australian genomics health alliance › __data › assets › pdf_file › 0009 › ...• vast...
Post on 30-May-2020
9 Views
Preview:
TRANSCRIPT
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
top related