(509 days)
No
The summary describes a genetic test that uses qualitative genotyping and proprietary software to analyze sequencing data and generate reports based on known genetic variants and published research. There is no mention of AI or ML being used in the analysis or interpretation process.
No.
The device provides information about genetic risk for disease, but it does not treat, cure, or mitigate a disease.
Yes
The device uses qualitative genotyping to detect clinically relevant variants in genomic DNA and reports if a person's genetic result is associated with an increased or decreased risk of developing late-onset Alzheimer's disease. This indicates its use in providing information about a health condition, which aligns with the definition of a diagnostic device.
No
The device description explicitly states it is a "DNA testing service" that involves a saliva collection kit, laboratory processing (DNA isolation, sequencing), and analysis using proprietary software. While software is a component, it is part of a larger system that includes hardware (sequencing instrumentation) and physical processes.
Based on the provided information, yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use explicitly states that the device uses qualitative genotyping to detect clinically relevant variants in genomic DNA isolated from human saliva for the purpose of reporting and interpreting Genetic Health Risks (GHR) related to late-onset Alzheimer's disease. This involves testing a sample taken from the human body (saliva) to provide information about a health condition.
- Device Description: The description details the process of collecting a human sample (saliva), isolating DNA from it, and performing genetic testing (sequencing and analysis) to determine specific genotypes in the APOE gene. The results are then used to generate personalized reports that provide information about the risk of disease associated with the detected genotype. This entire process aligns with the definition of an in vitro diagnostic device, which is used to examine specimens derived from the human body to provide information for the diagnosis, prevention, or treatment of a disease or condition.
- Regulatory Context: The mention of the device being used with the "Helix Laboratory Platform" and the laboratory being "CLIA-certified and College of American Pathologists (CAP) -accredited" further supports its classification as an IVD, as these are regulatory requirements for laboratories performing clinical diagnostic testing.
- Predicate Device: The listed predicate device, "23andMe PGS Genetic Health Risk Report for Late-onset Alzheimer's Disease," is also an IVD, indicating that devices with this intended use and technology are typically classified as such.
In summary, the Helix Genetic Health Risk App meets the criteria of an IVD because it is a device intended for use in vitro (outside the body) for the examination of specimens derived from the human body (saliva) to provide information about a disease or condition (late-onset Alzheimer's disease risk).
N/A
Intended Use / Indications for Use
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.
Product codes (comma separated list FDA assigned to the subject device)
PTA
Device Description
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 self-collected 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-to-understand 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.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
≥ 18 years
Intended User / Care Setting
Over-The-Counter Use
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
The device performance was evaluated in the analytical and clinical studies.
Method Comparison (Accuracy):
- Accuracy study with human saliva samples: Tested 99 human saliva samples with known APOE genotypes (confirmed by Sanger sequencing). The accuracy was 100% with a lower bound of 96.3% using a 95% CI for all samples tested.
- Accuracy study with human cell line samples: Tested 6 human cell lines with known APOE genotypes (e2/e3, e2/e4, e3/e3, e3/e4, e3/e4, and e4/e4). The accuracy was 100% for all samples tested.
- Accuracy study with 3,295 human saliva and cell line samples with known variants in genes other than APOE: Total of 4,282 true positive and 51,731 true negative calls for seventeen (17) variants in eleven (11) genes. No false positive and no false negative results were reported for the known variants tested.
Precision/Reproducibility:
Assessed by testing 24 samples (6 human B-lymphocyte cell lines and 18 unique saliva-derived DNA samples) in two independent studies. Call concordance for APOE genotypes was analyzed in clinical samples.
- Study 1: Tested 24 samples with up to 72 replicates. Correct Genotype Calls were 100% for all cell lines and clinical samples, with varying FQC percentages for clinical samples (e.g., 4.2% for e2/e3, 100% for one "Unknown" sample).
- Study 2: Tested 24 samples with up to 54 replicates. Correct Genotype Calls were 100% for most cell lines and all clinical samples, with one cell line (e4/e4) having 11.1% FQC.
Overall, genotyping results produced 100% replicates that were called correctly for all APOE genotypes.
DNA Input:
Evaluated the impact of different DNA input levels. All 19 saliva samples with known APOE genotypes showed 100% concordant test results when tested at sample DNA concentrations between 3.5 to 10 ng/μL.
Interfering Substances:
Four studies were performed to determine the effects of substances found in saliva. In all studies, the test performance for saliva samples was not affected, with 100% correct genotype calls for evaluable samples with varying percentages of FQC.
- Endogenous proteins: alpha-amylase, hemoglobin, immunoglobulin A (IgA), and albumin (29-30 evaluable samples across four proteins).
- Exogenous substances: eating food, drinking liquids, using mouthwash, or chewing gum (12-15 evaluable samples across testing time for four substances).
- Smoking: before, immediately after, and 30 minutes after smoking (15 evaluable samples across three conditions).
- Bacterial and yeast DNA: various amounts added to cell line DNA samples and saliva samples (11-18 evaluable samples across five levels of bacterial content, and 3 volunteers for yeast DNA).
Clinical Performance:
Information is provided about the association of APOE e2 and e4 alleles with late-onset Alzheimer's disease risk based on genetic studies, across different ethnicities. It outlines how different APOE genotype combinations (e2/e2, e2/e3, e3/e3, e2/e4, e3/e4, e4/e4) are associated with decreased, average, or increased risk of developing late-onset Alzheimer's disease. Likelihood ratios (LR) for these associations in different ethnicities (European, African, South Asian, East Asian descent) are presented, derived from meta-analyses.
Labeling Comprehension:
The average comprehension rate per comprehension category ranged from 85.2% to 100%. The overall comprehension rate for all core concepts across each of the four study arms was greater than 90%.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Accuracy: 100% Correct Genotype Calls (with varying FQC rates for some studies/samples).
Precision/Reproducibility: 100% Correct Genotype Calls.
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 866.5950 Genetic health risk assessment system.
