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The Helix Genetic Health Risk App (HRA) uses qualitative genotyping to detect clinically relevant variants in genomic DNA isolated from human saliva collected from individuals ≥18 years with Oragene®Dx OGD-610 for the purpose of reporting and interpreting Genetic Health Risks (GHR):

The Helix Genetic Health Risk App (HRA) for late-onset Alzheimer's disease is indicated for reporting of the e2/e2, e2/e3, e2/e4 and e4/e4 genotypes in the APOE gene. The report describes if a person's genetic result is associated with an increased or decreased risk of developing late-onset Alzheimer's disease. The e2 and e4 variants included in this report are found and have been studied in many ethnicities. Detailed risk estimates have been studied the most in people of European descent.

The Helix Genetic Health Risk App (HRA) is to be used with the Helix Laboratory Platform.

The Helix Genetic Health Risk App 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 Helix Genetic Health Risk App is a currently marketed, non-invasive genetic information service that combines qualitative genotyping data indicate for late-onset Alzheimer's disease for reporting of the e2/e2, e2/e3, e2/e4, e3/e3, e3/e4 and e4/e4 genotypes in the APOE gene with descriptive information derived from peer reviewed, published genetic research studies. It is a home use, over-the-counter (direct-to-consumer) DNA testing service intended to provide information and tools for consumers to learn about and explore their DNA. Customer saliva is selfcollected using the FDA cleared Oragene®·Dx OGD-610 saliva collection kit manufactured by DNA Genotek, Inc. (K192920), which consists of a sealable collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to the CLIA-certified and College of American Pathologists (CAP) -accredited Helix laboratory for testing.

DNA is isolated from the saliva and tested using Helix's proprietary whole exome sequencing assay authorized under DEN190035 in the Helix laboratory. The genomic DNA is processed and sequenced using next generation sequencing (NGS) reagents and instrumentation manufactured by Illumina. The sequencing data is analyzed using Helix's proprietary software, where the genetic variants of interest are determined. All samples must pass Helix's stringent quality control metrics prior to analysis. Samples that do not pass quality thresholds will undergo re-sequencing and/or sample re-collection.

The genetic variant results are used to generate personalized reports that provide information about the detected genotype for the customer. These reports tell the user which genotype has/have been detected in their sample and provide information on the risk of disease associated with the genotype. If no genotype was determined, that information is also provided. The personalized reports are designed to present scientific concepts to users in an easy-tounderstand format. The reports provide scientifically valid information about the risks associated with the presence of a particular genetic 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.

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The Helix Laboratory Platform is a qualitative in vitro diagnostic device intended for exome sequencing and detection of single nucleotide variants (SNVs) and small insertions and deletions (indels) in human genomic DNA extracted from saliva samples collected with Oragene® Dx OGD-610. The Helix Laboratory Platform is only intended for use with other devices that are germline assays authorized by FDA for use with this device. The device is performed at the Helix laboratory in San Diego, CA.

The Helix Laboratory Platform (HLP) is a high throughput DNA sequencing platform for targeted sequencing of an individual's whole exome. It is intended for targeted sequencing of an individual's whole exome for use with a genetic test application. Genetic test applications may be third party partner ("Partner") genetic test applications or a Helix genetic test application such as the Helix Genetic Health Risk App (HRA; K192073). The DNA sequence generated by this device is intended as input to clinical germline DNA assays intended for use with this device that have FDA marketing authorization. A brief overview of the commercialized workflow is shown in Figure 1 (refer to the section titled "Test Principle" for more specific information regarding the commercialized workflow.) HLP consists of a HiSeq sequencing instrument, cBot system, library preparation reagents, sequencing reagents, and data analysis software. The Helix Laboratory Platform also interacts with the Helix Laboratory Automation Systems and Content Mapping Systems which serve as repositories for the data and do not perform data analysis. The test detects single nucleotide variants (SNVs) insertions and deletions (indels) up to 20 base pairs (bp) and is limited to making high-confidence variant calls that meet prespecified quality metrics (i.e., the analytical range) within the reportable range. Sequencing is performed at the Helix clinical laboratory in San Diego. CA.

Acceptance Criteria and Device Performance Study

This document describes the acceptance criteria for the Helix Laboratory Platform (HLP) and the studies conducted to demonstrate that the device meets these criteria. The HLP is a qualitative in vitro diagnostic device intended for exome sequencing and detection of single nucleotide variants (SNVs) and small insertions and deletions (indels) in human genomic DNA extracted from saliva samples, for use with other FDA-authorized germline assays.

1. Table of Acceptance Criteria and Reported Device Performance

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

The major testing was performed across several studies:

