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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).

Ask a specific question about this device

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.

Ask a specific question about this device

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:

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. This report describes 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. 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 PGS is a non-invasive DNA testing service that uses qualitative genotyping. It is a direct-to-consumer, over-the-counter, DNA genetic test. 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. 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 by the scanning instrument's software, and then sent to 23andMe (the Manufacturer). The data are analyzed using the Manufacturer's proprietary 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 predicted metabolic function of the tested variants.

Personalized reports are generated for each user to 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 predicted metabolic function of the specific genetic variants. The genetic variants detected by the test are associated with the metabolism of some therapeutics. If no variant is detected, that information is also provided. If the association between the predicted metabolic function and the combination of detected variants has not been established, the report indicates that the results cannot be determined. The personalized reports are intended to present scientific concepts to users in an easy-to-understand format. The reports provide information about the association between the detected variant and the predicted metabolic function that has been associated with the metabolism of some drugs, further described below. The reports are designed to help users understand the meaning of their results and inform conversations with their doctor or other healthcare professional. The test reports do not provide any information on associations between the detected variants and any specific therapeutic and therefore, the test does not describe if a person will or will not respond to any specific therapeutic.

The 23andMe PGS Pharmacogenetic Reports detect 33 variants in 8 genes: CYP2C19, CYP2C9, CYP2D6, CYP3A5, CYP2D6, DPYD, TPMT, and UGT1A1. The 23andMe PGS Pharmacogenetic Reports provide information on the associated enzyme or protein function and the predicted metabolizer phenotype for variants in drug metabolizing enzymes: CYP2C19, CYP2C9, CYP2D6, CYP3A5, CYP2D6, DPYD, TPMT, and UGT1A1. The predicted metabolizer phenotype is identified according to the number and consequence of each allele where two no-function alleles are associated with being poor metabolizers, one no-function allele is associated with being an intermediate metabolizer, two functional alleles are associated with being normal metabolizers, one gain-of-function allele is associated with being a rapid metabolizer, and two gain-of-function alleles are associated with being an ultrarapid metabolizer. The predicted metabolizer phenotype or protein function is then used to provide information on the potential consequence on metabolism of some medications. For example, poor metabolizers may process some medications slower, internediate metabolizers may process some medications slightly slower than normal, normal metabolizers may process some medication at a normal rate. rapid metabolizers may process some medications slightly faster than normal, and ultrarapid metabolizers may process some medications faster than normal.

The 23andMe PGS Pharmacogenetic Report for SLCO1B1 will indicate that the detected variant is associated with a loss-of-function and slightly decreased transport of some medications.

Here's a breakdown of the acceptance criteria and the study details for the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports, based on the provided text:

Acceptance Criteria and Device Performance for 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports

1. Table of Acceptance Criteria and Reported Device Performance (Analytical Performance for CYP2C19)

The document primarily details the analytical performance for **CYP2C19 variants (*2, 3, 17) as the representative study for the broader pharmacogenetic reports. Protocols and acceptance criteria for other genes (CYP2C9, CYP2D6, CYP3A5, DPYD, TPMT, UGT1A1, and SLCO1B1) were reviewed and found acceptable, with the plan for the sponsor to perform testing and add them if validation data meet criteria.

Note: The provided text does not explicitly state numerical acceptance criteria for performance metrics like PPA/NPA. However, the reported results demonstrate 100% agreement with the reference method (Sanger sequencing), which can be inferred as meeting implicit high accuracy requirements. The special controls mention the need for "Data appropriate, as determined by FDA, to demonstrate the analytical (i) accuracy and reliability of the device."

2. Sample Size and Data Provenance

• Test Set (Analytical Studies - CYP2C19):

  • Reproducibility/Precision:
    • CYP2C19*2: 4 samples (GG, AG, AA) at Site 1; 4 samples (GG, AG, AA) at Site 2. Each sample replicated 81 times. (Total 81 replicates * 4 samples * 2 sites = 648 technical replicates, plus FQCs/no calls).
    • CYP2C19*3: 4 samples (GG, AG, AA) at Site 1; 4 samples (GG, AG, AA) at Site 2. Each sample replicated 81 times. (Total 648 technical replicates, plus FQCs/no calls).
    • CYP2C19*17: 5 samples (CC, CT, TT) at Site 1; 5 samples (CC, CT, TT) at Site 2. Each sample replicated 81 times. (Total 810 technical replicates, plus FQCs/no calls).
    • Additional precision study: One sample of each genotype for each allele was genotyped in replicates of three at two sites.
    • Data Provenance: DNA samples obtained from an "external vendor." Not explicitly stated, but typically these are commercially available, characterized genomic DNA samples. The study was retrospective in nature as samples were pre-selected.
  • Limit of Detection (LoD): Not explicitly stated, but samples included homozygous common, heterozygous common, and homozygous rare genotypes for each allele (CYP2C19*2, *3, *17). Three replicates of each sample were diluted to three DNA concentrations.
    • Data Provenance: Samples obtained from an "external vendor." Retrospective.
  • Comparison with Sanger Bidirectional Sequencing (Accuracy):
    • CYP2C19*2: 47 (Homozygous Common), 49 (Heterozygous), 48 (Homozygous Rare).
    • CYP2C19*3: 48 (Homozygous Common), 45 (Heterozygous), 39 (Homozygous Rare).
    • CYP2C19*17: 49 (Homozygous Common), 45 (Heterozygous), 47 (Homozygous Rare).
    • Data Provenance: Saliva samples selected from the "23andMe customer biobank" based on predetermined genotypes. This implies a retrospective data provenance, and the potential for selection bias ("samples were chosen from a biobank based on the variants already detected by the candidate assay") is explicitly noted by the FDA. The country of origin of the biobank is not specified, but 23andMe is a US-based company, suggesting primarily US customers.