(a)
Identification. A genetic health risk assessment system is a qualitative in vitro molecular diagnostic system used for detecting variants in genomic deoxyribonucleic acid (DNA) isolated from human specimens that will provide information to users about their genetic risk of developing a disease to inform lifestyle choices and/or conversations with a health care professional. This assessment system is for over-the-counter use. This device does not determine the person's overall risk of developing a disease.(b)
Classification. Class II (special controls). The genetic health risk assessment system device, when it has previously received a first-time FDA marketing authorization (e.g., 510(k) clearance) for the genetic health risk assessment system (a “one-time FDA reviewed genetic health risk assessment system”), is exempt from the premarket notification procedures in part 807, subpart E, of this chapter subject to the limitations in § 866.9. The device must comply with the following special controls:(1) The 21 CFR 809.10 compliant labeling and any prepurchase page and test report generated, unless otherwise specified, must include:
(i) A section addressed to users with the following information:
(A) The limiting statement explaining that this test provides genetic risk information based on assessment of specific genetic variants but does not report on a user's entire genetic profile. This test [does not/may not, as appropriate] detect all genetic variants related to a given disease, and the absence of a variant tested does not rule out the presence of other genetic variants that may be related to the disease.
(B) The limiting statement explaining that other companies offering a genetic risk test may be detecting different genetic variants for the same disease, so the user may get different results using a test from a different company.
(C) The limiting statement explaining that other factors such as environmental and lifestyle risk factors may affect the risk of developing a given disease.
(D) The limiting statement explaining that some people may feel anxious about getting genetic test health results. This is normal. If the potential user feels very anxious, such user should speak to his or her doctor or other health care professional prior to collection of a sample for testing. This test is not a substitute for visits to a doctor or other health care professional. Users should consult with their doctor or other health care professional if they have any questions or concerns about the results of their test or their current state of health.
(E) Information about how to obtain access to a genetic counselor, board-certified clinical molecular geneticist, or equivalent health care professional about the results of a user's test.
(F) The limiting statement explaining that this test is not intended to diagnose a disease, tell you anything about your current state of health, or be used to make medical decisions, including whether or not you should take a medication or how much of a medication you should take.
(G) A limiting statement explaining that the laboratory may not be able to process a sample, and a description of the next steps to be taken by the manufacturer and/or the customer, as applicable.
(ii) A section in your 21 CFR 809.10 labeling and any test report generated that is for health care professionals who may receive the test results from their patients with the following information:
(A) The limiting statement explaining that this test is not intended to diagnose a disease, determine medical treatment, or tell the user anything about their current state of health.
(B) The limiting statement explaining that this test is intended to provide users with their genetic information to inform lifestyle decisions and conversations with their doctor or other health care professional.
(C) The limiting statement explaining that any diagnostic or treatment decisions should be based on testing and/or other information that you determine to be appropriate for your patient.
(2) The genetic test must use a sample collection device that is FDA-cleared, -approved, or -classified as 510(k) exempt, with an indication for in vitro diagnostic use in over-the-counter DNA testing.
(3) The device's labeling must include a hyperlink to the manufacturer's public Web site where the manufacturer shall make the information identified in paragraph (b)(3) of this section publicly available. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a hyperlink to the Web page containing this information and must allow unrestricted viewing access. If the device can be purchased from the Web site or testing using the device can be ordered from the Web site, the same information must be found on the Web page for ordering the device or provided in a publicly accessible hyperlink on the Web page for ordering the device. Any changes to the device that could significantly affect safety or effectiveness would require new data or information in support of such changes, which would also have to be posted on the manufacturer's Web site. The information must include:
(i) An index of the material being provided to meet the requirements in paragraph (b)(3) of this section and its location.
(ii) A section that highlights summary information that allows the user to understand how the test works and how to interpret the results of the test. This section must, at a minimum, be written in plain language understandable to a lay user and include:
(A) Consistent explanations of the risk of disease associated with all variants included in the test. If there are different categories of risk, the manufacturer must provide literature references that support the different risk categories. If there will be multiple test reports and multiple variants, the risk categories must be defined similarly among them. For example, “increased risk” must be defined similarly between different test reports and different variant combinations.
(B) Clear context for the user to understand the context in which the cited clinical performance data support the risk reported. This includes, but is not limited to, any risks that are influenced by ethnicity, age, gender, environment, and lifestyle choices.
(C) Materials that explain the main concepts and terminology used in the test that include:
(
1 )Definitions: Scientific terms that are used in the test reports.(
2 )Prepurchase page: This page must contain information that informs the user about what information the test will provide. This includes, but is not limited to, variant information, the condition or disease associated with the variant(s), professional guideline recommendations for general genetic risk testing, the limitations associated with the test (e.g., test does not detect all variants related to the disease) and any precautionary information about the test the user should be aware of before purchase. When the test reports the risk of a life-threatening or irreversibly debilitating disease or condition for which there are few or no options to prevent, treat, or cure the disease, a user opt-in section must be provided. This opt-in page must be provided for each disease that falls into this category and must provide specific information relevant to each test result. The opt-in page must include:(
i ) An option to accept or decline to receive this specific test result;(
ii ) Specification of the risk involved if the user is found to have the specific genetic test result;(
iii ) Professional guidelines that recommend when genetic testing for the associated target condition is or is not recommended; and(
iv ) A recommendation to speak with a health care professional, genetic counselor, or equivalent professional before getting the results of the test.(
3 )Frequently asked questions (FAQ) page: This page must provide information that is specific for each variant/disease pair that is reported. Information provided in this section must be scientifically valid and supported by corresponding publications. The FAQ page must explain the health condition/disease being tested, the purpose of the test, the information the test will and will not provide, the relevance of race and ethnicity to the test results, information about the population to which the variants in the test is most applicable, the meaning of the result(s), other risk factors that contribute to disease, appropriate followup procedures, how the results of the test may affect the user's family, including children, and links to resources that provide additional information.(iii) A technical information section containing the following information:
(A) Gene(s) and variant(s) the test detects using standardized nomenclature, Human Genome Organization nomenclature and coordinates as well as Single Nucleotide Polymorphism Database (dbSNP) reference SNP numbers (rs#).
