Search Results

The 23andMe Personal Genome Service (PGS) Test uses qualitative genotyping to detect the following clinically relevant variants in genomic DNA isolated from human saliva collected from individuals ≥18 years with the Oragene Dx model OGD-500.001 for the purpose of reporting and interpreting Genetic Health Risks (GHR):

The 23andMe PGS Genetic Health Risk Report for Hereditary Thrombophilia is indicated for reporting of the Factor V Leiden variant in the F5 gene, and the Prothrombin G20210A variant in the F2 gene. This report describes if a person has variants associated with a higher risk of developing harmful blood clots, but it does not describe a person's overall risk of developing harmful blood clots. This test is most relevant for people of European descent.

The 23andMe PGS Genetic Health Risk Report for Alpha-1 Antitrypsin Deficiency is indicated for reporting of the PIZ and PIS variants in the SERPINA1 gene. This report describes if a person has variants associated with AAT deficiency and a higher risk for lung or liver disease, but it does not describe a person's overall risk of developing lung or liver disease. This test is most relevant for people of European descent.

The 23andMe PGS Genetic Health Risk Report for Late-onset Alzheimer's Disease is indicated for reporting of the £4 variant in the APOE gene. The report describes if a person's genetic result is associated with an increased risk of developing Late-onset Alzheimer's Disease, but it does not describe a person's overall risk of developing Alzheimer's Disease. The £4 variant included in this report is found and has been studied in many ethnicities. Detailed risk estimates have been studied the most in people of European descent.

The 23andMe PGS Genetic Health Risk Report for Parkinson's Disease is indicated for reporting of the G2019S variant in the LRRK2 gene and the N370S variant in the GBA gene. The report describes if a person's genetic result is associated with an increased risk of developing Parkinson's disease, but it does not describe a person's overall risk of developing Parkinson's disease. The test is most relevant for people of European, Ashkenazi Jewish, and North African Berber descent.

The 23andMe PGS Genetic Health Risk Report for Gaucher Disease Type 1 is indicated for reporting of the N370S, 84GG, and V394L variants in the GBA gene. This report describes if a person has variants associated with an increased risk for developing symptoms of Gaucher Disease Type 1, but it does not describe a person's overall risk of developing Gaucher Disease Type 1. This test is most relevant for people of Ashkenazi Jewish descent.

The 23andMe PGS Genetic Health Risk Report for Factor XI Deficiency is indicated for reporting of the variants F283L. E117X. IVS14+1G>A in the F11 gene. This report describes if a person has a variant associated with Factor XI deficiency and the potential for a higher risk of excessive bleeding following trauma or surgery, but it does not describe a person's overall risk for excessive bleeding. This test is most relevant for people of Ashkenazi Jewish descent.

The 23andMe PGS Genetic Health Risk Report for Celiac Disease is indicated for reporting of a variant associated with the HLA-DQ2.5 haplotype. The report describes if a person has a haplotype associated with an increased risk of developing celiac disease, but it does not describe a person's overall risk for developing celiac disease. This report is most relevant for people of European descent.

The 23andMe PGS Genetic Health Risk Report for Glucose-6-Phosphate-Dehydrogenase Deficiency is indicated for reporting of the Val68Met variant in the G6PD gene. This report describes if a person has a variant associated with G6PD deficiency and a higher risk for episodes of anemia, but it does not describe a person's overall risk of developing anemia. This test is most relevant for people of African descent.

The 23andMe PGS Genetic Health Risk Report for Hereditary Hemochromatosis is indicated for reporting of the C282Y and H63D variants in the HFE gene. This report describes if a person has variants associated with hereditary hemochromatosis and a higher risk for iron overload, but it does not describe a person's overall risk of developing iron overload. This report is most relevant for people of European descent.

The 23andMe PGS Genetic Health Risk Report for Early-Onset Primary Dystonia (DYT1/TOR1A-Related) is indicated for reporting of the deltaE302/303 variant in the DYT1 gene. This report describes if a person has variants associated with a higher risk for early-onset primary dystonia, but it does not describe a person's overall risk of developing dystonia. This report is most relevant for people of Ashkenazi Jewish descent.

The 23andMe 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 direct-toconsumer, over-the-counter, non-diagnostic, DNA genetic testing service 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 processing.

