Building an Evidence Base for the Future of

Genomics

Robert C. Green, MD, MPH

Professor of Medicine, Harvard Medical School

@RobertCGreen

Director, Genomes2People Research Program

Brigham and Women’s Hospital and Broad Institute

Support and Disclosures

Research: US National Institutes of Health

US Department of Defense

Broad Institute of MIT & Harvard

Franca Sozzani Fund for Preventive Genomics

Advisory: AIA, Applied Therapeutics, Helix, Ohana

Biosciences, OptraHealth, Prudential, Veritas

Co-Founder: Genome Medical - a technology and services company

providing genetics expertise to patients, providers,

employers and care systems (www.genomemedical.com)

The Promise of Precision Medicine

Health Care – not “Sick Care”

Why is preventive genomics

using sequencing not in use?

The harms and costs will

outweigh and benefits.

Participants (or their providers) will

misunderstand genomic information.

Genetic information is toxic.

Too much information.

The REVEAL Study

The PGen (DTC) Study

The MedSeq Project

The BabySeq Project

The PeopleSeq Consortium

The MilSeq Project

Is genomic information toxic?

REVEAL Study of APOE DisclosureNIH HG02213 / AG047866 (2000-2019)

3/3 (67%)

2/3 (8%)

2/2 (1%)

3/4 (20%)

4/4 (2%)

2/4 (3%)

Roberts et al, Genet Med, 2004

Cupples et al, Genet Med, 2004

LaRusse et al, Genet Med, 2004

Zick et al, Hlth Aff, 2005

Eckert et al, Genet Med, 2006

Green et al, NEJM, 2009

Green et al, Alz Dement, 2011

Roberts et al, Genet Med, 2012

Christensen et al, Ann Int Med, 2016

Christensen et al, Genet Med, 2017

Chao et al, Alz Dement, 2008

Christensen et al, Genet Med, 2008

Fanshawe et al, Genet Test, 2008

Cassidy et al, Alz Dement, 2008

Chung et al, Alz Dement, 2009

Zick et al, Health Affairs, 2005; Chao et al, Alzheimer’s & Dementia, 2008;

Green et al, New Engl J Med, 2009; Taylor et al, Health Affairs, 2010

0%

10%

20%

30%

40%

50%

60%

APOE ε4+ APOE ε4- Control

The REVEAL Study: Disclosing APOE Genotype

Is genomic information misunderstood?

Impact of Personal Genomics

(PGen) Study

NIH HG005092 (2010-2014)

Green and Farahany, Nature, 2014

Ostergren et al, Publ Hlth Genomics, 2015

Carere et al, BMC Med Genetics, 2015

Van der Wouden et al, Ann Int Med, 2016

Krieger et al, Nature Biotech, 2016

Carere et al, Genet Med, 2016

Gray et al, J Clin Onc, 2017

Roberts et al, Publ Hlth Genomics,

2017

Landry et al, J Comm Genet 2017

Koeller et al, J Genet Couns, 2017

Nielsen et al, BMC Med Genomics,

2017

Gollust et al, Milbank Quart, 2017

What are the medical, behavioral and economic outcomes

associated with unanticipated findings from sequencing?

The MedSeq Project

How can we manage the interpretation of the vast amount

of information that genome sequencing provides?

All variants ≥10% in

WGS

Cases

ClinVar >5%

Medical

exome

>1%

Gene

exclusions

Variant

exclusions

~2

00

-30

0

va

ria

nts

Data Set A ≥ 10% MAF WGS Cases

Excludes common technical FPs

Common indels wrong nomenclature

Exceptions FV, HFE, SERPINA1

Data Set B - Gene Exclusions

• Evidence for gene-disease association

= none, limited, or disputed

• Non medically relevant phenotype

Data Set C - Variant Exclusions

• Benign interpretation

• LOF but LOF not disease

mechanism

• GWAS or PGx association only

Original filters Curated Exclusion Datasets

A B C

Genome Filtering Approach

71

3111

2

611PathogenicLikely PathogenicVUS-Favor PathogenicOtherNot reported

Not reported variants: 82%• VUS, Likely Benign, Benign

• False positive variants

Reported

variants: 18%

C5%

Assessed13%

A69%

B13%

HGMD

Novel

LOF

<60

variants20-40

variants

10-30

variants

McLaughlin et al, BMC Med Genetics, 2014

How can we simplify the medical reporting of genomic

sequencing to avoid provider misunderstanding?

• Monogenic risk variants

• Polygenic risk variants

• Carrier variants

• Pharmacogenomic variants

• Blood groups

• Additional Pages…

• Structured variant data

• Variant evidence

• Disease/inheritance

• Supporting references

Understandable

reporting

Vassy et al, Trials, 2014

McLaughlin et al, BMC Med Genetics, 2014

Do we find anything useful?

Monogenic Conditions

Analysis of Pathogenic Variants in All ~5000

Known Disease Associated Genes

Mendelian

Disease Risk

SFs

% of patients 21%

Mean reported variants per

patient.21

Range of reported variants per

patient0-1

McLaughlin et al, BMC Med Genetics, 2014

Vassy et al, Ann Int Med, 2017

Gene Disease Classification Phenotype?

