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Direct-to-Consumer Genetic Testing
Hunter Best, Ph.D., FACMG
Assistant Professor of Pathology
University of Utah School of Medicine
Medical Director, Molecular Genetics and Genomics
ARUP Laboratories
Financial Interest Statement:
Nothing to Disclose
Overview
• What is direct-to-consumer (DTC) genetic testing?
• DTC Genetic Testing Example – 23andMe original testing panel
• Research/Patent Controversy
• 23andMe/FDA Intervention
• An Interesting Case Study
Direct-to-Consumer (DTC) Genetic Testing
• Genetic tests that are marketed directly to consumers
via television, print ads, or the internet
• Also known as “at-home genetic testing”
• Provides access to a person’s genetic information
without necessarily involving a doctor or insurance
company in the process
DTC Genetic Testing – The Good
• May promote awareness of genetic diseases
• Allows consumers to take a more proactive
role in their health care
• Offers a means for people to learn about their
ancestral origins
DTC Genetic Testing – The Bad
• Testing may be performed by questionable methods
which can lead to misleading results
• May lead consumers to make important decisions
about treatment or prevention based on incomplete or
misunderstood information; typically avoided in
traditional healthcare where a provider can give
guidance
• Invasion of genetic privacy if companies use genetic
information in an unauthorized way
• Other factors (i.e. environment) play a role in
the development of many diseases; these
factors are typically not addressed by DTC
genetic testing
• Many people do not understand that this is not
diagnostic testing
DTC Genetic Testing – The Bad
Issues Associated with DTC Genetic Testing
Quality/Analytical Validity
1. Not all testing performed in CLIA labs
2. Standards of sample collection
On whom?
Integrity of specimen?
3. Shift in communication of results with no medical professional involved – lacks appropriate individual/family variables required for appropriate interpretation of results; perhaps false reassurances
4. Intricacies of many associations not established – gene/gene & environmental interactions
Follow-up Care is Difficult
Primary care physician is often not well trained in this area
Clinical Validity Questionable
Sensitivity, specificity & positive predictive value of the testing - unknown
Clinical Utility Unknown
Effectiveness of interventions based upon these test results not established
Issues Associated with DTC
Where Do Professional Organizations Stand?
• In 2008 the American College of Medical Genetics (ACMG)
released a statement regarding DTC Genetic Testing
• The statement suggested the following minimum requirements
for ANY genetic testing protocol:
– A knowledgeable professional should be involved in the process of
ordering and interpreting a genetic test
– The consumer should be fully informed regarding what the test can and
cannot say about his/her health
– The scientific evidence on which a test is based should be clearly stated
– The clinical testing laboratory must be accredited by CLIA, the State
and/or other applicable accrediting agencies
– Privacy concerns must be addressed
Source: ACMG Statement on Direct-to-Consumer Genetic Testing available at: http://www.acmg.net
Other Professional Organizations With Public
Statements on DTC Genetic Testing
• American Society of Human Genetics (ASHG)
• American College of Clinical Pharmacology (ACCP)
• National Society of Genetic Counselors (NSGC)
• Association for Molecular Pathology (AMP)
Personal Genetic Information
Services
“Genetics just got personal”
Source: http://www.23andme.com
Believe genetic research tools should be used to give us a deeper
understanding of the role genes play in our lives
Screens approximately 1 million SNPs via the Illumina OmniExpress Plus Genotyping Beadchip; uses GWAS data or disease specific SNPs to calculate risks
