Transcript A Decade of Direct Access Genetics: What Have We Learned? Jill Hagenkord, MD Chief Medical Officer, 23andMe March 2015 Copyright © 2014 23andMe, Inc.

A Decade of Direct Access
Genetics: What Have We
Learned?
Jill Hagenkord, MD
Chief Medical Officer, 23andMe
March 2015
Copyright © 2014 23andMe, Inc. All Rights Reserved.
Overview
•
Review and Impact of Consumer Genetics
•
23andMe: What We Believe and How it Works
•
Accessible, affordable genetic information
•
•
Changing the Research Paradigm
•
•
•
•
Health and wellness
Ancestry
Faster discoveries
Better diagnoses
Looking Ahead
Copyright © 2014 23andMe, Inc. All Rights Reserved.
Each human
has approximately
6 billion
single letters in
their DNA
Copyright © 2014 23andMe, Inc. All Rights Reserved.
3
Types of Consumer Genomics
•
•
•
•
•
•
•
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Ancestry
Carrier Status (Cystic Fibrosis)
Adult onset genetic conditions (BRCA)
Drug Response (Warfarin, Clopidogrel)
Complex Common Conditions (Diabetes type II)
Nutrition (Vitamins)
Lifestyle (Exercise)
Sports (Injury and Performance)
Risk Allele Frequency and Strength of Genetic Effect
X
McCarthy MI, et al. Genome-wide association studies for complex traits:
consensus, uncertainty and challenges. Nature Rev. Genet.2008;9:356–369
Regulation of DTC Genetics: Historical Perspective
2007
2008
Launch of DeCode and 23andMe
SACGHS and Letters from the States
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•
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2010
DTC Goes to Washington. “Letters to Industry”
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2013
May: Pathway Genomics and Walgreens
June: FDA sends notice to 5 companies that they are manufacturing and selling medical devices without appropriate FDA
premarket review and approval. Tells them to act “promptly.”
FDA takes action
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•
2015
Following publication of Secretary’s Advisory Committee on Genetics, Health and Society (SACGHS), public health
officials in NY and CA sent “cease and desist” letters to DTC genetics companies warning that they were operating
without necessary state licenses.
Some DTC companies stopped being DTC, some ceased selling to customers in specific jurisdictions, and some simply
went out of business.
23andMe’s DTC genetic product named Time’s Invention of the Year for 2008.
August: 23andMe launches national TV advertising campaign
November: FDA warning letter to 23andMe; company discontinues marketing and offering health reports to PGS
consumers in the United States.
Finding a path forward
•
•
23andMe submits first 510(k)
Association for Molecular Pathology (AMP) releases revised policy statement in support of DTC genetics,
provided certain conditions are met.
www.genomicslawreview. The Past, Present and Future of DTC Genetic
Testing Regulation
Some of the concerns about DTC Genetic Information
1. Analytical validity: Are the genotypes correct?
2. Clinical validity: Is the variant associated with the disease?
3. Mathematical combination of Odds Ratios: Identical samples assessed by three DTC
genetic testing companies offered different risk assessments.
4. Clinical Utility: Lack of agreed upon definition. Ranges from “Does it change treatment?” to
“Do individuals consider it important to know?”
5. Allowing direct access: Does the product prey on hypochondriacs or “worried well?”
6. Delivering health-related results directly to consumers: Consumers might overreact or
misunderstand the information; consumers might be more distressed; consumers might “selftreat” or “self-diagnose” or have “unnecessary surgery”
7. Overburdening the healthcare system: Do consumers demand or physician’s perform
unnecessary follow up testing?
8. Privacy: protecting personal information from others using without our consent or using
against us
Simplifying the Debate on Consumer Genetics:
•
Analytical validity: Assume analytic validity. Appropriately credentialed clinical laboratories
are competent and experienced at genotyping and sequencing assays
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Clinical validity: Focus on Mendelian disorders, carrier status, pharmacogenetics, traits
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Mathematical combination of Odds Ratios: Set aside low-impact risk alleles and multiplied
odds ratios.
Positions must be data-driven, not based on anecdotal stories
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Clinical Utility
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Allowing direct access
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Delivering health-related results directly to consumers
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Overburdening the healthcare system
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Privacy
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Let the Data Speak
“… the data suggest that consumer genomics does not provoke distress or
inappropriate treatment.”