DNA is isolated from the saliva and tested in a multiplex assay using a customized genotyping chip and instrumentation manufactured by Illumina. The multiplex assay simultaneously tests for more than 500,000 variants, including those for the indications 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 are used to generate personalized reports for users that provide information about the diseases associated with the detected variant.

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.

Acceptance Criteria and Device Performance Study for 23andMe Personal Genome Service (PGS) Genetic Health Risk Test

The 23andMe Personal Genome Service (PGS) Genetic Health Risk Test is a qualitative in vitro molecular diagnostic system for detecting genetic variants associated with various diseases. The regulatory approval details the acceptance criteria and performance study results.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for analytical performance (Precision/Reproducibility, Limit of Detection, and Accuracy) are derived from the Special Controls outlined in 21 CFR 866.5950, specifically paragraph (b)(3)(iii)(J).

• PA (CC|CC) = 100% (95% CI: 94.7% to 100%)
• PA (CT|CT) = 100% (95% CI: 94.7% to 100%)
• PA (TT|TT) = 100% (95% CI: 94.6% to 100%)
  Hereditary Thrombophilia (Prothrombin G20210A F2):
• PA (GG|GG) = 100% (95% CI: 94.7% to 100%)
• PA (AG|AG) = 100% (95% CI: 94.6% to 100%)
• PA (AA|AA) = 100% (95% CI: 94.5% to 100%)
  Alpha-1 Antitrypsin Deficiency (PI*Z SERPINA1):
• PA (CC|CC) = 100% (95% CI: 94.8% to 100%)
• PA (CT|CT) = 100% (95% CI: 94.7% to 100%)
• PA (TT|TT) = 100% (95% CI: 94.7% to 100%)
  Alpha-1 Antitrypsin Deficiency (PI*S SERPINA1):
• PA (TT|TT) = 100% (95% CI: 94.4% to 100%)
• PA (AT|AT) = 100% (95% CI: 94.7% to 100%)
• PA (AA|AA) = 100% (95% CI: 94.7% to 100%)
  Late-onset Alzheimer's Disease (APOE s4):
• PA (TT|TT) = 100% (95% CI: 98.8% to 100%)
• PA (CT|CT) = 99.2% (95% CI: 95.7% to 99.9%)
• PA (CC|CC) = 100% (95% CI: 96.3% to 100%)
  Parkinson's Disease (G2019S LRRK2):
• PA (GG|GG) = 100% (95% CI: 86.7% to 100%)
• PA (AG|AG) = 100% (95% CI: 93% to 100%)
• PA (AA|AA) = 100% (95% CI: 51.0% to 100%)
  Parkinson's Disease (N370S GBA):
• PA (TT|TT) = 100% (95% CI: 86.7% to 100%)
• PA (CT|CT) = 100% (95% CI: 94% to 100%)
• PA (CC|CC) = 100% (95% CI: 87.1% to 100%)
  Gaucher Disease Type 1 (N370S GBA):
• PA (TT|TT) = 100% (95% CI: 86.7% to 100%)
• PA (CT|CT) = 100% (95% CI: 94% to 100%)
• PA (CC|CC) = 100% (95% CI: 87.1% to 100%)
  The Manufacturer affirmed that comparison studies for other variants (84GG, V394L in GBA; F283L, E117X, IVS14+1G>A in Factor XI; HLA-DQA1 for Celiac Disease; Val68Met in G6PD; C282Y, H63D in HFE; deltaE302/303 in DYT1) were completed with identical study design, acceptance criteria, and results as the reported variants, including 100% accuracy for all valid calls. |
  | Precision/Reproducibility | The percentage of samples that failed quality control must be indicated (i.e., the total number of sample replicates for which a sequence variant cannot be called (no calls) or that fail sequencing quality control criteria divided by the total number of replicates tested). (b)(3)(iii)(J)(2) | General: All analytical performance studies met the pre-determined acceptance criteria.
  Factor V Leiden: 98.0% correct calls, 2.01% FQCs (0.04% anticipated 2 FQCs).
  Prothrombin G20210A: 98.1% correct calls, 1.85% FQCs (0.03% anticipated 2 FQCs).
  PI*Z SERPINA1: 98.4% correct calls, 1.63% FQCs (0.03% anticipated 2 FQCs).
  PI*S SERPINA1: 98.2% correct calls, 1.76% FQCs (0.03% anticipated 2 FQCs).
  APOE s4: 98.5% correct calls, 1.54% FQCs (0.02% anticipated 2 FQCs).
  G2019S LRRK2: 98.5% correct calls, 1.54% FQCs (0.02% anticipated 2 FQCs).
  N370S GBA (Parkinson's): 96.2% correct calls, 3.81% FQCs (0.15% anticipated 2 FQCs).
  N370S GBA (Gaucher): 97.5% correct calls, 3.12% FQCs (0.10% anticipated 2 FQCs).
  All valid calls in these studies were 100% correct at both sites. The Manufacturer affirmed that reproducibility studies were completed for all other listed variants (84GG, V394L in GBA; F283L, E117X, IVS14+1G>A in Factor XI; HLA-DQA1 for Celiac Disease; Val68Met in G6PD; C282Y, H63D in HFE; deltaE302/303 in DYT1) with identical study design, acceptance criteria, and results. |
  | Limit of Detection (LoD) | Data must be provided demonstrating the minimum amount of DNA that will enable the test to perform correctly in 95 percent of runs. (b)(3)(iii)(J)(5) | The LoD study yielded 100% correct genotype calls for all samples and all reagent lots tested at sample DNA concentrations of 5, 15, and 50 ng/uL. The study passed LoD acceptance criteria at 5 ng/uL. Manufacturer claimed LoD of 15 ng/uL.
  The Manufacturer affirmed that LoD studies were completed for all other listed variants (84GG, V394L in GBA; F283L, E117X, IVS14+1G>A in Factor XI; HLA-DQA1 for Celiac Disease; Val68Met in G6PD; C282Y, H63D in HFE; deltaE302/303 in DYT1) with identical study design, acceptance criteria, and results. |
  | User Comprehension | The user study must meet predefined primary endpoint criteria, including a minimum of a 90 percent or greater overall comprehension rate (i.e., selection of the correct answer) for each comprehension concept. (b)(3)(iii)(M)(4)(vi) | The overall comprehension score for all concepts across all test reports studied was greater than 90%. For the G6PD Deficiency report scenario ("1 Variant Detected"), the report-specific comprehension score was 73.3%, which the Manufacturer mitigated with planned labeling changes in the FAQ section. |