Google is the primary investor but several venture capital firms are also involved; Also partnered with LabCorp (who performs the actual testing)
23andMe DTC
Genetic Testing
Order your kit online - $99
This price changes frequently
Typically $99-299
Spit into the tube and mail to the lab
CLIA certified lab analyzes
your DNA in 2-3 weeks
Log in and start exploring
your genome
How it Works…
Health and Traits – 244 Traits and mutations tested are based on established
genetic associations (those supported by multiple, large, peer-reviewed studies), as well as preliminary research data that has not been replicated (and contradictory evidence may exist)
Ancestry – 50 ethnic groups analyzed
-maternal line – mtDNA
-paternal line – Y chromosome
-autosomal DNA to increase detail about ancestry and regions where ancestors originated
23andMe
Comprehensive Testing
Includes:
23andMe Testing
Breakdown
• Carrier status for 48 Genetic Diseases
• “Risk” for 119 Diseases
• 20 Drug Response Loci
• 57 Genetic Traits
Carrier Status
(48 Disorders)
Alpha-1 Antitrypsin Deficiency
BRCA Cancer Mutations (Selected)
Beta-Thalassemia
Bloom Syndrome
Canavan Disease
Connexin 26-Related Sensorineural Hearing Loss
Cystic Fibrosis (31 mutations)
Factor XI Deficiency
Familial Dysautonomia
Familial Hypercholesterolemia (Type B)
Familial Mediterranean Fever
Fanconi Anemia (FANCC-related)
G6PD Deficiency
Gaucher Disease
Glycogen Storage Disease Types 1a/1b
Hemochromatosis
Hypertrophic Cardiomyopathy (MYBPC3)
Limb-Girdle Muscular Dystrophy
Maple Syrup Urine Disease
Mucolipidosis IV
Niemann-Pick Disease Type A
Phenylketonuria (PKU)
Polycystic kidney disease
Rhizomelic Chondrodysplasia Punctata Type 1
Sickle Cell Anemia and Malaria Resistance
Tay-Sachs Disease
Torsion Dystonia
Tyrosinemia Type I
Zellweger Syndrome Spectrum
Drug Response
(20 Loci)
Abacavir Hypersensitivity
Alcohol Consumption, Smoking and Risk of Esophageal Cancer
Antidepressant Response**
Beta-Blocker Response**
Caffeine Metabolism**
Clopidogrel Efficacy
Floxacillin Toxicity**
Fluorouracil Toxicity
Hepatitis C Treatment Side Effects**
Heroin Addition**
Lumiracoxib Side Effects**
Metformin Response**
Naltrexone Treatment Response**
Oral Contraceptives, Hormone Replacement Therapy and Risk of Venous Thromboembolism
Postoperative Nausea and Vomiting**
Pseudocholinesterase Deficiency
Response to Hepatitis C Treatment
Response to Beta Therapy
Statin Response**
Warfarin Sensitivity
**Findings have not been replicated in multiple scientific studies
Disease Risk Loci (119)
Age-Related Macular Degeneration
Alcohol Dependence**
Asthma**
Back Pain**
Bipolar Disorder
Bladder Cancer**
Celiac Disease
Chronic Lymphocytic Leukemia**
Breast Cancer
Cleft Lip/Cleft Palate**
Crohn’s Disease
Endometriosis**
Follicular Lymphoma**
Heart Attack
Amyotrophic Lateral Sclerosis (aka Lou Gehrig’s Disease)**
Lung Cancer
Male Infertility**
Melanoma**
Meningioma**
Multiple Sclerosis
Neuroblastoma**
Nicotine Dependence**
Pancreatic Cancer**
Schizophrenia**
**Findings have not been replicated in multiple scientific studies
Alcohol Flush Reaction
Asparagus Metabolite Detection**
Avoidance of Errors**
Birth Weight**
Bitter Taste Perception
Blood Glucose**
Breastfeeding and IQ**
C-reactive Protein Level**
Earwax Type
Eye Color
Food Preference**
Freckling**
HDL Cholesterol level**
HIV Progression**
Hair Color**
Hair Curl
Hair Thickness**
Height**
Lactose Intolerance
Leprosy Susceptibility**
Longevity**
Malaria Complications**
Malaria Resistance
Male Pattern Baldness
Measures of Intelligence**
Measures of Obesity**
Memory**
Muscle Performance
Non-ABO Blood Groups
Norovirus Resistance
Odor Detection**
Pain Sensitivity**
Persistent Fetal Hb**
Photic Sneeze Reflex**
HIV/AIDS Resistance
Sex Hormone Regulation**
Smoking Behavior
Tb Susceptibility**
Genetic Traits (57)
**Findings have not been replicated in multiple scientific studies
Breast/Ovarian Cancer
• Whether or not you are a carrier for several mutations linked to breast/ovarian cancer risk.