Robert Green, et al. Nature, Jan 2014 Regulation: The FDA is overcautious on consumer genomics
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Psychological ramifications
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Consumer understanding
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Consumer satisfaction
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Healthcare utilization
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Appropriateness of follow-up
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Utility
Dozens of studies have been published studying the impact of DTC genetics
for pharmacogenomics (PGx), common complex disorders, intermediate
impact disorders, and Mendelian inherited disorders.
Let the Data Speak: Examples
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Mendelian inherited disorders
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Intermediate effect disorders
•
PGx and common complex
disease risk
X
Copyright © 2014 23andMe, Inc. All Rights Reserved.
Mendelian Inherited Disorders: BRCA
Francke et al. Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing (2013) PeerJ 1:e8
Methods:
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136 BRCA1/2 positive individuals in the 23andMe database; 160 negative matched for age, sex and ancestry.
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Phone interviews were completed for 32 mutation carriers, 16 women and 16 men, and 31 non-carriers.
Results: 11 women and 14 men had received the unexpected result that they have a mutation.
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Psychological Ramifications: 0 reported extreme anxiety, 4 experienced moderate anxiety that was transitory.
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Appropriateness of follow-up:
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All had consulted healthcare professionals with their results, and all but 1 (who elected for surveillance and not surgery) had
their tests repeated.
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Sharing with family members led to screening of at least 30 relatives and identification of 13 additional carriers.
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Non-carriers did not report inappropriate actions, such as foregoing cancer screening.
Utility:
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Male carriers realized that their test results implied genetic risk for female relatives.
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All but one of the 32 mutation-positive participants appreciated learning their BRCA mutation status.
Conclusion: Carriers’ behavior after learning this information was no different from that of people
who discover these mutations through medical channels.
Intermediate Impact: ApoE and Alzheimers Disease
Risk Evaluation and Education for Alzheimer’s Disease (REVEAL)
Randomized controlled trial of over 1100 asymptomatic adults who had a parent with Alzheimer’s
Results
• Psychological ramification: No
• Consumer Satisfaction: Many participants believed that information would be helpful
even in the absence of proven medical care options to reduce their AD risk.
Conclusion:
• Many are interested in genetic testing for non-medical reasons.
• Provision of test results does not generally result in adverse psychological effects if
delivered by trained professionals using appropriate educational approaches.
• Streamlined genetic counseling process did not increase participant distress or
misunderstanding.
1.
2.
Green R et al. Changes to perceptions of the pros and cons of genetic susceptibility testing after APOE genotyping for Alzheimer disease risk.
NEJM 361;3; july 16, 2009
Roberts JS et al. Using Alzheimer’s disease as a model for genetic risk disclosure: implications for personal genomics. Clinical Genetics, 80: 407-414,
2011
Scripps Genomic Health Initiative (SGHI): PGx and Common Complex
Disease
Prospective longitudinal cohort study of ~3000 adults who purchased commercially available
genomic test. Surveyed before receipt of results and at 3 and 12 months.
Results
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Psychological ramification: No, 96% had no test related distress
Consumer Understanding: 75% felt they understood their results
Consumer Satisfaction: 62% had high perceived utility of the test
Privacy Concerns: 75% no
Healthcare Utilization: 36% shared their results with a physician. Sharing results
associated with increased compliance with screening guidelines.
If DTC included PGx, recipients were more share and more likely to report that their
physician ordered additional tests.
75% understand
results
Conclusion: Consumers’ spontaneous sharing of genomic information with their physician,
suggest the possibility that a new model in which patients and physicians are partners may
be optimal.
Bloss CS et al. Impact of direct-to-consumer genomic testing at long term follow-up. J Med Genet. 2013 Jun;50(6):393-400.
Bloss CS, et al. Direct-to-consumer pharmacogenomic testing is associated with increased physician utilisation. J Med Genet. 2014 Feb;51(2):83-9.
Impact of Personal Genomics (PGen) Study
Surveyed over 1800 customers from two consumer genomics companies
Source: Preliminary data from PGen
Study, 2012–13
Robert Green, et al. Nature, Jan
2014 Regulation: The FDA is
overcautious on consumer
genomics
Copyright © 2007-2014 23andMe, Inc. All Rights Reserved.
ASHG: Consumer Views of DTC Genetic Testing.
Room for improvement
Online survey of random sampling of 1048 customers who had received genetic test
results from three DTC genetic testing companies in 2010.
