next generation sequencing: a policy...
TRANSCRIPT
Next Generation
Sequencing:
A Policy Perspective
Koen Devriendt
Centre for Human Genetics
University of Leuven, Leuven, Belgium
METAFORUM Total genome analysis 25 statements
Prof. Jan Aerts (bio-informatics)
Prof. Pascal Borry (medical ethics)
Prof. Koen Devriendt (human genetics)
Prof. Kris Dierickx (medical ethics)
Prof. Gert Matthijs (human genetics)
Prof. Yves Moreau (bio-informatics)
Prof. Erik Schokkaert (economics)
Prof. Ann Swillen (educational psychology)
Prof. Hilde Van Esch (human genetics)
Mevr. Griet Verhenneman (ICT-law)
Prof. Joris Vermeesch (human genetics)
http://www.kuleuven.be/metaforum/page.php?FILE=wg_text&ID=14&TID=3&LAN=E
enthousiasm
expectations
(time) pressure
exome and genome sequencing
- hereditary risks?
- presumed causes can be disproved
- predictive test for late onset disorders
- prognosis – sometimes even personalized therapy
long term vision
rational use
priorities
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
intelligence
height
physical strength
attractivity
variationin normalcharacteristics
personality
cleft lip and palate
obesity
cystic fibrosis
dementia
variation
in disease
Monogenic
albinism
Multifactorial
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
lipverhemeltespleet
zwaarlijvigheid
mucoviscidose
dementie
variatie
in ziekten
Monogeen
albinisme
Multifactorieel
intelligentie
gestalte
Fysische kracht
attractiviteit
VARIATIE IN NORMALEKENMERKEN
persoonlijkheid
interpretation ?
statement
In the debate, it is essential to distinguish
the uninterpreted (raw) genome sequence
and interpreted genomic information.
biobank
TTGGTTGGAACGTAGACTGAATGCGACTGAATGC
CAACCCTGGTATTGGTGACTGAATGCGTCCCGTG
TACAAGGTTAGTAATGTACGACTGAATGCCATTGA
CCAGTGGAATTTCCGTAATACGTGTGGCGCGTGC
GTAACAGACTGAATGCCACTGACTGACCATCCTG
GTAGCTAGTCCCAGTGGAATAAGTCGTAGCTGTC
GTGACGACTGAATGCGTAACGTATATGACACACG
TCAGCCAGTGGAATTACGGTCAGTACACACATGC
TGTGGTGCAGGACTGAATGCTACAGATACAGTAC
AGATTAGCAGAAATGCGACTGAATGCAGATTTAGT
sequence database
statement
The (uninterpreted) genome sequence
is an annex of the medical file
with a special status of uninterpreted data.
genome sequence and
genetic testing ?
Long QT syndrome ?
LQT1
LQT2
LQT3
LQT4
LQT5
LQT6
LQT7
LQT8
LQT9
LQT10
LQT11
LQT12
LQT13
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
sequence
database
LQTS?
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
LQT1 LQT2 LQT3
LQT4 LQT5 LQT6
LQT7 LQT8 LQT9
LQT10 LQT11 LQT12
LQT13
expert and analysis
system
clinical question
LQTS ?
LQT5medical
file
• real-time = faster and cheaper
• limited to clinically relevant information
at this moment
• avoiding too much information
- irrelevant at this moment
- not interpretable (unclassified variants)
- unwanted (incidental findings)
• when this occurs: there is a clinical context
to deal with these issues
sequence
database
LQTS?
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
LQT1 LQT2 LQT3
LQT4 LQT5 LQT6
LQT7 LQT8 LQT9
LQT10 LQT11 LQT12
LQT13 LQTS14 LQTS15
LQTS16
expert and analysis
system
unanswered
clinical questions
MEDICAL FOLLOW-UP
LQT15medical
file
statement
The genome sequence is preserved
thus ensuring optimal medical care
for a specific medical problem
through a continuous interpretation
of the genome sequence
based on novel insights.
“In the debate, it is essential to distinguish the uninterpreted genome
sequence from the interpreted genomic information.”