RDH5 Fundus albipunctatus (x2) P

PPOX Variegate porphyria P

LHX4 Combined pituitary hormone deficiency P

HFE Hereditary hemochromatosis (x2) P

COL2A1 Spondyloepiphyseal dysplasia congenita LP

ANK2 Ankyrin-B related cardiac arrhythmia LP

KCNQ1 Romano-Ward syndrome LP

F5 Factor V Leiden thrombophilia Risk allele

ARSE Chondrodysplasia punctata VUS: FP

TNNT2 Hypertrophic cardiomyopathy VUS: FP

PDE11A Primary pigmented micronodular adrenocortical disease VUS: FP

”White spots” in

fundi, difficulty with

dark adaptation“Odd rashes,”

family history of

photosensitivity

Normal ferritin,

elevated transferrin

saturationNegative ECG and

stress test

Unanticipated monogenic disease risk variants

Vassy et al, Ann Int Med, 2017

Do we find anything useful?

Carriers for Recessive Conditions

Analysis of Pathogenic Variants in All ~5000

Known Disease Associated Genes

Mendelian

Disease Risk

SFs

Carrier

Status

SFs

# of patients 21% 92%

Mean reported variants per

patient.21 2.3

Range of reported variants per

patient0-1 0-7

McLaughlin et al, BMC Med Genetics, 2014

Vassy et al, Ann Int Med, 2017

Do we find anything useful?

Pharmacogenomic Information

Mendelian

Disease Risk

Variants

Carrier

Status

Variants

PGx

Atypical

Responders

% of patients 21% 92% 80%

Mean reported variants per patient .21 2.3

Range of reported variants per patient 0-1 0-7

McLaughlin et al, BMC Med Genetics, 2014

Vassy et al, Ann Int Med, 2017Scharfe et al, Genome Med, 2017

Analysis of Pathogenic Variants in All ~5000

Known Disease Associated Genes

Do we find anything useful?

Polygenic Risk for Common Disorders

Kong et al, Genetics in Medicine, 2015

Vassy et al, Ann Int Med, 2017

Reporting Polygenic Risk Scores in the MedSeq Project

Kullo et al, Circulation, 2016

Polygenic Risk Scores Can Promote Clinical Change

Chatterjee et al, Nature Rev Gen, 2016

Khera et al, Nature Gen, 2018

20% of the

population has

3-4x the risk

of common

conditions!

Will healthcare costs explode

after identification of genomic risks?

Median:

$2,756 vs $2,819

p=0.20

Prolonged hospitalization

New diagnostic

findings

Vassy et al, Ann Int Med, 2017

Christensen et al, Genet Med, 2018

Medical Costs After Sequencing

“…whether you like it or not, a complete

sequencing of newborns is not far away”

Francis Collins, 2012

The BabySeq Project

BabySeq Project

Preliminary Medical Outcomes

BabySeq Unanticipated

Monogenic Disease Risks

163newborns sequenced

11% w/ findings predictive of monogenic disease

(18 cases)

89% w/ no findings or only carrier status variants

(145 cases)

Yu et al, in preparation

18cases w/

pathogenic or likely

pathogenic findings

4cases

w/diagnosticfindings

cases w/out clinical or family hx for disease (some workups pending)

MYBPC3, VCL, TTN (2), CD46, G6PD

findings prompted discovery of unrecognized clinical phenotype

BTD, ELN, GLMN

1finding explains observed clinical phenotypeANKRD11

3

6

cases w/consistent family history of the diseaseKCNQ4, SLC7A9, TTN (2), BRCA2 (2), MSH28

BabySeq Unanticipated Monogenic

Disease Risks and Findings

Yu et al, in preparation

BabySeq Project

Preliminary Behavioral Outcomes

4.0

8.0

12.0

16.0

20.0

Baseline Post-Disclosure 3-Month 10-Month

Avera

ge P

are

nt

VB

S S

core

Average Parent VBS Scores Across TimeParent N=168 || Infant N=122

Control (Parent n=73, Infant n=54) WES (Parent n=95, Infant n=68)

Pereira et al, in preparation

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

18.0

20.0

22.0

24.0

Baseline Post-Disclosure 3-Month 10-Month

Avera

ge P

are

nt

MIB

Q S

core

Average Parent MIBQ Score Across TimeParent N=168 || Infant N=122

Control (Parent n=73, Infant n=54) WES (Parent n=95, Infant n=68)

Pereira et al, in preparation

7.4

11.2

4.0

8.0

12.0

16.0

20.0

No Monogenic Finding(Parent n=105, Infant n=71)

Yes Monogenic Finding(Parent n=7, Infant n=4)

Avera

ge P

are

nt

VB

S S

core

at

10

-Month

s

Average WES Parent VBS Scores by Monogenic Finding at 10-MonthsParent N=112 || Infant N=75

Pereira et al, in preparation

BabySeq Project

Preliminary Economic Outcomes

p=0.042

(randomization)

Mean

num

ber

Christensen et al, in preparation

But wait, there’s more!

The Problem of Penetrance

Natarajan et al, Science Trans Med, 2016.

Framingham Heart Study (N=462) and Jackson Heart Study (N=3218)

Aggregate Value in Public Health Genomics

91%

18%

80%

20% x ??

Web: genomes2people.org

Twitter: @robertcgreen

@genomes2people

Email: rcgreen@bwh.harvard.edu

New Boston Preventive Genomics Clinic !

Thank you !

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