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The 23andMe Personal Genome Service (PGS) is a qualitative genotyping assessment system applied to genomic DNA isolated from human saliva collected using the Oragene Dx OGD-500.001 to simultaneously detect, report, and interpret genetic variants in a broad multigene test. The assessment system is intended to enable users to access information about their genetics that could aid discussions with a healthcare professional. The 23andMe Personal Genome Service Pharmacogenetic Reports are indicated for reporting of the following variants:

Gene: CYP2C19 Variant(s): *2, *3, *17
Gene: CYP2C9 Variant(s): *2, *3, *5, *6, rs7089580
Gene: CYP3A5 Variant(s): *3
Gene: UGT1A1 Variant(s): *6, *28
Gene: DPYD Variant(s):*2A, rs67376798
Gene: TPMT Variant(s): *2, *3C
Gene: SLCO1B1 Variant(s): c.521T>C (rs4149056)
Gene: CYP2D6 Variant(s): *2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *15, *17, *20, *29, *35, *40, *41

This report is for over-the-counter use by adults over the age of 18 and provides genetic inform discussions with a healthcare professional about metabolism of therapeutics.

The 23andMe Personal Genome Service pharmacogenetic reports for CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT and CYP2D6 describe if a person has variants associated with metabolism of some therapeutics but does not describe if a person will or will not respond to a particular therapeutic and does not describe the association between detected variants and any specific therapeutic.

23andMe Personal Genome Service pharmacogenetics report for CYP2C19 describes if a person has variants associated with metabolism of some therapeutics and provides interpretive drug information regarding the potential effect of the identified metabolizer phenotype on citalopram and clopidogrel therapy.

23andMe Personal Genome Service pharmacogenetics report for SLCO1B1 describes if a person has variants associated with the processing of some therapeutics and provides interpretive drug information regarding the potential effect of the identified transport function phenotype on simvastatin therapy.

The PGS Pharmacogenetic Reports are not a substitute for visits to a healthcare professional. The information provided by this report should not be used to start, stop, or change any course of treatment.

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

The 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.

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 (K141410, DEN140044, DEN160026. DEN170046. DEN180028. K182784. K193492. and K211499), which consists of a sealable collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory 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 device simultaneously tests for more than 600,000 variants, including those reported under the previously authorized PGS test indications.

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 variant(s) has/have been detected in their sample and provide information on the metabolizer or transporter profile associated with the 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 metabolizer or transport function phenotype associated with the presence of a particular variant, or a combination of variants.

In the pharmacogenetic report for SLCO1B1. information regarding interpretive drug information to certain medications will be provided to the user in a medication "mini report", which is accessed via a link in the pharmacogenetic report for SLCO1B1. 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.

As noted in Table 5.2, the PGS assay components for the SLCO1B1 Drug Transport report such as the custom beadchip, reagents, and instrumentation are the same as the predicate devices. No new reagents were needed and the beadchip was unchanged to test for the c.521T>C (rs4149056) variant. The probes to detect c.521T>C (rs4149056) already existed on the beadchip.

The novel components in this Traditional 510(k) submission are to provide interpretive drug information to one specific medication (simvastatin), and to remove the limitation language requiring confirmatory testing in the 23andMe pharmacogenetics report for SLCO1B1. Pharmacogenetic reports for other genes authorized in DEN180028 will not be modified to remove the confirmatory testing limitation, include interpretive drug information, or add a prescription indication.

Engineering drawings, schematics, etc. of the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports are not applicable to this device.

The provided document, a 510(k) Summary for the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports (K221885), focuses on the modifications to the SLCO1B1 pharmacogenetic report. The primary changes are the addition of interpretive drug information for simvastatin and the removal of the confirmatory testing requirement for SLCO1B1. The summary details analytical performance studies conducted to support these changes.