2. Sample Sizes and Data Provenance for Test Set

Test Set for Analytical Accuracy (Comparison to Sanger Bidirectional Sequencing):

• Hereditary Thrombophilia (Factor V Leiden): 68 Homozygous Common (CC), 68 Heterozygous (CT), 67 Homozygous Rare (TT) samples. Total = 203.
• Hereditary Thrombophilia (Prothrombin G20210A): 68 Homozygous Common (GG), 67 Heterozygous (AG), 66 Homozygous Rare (AA) samples. Total = 201.
• Alpha-1 Antitrypsin Deficiency (PI*Z SERPINA1): 70 Homozygous Common (CC), 68 Heterozygous (CT), 69 Homozygous Rare (TT) samples. Total = 207.
• Alpha-1 Antitrypsin Deficiency (PI*S SERPINA1): 65 Homozygous Common (TT), 68 Heterozygous (AT), 69 Homozygous Rare (AA) samples. Total = 202.
• Late-onset Alzheimer's Disease (APOE s4): 316 Homozygous Common (TT), 126 Heterozygous (CT), 101 Homozygous Rare (CC) samples with correct calls. (Total raw samples: 320 TT, 129 CT, 106 CC, including those with "no calls" or "invalid"). Total = 555.
• Parkinson's Disease (G2019S LRRK2): 25 Homozygous Common (GG), 51 Heterozygous (AG), 4 Homozygous Rare (AA) samples. Total = 80.
• Parkinson's Disease (N370S GBA): 25 Homozygous Common (TT), 60 Heterozygous (CT), 26 Homozygous Rare (CC) samples. Total = 111.
• Gaucher Disease Type 1 (N370S GBA): 25 Homozygous Common (TT), 60 Heterozygous (CT), 26 Homozygous Rare (CC) samples. Total = 111.
• Other variants: For Gaucher Disease Type 1 (84GG, V394L), Factor XI Deficiency (F283L, E117X, IVS14+1G>A), Celiac Disease (HLA-DQA1), G6PD Deficiency (Val68Met), Hereditary Hemochromatosis (C282Y, H63D), and Early-Onset Primary Dystonia (deltaE302/303), the manufacturer affirmed that comparison studies were completed with the same design, acceptance criteria, and results as the explicitly detailed studies, testing wild-type, heterozygous, and homozygous samples where applicable, adhering to minimum sample size requirements (e.g., at least 20 unique samples for common genotypes, 3 for rare heterozygous, 3-20 for rare homozygous based on frequency).

