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The AncestryDNA Saliva Collection Kit is intended for use in the noninvasive collection of saliva samples for in vitro diagnostic testing of human DNA. Saliva may be collected by spitting directly into the AncestryDNA Saliva Collection Kit by a lay user. Saliva samples collected using the AncestryDNA Saliva Collection Kit are stabilized and isolated for use with over-the-counter AncestryDNA Genetic Health Risk Tests. Saliva samples collected using the AncestryDNA Saliva Collection Kit can be transported and/or stored long term at ambient conditions.

The AncestryDNA Saliva Collection Kit consists of: saliva collection tube, funnel, cap, blister pack, collection bag with absorbent pad, return mailer, and Instructions for Use. The collection device consists of the saliva collection tube, funnel, and cap. The cap contains DNA stabilization solution. Saliva is delivered directly by spitting into the collection tube via the funnel. Once the user has provided the saliva sample, s/he removes the funnel from the saliva collection tube and affixes the cap. Affixing the cap by screwing on releases the stabilization solution. The user is then instructed to shake the tube for at least five seconds to mix the saliva sample with the stabilization solution. After collecting the saliva sample, the user places the closed saliva collection tube in the collection bag. The collection bag with the enclosed saliva collection tube is shipped to a designated Ancestry Genomics location for testing via the pre-addressed postage paid return mailer.

Acceptance Criteria for the AncestryDNA Saliva Collection Kit and Supporting Study

The AncestryDNA Saliva Collection Kit is intended for non-invasive collection, stabilization, transportation, and long-term storage of saliva samples for in vitro diagnostic testing of human DNA, specifically for use with the AncestryDNA Factor V Leiden Genetic Health Risk Test. The following acceptance criteria were established and demonstrated through analytical and user studies.

1. Table of Acceptance Criteria and Reported Device Performance

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

The primary test set for demonstrating accuracy (Method Comparison) involved 209 donors (200 initial + 9 alternate).

Data Provenance: The study was conducted by a CLIA-certified laboratory (Ancestry Genomics' designated location) on collected saliva samples. The bi-directional sequencing for ground truth was performed by a third-party laboratory. The country of origin of the data is not explicitly stated, but the submission is to the U.S. FDA, suggesting the data is likely from the U.S. (or at least collected with U.S. regulatory oversight in mind). The study appears to be prospective as samples were collected specifically for the purpose of the study and then processed.

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

The ground truth for the test set (Factor V Leiden genotypes) was established using bi-directional sequencing analysis performed by a third-party laboratory. The document does not specify the number of individual experts (e.g., geneticists or laboratory personnel) involved in interpreting the sequencing results, nor their specific qualifications (e.g., years of experience). However, the use of "bi-directional sequencing" by a "third-party laboratory" implies a robust and standard method for genotype determination.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method involving multiple human readers for discrepancies in the ground truth for the test set. The ground truth (true variant status) was determined solely by bi-directional sequencing.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not conducted. This device is a saliva collection kit, and the performance evaluation focuses on the analytical accuracy of DNA collection and subsequent genotyping, not on human interpretation of images or other data where AI might assist.

6. If a Standalone Study Was Done

Yes, a standalone performance study was done for the AncestryDNA Factor V Leiden GHR Test in combination with the AncestryDNA Saliva Collection Kit. The reported performance metrics (reproducibility, analytical sensitivity, interference, sample volume tolerance, and accuracy) directly reflect the algorithm's (genotyping test's) ability to correctly identify genotypes from samples collected by the device, without human intervention in the genotype determination process itself. The user comprehension study also evaluated the standalone usability of the collection kit by lay users.

7. The Type of Ground Truth Used

The ground truth used for determining the true variant status of the Factor V Leiden genotype was bi-directional sequencing. This is considered a gold standard method for confirming genetic sequences.

8. The Sample Size for the Training Set

The document does not provide information regarding a specific "training set" sample size for the AncestryDNA Factor V Leiden GHR Test algorithm. It describes analytical and clinical validation studies for the device and its compatibility with the GHR test. Since this is for a collection kit and an established genotyping method (Illumina Infinium array platform), it's less likely to involve a distinct "training set" in the same way machine learning models typically do for image analysis, for example. The genotyping methodology itself has inherent validation processes, and the studies here validate the use of the collection kit with that methodology.

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

As a specific "training set" is not explicitly mentioned or relevant in the common AI/ML sense for this type of device (a collection kit and a genotyping test on an array platform), the method for establishing ground truth for a training set is not applicable and therefore not described in the document.

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The AncestryDNA Factor V Leiden Genetic Health Risk Test for Hereditary Thrombophilia uses qualitative genotyping to detect clinically relevant variants in genomic DNA isolated from human saliva collected from individuals 18 years and older with the AncestryDNA Saliva Collection Kit for the purpose of reporting and interpreting Genetic Health Risks (GHR).

The AncestryDNA Factor V Leiden Genetic Health Risk Report for Hereditary Thrombophilia is indicated for reporting of the Factor V Leiden variant in the F5 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.

A user's saliva is self-collected using the AncestryDNA Saliva Collection Kit, 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, quantified, 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 indication proposed herein.

The raw data is generated using Illumina GenomeStudio software, and then sent to Ancestry Genomics (the Manufacturer). The data are analyzed using the Manufacturer's proprietary GHR software, and a genotype is determined for each tested variant. The results for the Factor V Leiden variant are used to generate personalized reports for users that provide information about the disease 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.

