Precision Medicine:The Future is Now

Kathryn NorthDirector Murdoch Children's Research InstituteDavid Danks Chair of Child Health Research University of MelbourneLead Investigator, Australian Genomics

Precision MedicineA personal, global and local perspective

• The Olden Days

• The Global Scene

• Right Here. Right Now.

Precision MedicineA personal, global and local perspective

• The Olden Days

• The Global Scene

• Right Here. Right Now.

Inherited Muscle Diseases

Ye olde diagnostic flowchart

Patient

Clinical FeaturesAncillary tests – CK MRI

Family History

Muscle pathology

Protein expressionImmunohistochemistry Western blot

Protein abnormalities

Gene sequencing

Congenital myopathies are defined by muscle pathology

Central Core Nemaline

Multiminicore Centronuclear

Congenital myopathies with identified gene loci - 1996

Disorder Inheritance Gene/Protein

Nemaline myopathy AD, AR -tropomyosin slow

Central Core disease AD ryanodine receptor

Myotubular myopathy

Centronuclear myopathy

Multiminicore disease

Myosin storage/Hyaline body myopathy

Congenital fibre type disproportion

Zebra body myopathy

Cap Disease

Congenital myopathies with identified gene loci – 2012

Disorder Inheritance Gene/Protein

Nemaline myopathy

Cap Disease

Zebra body myopathy

AD, AR

AD, AR,

AD

AR

AR

AR

AD

AD

-tropomyosin slow

skeletal - actin

-tropomyosin

nebulin

troponin T1

Cofilin

-tropomyosin slow, skeletal - actin

-tropomyosin

skeletal - actin

Central Core disease

Core-Rod myopathy

AD, AR ryanodine receptor

ryanodine receptor, skeletal -actin, nebulin

Myotubular myopathy

Centronuclear myopathy

X linked

AD

AR

AR

myotubularin

dynamin 2

amphiphysin 2

ryanodine receptor

Multiminicore disease AD, AR

AR

AD

AR

ryanodine receptor

selenoprotein N

skeletal -actin

titin

Hyaline body (myosin storage) myopathy AD slow myosin heavy chain

Congenital fibre type disproportion AD

AD

AR

AD

AR

skeletal -actin

-tropomyosin slow

selenoprotein N

-tropomyosin

ryanodine receptor

Nemaline myopathy

Genetic Investigations 2005-2010• Extensive protein studies

• Sequencing:

– ACTA1, TPM2, TPM3, TNNT1 – all normal

– Nebulin excluded by linkage

– No genetic diagnosis

2012: Collaboration with

Daniel MacArthur, Monkol Lekand Mark Daly

at the Broad Institute, Harvard, MGH, Boston

Whole exome sequencing of neuromuscular disorders

• High throughput

• Rapid sequencing of all gene

coding regions (exomes) in an

individual

• Becoming quicker and cheaper

Exome Sequencing 2012

• non consanguineous Caucasian family

• 2 affected siblings

• compound heterozygous variants in LMOD3

• in-frame deletion and nonsense mutation

• confirmed on Sanger sequencing in both affected

children, parents carriers

Leiomodin 2

Science 2008:11;239-43

Biological plausibility of candidate gene

• high homology with tropomodulin (Tmod)

• co-localises with Tmod

• Able to bind three actin monomers – acts as a nucleating factor for thin filament formation

Finding additional families….

• Emailing your mates….

• Genetic screening in over

540 additional cases of

NM identified 17 patients

from 12 additional families.

Clinical features and cohort screeningFamily Affected siblings Mutation 1 Mutation 2 Disease severity

Sydney 1 2 p.367delN p.R401X Intermediate congenital

Japan 1 1 p.T101fsX104 p.N201fsX209 Severe congenital

Japan 2 1 p.W77X Severe congenital

Japan 3 1 p.Q117X Severe congenital

Japan 4 1 p.Q117X p.K406fsX416 Severe congenital

Portugal 1 ? p.M52X Severe congenital

France 1 2 p.S47fs59X Severe congenital

Italy 1 1 p.F287fs289X Severe congenital

USA 3 ? p.G326R p.Q458X Severe congenital

USA 1 1 p. N367fs377X Severe congenital

Fin 1 1 p.N368fr377X ?