• A look at how Breast/Ovarian Cancer works, and a list of counselors, links and support groups for BRCA1/2 Cancer Mutations in your area.
• 23andMe disclaimer: This report has information that may indicate substantial odds of developing the disease. Because of the potential impact of this report, we require that you opt-in before viewing your results. It is possible to use the rest of the 23andMe service without viewing your results for this disease. In addition, no one else can see your data for this disease, including those with whom you have basic and extended sharing.
Penetrance? Allelic Heterogeneity?
23andMe Results Example
23andMe Results Example
Disease Specific Risk Info
The Fine Print…
23andwe – participate in research and we will share your DNA
“Strength in Numbers” online initiatives – “take surveys and help advance research into the roots of Parkinson’s Disease”
Participation with Research Partners with access to their databases and corresponding phenotypic information (HIPAA compliant?)
Direct-to-Consumer
Research Studies
• Share your information – social networking like Facebook
• Blog site – “the spittoon”: reports results of new scientific studies (they are also doing this via Twitter)
• Updates your risk as new information becomes available for each SNP
• Provides links to genetic counselors and genetic clinics in your area but no direct service to consumer
Direct-to-Consumer
Services Provided
Considerations before
joining 23andMe
• You may learn surprising things about yourself:
1. Your father is not your biological father
2. You may be at an increased risk for an incurable disease
• The lab process can result in errors
• Genetics is not destiny
• Genetic research is not yet complete and the information is incomplete for some ethnic groups
• Future studies may change the interpretation of your DNA
• You should consider how others will use your data before sharing it
Sharing of Your Genetic Data
Sharing Considerations
23andMe Research Related
Controversy
23andMe Research
• Consumers are given the opportunity to contribute phenotypic
information via web-based surveys
• The result of these surveys is “a single, continually expanding
cohort, containing a self-selected set of individuals who
participate in multiple studies in parallel”
• 23andMe claims that research done this way “can produce
revolutionary findings that will benefit us all”
• They suggest consumers “direct research by participating in
studies of conditions and traits you care about” and to “join an
effort to translate basic research into improved health care for
everyone”
23andMe Research Patent Controversy
• In May of 2012, 23andMe announced that was granted a
patent for “polymorphisms associated with Parkinson’s
disease”; Obviously, in contrast to their “public good”
statements
• The announcement was made merely a day before the patent
was granted. This is odd given that 23andMe has claimed that
“open dialogue about complicated issues like patents is
important”
• Many 23andMe consumers (and the general public) were
outraged at the lack of transparency regarding their intention to
patent any discoveries made about Parkinson’s disease
23andMe Research Patent Controversy
Continued
• A recent publication in Genetics in Medicine looking at the
effect of patenting on 23andMe suggests that consumers are
much less likely to contribute to the research now that it is
clear that altruism is not the motivator
• This speaks to the incomplete consent process that individuals
go through in order to contribute their information to
23andMe’s research. In a traditional informed consent process
the consumer would have had the opportunity to ask questions
regarding intent instead of making assumptions.
