance of the device. There isn't a "human-in-the-loop" aspect to the genotyping process itself; the device generates the genotype call automatically.

7. Type of Ground Truth Used

• The ground truth used for the analytical validation test set was bidirectional Sanger sequencing, considered the gold standard for confirming specific DNA sequences and variants.

8. Sample Size for the Training Set

• The document does not specify the sample size for the training set. This is typical for in vitro diagnostic devices like genetic tests where the underlying technology (genotyping method) is well-established. The performance is primarily evaluated through robust analytical validation on a test set, rather than machine learning model training. The device leverages a "customized genotyping beadchip" and "proprietary Coregen software," indicating a deterministic or rule-based approach for genotype calling, or a machine learning model that was developed and validated internally but whose training set details are not part of this 510(k) summary.

9. How Ground Truth for the Training Set Was Established

• Given that the document does not explicitly mention a training set or machine learning model development in the traditional sense, it does not describe how ground truth for a training set was established. For molecular genetic tests, the principles of operation are typically based on molecular biology and chemistry, with performance validated through analytical studies against highly accurate reference methods like Sanger sequencing, rather than training on labeled datasets. If machine learning is involved in the "Coregen software" for genotype determination, the ground truth for any such training would logically have been established through a similar process of comparing assay results to known, validated reference genotypes (e.g., from Sanger sequencing or other established methods).

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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.

Ask a specific question about this device

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 MUTYH-Associated Polyposis. The 23andMe PGS Genetic Health Risk Report for MUTYH-Associated Polyposis is indicated for reporting of the Y179C and the G396D variants in the MUTYH gene. The report describes if a person is at increased risk of developing colorectal cancer. The two variants included in this report are most common and best studied in people of Northern European descent and may not represent the majority of the MUTYH variants found in people of other ethnicities. 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 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-the-counter (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. 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, 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. The raw data is generated using Illumina GenomeStudio software, and then sent to 23andMe. The data is then analyzed using the 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 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 any appropriate actions that may be taken based on their results. The novel components in this traditional 510(k) submission are only (a) the variants to be reported, and (b) the qualitative reporting of risk for MAP.

Here's a breakdown of the acceptance criteria and study information for the 23andMe Personal Genome Service (PGS) Genetic Health Risk Report for MUTYH-Associated Polyposis (MAP), based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance:

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

• Accuracy (Method Comparison): Saliva samples were selected from the 23andMe customer biobank based on pre-determined BeadChip genotype and minimum volume required. The exact number of samples for the MUTYH variants specifically isn't explicitly stated, but the study compared against Sanger sequencing.
• Precision/Reproducibility: Confirmed genotype DNA samples (commercially available or from 23andMe biobank) for G3696 variants and Y179C common homozygous and heterozygous variants. The Y179C rare homozygous variant was excluded. The exact number of samples for this specific study is not provided, but it involved "multiple days, operator teams, instruments, and reagent lots at two independent laboratory sites."
• DNA Input: DNA samples obtained from commercial sources or 23andMe biobank based on listed genotypes. The exact number of samples for this study is not provided. The study involved diluting each sample to 3 different DNA concentrations and genotyping in a blinded fashion using 3 lots of reagents.
• Interfering Substance: "More than 35,000 sample replicates were tested" across various prior studies (DEN140044).
• Clinical Performance (Allele Frequencies): Frequencies are based on approximately:
  • 872,000 individuals with European ancestry
  • 47,500 individuals with African-American ancestry
  • 38,500 individuals with Ashkenazi Jewish ancestry
  • 35,000 individuals with East Asian ancestry
  • 123,500 individuals with Hispanic/Latino ancestry
  • 10,000 individuals with South Asian ancestry
• Data Provenance: The document generally indicates the use of the 23andMe customer biobank for many of the analytical studies. For allele frequencies, it uses both the 23andMe Database and published literature (e.g., ExAc database, Poulsen and Bisgaard 2008). These would primarily be retrospective data sets from existing samples or databases.

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

The document does not explicitly state the number of experts or their qualifications for establishing ground truth for the test set specifically.

• Accuracy (Method Comparison): Ground truth was established by Sanger bi-directional DNA sequencing, which is a laboratory gold standard method, not by human expert consensus or interpretation.
• Precision/Reproducibility: Ground truth was established by bi-directional Sanger sequencing for each sample.
• DNA Input: Ground truth was established by bi-directional Sanger sequencing for each sample.
• Labeling Comprehension: Human input was used to assess comprehension rates among typical users, but these are not "experts" establishing a clinical ground truth.

4. Adjudication Method for the Test Set:

Not applicable, as the ground truth for analytical studies was primarily established by Sanger sequencing, a direct molecular method, rather than expert interpretation requiring adjudication.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. The device (23andMe PGS Genetic Health Risk Report for MUTYH-Associated Polyposis) is a standalone genetic test for direct-to-consumer use. The studies performed focused on the analytical performance (accuracy, precision, DNA input, interfering substances) and labeling comprehension of the report itself, not on how human readers (e.g., clinicians) would improve their diagnostic accuracy with or without AI assistance. The report is intended to inform conversations with healthcare providers, not to be directly used for diagnosis or treatment decisions by those providers without confirmatory testing.

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

Yes, a standalone performance study was done. The vast majority of the analytical performance studies (Method Comparison, Precision/Reproducibility, DNA Input, Interfering Substances) evaluate the performance of the "23andMe BeadChip assay" and the "PGS multiplex assay" as an automated genotyping process without human intervention in the result generation. The "Coregen software" analyzes the data to determine genotypes, which are then used to generate personalized reports. This represents the algorithm's standalone performance in genotyping.

7. Type of Ground Truth Used:

• Analytical Studies (Accuracy, Precision, DNA Input): Sanger bi-directional DNA sequencing was consistently used as the "truth" for genotype confirmation against which the BeadChip assay results were compared. This is considered a gold standard molecular method.
• Clinical Performance: Allele frequencies were derived from the 23andMe customer database and published scientific literature/databases (e.g., ExAc database, Poulsen and Bisgaard 2008). This is not a "ground truth" for individual cases, but rather statistical data based on large populations and research findings.
• Labeling Comprehension: Assessed by measuring user understanding of genetic health risk concepts, not by a clinical or pathological ground truth.

8. Sample Size for the Training Set:

The document does not provide information on the sample size used for the training set of the 23andMe PGS system or its Coregen software. The studies described are primarily analytical validation studies of the genotyping platform and the specific variants being reported. The "BeadChip" is a pre-designed array, and while software (Coregen) interprets the data, details about its specific "training" with a dataset are not available in this regulatory submission summary. The system itself (the PGS platform) was previously authorized, and this submission focuses on adding new variants.

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

As the document does not detail a specific "training set" for the genotyping algorithm or system, there is no information on how its ground truth was established. The underlying technology (Illumina Infinium BeadChip, Illumina iScan, GenomeStudio software, and 23andMe's Coregen software) is a sophisticated genotyping workflow that would have been developed and validated by the manufacturers. For the specific variants (Y179C and G396D) being reported for MUTYH-Associated Polyposis, their clinical relevance and association with disease are based on established scientific literature and understanding of genetics, rather than a training dataset for the algorithm. The analytical studies confirm the assay's ability to accurately detect these variants, with Sanger sequencing acting as the ground truth for that detection capability.

Ask a specific question about this device

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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