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Legal Impediments to Advances in
Medical ResearchInstitute of Biotechnology Law and Ethics
Sheffield June 17th 2011
Sir John Burn MD FRCP(Lond. & Edin.) FRCPCH FRCOG F MedSci
Honorary Consultant Newcastle Hospitals NHS Foundation Trust
Professor of Clinical Genetics, Newcastle University
NHS North East Lead Clinician
Genetics Chair, National Institute of Health Research
CEO Northgene Ltd, non-exec director Newgene Ltd, Medical Director Quantum Dx
Institute of Genetic Medicine
Newcastle University
Centre for Life, Newcastle UK
Manhattan plot for flucloxacillin GWAS
HLA B*5701 responsible for liver toxicityDaly A et al Nature Genetics 2009
MHC region
Strongest signal with
HCP5 SNP-marker for
B*5701
In defined populations we can
limit our tests to only those changes
we know the meaning of
Sequenom mass spectrometry
Direct to consumer genetic testing
2011
The current crop of tests for sale on the
internet are mostly pointless or
misleading
Only by massive data merger and
analysis will real health gains be
achieved
Functional classification of JDW
SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
Imagine if there were only 2
genes for height, each with only 2 alleles H
or T of equal frequency
T T T T
T T
T T
H
T
H
H
H
H
HH H
H
H
H
H H
HH
H H H H H H T T T
T
T
TTT T
T T
H
HH H T
T
T
H H H
H HH
HT TT
T T
T T
T T
43210
10
We discover one of the genes and
call it BYH1: somebody would suggest using it
for disease prediction
T T T T
T T
T T
H
T
H
H
H
H
HH H
H
H
H
H H
HH
H H H H H H T T T
T
T
TTT T
T T
H
HH H T
T
T
H H H
H HH
HT TT
T T
T T
T T
43210
averageshortVery
shorttall
Very
tall
Always bump
your head
Often bump
Your head
What causes inflammatory bowel
disease?
2001
NOD2
2007
IL23R
ATG16L1
IRGM
First 2 millennia
IBD is “genetic”:
Twin studies
Ethnicity
Family studies
Linkage analysis
timeline
2009
IL23R
ATG16L1
IRGM
2011- at least 32 genes
Innate immune signalling
Autophagy
ER biology
Pathogenic Th17-Treg balance
2ndary immune response
Henderson P& Satsangi J Clin Med 2011:11;8-10
RISK SCORE METHOD
PROCAM/Framingham
HDL score
LDL score
+Diabetes score
Total for every subject
Assign a value to each level of risk factor
Trait PROCAM F’Ham
Age <55
55-59
>60
SYS <120
120-129
130-139
140-159
>160
Smoke no
yes
+16
+21
+26
0
+2
+3
+5
+8
0
+8
+6
+8
+10
0
0
+1
+1
+2
0
+3
0
0.2
0.4
0.6
6 7 8 9 10 11 12
Risk score
Pro
ba
bil
ity
5%
24%
Risk
Of MI
What % of events does
score predict in NPHSII?
19
RISK SCORE METHOD
PROCAM/FraminghamClassical Risk factors
0
0.25
0.5
0.75
1
10 10.5 11 11.5 12 12.5 13 13.5
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5% False Positive
in no-CAD
11% of men who get
CAD have baseline
score over cut-off
89% of the events that occurred over 10 years
would not be predicted by the score !!.
Can we improve on this with genotypes?
Whıch genes
to study ?
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes p<0.0001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
0.2
0.4
0.6
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER!
24% of cases
have score
over cut-off
5% FPR
Classical Risk factors + Genotypes + Smokıng
22
Human Variome Project
Aims to create a network of locus specific databases linked to a shared
repository to enable efficient and effective interpretation of himan genomic
variation
Written and verbal consent given to any ethical use to investigate the gentic factors in childhood disease
(January 1996-January 2002)
0
10
20
30
40
50
60
70
80
90
100
% T
otal
mon
thly
bir
ths
The North Cumbria Community genetics project
Chase et al J Med Genet 1998;35:413-416
6000 cord bloods
3000 mothers
Legal Issues for consideration
Human Tissue Act
Data Protection Act
Section 251 NHS Act 2006
Article 8 Eu Convention on
Human Rights
Can the NHS collect generic consent
to use of genomic information?
Recognise the need for more
knowledge
Standardise hospital consents to
allow generic use of material
Consider security
Consider incidental findings
Engage with ethics committees