Here's a breakdown of the requested information based on the provided document:

1. Table of acceptance criteria and the reported device performance

The document specifies acceptance criteria for analytical performance studies. These are primarily related to accuracy (method comparison) and precision (reproducibility) for the c.521T>C (rs4149056) variant in the SLCO1B1 gene.

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

• Test Set Sample Size: The document does not explicitly state a total numerical sample size for the method comparison and precision studies. It mentions that for the method comparison, samples were selected from 23andMe's database to enrich for prevalent variants in specific ethnicities, and allele and diplotype frequencies were used to inform the number of samples selected. For the precision study and MDI, "intended use (saliva) samples were selected from the 23andMe customer biobank based on their putative genotype" and "obtained for each of the c.521C>T genotype combinations." While specific numbers aren't given, the language suggests a controlled selection of samples representing relevant genotype combinations.
• Data Provenance: The samples for performance testing were obtained from the "23andMe customer biobank." This suggests that the data is from real-world customer samples. The document does not specify the country of origin of these customers, but 23andMe is a US-based company, implying a significant US customer base. The data would be considered retrospective as it's from pre-existing biobank samples.

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 performance studies (method comparison, precision, MDI) was established using bidirectional Sanger sequencing, which is a widely accepted laboratory gold standard for genetic variant confirmation.
• The document does not mention the use of human experts (like radiologists or genetic counselors) to establish the ground truth for these analytical performance tests, as the ground truth is a direct genetic sequencing result, not an interpretation of an image or a clinical diagnosis.

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

• Since the ground truth for the analytical performance studies was established by bidirectional Sanger sequencing, there was no human adjudication method employed for these specific tests. The comparison was directly between the device's genotyping result and the sequencing result.

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 comparative effectiveness study was performed or is relevant for this type of device. The 23andMe Personal Genome Service is a direct-to-consumer genetic testing product that provides raw genetic data and interpretive reports; it is not an AI-assisted diagnostic imaging tool or a system where human readers interpret data with or without AI assistance. The "human readers" in this context are the end-users (consumers) who read the reports, and their "improvement" is not measured in the traditional MRMC sense.
• The document does mention "robust user comprehension testing, previously reviewed and authorized under DEN180028 and K193492," indicating that the readability and understanding of the reports by users were assessed. However, this is distinct from an MRMC study and the specific results of this comprehension testing (e.g., effect size) are not detailed in this 510(k) summary, only referenced as having been sufficient for prior clearances.

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

• Yes, standalone performance was evaluated. The method comparison, precision, and minimum DNA input studies directly assess the accuracy and reliability of the 23andMe BeadChip assay and its associated software (Genome Studio, Coregen) in determining genotypes, without direct human intervention or interpretation during the genotyping process itself. The reported performance (e.g., 100% agreement with Sanger sequencing) is the standalone performance of the genotyping system.

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

• The ground truth used for the analytical performance studies (method comparison, precision, MDI) was bidirectional Sanger sequencing, which is a highly accurate and widely accepted method for determining the true genetic sequence/variant status.

8. The sample size for the training set

• The document does not explicitly state the sample size for the training set for the device's algorithms. As the device involves a genotyping array and software for data analysis (Coregen), it's likely that a substantial amount of genetic data was used in the development and initial training/optimization of these systems. However, this 510(k) summary focuses on the validation of modifications to a previously cleared device rather than the initial development of the core genotyping platform.

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

• The document does not detail how the ground truth for the training set (if any specific to training was used for this modification) was established. For a genotyping platform like this, the "training" (or more accurately, the development and verification) would typically involve using samples with known genetic variations confirmed by gold-standard methods like Sanger sequencing or whole-genome sequencing. The 510(k) focuses on the validation of the current device's performance against a gold standard (Sanger sequencing).