Here is a summary of the acceptance criteria and the study that proves the device meets the acceptance criteria, based on the provided text:

Acceptance Criteria and Reported Device Performance

Study Details

2. Sample Size and Data Provenance (Test Set):

• Reproducibility/Precision:
  • Total replicates: 2,340 genotyping events (combining all replicates from Lab 1, Lab 2, inter-laboratory, by site/operator team, by site/instrument, and by site/reagent lot).
  • Donors: 9 donors with known Factor V Leiden genotypes (3 homozygous common, 3 heterozygous, 3 homozygous rare).
  • Provenance: Samples were collected using AncestryDNA Saliva Collection Kits (SCKs) and tested at two CLIA-certified laboratories (Lab 1 and Lab 2). The study was prospective in nature for data collection.
• Analytical Sensitivity:
  • Saliva Study: 15 donors (5 homozygous common, 5 heterozygous, 5 homozygous rare). 450 replicates tested.
  • Cell Line Study: 4 cell lines. 216 data points per cell line for dilutions, and 855 blank replicates.
  • Provenance: Saliva samples collected using Oragene® Dx Collection Device and AncestryDNA SCK. Cell lines. Data collected prospectively for the study.
• Interfering Substances (Endogenous):
  • Donors: 10 saliva donors. 450 initial genotyping attempts (3 replicates for each of 10 donors per interferent + 30 control replicates).
  • Provenance: Saliva samples collected using Oragene® Dx Collection Device. Data collected prospectively for the study.
• Interfering Substances (Exogenous):
  • Donors: 10 non-smokers and 10 smokers. 594 data points.
  • Provenance: Saliva samples collected using AncestryDNA SCKs. Data collected prospectively for the study.
• Interfering Substances (Microbial):
  • Cell Lines: 6 human cell lines (4 homozygous common, 1 heterozygous, 1 homozygous rare). 432 genotyping results.
  • Provenance: Human cell lines. Data collected prospectively for the study.
• Accuracy / Method Comparison:
  • Donors: 209 donors with known Factor V Leiden genotypes (73 homozygous common, 69 heterozygous, 67 homozygous rare). 198 samples passed QC.
  • Provenance: Saliva samples collected using Oragene Dx Ogd-500.001 (OGD) and AncestryDNA SCK. Data collected prospectively for comparison.
• User Comprehension (Study 1):
  • Participants: 378 individuals (N=96, N=86, N=106, N=90 for each of four study arms).
  • Provenance: Participants were recruited from the U.S. matching demographics for education, age, sex/gender, and race/ethnicity, and geographic diversity across four U.S. Census regions. Performed in-person. Prospective study.
• User Comprehension (Study 2):
  • Participants: 213 individuals (N=103 for "1 Variant", N=110 for "Result Not Determined").
  • Provenance: Participants were recruited from the U.S., matching demographics and geographic diversity as in Study 1. Performed via live televideo interviews. Prospective study.

3. Number of Experts and Qualifications for Ground Truth (Test Set):
For analytical studies (Reproducibility, Analytical Sensitivity, Interfering Substances, Accuracy/Method Comparison), the ground truth for Factor V Leiden genotype was primarily established using bi-directional sequencing analysis at a third-party laboratory. The specific qualifications of the experts performing the bi-directional sequencing were not detailed in the provided text.

For User Comprehension Studies, the materials were reviewed by a Certified Genetic Counselor to confirm that the materials met specific criteria for explaining test concepts.

4. Adjudication Method (Test Set):
The text does not explicitly describe an adjudication method like 2+1 or 3+1 for the analytical studies. Instead, direct comparison was made between the device's genotype calls and the ground truth established by bi-directional sequencing. Any discrepancies would presumably be investigated, though the method is not detailed. For User Comprehension studies, a questionnaire was administered by a trained interviewer/moderator to assess comprehension.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
No, an MRMC comparative effectiveness study involving human readers with and without AI assistance was not performed. This device is a genetic health risk test (an in vitro molecular diagnostic system), not an imaging device typically associated with MRMC studies in the context of human reader performance improvements with AI.

6. Standalone Performance:
Yes, standalone performance (algorithm only) was done. The studies described (reproducibility, analytical sensitivity, interfering substances, and accuracy/method comparison) evaluate the performance of the device itself (AncestryDNA Factor V Leiden GHR Test) in determining genotype status, independent of human interpretation of raw data. The "AncestryDNA GHR software" processes data from the instrumentation and generates the final analytical genotype information for each sample, which is then used to generate personalized reports.

7. Type of Ground Truth Used (Test Set):
The primary ground truth used for determining the Factor V Leiden genotype in analytical studies was bi-directional sequencing analysis.

8. Sample Size for the Training Set:
The document does not explicitly specify a "training set" sample size for the AncestryDNA Factor V Leiden Genetic Health Risk Test in the context of its 510(k) submission. For molecular diagnostic systems like this, the "training" aspect often refers to the development and optimization of the assay and software algorithms. The document instead focuses on analytical validation studies (test sets) for device performance. If the AncestryDNA GHR software performs certain control checks and analyses (as described in section "P. SYSTEM DESCRIPTION" - "Software"), the underlying algorithms would have been developed and potentially "trained" or optimized during the device's development phase, but specific training set sizes are not provided.

9. How the Ground Truth for the Training Set was Established:
Since a specific training set sample size is not explicitly mentioned for the reported studies, the method for establishing ground truth for a training set is also not detailed. However, for any developmental work or optimization, it is highly probable that the ground truth would have been established using bi-directional sequencing or other highly accurate, established reference methods, similar to how the ground truth for the test sets was established.

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