(B) Scientifically established disease-risk association of each variant detected and reported by the test. This risk association information must include:
(
1 ) Genotype-phenotype information for the reported variants.(
2 ) Table of expected frequency and risks of developing the disease in relevant ethnic populations and the general population.(
3 ) A statement about the current professional guidelines for testing these specific gene(s) and variant(s).(
i ) If professional guidelines are available, provide the recommendations in the professional guideline for the gene, variant, and disease, for when genetic testing should or should not be performed, and cautionary information that should be communicated when a particular gene and variant is detected.(
ii ) If professional guidelines are not available, provide a statement that the professional guidelines are not available for these specific gene(s) and variant(s).(C) The specimen type (
e.g., saliva, capillary whole blood).(D) Assay steps and technology used.
(E) Specification of required ancillary reagents, instrumentation, and equipment.
(F) Specification of the specimen collection, processing, storage, and preparation methods.
(G) Specification of risk mitigation elements and description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.
(H) Information pertaining to the probability of test failure (
i.e., percentage of tests that failed quality control) based on data from clinical samples, a description of scenarios in which a test can fail (i.e., low sample volume, low DNA concentration, etc.), how users will be notified of a test failure, and the nature of followup actions on a failed test to be taken by the user and the manufacturer.(I) Specification of the criteria for test result interpretation and reporting.
(J) Information that demonstrates the performance characteristics of the test, including:
(
1 ) Accuracy of study results for each claimed specimen type.(
i ) Accuracy of the test shall be evaluated with fresh clinical specimens collected and processed in a manner consistent with the test's instructions for use. If this is impractical, fresh clinical samples may be substituted or supplemented with archived clinical samples. Archived samples shall have been collected previously in accordance with the instructions for use, stored appropriately, and randomly selected. In some limited circumstances, use of contrived samples or human cell line samples may also be appropriate and used as an acceptable alternative. The contrived or human cell line samples shall mimic clinical specimens as much as is feasible and provide an unbiased evaluation of the device accuracy.(
ii ) Accuracy must be evaluated by comparison to bidirectional Sanger sequencing or other methods identified as appropriate by FDA. Performance criteria for both the comparator method and the device must be predefined and appropriate to the device's intended use. Detailed study protocols must be provided.(
iii ) Test specimens must include all genotypes that will be included in the tests and reports. The number of samples tested in the accuracy study for each variant reported must be based on the variant frequency using either the minimum numbers of samples identified in this paragraph or, when determined appropriate and identified by FDA, a minimum number of samples determined using an alternative method. When appropriate, the same samples may be used in testing to demonstrate the accuracy of testing for multiple genotypes by generating sequence information at multiple relevant genetic locations. At least 20 unique samples representing the wild-type genotype must be tested. To test samples that are heterozygous for the reported variant(s), common variants (>0.1 percent variant frequency in the relevant population) must be tested with at least 20 unique samples. Rare variants (≤0.1 percent variant frequency in the relevant population) must be tested with at least three unique samples. To test samples that are homozygous for the reported variant(s), variants with ≥2 percent variant frequency in a relevant population must be tested with at least 20 unique samples. Variants with a frequency in the relevant population
0
Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food & Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
December 23, 2020
Helix OpCo, LLC Gloria Lee Senior Director Regulatory Affairs 96 Colbeck Street Toronto, M6S1 V2 Ontario Canada
Re: K192073
Trade/Device Name: The Helix Genetic Health Risk app for late-onset Alzheimer's disease Regulation Number: 21 CFR 866.5950 Regulation Name: Genetic health risk assessment system Regulatory Class: Class II Product Code: PTA Dated: July 31, 2019 Received: August 2, 2019
Dear Gloria Lee:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part
1
801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4. Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Ying (Katelin) Mao Branch Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Ouality Center for Devices and Radiological Health
Enclosure
2
Indications for Use
510(k) Number (if known) K192073
Device Name
Helix Genetic Health Risk App for late-onset Alzheimer*s disease
Indications for Use (Describe)
The Helix Genetic Health Risk App (HRA) uses qualifative 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.
Type of Use (Select one or both, as applicable)
Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
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3
510(k) SUMMARY
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of Safe Medical Devices Act of 1990 and 21 CFR 807.92
The assigned 510(k) number is: K192073
Submitter / Company
Helix OpCo LLC (Head Office) 101 S Ellsworth Avenue, Suite 350 San Mateo, CA94401 www.helix.com
Company Contact
Gloria Lee, Ph.D. Sr. Director Regulatory Affairs gloria.lee@Helix.com Phone: 647-248-2577
Date Prepared
December 1, 2020
5.1 Regulatory Information
| Type of Submission: | Traditional 510k |
|---|---|
| Common/ Usual Name: | Helix Genetic Health Risk App |
| Regulation Name: | Genetic Health Risk Assessment System |
| Regulation Description: | Genetic health risk assessment system is a qualitative in vitro molecular |
| test that detects variants in genomic DNA isolated from human specimens. | |
| This assessment system provides users with a genetic health risk | |
| assessment of developing a disease and is intended to inform users of | |
| lifestyle choices and/or encourage conversations with a healthcare | |
| professional. This assessment system is for over-the-counter use. This | |
| device does not determine the person's overall risk of developing a | |
| disease. | |
| Regulation Number: | 21 CFR 866.5950 |
| Product Code: | PTA |
| Class: | 2 |
Table 5.1 Proposed new device
4
| Predicate Device: | 23andMe PGS Genetic Health Risk Report for Late-onset Alzheimer's Disease |
|---|---|
| ------------------- | --------------------------------------------------------------------------- |
5.2 Intended Use / Indications for Use
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, e3/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.
