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!!