insights into successful research in rare diseases
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Insights into successful Research in Rare Diseases. Work by the Irish Motor Neurone Disease Research Group Orla Hardiman BSc MD FRCPI HRB Clinician Scientist Trinity College & Beaumont Hospital Dublin. What is a Rare Disease?. - PowerPoint PPT PresentationTRANSCRIPT
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Insights into successful Research in Rare Diseases
Work by the Irish Motor Neurone Disease Research Group
Orla Hardiman BSc MD FRCPIHRB Clinician Scientist
Trinity College & Beaumont Hospital Dublin
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What is a Rare Disease?
• “Life-threatening or chronically debilitating diseases which are of such low prevalence (fewer than 1 in 2,000) that special combined efforts are needed to address them.“
European Commission on Public Health
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Problems with Studying Rare Disease
• They are rare!• Knowledge deficit
– Delayed diagnosis– Low quality of care
• Limited access to new drugs.– Cost of drug development– Cost of post-approval drugs
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Solutions
• Population based Registers
• Centralized care
• Orphan drug legislation
• Advocacy
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Clinical Research in Rare Diseases
• Applied epidemiology– Databases and Registers
• Good clinical monitoring with attention to detail• Determination of relevant clinical questions• Phenotype genotype correlations• Biomarkers
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Advantages of Population Based Registers
• More accurate reflection of range of disease phenotypes
• Nobody is “lost to follow-up”• Captures patients that might not attend specialist
clinic– Too old– Too sick– Too poor
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Imperatives for Valid and Clinically Relevant Study
• Prospective study of incident cases • Adequate sources• “Capture recapture” methodology• Standardisation of population demography• Large numbers over sufficiently long follow up
period• Attention to clinical detail
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Motor Neuron Disease
• Commonest neurodegeneration of young and middle aged adults • Incidence 2.6/100,000• Prevalence: 1in 16,000• Lifetime risk 1:400• Unknown aetiology• 10% familial• Fatal within 3-5 years• No cure
Lou Gehrig1903 - 1941
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Irish Register of Motor Neurone Disease
• Commenced in 1993
• Ascertainment complete by 1995
• First epidemiologic data analysed for 1995-1997; Second 2005-2007
• Data collection ongoing: >1400 patients enrolled to date
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Experiences of the Irish Register over 15 years
• Basic epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Complex Genetics
• Comparison with other population
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WORLD EPIDEMIOLOGY OF ALS/MND
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Population Based Incidence of ALS/MND
0
2
4
6
8
10
12
Ireland Scotland Tx.,USA Wa.,USA Mn.,USA Denmark Israel Finland Sardinia On,Canada
Sweden N.Sweden
Incid
ence p
er
100,0
00 (
age 4
5-7
5)
True incidence and prevalence outside True incidence and prevalence outside predominantly Caucasian populations not predominantly Caucasian populations not widely knownwidely known
Traynor et al, 1999
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IRISH MND
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Experiences of the Irish Register over 15 years
• Basic epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Complex Genetics
• Comparison with other populations
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Age related Incidence Rates of ALS1997-2004
0.0
2.0
4.0
6.0
8.0
10.0
12.0
0-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+
Inc
ide
nc
e p
er
10
0,0
00
pe
rso
n-y
ea
rs
Age group (years)
male limb
male Bulbar
Female Limb
female bulbar
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SURVIVAL FROM MND
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Survival Effect of Multidisciplinary Clinics
0
.2
.4
.6
.8
1
0 .5 1 1.5 2 2.5 3 3.5 4 4.5Time from diagnosis (years)
Cum. Survival (multi-disciplinary) n = 108 pts.
Cum. Survival (general)n = 258 pts.