5.4. Substantially Equivalent Predicate Device
See Table 5.2 for list of similarities and differences with the predicate device.
| | Helix Genetic Health
Risk App for late-onset
Alzheimer's disease | 23andMe PGS Genetic
Health Risk Report for
Late-onset Alzheimer's
Disease (DEN160026) | Similarities and
Differences |
|------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|
| Intended Use /
Indications for use | 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 | 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 | Similar |
| | interpreting Genetic
Health Risks (GHR): | for the purpose of
reporting and
interpreting Genetic
Health Risks (GHR) | |
| Target Population | ≥ 18 years old | ≥ 18 years old | Similar |
| Interpretation of Results | For over-the-counter
use (OTC). Specialized
interpretation by a
physician not required | For over-the-counter
use (OTC). Specialized
interpretation by a
physician not required | Similar |
| Human Factors | User comprehension
testing | User comprehension
testing | Similar |
| Compatibility with the
environment and other
devices | NA - it is a software
application to be
viewed on a mobile
phone or desktop | NA - it is a software
application to be
viewed on a mobile
phone or desktop | Similar |
| | The Helix Genetic
Health Risk App
(HRA) for late-onset
Alzheimer's disease is
indicated for reporting
of the e2/e2, e2/e3,
e3/e3, e2/e4, e3/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 23andMe PGS
Genetic Health Risk
Report for Late-onset
Alzheimer's Disease is
indicated for reporting
of the e4 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 e4 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. | |
| | computer | computer | |
| Design | Software application
that includes product
information page, e-
commerce (registration
and order DNA kit),
secure login, download
genetic report. | Software application
that includes product
information page,
ecommerce
(registration and order
DNA kit), secure login,
download genetic
report. | Similar |
| Specimen Collection
Kit | DNA Genotek Inc.,
Oragene®·Dx (OGD-
610) | DNA Genotek Inc.,
Oragene®·Dx
(OGD500.001) | Similar |
| Sample matrix | Saliva | Saliva | Similar |
| Variants detected | The APOE e2, e3, and
e4 alleles at rs429358
and rs7412 SNPs.
rs429358 is a SNP at
position
chr19::44908684
(GRCh38).
rs7412 is a SNP at
position
chr19:44908822
(GRCh38). | Only reports at APOE
e4, and looks at
rs429358 SNPs that
define APOE e4.
The 23andMe PGS
Genetic Health Risk
Report for Late-onset
Alzheimer's Disease
only looks at: rs429358
is a SNP at position
chr19:
NC_000019.10:g.44908
684 (GRCh38) | Different |
| Sequencing Platform | Helix Laboratory
Platform, sequencing
and pipeline analysis
(authorized under
DEN190035) | Tecan Evo Illumina
iScan
Illumina Infinium
BeadChip genotyping
chip customized for the
PGS. The chip is
designed to detect
specific single
nucleotide
polymorphisms (SNPs)
as well as other genetic
variants; all markers
refer to specific
positions in the
National Center for
Biotechnology
Information (NCBI) | Different |
| | | reference human
genome. | |
| Software | Helix Bioinformatics
Pipeline (authorized
under DEN190035) | Genome Studio
Coregen | Different |
| Technology | Next Generation
Sequencing | Microarray genotyping | Different |
Table 5.2 Substantial Equivalence
5
6
7
The Helix Genetic Health Risk App for late-onset Alzheimer's disease is intended for over-thecounter, direct-to-consumer use without prescription order. When a customer purchases the Helix Genetic Health Risk App for late-onset Alzheimer's disease, the customer must first opt-in to receive the late-onset Alzheimer's disease risk report. As instructed in predicate device authorization DEN160026, similar healthcare provider limitations applicable to results for late-onset Alzheimer's disease are included in the package insert:
- This test is not intended to diagnose a disease, determine medical treatment or other medical intervention, or tell the user anything about their current state of health.
- . This test is intended to provide users with their genetic information, which may inform health-related lifestyle decisions and conversations with their doctor or other healthcare professional.
- . Any diagnostic or treatment decisions must be based on confirmatory prescription testing and/or other information that you determine to be appropriate for your patient, such as additional clinical testing and other risk factors that may affect individual risk and health care.
Thus, the Helix Genetic Health Risk App for late-onset Alzheimer's Disease is substantially equivalent to the predicate 23andMe Personal Genome Service (PGS) Genetic Health Risk Test for Alzheimer's disease authorized under DEN160026.
5.5 Device Description
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
8
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.
5.6 Technological Characteristics
Test Type: Qualitative genetic test for single nucleotide polymorphism detection in the APOE gene.
Sample Type: Genomic DNA obtained from a human saliva sample.
Target of detection: Single-nucleotide polymorphism.
DNA extraction: Automated method.
Gene: APOE
Alleles: e2, e3 and e4 alleles in the APOE gene
SNPs: rs429358 and rs7412.
Testing principle: DNA is isolated from saliva and tested on the Helix Laboratory Platform. The genomic DNA is processed and sequenced using next generation sequencing (NGS) reagents and instrumentation. The sequencing data is analyzed using Helix's proprietary software, where the genetic variants of interest are determined.
Instrument: Illumina HiSeq system.
Assay results: The raw sequencing data is analyzed, and the genotypes are determined and integrated into a report.
5.7 Performance Testing Summary
The laboratory may not be able to process a user's sample. The probability that the laboratory cannot process a sample can be up to 2.5%. The device performance was evaluated in the analytical and clinical studies as follows.
9
All results presented below met the pre-defined acceptance criteria outlined in the Special Controls of 21 CFR 866.5950. Information regarding samples that failed quality control (FQC) was also evaluated and presented in each study below.
5.7.1 Method Comparison (Accuracy)
For evaluation of accuracy, three studies were conducted: the first study was conducted with human saliva samples with known genotypes and a second study was conducted with human cell line samples with known genotypes to determine the rates of correct APOE genotype calls. A third study was conducted with human saliva and/or human cell line samples with known variants in genes other than the APOE gene to determine the agreement of the genotype calls.