Results:
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Top three reasons for being tested: curiosity, disease risks and ancestry
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Consumer Understanding: 88% agreed their risk report was easy to understand, 38% said the conclusions
were too vague. Between 4% and 7% misinterpreted examples of risk results
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Appropriateness of follow-up: 34% adopted a more healthful diet, 16% changed a drug or supplement, 14%
exercise more.
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Healthcare Utilization: 43% sought additional information on at least one tested condition, 28% discussed
findings with a healthcare professional, and 9% followed up with additional lab tests.
Conclusion: Customers were generally satisfied with the testing services. Nevertheless,
there is room to improve the clarity of information provided to customers in their personal
test result reports, and to improve the way information is being delivered.
Kaufman D. et al. American Society of Human Genetics (ASHG) 60th Annual Meeting: Abstract 390. Presented November 5, 2010.
http://abstracts.ashg.org/cgi-bin/2010/showdetail.pl?absno=21043
Let the Data Speak: Summary
“… the data suggest that consumer genomics does not provoke distress
or inappropriate treatment.”
Robert Green, et al. Nature, Jan 2014 Regulation: The FDA is overcautious on consumer genomics
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Psychological ramifications: Low
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Consumer understanding: High, but could be “less vague”
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Consumer satisfaction: High
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Healthcare utilization: Appears low
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Appropriateness of follow-up: Appears appropriate, increased compliance
with recommended screening
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Utility: Sustained healthy behaviors, health awareness, family health
discussions, opportunity for prevention in high risk diseases
Copyright © 2014 23andMe, Inc. All Rights Reserved.
23andMe: What We Believe
•
Everyone has the right to access and
understand their personal genetic information
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Genetic information is the basis for personalized
medicine
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Big data will improve your health and accelerate
research discoveries
Copyright © 2014 23andMe, Inc. All Rights Reserved.
What You Can Learn From Your DNA
Medication
Response
Disease
Risks
Ancestry
Inherited
Conditions
Interesting
Traits
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Greg Parkeh
“
We’re just happy that he got
diagnosed a lot younger
than normally.
”
Monica
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Consent, Privacy, Security
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23andMe Research is opt-in
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Customers must consent to participate in research and can cease participation at
any time.
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80% of all 23andMe customers consent to research; the same percentage holds
true for UK customers.
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The data we use for research purposes is aggregate and anonymized no individual level data is ever shared
•
For customers who opt-in to participate in 23andMe research, their
genetic information is stored in a third physically separate computing
environment and assigned a random ID number
23
A New Research Paradigm:
Building the World’s Largest
Database of Engaged Genotyped and
Phenotyped Participants
Copyright © 2014 23andMe, Inc. All Rights Reserved.
24
850K
genotyped
customers
80%
customers
consent
to research
250M
research questions
answered by
genotyped customers
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Customer Demographics
77%
48%
European
Female
10%
52%
Latino
Male
5%
African
American
4%
East Asian
2%
South Asian
2%
Other
10
20
30
40
50
60
70
80
90
Age Distribution
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100
Types of Analysis on World’s Largest
Recontactable Database
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Data Analysis: access and analyze cohorts from the
existing database (GWAS, PheWAS, etc.)
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Surveys: collect new data from the existing genotyped
database for analysis
•
Registries: recruit new individuals for genotyping,
phenotyping and longitudinal studies.
Copyright © 2014 23andMe, Inc. All Rights Reserved.
Making Research Easy
22,012 Cases
31,850 Controls
Results include the
discovery of 16 new
genetic associations
for allergies and eight
shared associations
with asthma.
Copyright ©2014 23andMe, Inc. All Rights Reserved.
Making Research Easy
13,068 Cases
20,862 Controls
Results indicate that
elastin could be key to
more effective
prevention and
treatment of stretch
marks
Copyright © 2014 23andMe, Inc. All Rights Reserved.
Yes
a few
hours
we were
Canwe
wecan.
seeInthis
same
association
able to find
similar association
between
theanumber
of moles a
doing
analysis
usingher
a cohort
woman
has and
risk
of about
45,000
women.
for breast
cancer?
Copyright © 2014 23andMe, Inc. All Rights Reserved.
P603R: What Does It Do?
157 23andMe customers
carry the P603R mutation*
*As of November 22, 2013.
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Cancer Survey E-mail
Added 10,805 survey
responses in 12 hours
P603R: What does it do?