Fin 2 ? p.E357X ?

Fin 3 ? p.A116fsX125 ?

Fin 4 ? p.S311fsX321 p.427Glu>Arg ?

USA 2 2 p.P552H p.I263Tp.K438M

Typical congenital

Finding additional families….

Clinical features13 families (90%):

severe congenital NM(16% of NM severe congenital phenotype)

Polyhydramnios 62%,

Reduced fetal movements 52%

Joint contractures 48%

Prematurity 24%

18

All patients:

Severe generalized hypotonia and weaknessRespiratory insufficiency

Feeding difficulties

Bulbar weakness

Only our two patients known to have survived

beyond few months of life – still dependent

on nocturnal ventilation. Walked age 7 years.

Functional Genomics: Zebrafish knockdown model

LMOD3 Mutations are pathogenic

Morphology at 3 days post fertilization

Brightfield

Bifringence

Short bodies, bent tails, reduced

musculature and reduced tail

birefringence - abnormal

skeletal muscle organisation

Yuen et al. J Clinical Investigation 2014

Results of exome sequencing

2012-2015; n=181

Solved

• Nemaline myopathy 90%

• Centronuclear myopathy 75%

• Limb girdle muscular dystrophy 43%

• Congenital muscular dystrophy 55%

• Targeted therapy

“Precision Medicine”

• Better manage

disease risk

• Prevention

• Faster diagnosis

• Improved prognosis

Genomic medicine in healthcareWHAT COULD IT MEAN FOR THE PUBLIC?

Precision MedicineA personal, global and local perspective

• The Olden Days

• The Global Scene

• Right Here. Right Now.

The challenge : 2013

Data from millions of samples will be needed to address questions in rare disease, complex disease and cancer

The Challenge:

• Data is typically in silos: by type, by disease, by country, by institution

• Analysis methods are non-standardized, few at scale

• Approaches to regulation, consent and data sharing limit interoperability

genomicsandhealth.org

GA4GH Mission 2013

To accelerate progress in human health by establishing a common framework of harmonized approaches to enable effective and responsible sharing of genomic and clinical data.

“No one country can do this alone”

500+

partnersAcross 71

countries

Supported by NIH, Wellcome Trust, Broad Institute,

OICR, Canada

Establishment Phase2014-2017

DataChair: David Haussler

USA

Benchmarking

Containers and Workflows

File Formats

Genotype2Phenotype Association

Metadata

Reference Implementation

Reference Variation

RNA and Gene Expression

Variant Annotation

Demonstration Projects

Beacon

Completed:

- Reads

ClinicalChair: Kathryn North

Australia

eHealth - Pedigree Consent

eHealth - Family History

eHealth - Federated Queries

eHealth - Data Sharing

Phenotype Ontologies -Cancer / Complex Diseases

Demonstration Projects

Matchmaker Exchange

BRCA Exchange

Completed

Phenotype Ontologies - Rare Diseases

Rare Disease – catalogue of Activities

eHealth - Catalogue of Activities

Clinical Cancer Genome -Cancer Data Sharing

EthicsChair: Bartha Knoppers

Canada

Accountability (Policy)

Ageing and Dementia

BRCA Ethico-Legal and Advocacy

Data Protection Regulation

Data Sharing Lexicon

Ethics Review Equivalency

Individual Access

Machine-Readable Consent

Paediatric

Privacy Breach Notification

Registered Access (Tool)

Completed:

- Framework for Responsible Sharing of Genomic and Health-Related Data

- Consent Policy

- Privacy and Security Policy

SecurityChair: Paul Flicek

England

Cloud Security

Incident Response

Security Infrastructure

Software Security

Completed:

‐ Data Safe Havens

genomicsandhealth.org

GA4GH approach

Don’t reinvent the wheel

Be practical – systems must work now,

build a path from existing systems

Embrace federation and “data islands

with analysis clouds” approach

Matchmaker Exchange

A federated

Platform (Exchange)

to facilitate the

matching of cases with

similar phenotypic and

genotypic profiles

(Matchmaking)

through application

programming interfaces

(APIs)

genomicsandhealth.org

GA4GH vision to 2022Delivery focused, setting ethical and technical standards for genomic data sharing

New strategic planLaunched October 2017

genomicsandhealth.org

GA4GH ‘Connect’

VISION FOR GENOMIC & HEALTH RELATED DATA SHARING IN 2022

In 2022, genomic data on tens of millions of individuals are responsibly accessible via GA4GH standards.

• Vast majority of this data has been generated due to healthcare approaches rather than research commissioned genomes.

• Both research-commission genomes and secondary use of healthcare genomes for research is accessible due to the consistent application of the GA4GH APIs, SOPs and tools.

• Genomics data that can be shared responsibly, are shared responsibly, meaning every qualified clinician, researcher, and corporate entity around the globe, shares and has access to, the maximal dataset that is privacy preserving within the context of the relevant and localised consent and authorization policies.

• Genomic and phenotypic are integrated in clinical records and form a “healthcare learning system”.

• GA4GH collaborates and coordinates with the many other global, national, regional, and enterprise activities and regularly engages policymakers to ensure ongoing funding of genomic testing and sustainability

Clinicians Patients Ethics

Data

storage

Electronic Medical Record

Sequencing Laboratories

Government

Diagnostics

Hospitals

Data security

Insurers

Pathology

Bioinformaticians

Whole of

system

change is

needed

Precision MedicineThe Future is Now

• The Olden Days

• The Global Scene

• Right Here. Right Now.

The Australian Health Care System

Australia’s Health 2014, AIHW

Health service funding and responsibilities

Shared models,

common leads

Building

evidence +

infrastructure

Mapping + piloting

approaches

Global reach

Standardising

practices + policy

Sequencing,

diagnostics + data

infrastructure

Addressing ethical,

legal & social

implications

Melbourne Genomics Health Alliance formed

Queensland Genomics Health Alliance

commenced

Sydney Genomics Collaborative commenced

2013 2014 20152014 2016 2016

Australian Genomics formed

2016

Melbourne Genomics Health Alliance gov + partner

funding launched

Australian Genomics commenced

2017

Canberra Clinical Genomics launched

2017

Zero Childhood Cancer launched trials

SA Genomics Health Alliance

formed

2017

Genomic InitiativesLINKED AND COLLABORATIVE

Melbourne Genomics Health AllianceDemonstration Project 2014 – 2015

34

Establishing state-wide platform for genomic information.

Developed prototype system

multiple organisations & different conditions.

Evaluate prototype compared to standard care

what worked, what didn’t, potential solutions,

detection rate, change in management, cost effectiveness

Shared approaches.

Approach:

Prospective recruitment (n=315 patients).

Five flagships – childhood syndromes, inherited neuropathy, focal epilepsy, colorectal cancer, acute myeloid leukemia

Whole exome sequencing.

Targeted analysis.

In parallel with usual investigations.

Shared approaches

Multidisciplinary review

meetings

Curation

guidelines

Common clinical consent

form

(germline)

Data

standards

Common report formatCommon informatics

pipeline

State-wide approach to genomic data

management in Victoria

Melbourne Genomics Health Alliance

Key findings

Almost every patient agreed to additional use of re-identifiable data for research

99% agree to additional use of re-identifiable genomic data (954/966)

Majority of patients have no concerns about sharing their data after genetic counselling

97% received enough information (381/394)

93% have no remaining concerns (360/387)

13 had concerns (privacy, potential for discrimination – employment, insurance)

Patients accept genomic sequencingMore than 96% of patients consented

Commonclinical consent form

Opt in to share reidentifiable data for activities related to their condition

Sharing of ‘anonymized’ data

Evidence generation

Usual care WES

Diagnostic yield 11% 58%

Change in Mx 4% 16%

Cost per diagnosis AU$27,050 $6,003

Diagnosis

N=48

No diagnosis

N=32

N=80

Infants

? Monogenic

disorder

* Stark et al (2016,2017) Genet. Med.