- a) Accuracy study with human saliva samples:
Accuracy of the HRA for late-onset Alzheimer's disease was evaluated by testing human saliva samples with known APOE genotypes. Presence of the two variants in the APOE gene was analyzed on the HLP and the genotyping results were compared to the known genotypes confirmed by Sanger sequencing (comparator). The accuracy for detecting the two variants in the APOE gene on the HLP (genotype call) using DNA isolated from human saliva samples (n=99) was 100% with a lower bound of 96.3% using a 95% CI for all samples tested. The test results are shown in the table below.
| APOE
Genotype | N | No. of
Correct
Genotype
Calls | No. of
Incorrect
Genotype
Calls | No. of FQC | Percent of
FQC
(%) | Percent
Correct
Genotype
Calls
(%) |
|------------------|----|----------------------------------------|------------------------------------------|------------|--------------------------|------------------------------------------------|
| e2/e2 | 12 | 12 | 0 | 0 | 0 | 100 |
| e2/e3 | 17 | 17 | 0 | 0 | 0 | 100 |
| e2/e4 | 10 | 10 | 0 | 0 | 0 | 100 |
| e3/e3 | 20 | 20 | 0 | 0 | 0 | 100 |
| e3/e4 | 20 | 20 | 0 | 0 | 0 | 100 |
| e4/e4 | 20 | 20 | 0 | 0 | 0 | 100 |
| All | 99 | 99 | 0 | 0 | 0 | 100 |
b) Accuracy study with human cell line samples:
Accuracy for detecting two variants, rs7412 and rs429358, in the APOE gene on the HLP was evaluated by using six cell lines with known APOE genotypes
10
(e2/e3, e2/e4, e3/e3, e3/e4, e3/e4, and e4/e4). The accuracy of detecting the two variants in the APOE gene was 100% for all samples tested.
| Cell Line | N | APOE
Genotype | No. of
replicates | No. of Correct
Genotype Calls | No. of Incorrect
Genotype Calls | No. of
FQC | Percent
of FQC
(%) | Percent Correct
Genotype Calls
(%) |
|-----------|---|------------------|----------------------|----------------------------------|------------------------------------|---------------|--------------------------|------------------------------------------|
| NA24385 | 1 | e2/e3 | 1 | 1 | 0 | 0 | 0 | 100 |
| NA24149 | 1 | e2/e4 | 1 | 1 | 0 | 0 | 0 | 100 |
| NA12878 | 1 | e3/e3 | 1 | 1 | 0 | 0 | 0 | 100 |
| NA12877 | 1 | e3/e4 | 1 | 1 | 0 | 0 | 0 | 100 |
| NA24143 | 1 | e3/e4 | 1 | 1 | 0 | 0 | 0 | 100 |
| NA24631 | 1 | e4/e4 | 1 | 1 | 0 | 0 | 0 | 100 |
- c) Accuracy study with 3,295 human saliva and cell line samples with known variants in genes other than APOE:
In addition to the two variants in the APOE gene, accuracy of the HLP for detecting variants in the genes associated with other clinical conditions included in DEN160026 was evaluated on the HLP using specimens carrying unique genetic variants linked to the specific clinical conditions as listed in the table below:
| Clinical condition | Gene | SNP |
|---|---|---|
| Hereditary Thrombophilia | FS | rs6025 |
| Hereditary Thrombophilia | F2 | rs1799963 |
| Alpha-1 Antitrypsin Deficiency | SERPINA1 | rs28929474 |
| Alpha-1 Antitrypsin Deficiency | SERPINA1 | rs17580 |
| Late-Onset Alzheimer's Disease | APOE | rs429358 |
| Parkinson's Disease | LRRK2 | rs34637584 |
11
| Parkinson's Disease; Gaucher Disease
| Type 1 | GBA | rs76763715 |
|---|---|---|
| Gaucher Disease Type 1 | GBA | rs387906315 |
| Gaucher Disease Type 1 | GBA | rs80356769 |
| Factor XI Deficiency | FXI | rs121965064 |
| Factor XI Deficiency | FXI | rs121965063 |
| Factor XI Deficiency | FXI | rs373297713 |
| Celiac Disease | HLA-DQA1 | rs2187668 |
| Glucose-6-Phosphate-Dehydrogenase | ||
| Deficiency | G6PD | rs1050828 |
| Hereditary Hemochromatosis | HFE | rs1800562 |
| Hereditary Hemochromatosis | HFE | rs1799945 |
| Early-Onset Primary Dystonia | DYT1 | rs724159981 |
The overall number of true positive, false positives, true negative and false negatives were analyzed for seventeen (17) variants in eleven (11) genes. A total of 4,282 true positive and 51,731 true negative calls were reported. There were no false positive and no false negative results reported for the known variants tested. One no call was reported each for rs76763715 and rs429358.
5.7.2 Precision/Reproducibility
Reproducibility of the APOE genotype calls made by the HRA for late-onset Alzheimer's disease was assessed by testing 24 samples that include 6 human B-lymphocyte cell lines hereafter) and 18 unique saliva-derived DNA samples) in two independent studies (Study 1 and Study 2). The calls for the APOE genotypes in the well-characterized cell line samples were compared to known APOE genotypes.