Emails went out at
12pm, April 11 to all
genotyped accounts
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Experiments in Nature: Human Knock-Out
Profile
• 40 year-old
• Aerobic teacher
• Mother of two
• Dallas, TX
Unusual Phenotype
• LDL: 14 mg/dl (very low)
Mutation
• PCSK9
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Special Phenotypes And Drug Development
Copyright © 2007-2014 23andMe, Inc. All Rights Reserved.
5 Drugs in Development
SAR236553
(anti-PCSK-9 mAb)
Regeneron Pharmaceuticals
Tarrytown, NY
Sonofi US
Bridgewater, NJ
BMS-96247476
(PCSK9 adnectin)
Bristol-Myers Squibb
RG7652
(PCSK9 protein inhibitor)
Genentech
ALN-PCS
(PCSK9 protein inhibitor)
Alnylam Pharmaceuticals
heterozygous familial
hypercholesterolemia,
hypercholesterolemia
Phase III
www.regeneron.com
atherosclerosis
Phase I
www.bms.com
coronary heart disease
Phase II
www.gene.com
hypercholesterolemia
Phase I
www.alnylam.com
www.themedicinescompany.
com
heterozygous familial
hypercholesterolemia,
hypercholesterolemia
Phase I
www.amgen.com
Princeton, NJ
South San Francisco, CA
Cambridge, MA
The Medicines Company
Parsippany, NJ
AMG 145
(PCSK9 inhibitor mAb)
Amgen
Thousand Oaks, CA
23andMe Extreme Phenotypes
•
LRRK2 G2019S + GBA N370S double mutants without Parkinson’s
Disease at advance age
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MYBPC3 homozygotes, originally thought to be non-viable
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CFTR deltaF508 asymptomatic homozygote at ~50 years old
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ApoE ε4/ε4 >75 and no cognitive impairment
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World’s Largest Recontactable
APOE e4 Cohort
APOE e4 Distribution
122K+
e2/e4
e3/e4
e4/e4
20000
Count
APOE e4
Carriers
25000
15000
10000
5000
0
13-23
23-33
33-43
43-53
53-63
63-73
73-83
83-93
Age
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93-103
World’s Largest Genotyped Parkinson’s
Cohort
Parkinson’s Patients
4,000
10,000+
Count
Genotyped
Parkinson’s
Patients
3,000
2,000
1,000
0
0-10
10-20
20-30
30-40
40-50
50-60
60-70
70-80
80-90
Age
Copyright © 2014 23andMe, Inc. All Rights Reserved.
90+
“
What 23andMe did in a matter of years
would have taken several decades
and tens of millions
done conventionally.
of dollars if
”
-Haydeh Payami, PhD, a neurodegenerative disease
researcher at the New York State Department of Health.
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39
Making 23andMe Available to Researchers Globally
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Obama’s Precision
Medicine Objectives
January 2015
Creation of a voluntary national research cohort:
•
•
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NIH will launch a national, patient-powered research cohort of one million or more Americans who
volunteer to participate in research.
Participants will have the opportunity to contribute diverse sources of data—including medical records;
profiles of the patient’s genes, metabolites, and microorganisms in and on the body; environmental and
lifestyle data; patient-generated information; and personal device and sensor data.
Leverage existing research and clinical networks and build on innovative research models that enable
patients to be active participants and partners.
The cohort will be broadly accessible to qualified researchers and will have the potential to inspire
scientists from multiple disciplines to join the effort and apply their creative thinking to generate new insights.
The ONC will develop interoperability standards and requirements to ensure secure data exchange with
patients’ consent, to empower patients and clinicians and advance individual, community, and
population health.
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23andMe Academic
www.23andme.com/academic
•
Access a free, growing repository of teaching resources on
genomics
•
Personalize undergraduate/graduate class by providing
students with hands-on experience of DNA testing. Studies have
shown that personal DNA testing enhances student interest,
engagement and learning.
•
Analyze and explore real, anonymized sample genetic profiles.
•
Collaborate with other educators on best practices through the
23andMe Academic Forum.