Sterckx et al. (2013) Genetics in Medicine. 15(5):382-7
23andMe Consent Issues
• Informed consent in research serves to respect and promote the autonomy of people considering whether to participate in research
• Based on the response of 23andMe consumers after the patent announcement it is clear that their consent did not meet this requirement
• As mentioned in Genetics in Medicine the consent process is “ethically inadequate”
• One user of 23andMe noted on their blog that “stating that it is written in sections 13 and 22 and sections 3 and 5 that people signed is not close to a decent answer to people you asked for partnering with you to advance research on Parkinson’s”
Sterckx et al. (2013) Genetics in Medicine. 15(5):382-7
• This example underscores one of the drawbacks to direct-to-
consumer genetic testing
• In a traditional physician driven environment the consent
process (while not perfect) is much more effective in providing
transparency
23andMe Consent Issues
Congressional Hearings on DTC Genetic
Testing
Congressional Hearings on DTC Genetic
Testing
• Hearings held by the Subcommittee on Oversight and
Investigations on July 22, 2010
• Hearings largely held to discuss findings of a report
generated by a Government Accountability Office
(GAO) investigation into DTC genetic testing
• Report title: “Direct-to-Consumer Genetic Tests:
Misleading Test Results are Further Complicated by
Deceptive Marketing and Other Questionable
Practices” -- clearly unbiased
GAO Investigation
• GAO performed a year-long, two-part investigation
into the tests and marketing practices of DTC genetic
testing companies
• GAO “did not conduct a scientific study but instead
documented observations that could be made by any
consumer”
• Concluded that “results are misleading and of little or
no practical use”
GAO Investigation
Part 1: The Tests
• GAO purchased 10 tests each from 4 companies (23andMe, Navigenics, Pathway Genomics, and deCODE Genetics)
• 2 samples were used from 5 donors; 1 sample was accompanied by correct clinical info (age, race, ethnicity) and 1 sample with incorrect info
• Report found that 58% of the time donors received different predictions for the same disease
• Often times donors were predicted to be at low risk for disorders from which they were already suffering
One donor with an implanted pacemaker for an irregular
heartbeat was told that he was at decreased risk for
developing such a condition
Caveat: Risk prediction ≠ Diagnosis; a point that
congress conveniently did not discuss
GAO Investigation
Part 1: The Tests
• After receiving test results on all of their donors the GAO
followed up by placing “undercover calls to the companies
seeking health advice”
• The first conversation was between a GAO investigator and a
Navigenics representative discussing the woman’s breast
cancer risk assessment results:
– Fictitious Customer: “So if I’m high risk, does that mean I’ll
definitely get breast cancer?”
– Company Representative: “You, you’d be in the high risk of, you
know, pretty much getting it” ----OOPS!!!!
GAO Investigation
Part 2: The Follow-Up
GAO Investigation: More Phone Call Excerpts
– Company Representative: We’ve found out recently that we can repair DNA damage; this has been known for awhile and demonstrated.
– Fictitious Customer: You can really?
– Company Representative: Oh yeah, it’s called epigenetics
– Fictitious Customer: That’s repairing DNA?
– Company Representative: Yeah.
• Note: Epigenetics is the study of inherited changes in phenotype or gene expression caused by mechanisms other than changes in the DNA sequence (i.e. methylation of gene promoters to turn off gene expression)
• Fictitious Customer: I thought it would be an awesome gift to
give my fiancé his DNA tested with mine
• Company Representative: Oh yeah, that would be great!
• Fictitious Customer: And I was planning on submitting it for
him and surprising him, is that OK?
• Company Representative: You could surprise him and let
him know that it’s the ancestry test and then surprise him with
the health information too, or I don’t know.
• Fictitious Customer: OK, so as long as I can get the vial of
saliva somehow, I can send it in and you can test it for me.
• Company Representative: Absolutely!
GAO Investigation: More Phone Call Excerpts
GAO Investigation: Summary
• Concluded that 10/15 companies investigated
engaged in “deceptive marketing, misinformation,
and questionable practices”
• As a result of these studies the FDA is becoming
more active in the regulation genetic testing
Problems with GAO Report
• Report failed to identify which companies were
deceptive and which were not
– (1/3 of companies did not exhibit questionable
marketing behavior)
• Only the “horrifying” encounters with DTC Genetic
Testing companies were highlighted
Response to Congressional Hearings
Several companies involved with both DTC genetic
testing and risk assessment released statements
condemning the congressional hearings. Most of
these statements point out that it isn’t possible to
compare risk assessment among different companies
as each one uses a different model (and variants) to
determine one’s genetic risk.