Study 1 tested 24 samples (6 cell lines and 18 unique saliva-derived DNA samples) with up to 72 replicates (3 replicates / sample / library prep plate x 3 plates x 2 enrichments x 4 independent runs of cBot and HiSeq instruments) for the APOE genotype calls. The test results are summarized below:
| Cell Line | N | APOE
Genotype | No. of
replicates | No. of
Correct
Genotype
Calls | No. of
Incorrect
Genotype
Calls | No. of
FQC | Percent of
FQC
(%) | Percent
Correct
Genotype
Calls
(%) |
| ----------- | --- | ------------------ | ---------------------- | ---------------------------------------- | ------------------------------------------ | --------------- | -------------------------- | ------------------------------------------------ |
|---|
12
| Study 1: Cell lines | ||||||||
|---|---|---|---|---|---|---|---|---|
| NA24385 | 1 | e2/e3 | 72 | 72 | 0 | 0 | 0 | 100 |
| NA24149 | 1 | e2/e4 | 72 | 72 | 0 | 0 | 0 | 100 |
| NA12878 | 1 | e3/e3 | 72 | 72 | 0 | 0 | 0 | 100 |
| NA12877 | 1 | e3/e4 | 72 | 72 | 0 | 0 | 0 | 100 |
| NA24143 | 1 | e3/e4 | 72 | 72 | 0 | 0 | 0 | 100 |
| NA24631 | 1 | e4/e4 | 72 | 72 | 0 | 0 | 0 | 100 |
| Study 1: Clinical Samples | ||||||||
| 4 | e2/e3 | 288 | 276 | 0 | 12 | 4.2 | 100 | |
| 2 | e2/e4 | 144 | 141 | 0 | 3 | 2.1 | 100 | |
| 7 | e3/e3 | 504 | 484 | 0 | 20 | 4.0 | 100 | |
| 2 | e3/e4 | 144 | 136 | 0 | 8 | 5.6 | 100 | |
| 2 | e4/e4 | 144 | 141 | 0 | 3 | 2.1 | 100 | |
| 1 | Unknown | 72 | N/A | N/A | 72 | 100 | N/A |
Study 2 tested 24 samples (6 cell lines and 18 unique saliva-derived DNA samples) with up to 54 replicates (3 replicates / sample / library prep plate x 3 plates x 2 enrichments x 3 reagent lots) for the APOE genotype calls. The test results are summarized below:
| Cell Line | N | APOE
Genotype | No. of
replicates | No. of
Correct
Genotype
Calls | No. of
Incorrect
Genotype
Calls | No. of
FQC | Percent of
FQC
(%) | Percent
Correct
Genotype
Calls
(%) |
| ----------- | --- | ------------------ | ---------------------- | ---------------------------------------- | ------------------------------------------ | --------------- | -------------------------- | ------------------------------------------------ |
|---|
13
| Study 2: Cell lines | ||||||||
|---|---|---|---|---|---|---|---|---|
| NA24385 | 1 | e2/e3 | 54 | 54 | 0 | 0 | 0 | 100 |
| NA24149 | 1 | e2/e4 | 54 | 54 | 0 | 0 | 0 | 100 |
| NA12878 | 1 | e3/e3 | 54 | 54 | 0 | 0 | 0 | 100 |
| NA12877 | 1 | e3/e4 | 54 | 54 | 0 | 0 | 0 | 100 |
| NA24143 | 1 | e3/e4 | 54 | 54 | 0 | 0 | 0 | 100 |
| NA24631 | 1 | e4/e4 | 54 | 48 | 0 | 6 | 11.1 | 100 |
| Stud 2: Clinical Samples | ||||||||
| 2 | e2/e3 | 108 | 108 | 0 | 0 | 0 | 100 | |
| 7 | e3/e3 | 378 | 377 | 0 | 1 | 0.3 | 100 | |
| 7 | e3/e4 | 378 | 376 | 0 | 2 | 0.5 | 100 | |
| 2 | e4/e4 | 108 | 108 | 0 | 0 | 0 | 100 |
The calls for concordance on the APOE genotypes were analyzed in the clinical samples. Genotyping results produced 100% replicates that were called correctly for all APOE genotypes.
5.7.3 DNA Input
This study evaluated the impact of different levels of DNA input on the performance of the HRA for late-onset Alzheimer's disease. The study yielded concordant test results for all 19 saliva samples with known APOE genotypes when tested at sample DNA concentrations between 3.5 to 10 ng/μL, an input corresponding to a range of 35 to 100 ng of DNA in the library preparation.
| APOE
Genotype | No. of
replicates | No. of
Correct
Genotype
Calls | No. of
Incorrect
Genotype
Calls | No. of
FQC | Percent of
FQC
(%) | Percent
Correct
Genotype
Calls
(%) |
|------------------|----------------------|----------------------------------------|------------------------------------------|---------------|--------------------------|------------------------------------------------|
| e2/e3 | 12 | 12 | 0 | 0 | 0 | 100 |
14
| e3/e3 | 84 | 79 | 0 | 5 | 6 | 100 |
|---|---|---|---|---|---|---|
| e3/e4 | 18 | 18 | 0 | 0 | 0 | 100 |
5.7.4 Interfering Substances
Four studies were performed to determine the effects of substances found in saliva that may interfere with the performance of the HRA for late-onset Alzheimer's disease. Per study protocol, for sequenced samples to be included in the data analyses (e.g., evaluable samples), the sample(s) must pass pre-defined QC thresholds.
- a. In study 1. four endogenous proteins commonly found in saliva, including alphaamylase (395 U/mL), hemoglobin (20 mg/mL), immunoglobulin A (IgA) (0.43 mg/mL), and albumin (2.67mg/mL) were each added to saliva samples. These proteins did not affect test performance for saliva samples (n=29-30 evaluable samples across four endogenous proteins). The test results are shown below.
| APOE
Genotype | No. of
replicates | No. of
Correct
Genotype
Calls | No. of
Incorrect
Genotype
Calls | No. of
FQC | Percent
of FQC
(%) | Percent
Correct
Genotype
(%) |
|------------------|----------------------|----------------------------------------|------------------------------------------|---------------|--------------------------|---------------------------------------|
| e2/e3 | 18 | 18 | 0 | 0 | 0 | 100 |
| e2/e4 | 4 | 4 | 0 | 0 | 0 | 100 |
| e3/e3 | 76 | 75 | 0 | 1 | 1.3 | 100 |
| e3/e4 | 18 | 18 | 0 | 0 | 0 | 100 |
| e4/e4 | 4 | 4 | 0 | 0 | 0 | 100 |
- b. In study 2, saliva samples were tested before and after (either immediately or 30 minutes after) exposure to one of four exogenous substances: eating food, drinking liquids, using mouthwash, or chewing gum. This study showed that exogenous substances did not interfere with test performance for saliva samples (n=12-15 evaluable samples across testing time for four exogenous substances). The test results are shown below.