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The 23andMe Personal Genome Service (PGS) is a qualitative genotyping assessment system applied to genomic DNA isolated from human saliva collected using the Oragene Dx OGD-500.001 to simultaneously detect, report, and interpret genetic variants in a broad multigene test. The assessment system is intended to enable users to access information about their genetics that could aid discussions with a healthcare professional. The 23andMe Pharmacogenetic Reports are indicated for reporting of the following variants:

Gene: CYP2C19 Variant(s): *2, *3, *17
Gene: CYP2C9 Variant(s): *2, *3, *5, *6, rs7089580
Gene: CYP3A5 Variant(s): *3
Gene: UGT1A1 Variant(s): *6, *28
Gene: DPYD Variant(s):*2A, rs67376798
Gene: TPMT Variant(s): *2, *3C
Gene: SLC01B1 Variant(s): *5
Gene: CYP2D6 Variant(s): *2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *15, *17, *20, *29, *35, *40, *41

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 about metabolism of therapeutics.

The 23andMe Personal Genome Service pharmacogenetic reports for CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT, SLC01B1 and CYP2D6 describe if a person has variants associated with metabolism of some therapeutics, but does not describe if a person will or will not respond to a particular therapeutic, and does not describe the association between detected variants and any specific therapeutic.

23andMe Personal Genome Service pharmacogenetic reports for CYP2C19 describes if a person has variants associated with metabolism of some therapeutics and provides interpretive drug information regarding the potential effect of the identified metabolizer phenotype on citalopram and clopidogrel therapy.

The PGS Pharmacogenetic Reports are not a substitute for visits to a healthcare professional. The information provided by this report should not be used to start, stop, or change any course of treatment.

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 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.

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 (K141410, DEN140044, DEN160026, DEN170046, DEN180028, and K182784), which consists of a sealable collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory 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 device simultaneously tests for more than 600,000 variants, including those reported under the previously authorized PGS test indications.

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 variant(s) has/have been detected in their sample and provide information on metabolizer or transporter profile 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 metabolizer or transporter phenotype associated with the presence of a particular variant, or a combination of variants. In the pharmacogenetic report for CYP2C19, information regarding interpretive drug information to certain medications will be provided to the user in a medication "mini report", which is accessed via a link in the pharmacogenetic report for CYP2C19. 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 to provide interpretive drug information to two specific medications (citalopram and clopidogrel), and to remove the limitation language requiring confirmatory testing in the 23andMe pharmacogenetic report for CYP2C19. Pharmacogenetic reports for the other genes authorized in DEN180028 will not be modified to include interpretive drug information, or remove the confirmatory testing limitation.

Here's an analysis of the acceptance criteria and the supporting study for the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports, specifically focusing on the CYP2C19 gene, as described in the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document focuses on the analytic performance of the genotyping assay for CYP2C19 variants (*2, *3, *17). The primary acceptance criteria provided relate to accuracy (method comparison) and precision (reproducibility).

2. Sample Sizes and Data Provenance for the Test Set

• Method Comparison (Accuracy) & Precision (Reproducibility) Test Sets:

  • "Blinded Study 1" (single lab site, single day): Five 96-well plates of "incoming saliva samples." A specific numerical count of samples is not given, but 5 plates x 96 wells/plate = 480 samples.
  • Coriell Reference Samples: Genomic DNA for the three CYP2C19 variants of interest (*2, *3, *17) was obtained from the Coriell Institute for Medical Research. The exact number of Coriell samples used is not specified.
  • "Blinded Study 2" (East Asian ancestry): Intended use (saliva) samples "randomly selected in an unbiased manner from the 23andMe biobank based on their East Asian genetic ancestry." Numbers not specifically given. The purpose was to increase the likelihood of rare *3 allele combinations.
  • Supplemental Precision Study (saliva): Intended use (saliva) samples selected from the 23andMe customer biobank based on their "putative genotype." Numbers not specifically given but tested over 3 days, with 3 lots of reagents, by unique operator teams, using 3 different serial numbers of each of 2 instruments (Tecan and iScan), at each of 2 laboratory sites.
  • Minimum DNA Input (MDI) Test Set:
    • DNA samples obtained from Coriell and the 23andMe biobank. Exact numbers not specified, but tested at 3 different DNA concentrations with 3 reagent lots.
    • Supplemental MDI Study (saliva): Intended use (saliva) samples selected from the 23andMe customer database based on their "putative genotype." Numbers not specified, but each sample was diluted to 3 different DNA concentrations and genotyped with 3 reagent lots.