Outcome of Congressional Hearings
• Most companies offering DTC genetic (health) testing decided
to move to a more traditional route whereby testing is ordered
by a physician and then results are available directly to patient
• 23andMe was the exception and continued to offer DTC
testing
FDA Intervention
• On November 22, 2013 the Food and Drug Administration
(FDA) sent a “warning” letter to 23andMe
• This letter notified 23andMe that in the FDA’s view they were
marketing a device “intended for use in the diagnosis of
disease or other conditions or in the cure, mitigation,
treatment, or prevention of disease, or is intended to affect the
structure or function of the body”
• In the FDA’s view 23andMe was in violation of the Federal
Food, Drug and Cosmetic Act
• 23andMe was given 15 business days to respond
23andMe Response to FDA Letter
• On December 5, 2013 23andMe stopped offering new
consumers access to health-related genetic tests
• All testing after this date has been limited to ancestry-related
information
• Individuals already tested prior to 12/5/2013 continue to have
access to their health-related results
• 23andMe will provide the raw (uninterpreted) genetic data to
anyone that has had the ancestry test
23andMe Future Directions
• Clearly in the process of working with the FDA to get
approval to offer health-related their testing directly to
consumers
An Interesting Case Study
The Patient
• 33-year-old woman with a Ph.D. in bioinformatics from
Stanford
• Electively underwent DTC genetic testing in hopes of
exploring scientific collaboration
• Testing was done as a professional courtesy given academic
interest of sample donor
Tenenbaum et al. (2012) J Personalized Med. 2(4):192-200
DTC Results
• DTC testing results revealed that the patient was heterozygous
for the common Prothrombin (F2) gene mutation, G20210A
• No personal or family history of venous thromboembolism,
pregnancy loss, etc.
Factor II (Prothrombin)
• Factor II (Prothrombin)
– G20210A substitution
– Second most common genetic risk factor for venous thrombosis (behind Factor V Leiden)
– Found in 2-5% of individuals of European Caucasian ancestry
– 3’ untranslated region
– Increased mRNA expression
– Increased Factor II levels
– Strongly associated with adverse pregnancy outcomes
Clinical Scenario and Altered Care as a Result
of DTC Genetic Testing
• Due to fertility issues the patient was referred to a reproductive
endocrinology and infertility clinic
• With the help of fertility medication the patient became
pregnant with twins
• During a routine visit the fertility specialist the patient notified
the clinician that she was a carrier of the prothrombin mutation
• A confirmatory molecular genetic test was ordered
• After result confirmation, the patient was put on enoxaparin
(30mg twice daily) and Aspirin (81 mg daily) for the first 12
weeks of the pregnancy
• Patient was also referred to a high-risk obstetrician
• At 12 weeks gestation the patient was seen by a maternal-fetal
medicine physician specializing in clotting disorders
• At that time her enoxaparin was decreased to 40mg daily
through 28 weeks gestation when it was doubled
• Patient also underwent monthly ultrasounds and non-stress
tests
• Patient’s pregnancy was uncomplicated through 29 weeks but
experienced premature rupture of membranes and labor at 30
weeks (due to twin pregnancy, unrelated to her risk factor)
• Both twins are now age 2 and reportedly healthy
Clinical Scenario and Altered Care as a Result
of DTC Genetic Testing (continued)
Case Study Summary
• Given the lack of a family history it is unlikely that the patient would have otherwise found out about her prothrombin status
• This finding significantly altered her prenatal care
• The patient noted that had the testing not been free of charge for her she would not have elected to do the testing as it was $500 at the time her testing
• It was also noted that not everyone would have been able to afford the additional care required given her genotype. Additionally, the authors of this case study noted that “there remains the risk that elective DTC testing could further exacerbate existing healthcare disparities between socioeconomic groups”
DTC Genetic Testing Summary
• DTC genetic testing is largely in the embryonic stages and is
likely to become commonplace once regulatory issues are
resolved
• It is unlikely that (most) individuals without a medical
background will be able to adequately interpret and use their
test results to their benefit
• It is also clear that informed consent is likely to be an issue
that needs significant improvement in the DTC genetic testing
process
Resources
• 23andMe (http://www.23andMe.com)
• Watch the Congressional Hearing on DTC Genetic Testing by
visiting http://energycommerce.house.gov
• GAO Report on DTC Genetic Testing: http://www.gao.gov
• Tenenbaum et al. (2012) An altered treatment plan based on
direct-to-consumer (DTC) genetic testing: Personalized
Medicine from the patient/pin-cushion perspective. Journal of
Personalized Medicine 2(4):192-200
Photo Courtesy of Dr. Jason Shepherd
THANKS!!