15
| APOE
Genotype | No. of
replicates | No. of
Correct
Genotype
Calls | No. of
Incorrect
Genotype
Calls | No. of
FQC | Percent
of FQC
(%) | Percent
Correct
Genotype
Calls
(%) |
|------------------|----------------------|----------------------------------------|------------------------------------------|---------------|--------------------------|------------------------------------------------|
| e2/e4 | 12 | 12 | 0 | 0 | 0 | 100 |
| e3/e3 | 90 | 83 | 0 | 7 | 7.8 | 100 |
| e3/e4 | 24 | 21 | 0 | 3 | 12.5 | 100 |
| Unknown | 6 | N/A | N/A | 6 | 100 | N/A |
- C. In study 3, saliva samples were tested at 60 minutes before smoking, immediately after smoking, and 30 minutes after smoking and showed that smoking did not interfere with test performance (n=15 evaluable samples across three smoking conditions). The test results are shown below.
| APOE
Genotype | No. of
replicates | No. of
Correct
Genotype
Calls | No. of
Incorrect
Genotype
Calls | No. of
FQC | Percent
of FQC
(%) | Percent
Correct
Genotype
Calls
(%) |
|------------------|----------------------|----------------------------------------|------------------------------------------|---------------|--------------------------|------------------------------------------------|
| e3/e3 | 18 | 18 | 0 | 0 | 0 | 100 |
| e3/e4 | 12 | 12 | 0 | 0 | 0 | 100 |
- d. In study 4, bacterial DNA from a commercial source (American Type Culture Collection) was added in various amounts into six cell line DNA samples (NA24385, NA24149, NA12878, NA12877, NA24143, and NA24631) to evaluate the effects of bacterial contamination in the test performance. This bacterial sample (ATCC MSA-1003) is comprised of twenty (20) fully sequenced cultures that encompass a variety of characteristics including bacterial species found in mouse and oral cavity. The six cell lines were tested across five levels of bacterial content (0%, 10%, 20%, 30%, and 50%). This study showed that microbial DNA did not interfere with test performance (n=11-18 evaluable samples across five levels of bacterial content). In addition, study 4 tested various amounts of microbial and yeast DNA added to the saliva samples from 3 volunteers (0%, 10% Candida albicans, and 30% of ATCC MSA-1003). This study showed that yeast DNA did not interfere with test performance in clinical samples. The test results are shown below.
16
| APOE
Genotype | No. of
replicates | No. of
Correct
Genotype
Calls | No. of
Incorrect
Genotype
Calls | No. of
FQC | Percent of
FQC
(%) | Percent
Correct
Genotype
Calls
(%) |
|------------------|----------------------|----------------------------------------|------------------------------------------|---------------|--------------------------|------------------------------------------------|
| Cell lines | | | | | | |
| e2/e3 | 15 | 15 | 0 | 0 | 0 | 100 |
| e2/e4 | 15 | 13 | 0 | 2 | 13.3 | 100 |
| e3/e3 | 15 | 11 | 0 | 4 | 26.7 | 100 |
| e3/e4 | 30 | 28 | 0 | 2 | 6.7 | 100 |
| e4/e4 | 15 | 14 | 0 | 1 | 6.7 | 100 |
| Clinical samples | | | | | | |
| e3/e3 | 12 | 12 | 0 | 0 | 0 | 100 |
| e3/e4 | 6 | 6 | 0 | 0 | 0 | 100 |
5.7.5 Potentially Interfering Mutations
Not conducted
5.7.6 Matrix Comparison
Human saliva is the only suitable sample matrix, therefore Matrix Comparison studies are not applicable.
5.7.7 Shelf Life
The Helix Genetic Health Risk App requires the use of the same FDA-cleared saliva collection device that was reviewed and cleared in submission K192920. Shelf life data, summarized below, was previously reviewed and authorized in the clearance of the predicate device DEN160026.
5.7.8 Clinical Performance
17
Three common versions of the APOE gene are: e2, e3, and e4 alleles. Genetic studies on lateonset Alzheimer's disease have associated this disease with the APOE gene and more specifically the APOE e2 and APOE e4 allele, as the main link for late-onset Alzheimer's disease in all ethnicities. The APOE e2 allele is associated with a decreased risk to develop late-onset Alzheimer's disease after the age of 65 years, whereas the APOE e4 allele is associated with an increased risk to develop late-onset Alzheimer's disease after the age of 65 years. This test looks at the 2 SNPs, rs429358 and rs7412, that define the APOE e2, e3, and e4 versions of the gene.
The different combinations of the APOE gene's versions (e2, e3 and e4) were grouped based on their association with developing late-onset Alzheimer's disease:
- . Individuals with the APOE e3/e3 genotype are considered to have an average risk of developing late-onset Alzheimer's disease based on this genetic result.
- Individuals with the APOE e2/e2 or e2/e3 genotype are considered to have a decreased . risk of developing late-onset Alzheimer's disease compared to individuals with the APOE e3/e3 genotype.
- . Individuals with the APOE e2/e4, e3/e4, or e4/e4 genotypes are considered to have an increased risk of developing late-onset Alzheimer's disease compared to individuals with the APOEe3/e3 genotype.
- . Individuals who have none of these APOE combinations will not receive information on their relative risk to develop late-onset Alzheimer's disease due to the lack of studies in the scientific literature.