• Precision (Cell lines): 6 unique reference cell line samples (NA12877, NA12878, NA24385, NA24149, NA24143, NA24631). Each was tested with 72 replicates, for a total of 432 replicates.
• Precision (Clinical Specimens): 18 unique saliva (clinical) samples. Originally intended for 72 replicates each, resulting in ~1296 replicates. However, due to QC failures, 118 replicates were not evaluable, leaving 1178 evaluable replicates across 17 samples (one sample had all replicates fail).
• Between-Lot Reproducibility: 24 samples (6 cell lines and 18 saliva-derived DNAs). Each sample produced 54 replicate sequences with combinatorial sets of reagents, totaling 1296 intended replicates. 1287 evaluable replicates passed QC.
• DNA Input: 20 unique samples with known variants. Tested at 35ng, 50ng, 70ng, and 100ng DNA input, each in triplicate (totaling 240 intended samples). 219 samples were evaluable.
• Index Swapping - Barcoding: 48 saliva samples with known variants. Run in triplicate, totaling 160 libraries. 157 were used in analysis.
• Interfering Substances (Endogenous): 60 donors, each providing 3 aliquots (no treatment, plus 2 different endogenous substances). 180 no-treatment libraries and 120 treatment libraries were generated. 299 out of 300 samples were evaluable.
• Interfering Substances (Exogenous): 22 donors (originally 20, 2 added for food group), each providing samples for various conditions (before, immediately after, 30 min after consumption of food, drink, gum, mouthwash). 198 intended samples. Number of evaluable samples varied by condition.
• Interfering Substances (Microbial): 6 cell line DNA samples across 5 bacterial content conditions (0%, 10%, 20%, 30%, 50%), each in triplicate (totaling 90 samples). 81 samples evaluable. Also, fresh saliva from 3 donors tested across 3 conditions (baseline, bacteria spiked-in, yeast spiked-in), each in triplicate (totaling 27 samples).
• Interfering Substances (Smoking): 5 donors, each providing samples for 3 conditions (before, immediately after, 30 min after smoking), each in triplicate (totaling 45 samples).
• Accuracy Study 1 (Reference Cell Lines): 6 well-characterized cell lines (same as Precision study).
• Accuracy Study 2 (Clinical Specimens): 1002 clinical samples and 96 unique cell line samples.

Data Provenance:
The reference cell line samples (NA12877, NA12878, NA24385, NA24149, NA24143, NA24631) are publicly available from the Genome in a Bottle (GIAB) consortium and Platinum Genomes project, primarily representing Northern European (Utah) and Ashkenazim Jewish ethnicities. One GIAB sample was Asian Chinese.
Clinical samples were saliva samples collected from donors within the Helix lab's specimen collection. These are therefore retrospective samples. The country of origin is not explicitly stated for the clinical samples but is assumed to be the USA, where the Helix lab is located.

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

The ground truth for the reference cell lines (NA12877, NA12878, NA24385, NA24149, NA24143, NA24631) was established by publicly available reference datasets from the Genome in a Bottle (GIAB) consortium and the Platinum Genomes project. These consortia involve multiple expert groups and diverse sequencing technologies to establish highly confident variant calls. No specific number of, or qualifications for, individual experts are listed, as the ground truth relies on these highly vetted, community-accepted reference standards.

For the clinical samples in Accuracy Study 2, a validated Sanger sequencing method was used as the comparator method to confirm the accuracy of specific variants. This implies expert interpretation of Sanger sequencing results, but the number and qualifications of these experts are not explicitly stated.

4. Adjudication Method for the Test Set

The ground truth for reference cell lines was based on publicly available, highly vetted datasets (GIAB, Platinum Genomes), which typically involve a consensus-based approach from multiple sequencing technologies and analyses rather than active, real-time adjudication by a small group of experts for this specific study.

For samples where a reference sequence was generated within a study (e.g., Precision, DNA Input, Endogenous/Exogenous Substances, Microbial Interference, Smoking studies), it was established by majority call comparison over multiple replicates of a sample within the study. This implies an internal consensus mechanism rather than external expert adjudication.

For Accuracy Study 2 (clinical samples), Sanger sequencing was used as the comparator. Discrepancies between HLP and Sanger sequencing would be reviewed, but a formal adjudication method (e.g., 2+1, 3+1) involving external experts for these specific discrepancies is not described.

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

No MRMC comparative effectiveness study was performed or described in this document. The evaluation focuses on the standalone analytical performance of the Helix Laboratory Platform and its concordance with established ground truth or comparator methods, not on how human readers' performance improves with or without AI assistance from this platform.

6. Standalone Performance Study

Yes, extensive standalone performance studies were conducted. The entire "Performance Characteristics" section (Section L) details the intrinsic analytical performance of the Helix Laboratory Platform (HLP) without human intervention for variant calling and quality assessment. The reported PPA, NPA, and TPPV values across various studies (Precision, Between-Lot Reproducibility, DNA Input, Index Swapping, Interfering Substances, Accuracy) demonstrate the algorithm's performance in detecting SNVs and indels when operating independently.

7. Type of Ground Truth Used

The primary types of ground truth used were:

• Expert Consensus / Community Standards: For reference cell lines, publicly available datasets from the Genome in a Bottle (GIAB) consortium and the Platinum Genomes project were used. These are highly confident, multi-platform consensus truth sets.
• Validated Comparator Method: For clinical samples where specific variants were assessed (e.g., Accuracy Study 2), a validated Sanger sequencing method served as the comparator ground truth.
• Internal Majority Call: For various precision and interference studies where multiple replicates of a sample were generated and analyzed, a "majority call" across these replicates was used to establish an internal reference sequence for performance comparison.

8. Sample Size for the Training Set

The document does not explicitly state the sample size used for training the Helix bioinformatics pipeline's algorithms. It mentions optimization processes in Section L.1, such as "Optimization of variant read depth, allele fraction and callability thresholds" and "Establishment of filter and QC threshold for variant calling." These optimizations were "based on historical reference sample runs" and "analyzed with [...redacted...] of the bioinformatics pipeline representing different conditions relative to the quality metric criteria." While this indicates that data was used for optimizing and establishing parameters, specific training set sizes are not provided.

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

Similar to point 8, the document does not explicitly detail how the ground truth for any training set was established. However, the optimization efforts heavily relied on "historical reference sample runs" and "reference samples." It is highly likely that these reference samples would have included publicly available, well-characterized control genomes like those from the GIAB and Platinum Genomes projects, for which the "truth" variants are established through extensive, multi-platform sequencing and expert consensus by those consortia. The process described for establishing QC thresholds (e.g., in Section L.1.b) implies a comparison against these known reference datasets to fine-tune filtering parameters and improve accuracy.

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