Data Provenance: Saliva samples were selected from the 23andMe customer biobank based on their predetermined genotype. The data origin is not explicitly stated geographically, but it is indicated that genotype frequencies are considered for "individuals of European descent," "Ashkenazi Jewish descent," "North African Berber descent," "African descent," "South Asian," and "East Asian" depending on the variant, implying a diverse customer base. The samples are retrospective, as they were chosen from an existing biobank.

3. Number of Experts and Qualifications for Ground Truth

No external experts were explicitly mentioned for establishing the ground truth of the genetic variants in the test set. The ground truth for the test set was established by Sanger bidirectional sequencing, which is considered the "gold standard" for genetic variant determination. This method is an intrinsic, highly accurate laboratory technique, rather than requiring expert consensus interpretation.

4. Adjudication Method for the Test Set

Not applicable. The ground truth was established by Sanger bidirectional sequencing, an objective laboratory method, which means there was no human adjudication process involved for the genetic variant calls.

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

No MRMC comparative effectiveness study was performed in the context of human readers improving with or without AI assistance. This device is a direct-to-consumer genetic test for detecting specific variants, not an AI-assisted diagnostic imaging or interpretation tool.

6. Standalone (Algorithm-Only) Performance Study

Yes, the analytical performance studies (Accuracy, Precision/Reproducibility, Limit of Detection) represent the standalone performance of the 23andMe PGS device. The device's genotyping results were compared directly against the gold standard (Sanger bidirectional sequencing) without human intervention in the interpretation of the device's output for genetic calls.

7. Type of Ground Truth Used

The type of ground truth used for the analytical performance studies (accuracy, LoD) was Sanger bidirectional sequencing, which is a highly accurate molecular biology laboratory method for DNA sequencing, serving as the "truth" for genetic variants. This is an objective laboratory measure, not expert consensus, pathology, or outcomes data.

8. Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning or AI algorithm development for genetic variant detection. The methodologies described are for analytical validation of a qualitative genetic test. The robustness of the test is demonstrated through extensive reproducibility and accuracy studies using defined sets of samples (both cell lines and customer biobank samples).

For the analytical performance studies (Precision/Reproducibility and Limit of Detection), a range of sample sizes were used:

• Precision/Reproducibility for Hereditary Thrombophilia (Factor V Leiden): 10 DNA samples (3 wild type, 2 heterozygous, 1 homozygous rare, repeated multiple times) used for 1890 replicates.
• Precision/Reproducibility for Hereditary Thrombophilia (Prothrombin G20210A): 10 DNA samples (3 wild type, 1 heterozygous, 1 homozygous rare, repeated multiple times) used for 1620 replicates.
• Precision/Reproducibility for Alpha-1 Antitrypsin Deficiency (PI*Z SERPINA1): 8 DNA samples (2 wild type, 1 heterozygous, 1 homozygous rare, repeated multiple times) used for 1350 replicates.
• Similar numbers of DNA samples and replicates were used for other variants in the reproducibility studies.
• Limit of Detection: Samples were diluted to three different DNA concentrations (5, 15, and 50 ng/uL) and genotyped. The text does not specify the number of individual donor samples used for LoD beyond "each sample was diluted," implying the same initial set of samples used for accuracy/precision.

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

As mentioned above, a "training set" in the conventional machine learning sense for algorithm development is not explicitly described. The ground truth for the samples used in the analytical validation studies (which could be considered analogous to a "development/test set" for a traditional assay) was established through bidirectional Sanger sequencing, performed by an independent laboratory. This external, highly accurate, and objective method served as the reference standard for confirming the genotypes of the samples used in the performance evaluations.

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