18 months later…

A diagnosis restores reproductive confidence

Australian Genomics TARGETED CALL FOR RESEARCH (start date: 2016)

• Demonstrate how patient benefit could be maximized through application of genomic data in one or more human diseases.

• Provide evidence to inform analysis on the cost effectiveness of implementing genomic data into the Australian health system.

• Demonstrate practical strategies for implementation that could be used by Australian health system planners and policymakers.

• Build Australia’s research and research translation capacity in the area of genomics and healthcare.

KEY ACTIVITY HUBS

Australian Genomics80 PARTNER INSTITUTIONS

Australian GenomicsOUR PURPOSE

Provide strategies to

government for the equitable, effective and sustainable delivery of genomic

medicine in healthcare.

Ensure genomic and medical

data is stored safely and

shared responsibly to increase our

understanding of health and

disease.

Build Australia’s research and

clinical expertise in

genomic medicine

Enhance Australia’s gene

discovery, functional

genomics and drug discovery

research capacity

Advance a new era in clinical

delivery where the patient is

informed, involved and empowered.

Promote ethical, legal

and social responsibility in the application

of genomic knowledge

Australian GenomicsHEALTH SERVICES RESEARCH PROGRAM

Australian GenomicsPROGRAMS, FLAGSHIPS AND PROJECTS

Australian Genomics NATIONAL DIAGNOSTIC AND RESEARCH NETWORK

Driven by clinical flagships – each flagship differs slightly in design,

technology application and maturity of genomic delivery in current

clinical practice, but have common elements:

• Mapping referral practices, methodologies and funding for standard of

care for the condition in each state

• Prospectively recruiting participants

• Applying genomic testing to demonstrate the relative diagnostic

efficacy

• Capturing health costs

• Identifying impacts of genomic testing (altered management or treatment, altered diagnostic interventions or family management,

improvement to patient choices)

• Undertaking participant surveys and evaluations

Australian Genomics sites

Royal Children’s

Alfred

St Vincent’s

Austin HealthMonash Health

Sydney Children’s Hospital Network

Royal North ShoreRoyal Adelaide

Women’s and Children’s

Princess Margaret Hospital

for Children

Royal Perth

Royal Brisbane and Women’s

Lady Cilento Children’s

The Wesley

Royal Hobart

Sir Charles Gairdner

King Edward Memorial

PathWest QEII

Royal Melbourne

Peter MacCallum

Canberra Hospital

Liverpool

Westmead (Adult)Prince of Wales

Royal Prince Alfred

Princess Alexandra

Australian GenomicsETHICS, GOVERNANCE FRAMEWORK

Fiona Stanley Hospital

John Hunter

St Vincent’s

Royal Darwin Hospital

Clinical Flagship Projects

OF THE AUSTRALIAN

GENOMIC ALLIANCES

The collective strength of the Genomic

Alliances across

Australia:

Melbourne Genomics,

Queensland

Genomics,

Sydney Genomics

Collaborative,

Australian Genomics.