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44
Teaching with 23andMe Resources
www.23andme.com/academic
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45
Looking ahead…
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46
Other Forces at Play…
Many molecular diagnostic labs are struggling to keep their lights on
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Increased transparency of the new molecular CPT codes have lead to a higher rate of denied
claims
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Gap-fill pricing for new molecular codes is significantly less than previous method stack codes
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Germline genetic testing often does not meet payer criteria for “clinical utility”
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CMS statutorily excludes preventative screening, carrier screening, testing at risk relatives,
prenatal testing for known pathogenic variants
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Moving from genetic scarcity to genetic abundance: Sequencing is becoming a commodity
•
Feb 2014 HHS ruling allowing patients to directly access their lab results
47
Familial Hypercholesterolemia
Hypercholesterolemia is common in Western societies
•
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1 in 3 or 34% or 71 million people in USA have high cholesterol1
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FH prevalence ranges from 0.1%-1% across populations. .Predicts >600,000 affected individuals in US2
Diagnosis of FH is currently done by clinical criteria and usually missed2
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High cholesterol present at birth but goes undetected until middle age, if diagnosed at all
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99% of FH goes unrecognized in routine practice in the US3
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FH heterozygotes have 100x greater mortality from heart disease in early adulthood
•
Heart disease risk estimation tools underestimate their risk and shouldn’t be used
•
More aggressive therapy needed
FH meets WHO criteria for screening programs, meets clinical utility standards4,5,6
1.
2.
CDC Fact Sheet (accesed June 2014)
Am. J. Epidemiol. 160 (5): 407-20 (2004)
3.
4.
Knowles J, A Call to Action, in press
BMJ. 2012 May 11;344:e3228. doi: 10.1136/bmj.e3228
5.
Int J Evid Based Healthc. 2012 Sep;10(3):211-21
6.
Curr Opin Lipidol. 2008 Aug;19(4):362-8
Hereditary Cancer
Hereditary breast and ovarian cancer
Li-Fraumeni syndrome
Peutz-Jeghers syndrome
Lynch syndrome
Familial adenomatous polyposis
MYH-associated polyposis
Von Hippel Lindau syndrome
Multiple endocrine neoplasia type1
Multiple endocrine neoplasia type 2
Familial medullary thyroid cancer
(FMTC)
PTEN hamartoma tumor syndrome
Retinoblastoma
Hereditary paragangliomapheochromocytoma syndrome
Tuberous sclerosis complex
WT1-related Wilms
Neurofibromatosis type 2
BRCA1
BRCA2
TP53
STK11
MLH1
MSH2
MSH6
PMS2
APC
MUTYH
VHL
MEN1
RET
RET
NTRK1
PTEN
RB1
SDHD
SDHAF2
SDHC
SDHB
TSC1
WT1
NF2
Hereditary Cardiovascular
MYBPC3
MYH7
TNNT2
TNNI3
TPM1
Hypertrophic cardiomyopathy, dilated
MYL3
cardiomyopathy
ACTC1
MYL2
PRKAG2
GLA
LMNA
Catecholaminergic polymorphic
ventricular tachycardia
RYR2
PKP2
DSP
Arrhythmogenic right ventricular
DSC2
cardiomyopathy
TMEM43
DSG2
KCNQ1
Romano-Ward long QT syndromes
KCNH2
types 1, 2, and 3, Brugada syndrome
SCN5A
LDLR
APOB
Familial hypercholesterolemia
PCSK9
Hereditary Connective Tissue
EDS - vascular type
Marfan syndrome, Loeys-Dietz
syndrome, and familial thoracic aortic
aneurysms and dissections
COL3A1
FBN1
TGFBR1
TGFBR2
SMAD3
ACTA2
MYLK
MYH11
Anesthesia Reactions Packet
RYR1
Malignant hyperthermia susceptibility
CACNA1S
Opportunity for a New Model
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Long term follow-up shows that consumers generally understood their
results and that the test had high personal utility.
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No adverse psychological outcomes observed
•
The AMA policy recommendation that genetic testing be carried out under
the personal supervision of a qualified health care professional.
•
Physicians have a poor understanding of genetics and genomics
•
Very low numbers of genetic counselors and medical geneticists in the USA.
•
Leaves patients with limited options.
…possibility of a new model in which patients and physicians are partners—
that is, patient direct access with support from physicians as desired—may be
optimal.
Bloss CS, Wineinger NE, Darst BF, Schork NJ, Topol EJ. J Med Genet. 2013
Jun;50(6):393-400. Impact of direct-to-consumer genomic testing at long term
Questions?
Jill Hagenkord, MD
Chief Medical Officer
[email protected]
@jhagenk
23andMe Genetics Image Contest 2014:
Do these genes make my butt look big?