The variants covered by this test are found in people of all ethnicities. The percentage of the population carrying each combination will vary from study based on the enrollment criteria to the genetic study. A summary of the frequency of each combination in different ethnicities gathered from multiple references is represented in the table below:
18
| | | e2/e2 | e2/e3 | e3/e3 | e2/e4 | e3/e4 | e4/e4 | Ref | Ethnicity | Test result | Genotype | LR | 95% CI
for LR | References | Study summary |
|------------------------|----------|----------------|---------|-----------------|----------------|-------|-------|---------------------|-------------------------|-------------------|----------|---------|------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | | Decreased risk | | Average
risk | Increased risk | | | European
descent | Decreased
risk | e2/e2 | 0.3 | 0.1-0.5 | Farrer et al.,
1997 | A meta-analysis of
5,930 patients who
met criteria for
probable or definite
Alzheimer's disease
and 8,607 controls.
Among study
participants, there
were 5,107
Alzheimer's disease
patients from
European descent,
and 6,262 controls
from European
descent. | |
| European descent | AD | 0.2% | 4.8% | 36.4% | 2.6% | 41.1% | 14.8% | | Farrer et
al., 1997 | | e2/e3 | 0.4 | | | 0.3-0.4 |
| European descent | controls | 0.8% | 12.7% | 60.9% | 2.6% | 21.3% | 1.8% | | | Average risk | e3/e3 | 0.6 | 0.57-0.62 | | |
| African descent | AD | 0.6% | 7.4% | 37.7% | 3.7% | 37.7% | 13.0% | | Murrell et
al., 2006 | Increased risk | e2/e4 | 1 | 0.8-1.3 | | |
| African descent | controls | 1.9% | 15.1% | 51.3% | 4.1% | 24.2% | 3.5% | | | | e3/e4 | 1.9 | 1.8-2.1 | | |
| South Asian
descent | AD | 0.2% | 6.2% | 44.8% | 6.2% | 37.2% | 5.3% | | Agarwal et al.,
2014 | | e4/e4 | 8.2 | 6.8-10.0 | | |
| South Asian
descent | controls | 2.0% | 11.8% | 72.0% | 1.5% | 11.7% | 0.9% | | African
descent | Decreased
risk | e2/e2 | 0.3 | 0.04-2.7 | Murrell et al.,
2006 | This study included
162 individuals from
African American
descent with
Alzheimer's disease
and 318 controls
from African
American descent |
| East Asian
descent | AD | 0.9% | 7.9% | 51.0% | 3.3% | 29.3% | 7.6% | Liu et al., 2014 | | | e2/e3 | 0.5 | 0.3-0.9 | | |
| East Asian
descent | controls | 0.8% | 11.8% | 73.1% | 1.7% | 12.4% | 0.3% | | | Average risk | e3/e3 | 0.7 | 0.6-0.9 | | |
| Increased risk | e2/e4 | 0.9 | 0.4-2.3 | | | | | | | | | | | | |
| | e3/e4 | 1.6 | 1.2-2.1 | | | | | | | | | | | | |
| | e4/e4 | 3.8 | 1.9-7.6 | | | | | | | | | | | | |
Table 5.3a. Frequency of APOE e2, e3 and e4 combinations in different ethnicities
AD = Alzheimer's disease.
Using the same references, it is possible to calculate likelihood ratios (LR), which represent an estimate of how the test result affects the chances of a condition.
19
Table 5.3b: Alzheimer's disease likelihood ratios (LR) for APOE e2, e3 and e4 combinations in different ethnicities. The table was adapted from table on p.35 of DEN160026 decision summary.
20
| South Asian
descent | Decreased
risk | e2/e2 | 0.1 | 0.02-0.9 | Agarwal et al.,
2014 | A meta-analysis of
417 individuals from
South Asian descent
with Alzheimer's
disease and 651 |
|------------------------|-------------------|--------|------|-----------|-------------------------|----------------------------------------------------------------------------------------------------------|
| | Decreased
risk | e2/e3 | 0.5 | 0.3-0.8 | | |
| | Average risk | e3/e3 | 0.6 | 0.6-0.7 | | controls from South
Asian descent. |
| | Increased risk | e2/e4 | 4.1 | 2.0-8.3 | | |
| | | e3/e4 | 3.2 | 2.5-4.1 | | |
| | | e4/e4 | 5.7 | 2.3-14.0 | | |
| East Asian
descent | Average risk | e2/e2* | 1.1 | 0.5-2.3 | Liu et al.,
2014 | A meta-analysis of
1,576 individuals
from East Asian |
| | | e2/e3 | 0.7 | 0.5-0.8 | | |
| | | e3/e3 | 0.7 | 0.6-0.7 | | |
| | Increased risk | e2/e4 | 1.9 | 1.2-3.0 | | descent with
Alzheimer's disease |
| | | e3/e4 | 2.5 | 2.2-2.9 | | and 1,741 controls
from East Asian
descent. |
| | | e4/e4 | 25.6 | 10.5-62.6 | | (*limited number of
e2/e2 samples used
for analysis) |
| | | | | | | |
5.7.9 Labeling Comprehension
All predefined demographic quotas and enrollment targets were met. Primary comprehension assessment addressed the following five core concepts: purpose of the test, limitations, relevant ethnicities, meaning of results, and appropriate follow-up. The average comprehension rate per comprehension category ranged from 85.2% to 100%, and the overall comprehension rate for all core concepts across each of the four study arms was greater than 90%. The representative Helix Genetic Health Risk report and supporting information provided in the pre-purchase page were effective in communicating relevant concepts to users unfamiliar with genetic testing sufficient for the safe use of the Helix Genetic Health Risk App for late-onset Alzheimer's disease.
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5.8. Discussion
The Helix Genetic Health Risk App (HRA) for late-onset Alzheimer's disease has a similar intended use as the predicate and therefore presents no new issues of safety or effectiveness when compared to the previously authorized predicate device (DEN160026).
5.9. Conclusion
The Helix Genetic Health Risk App (HRA) for late-onset Alzheimer's disease is substantially equivalent to the predicate device DEN160026 (23andMe PGS Genetic Health Risk Report for Late-onset Alzheimer's Disease). As presented, the Helix Genetic Health Risk App for lateonset Alzheimer's disease is a safe and effective consumer product that can safely and effectively assist and encourage users to discuss the report with their healthcare provider.