• Data Provenance:

  • Retrospective: Samples from the 23andMe biobank and customer database are retrospective, representing previously collected data.
  • Prospective (Implicit): "Incoming saliva samples" in the first blinded study could imply prospective collection for that specific study's initiation if they were fresh samples received for routine processing on that day.
  • External Reference: Coriell Institute for Medical Research samples are an external, well-characterized source.
  • Country of Origin: Not explicitly stated for all samples, but the 23andMe customer base is likely predominantly from the US and other countries where they operate.

3. Number of Experts and Qualifications for Ground Truth Establishment (Test Set)

This device is a genotyping system, and the ground truth for its analytical performance is established through genomic sequencing, not expert interpretation of phenotypic data or images.

• No human experts were used to establish the ground truth in the traditional sense of clinical interpretation.
• The "experts" in this context are the robust and established methods of bi-directional Sanger sequencing and Coriell Institute's characterization of their reference materials. These methods are considered the "source of truth" for genetic sequences and genotypes.

4. Adjudication Method for the Test Set

• No human adjudication method (like 2+1, 3+1) was used as the ground truth is based on objective genetic sequencing data.
• The comparison involved directly comparing the device's genotyping results against the known sequences/genotypes derived from Sanger sequencing or Coriell's reference data. Discrepancies would likely lead to re-sequencing or further investigation to ascertain the true genotype.

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

• No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done.
• This device is an automated genotyping system, not one that involves human "readers" interpreting output in a diagnostic setting in the way an imaging AI might. Its primary function is to accurately identify genetic variants. The "interpretive drug information" is a downstream output of the accurate genotyping, not something itself interpreted by multiple human readers in a study of this type.

6. Standalone Performance Study (Algorithm Only)

• Yes, the performance studies described (Method Comparison, Precision, Minimum DNA Input) are all standalone performance studies of the genotyping algorithm and associated laboratory process.
• The studies evaluate the accuracy and reliability of the device itself (the genotyping platform, reagents, and analysis software) in determining genetic variants, separate from how a human might interpret the final report.

7. Type of Ground Truth Used

• Expert Consensus (Genomic): The ground truth for the analytical performance studies was established using:
  • Bi-directional Sanger Sequencing: A gold standard method for DNA sequencing, considered highly accurate for confirming specific genetic variants.
  • Reference Samples from Coriell Institute for Medical Research: These are well-characterized genomic DNA samples with established and verified genotypes, essentially an expert-characterized reference.

8. Sample Size for the Training Set

• The document does not explicitly state a separate "training set" for the genotyping algorithm. Genetic genotyping algorithms often rely on established biochemical principles and mapping to known reference genomes rather than machine learning on a large, labeled training dataset of raw signals to call genotypes.
• However, the "23andMe database" is mentioned, with variant and allele frequencies from "8,004,302 customers" and "16,008,604 alleles." This massive dataset, along with public databases like gnomAD, would likely be used in the development and refinement of allele frequency estimation and potentially for algorithm fine-tuning or quality control, but not as a distinct "training set" in the typical AI sense for classifying novel inputs.

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

• Given that a distinct "training set" as understood in machine learning is not explicitly detailed, the ground truth establishment for algorithm development would implicitly rely on the same principles as the test set: established genetic sequencing methodologies (like Sanger sequencing) and comprehensive genetic reference databases (like the human reference genome and population-specific variant databases). These resources allow for the accurate mapping and identification of genetic variants within the raw genotyping data.

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