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Survival
Republic of Ireland v Northern Ireland
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Uses of the Irish Register of ALS
• Comparative epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Complex Genetics
• Comparision with other populations
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Uses of the Irish Register of ALS
• Comparative epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Complex Genetics
• Comparison with other populations
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Longitudinal Follow up
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Older, Aggressive Disease
Early Executive involvement
With time they develop
language/memory/VP
FTD Early memory and language difficulties
± subtle executive changes
More Benign course initially
High rate of developing executive dysfunction
Younger, Higher education and FSIQ
Slow motor progression
Small proportion develop abnormalities: mostly language or verbal fluency deficits
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Uses of the Irish Register of ALS
• Comparative epidemiology• Long term follow up of population• Accurate recording of clinical details• Identification of defined clinical subtypes• Genetics • Comparison with other populations
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FINDING FAMILIES
Manifestation definitions :
Amyotropic Lateral Sclerosis
Fronto Temperol Demetia
Pneumonia
Stroke
Congenital Cardiac Failure (CCF)
Depression
TB
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Finding Genes
16 causative genes known, accounting for ~15% of all MND
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Separating the Population by Causative Genes
Lancet Neurology 2012
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Uses of the Irish Register of ALS
• Comparative epidemiology• Long term follow up of population• Accurate recording of clinical details• Identification of defined clinical subtypes• Population Genetics • Comparison with other populations
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Looking for Susceptibility Genes
Genes of small effect that may contribute to risk
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Population Structure Within Europe(Novembre et al Nature 456 ; 6 , 2008)
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IRISH POPULATION ALSO DEMONSTRATES
GENETIC SUBSTRUCTURE:
Comparison With Dutch & US populations
Simon Cronin PhD Thesis
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Irish Population is Relatively Homogeneous
•Modern Ireland is derived from a restricted founding population with a higher degree of relatedness
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Angiogenin Mutations Are Associated with ALS
Nature Genetics 2006 38:4:411-12
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Uses of the Irish Register of ALS
• Comparative epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Complex Genetics
• Comparison with other populations
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EURALS(N= 25 million)
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EURALS: The Incident Cases
N=1028Piemonte
Lombardia
PugliaScotland
Ireland
Lancashire
231
15454265
194
130
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DRUG TRIALS
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RESEARCH INTO RARE DISEASES…..
Permits complete population based incidence & prevalence studies
•Identifies prognostic indicators
•Identifies subpopulation that can help to find new genes/ susceptibility factors
•Informs health services
•Facilitates international collaborations
•Provides well characterized populations for clinical trials
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Research Team and Collaborators• Clinical Epidemiology & Neuropsychology
– Dr.Marwa Elamin (Beaumont & TCD)– Dr.Niall Pender (Beaumont &TCD)– Ms.Catherie Lynch (Beaumont)– Dr.Peter Bede (Beaumont & TCD)– Dr.Susan Byrne (Beaumont &TCD)– Dr.Colin Doherty (St.James & TCD)
– Dr.Giancarlo Logroscino
– EURALS Steering Group (Europe)
Genetics, Prof.Dan Bradley (TCD) Mr.Russell McLaughlin (TCD) Mr.Kevin Kenna (TCD) Prof.Leonard Van Den Berg (Utrecht) Prof.Angnieska Slowik (Krakow) Prof.RH Brown Jr. (MGH Boston) Prof.Peter Andersen (Umea, Sweden)
Cuban CollaboratorsDr.Tatiana ZaldivarDr.Joel GutierrezDr. Gloria Lara Dr.Diana Garcia del Barco
Previous Research FellowsDr.Bryan J Traynor (NIH)Dr.Mike Alexander (LONDON /DUBLIN)Dr.Orna O’Toole (DUBLIN / NEW YORK)Dr.Matthew Greenway (TORONTO)Dr.Julie Phukan (LONDON)
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FUNDING SOURCES
• Health Research Board
• Irish Motor Neurone Disease Research Foundation
• Irish Motor Neurone Disease Association
• Irish Institute of Clinical Neuroscience
• Muscular Dystrophy Association USA
• American ALS Association
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FURTHER INFORMATION
RESEARCH MOTOR NEURONE
www.mnd.ie