• Test Set (User Comprehension Study):

  • Sample Size: 602 participants completed the study; 594 subjects included in primary analysis (after excluding 8 careless responders/previous users/technical issues). A second analysis excluded 63 participants who did not scroll/read the reports, resulting in 531 participants.
  • Data Provenance: Participants were "demographically diverse (e.g., age, education) set of users naive to the study subject." The direct-to-consumer nature implies diverse backgrounds, likely from the US, but not explicitly stated. This would be considered a prospective study as participants were recruited specifically for this evaluation.

3. Number of Experts and Qualifications for Ground Truth

• Analytical Studies (Reproducibility, LoD, Comparison with Sanger):

  • Number of Experts: Not applicable in the traditional sense of clinical experts.
  • Qualifications: The ground truth for the DNA samples used in analytical studies was established by bidirectional Sanger sequencing, which is considered a gold standard for genetic sequencing. The "external vendor" supplying samples would also have characterized them.

• User Comprehension Study:

  • Number of Experts: The study mentioned "moderators of the test" for identifying participants who did not scroll/read. Specific qualifications of these moderators are not provided. The "primary endpoint analysis" and "second analysis" indicate a statistical approach rather than expert consensus on individual comprehension.

4. Adjudication Method for the Test Set

• Analytical Studies:

  • Method: For reproducibility, LoD, and accuracy studies, the 23andMe PGS test results were compared to the results obtained from bidirectional Sanger sequencing. Discrepancies (incorrect calls) were counted. This is effectively a direct comparison to a gold standard, not a consensus-based adjudication among multiple interpretations of the same test.
  • Specifics (e.g., 2+1): Not applicable, as it's a comparison to a single reference method.

• User Comprehension Study:

  • Method: Quantitative assessment of participant answers to comprehension questions. Not a traditional adjudication method.

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

• Was one done? No, a MRMC comparative effectiveness study involving human readers improving with AI vs. without AI assistance was not mentioned or conducted for this device.
  • This device is a qualitative genotyping microarray intended for direct-to-consumer use, with results used to inform discussions with healthcare professionals. It does not involve a diagnostic image interpretation or similar task where human readers would typically "improve" with AI assistance in the way an MRMC study would measure.
• Effect Size: Not applicable.

6. Standalone Performance Study

• Was one done? Yes, the entire analytical performance section (Reproducibility/Precision, Limit of Detection, Analytical Specificity, Comparison with Sanger bidirectional Sequencing) represents a standalone (algorithm only, without human-in-the-loop performance) evaluation of the 23andMe PGS test's ability to accurately detect genetic variants. The user comprehension study assessed how well users understood the report generated by the algorithm, but the genotyping itself was assessed standalone.

7. Type of Ground Truth Used

• Analytical Studies: Sanger bidirectional sequencing was used as the ground truth for confirming genotypes in the reproducibility, LoD, and comparison studies.

• Clinical Studies (User Comprehension): The ground truth for the comprehension study was defined by pre-defined correct answers to questions about the information presented in the reports. This is a measure of objective understanding of the provided text, not directly related to a medical diagnosis or biological outcome.

8. Sample Size for the Training Set

• Training Set Sample Size: The document does not provide information regarding a specific "training set" sample size for the genotyping algorithm itself.
  • Genotyping microarrays from companies like Illumina (which 23andMe uses/adapts) are developed and validated using extensive reference genomes and known variant databases during their initial design and manufacturing. 23andMe's proprietary software analyzes the raw data, and while such software might undergo internal validation and refinement, the specific training data for the core genotyping calls (determining AG, GG, etc.) is not detailed in this regulatory summary. The focus is on the analytical validation of the test performed by 23andMe using their specific chip and processes.

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

• Ground Truth for Training Set: As no specific "training set" for the genotyping algorithm's core variant calling function is detailed, the method for establishing its ground truth is not provided in this document.
  • However, for the specific pharmacogenetic associations and predicted metabolizer phenotypes (e.g., "poor metabolizer"), the document states: "The impact of protein or enzyme function for each allele and the predicted metabolizer phenotypes were identified from data in the literature for each allele for each gene." This is ground truth established through expert consensus and published literature.

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