Flagship AllianceNumber of

RecruitsFlagship Lead(s) Flagship Alliance

Number of

RecruitsFlagship Lead(s)

Acute Lymphoblastic

Leukaemia Australian 300 Deborah White Neuromuscular Disorders Australian 300 Nigel Laing

Somatic Cancer

*with MGHAAustralian 165 Stephen Fox

Mitochondrial Disorders

*with AMDFAustralian 210

John Christodoulou

David Thorburn

Cancer Risk Paed / AYA

*with NSW Cancer Genomics Australian 1400 David Thomas Epileptic Encephalopathy Australian 105 Ingrid Scheffer

Hereditary Cancer

Syndromes * with ICConAustralian 200 Robyn Ward Brain Malformations Australian 120

Rick Leventer

Paul Lockhart

Hereditary Colorectal Cancer Melbourne 35 Alex Boussioutas Leukodystrophies Australian 50Rick Leventer

Paul Lockhart

Acute Myeloid Leukaemia Melbourne 45 Andrew RobertsRenal Genetics

*with KidGenAustralian 270 Andrew Mallett

Advanced non-Hodgkin

LymphomaMelbourne 105

Stephen Opat

Miles PrinceGenetic Immunology Australian 150 trios Matthew Cook

Solid Tumour Cancers

*with AGHAMelbourne 200 Jayesh Desai Intellectual Disabilities Australian 50 trios

Tony Roscioli

Mike Field

Cutaneous Malignant

MelanomaQueensland 380 Peter Soyer

ChILDRANZ Interstitial Lung

DiseaseAustralian 120 Adam Jaffe

Lung Cancer Queensland 400 Matt Brown Acute Care Australian 250Zornitza Stark,

Marcel Dinger,

Metastatic Melanoma Sydney 400 Graham MannCardiovascular Genetic

DisordersAustralian 400

Chris Semsarian

Julie McGaughranHIDDEN Renal Genetic

DisordersAustralian 200 Andrew Mallett

Perinatal Autopsy Melbourne 110 Jackie Collett Childhood Syndromes Melbourne 145 Sue White

Schizophrenia Sydney 400 Murray Cairns Hereditary Neuropathies Melbourne 50 Monique Ryan

Mendelian Disorders Sydney 100 Tony Roscioli Focal Epilepsy Melbourne 40 Patrick Kwan

Epilepsy Sydney 100 Tony Roscioli Complex Care Melbourne 140 Sue White

Maturity Onset Diabetes of

the YoungQueensland 490 John Prins Congenital Deafness Melbourne 112 David Amor

Complex Neurological /

Neurodegenerative diseaseMelbourne 110 Samuel Berkovic Dilated Cardiomyopathy Melbourne 100 Paul James

Immunology Melbourne 200 Jo Douglass

Controlling Superbugs Melbourne2000 - 3000

(bacterial)

Lindsay Grayson

Ben HowdenBone Marrow Failure Melbourne 150

David Ritchie

Piers Blombery

Nosocomial Infections Queensland1500

(bacterial)David Paterson Kidney Genetics (KidGen) Melbourne 200 Catherine Quinlan

Mendelian

ImmunodeficienciesSydney 100 Tony Roscioli

Mitochondrial Disease Sydney 370 Carolyn Sue Blinding Retinal Dystrophy Sydney 170 Robyn Jamieson

Congenital Heart Disease Sydney 185 Sally Dunwoodie Genetic Disorders of Bone Sydney 150 Andreas Zankl

Inherited Cardiomyopathies Sydney 160 Chris Semsarian Future Projects - all Alliances ~6000

Australian State Genomic Alliances - total planned recruitment 16,000 - 17,000 (2013 - 2021)

Cancers Rare Diseases

Complex Disorders

Infectious Diseases

Rare Diseases

• Establish clinical and laboratory pathways to deliver ultra-rapid genomic testing

• Comprehensive interdisciplinary evaluation of ultra-rapid genomic testing in acute paediatrics

Laboratory pathway

Clinical utility

Health economics

EthicsImplementation

science

Workforce

Patient and family

AcuteCare

Genomics

Standard vs Rapid GenomicsStandard

2014-2015N=80

Rapid2016-2017

N=40

Test time 136 days(71-277)

16 days(9-109)

Result during first hospital admission

0 78%

Diagnostic yield 58% 52%

Clinical utility 34% 57%

Cost per diagnosis $10,788 $13,388

Cost savings $16,206 $543,178

Stark et al (2016, 2017,2018) Genet. Med.

Acute Care FlagshipRECRUITMENT SITES

Royal Children’s

Royal Women’sMonash Health

Royal North Shore

Women’s and Children’s

Royal Brisbane and Women’s

Lady Cilento Children’s

Westmead (Adult)

Royal Prince Alfred

John Hunter

Royal Hospital for Women

Sydney Children’s Hospital Network

12 Hospitals, 9 Genetic Services

12 NICUs (Level 3), 6 PICUs

< 5 days

20 patients

8 PICU, 9 NICU, 3 ward

$12,000

per case

Average TAT

75 hrs

Diagnostic yield

55%

Clinical utility

63%

Creating a network to connect

researchers who can investigate

functional genomics of newly discovered

genes and variants of unknown

significance.

Australian Functional Genomics is being led by a group of researchers and

clinicians from across Australia with the

aim of integrating functional genomics

into the diagnostic paradigm for

managing rare diseases and cancer in

Australian patients.

functionalgenomics.org.au

Australian Functional Genomics

The patient’s genomics data journey

Pre-test care

Clinician Tools

Patient Tools

Data

Genome data

repository

Automated analysis

Analysis platform

Classification & Reporting

Curation tool

Post-test care

Clinician Tools

Patient Tools

PROGRAM LOGIC

Data TransformationServices

Clinical ProfileMS

Quantitative DataMS

PatientArchive

Query ExecutionEngine

Phenotype Analytics

MS

VariantAtlas

Phen-gen queries

Phen-gen-quality queries

Quantity-to-qualityanalytics

Reported outcomes(pathogenicity)

Curated Variant Store

P2

P3

P1

Genome DataStoreClinical Genome

Sequencing

P5

Clinical Data Capture

Quality Assessment and Annotation

FLAGSHIPS

P4

Clinical Variant Classification

qProfiler

Australian Genomics Program 2 Overview

OntoServer

Matchmaker

Exchange

Activities and interrelationships between the Data Program projects

Australian Genomics

National System for Sharing Data

Federal Budget May 2018AUD$500M

National Australian Genomics Mission

• Provide strategies to government for the equitable and effective delivery

of genomic medicine in healthcare.

What Next?

• Generate evidence in new areas –

acute care, prevention (RCS, NIPT,

NBS) and targeted therapies

• Enhance Australia’s gene discovery,

functional genomics and drug discovery research capacity.

• Promote ethical, legal and social

responsibility in the application of genomic knowledge.

Global ConsortiumOF NATIONAL GENOMICS INITIATIVES

• National Initiatives encouraged to

implement tools and standards being

developed by GA4GH (code of

conduct, ethics, consent standards).

• Established initiatives should share best

practices to assist emerging initiatives.

Oct 17, 2016 - Vancouver, CanadaMay 24, 2017 – London UK• Africa

• Australia• Brazil• Canada• Denmark • England• Finland

• France• GenomeAsia 100K• India• Japan• Netherlands • Qatar

• South Africa • Switzerland • Turkey • United States of America

May 2018 – Toronto, CanadaOctober 2018 – Basel, Switzerland

National Initiatives Meetings

Value of the network:

• Valuable to compare experiences to avoid "reinventing the wheel"

• Different stages of development. Complementary perspectives.

Opportunities for sharing:

• Implementation of GA4GH standards and tools.

• Beta testing of tools e.g. Capturing clinical phenotype.

• Minimal clinical dataset to interpret genome.

• Flexible consent for data sharing.

• Educational resources - including approaches to public engagement.

• Experience with Indigenous populations.

• Share reference populations.

• Evidence to support policy and government funding: cost effectiveness, diagnostic efficacy and changes in patient management.

• White Paper: State of the Nations..

Variant Atlas

Patient Archive

Tool

Thank youaustralian.genomics@mcri.edu.auaustraliangenomics.org.au