Increased medical knowledge
• uninterpreted genome sequence
= permanent, constant, static
• interpreted genome sequence
= a snapshot, changing, dynamic
=> Need to continuously
interrogate and interpret the genome sequence
during follow-up for an existing clinical problem
or in a novel clinical situation
Other questions in the course of life
sequence
database
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
Mutation(s)
in genes for
cleft lip and palate?
expert and analysis
system
clinical question :
• cause
• recurrence risk
• prognosis
medical
file
sequence database
clinical question :
• cause
• recurrence risk
• prognosis
medical
files
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
de novo mutation
in a gene
that can explain
the syndromic
presentation?
expert and analysis
system
father child mother
sequence
database
clinical question :
increased genetic risks?
medical
files
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
carrier for mutation(s)
in genes for
autosomal recessive
or X-linked
disorders ?
expert and analysis
system
sequence
database
clinical question
heredity?
medical
file
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
mutation(s) or
risk variants
in genes for
breast cancer?
expert and analysis
systemBreast cancer
Familial
sequence
database
clinical question :
prognosis, treatment …
medical
file
Breast cancer ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
Which mutation(s) /
variants
in genes that
determine the type of
cancer
expert and analysis
system
statement
The genome sequence is preserved
thus ensuring optimal medical care
for a specific medical problem
through a continuous interpretation
of the genome sequence
based on novel insights.
High requirements :
•To the users
•To the expert system
• to the DNA sequence
interpretation of the DNA sequence :
- only based on validated genotype-phenotype correlations
- include all additional variables that determine the
significance of a genetic variant :
- family history
- personal history
- clinical findings
- results of other tests
…
High requirements : to the users
& expert system
gene A7
gene C38gene B1
gene J01
environment
1
environment
11
environment
9
environment
3
environment
17
environment
35
gene ZA8
gene LL4
gene E2
gene ZA2
gene O0
gene 7l
gene M81
gene Z21gene F3
gene 007
gene N45
gene II
statement
The physician can interrogate the genome sequence
only for a specific clinical question / situation
for which he is qualified
High requirements : to the users
high requirements : to the users
Statement :
Total genome analysis for minors
is only justifiable if the interests
of the minor in question
are given priority.
clinical activity
sequence
database
medical
file
high requirements : to the users
statement
The genome sequence
and genomic information
are confidential
statement
Given the fact that genetic analysis is generally only
conducted once in a person’s life,
false-positive and false-negative results may have severe
consequences.
The technology must be advanced enough on this point
before information is passed from the research to the
clinical context,
and the service should meet the highest standards of
quality.
high requirements : to the technologie
Genetic results :
• medical implications for the person himself
• implications regarding heredity ?
- genetic risks
- family members :
* carrier diagnosis
* predictive testing
* prenatal / preimplantation diagnosis
counselling in Centre for Human Genetics
interpretation of the DNA sequence
in other situations ?
information
with clinical utility,
independently from
a direct medical context or
question
ATTGTACGTGATGACCAGTGGAAT
ACCGTAAGGTAAAGTACCGTGTAC
TTGGTTGGAACGTAGACTGAATGC
CAACCCTGGTATTGGTGTCCCGTG
TACAAGGTTAGTAATGTACCATTGA
TTCCGTAATACGTGTGGCGCGTGC
GTAACACACTGACTGACCATCCTG
GTAGCTAGTCAAGTCGTAGCTGTC
GTGACGTAACGTATATGACACACG
TCAGTACGGTCAGTACACACATGC
TGTGGTGCAGTACAGATACAGTAC
AGATTAGCAGAAATGCAGATTTAGT
sequence
database
• farmacogenetics
• risk factors for late-onset
disorders
• carrier for X-linked or
recessive conditions
• …
expert and analysis
system
?
Introduction at a population level is not straightforward:
- limited insight into the significance of many variants
(=> caution with interpretation)
- large differences in clinical utility for different diseases
(effect size of risk, prevention, severity, …)
- changing questions during life
(e.g. neonatally or at reproductive age)
- how to deal with informing family members
-…
statement
It will become possible to generate systematically
additional genomic information with clinical utility
independently from a specific medical question.
However, it is not feasible
to provide the required extensive counselling
on an individual basis
within our current public health system
* Will be realized progressively
* transfer = depending on clinical utility,
based on the acquired medical evidence
for each specific disorder.
Long term goal :
statement
In the light of the growing amount of information
there will be an increasing need for a sufficient number of
well trained professionals who are capable of interpreting the
genetic information and translating this into health measures
In additional it wil be essential to inform the general public
on the opportunities and limitations of genetic information.
Who oversees all of this ?
sequence
database
interpreted genomic information
* Clinical questions
* Additional information with clinical utility
* screening
(global) medical file
statement : the general physician ?
METAFORUM Total genome analysis 25 statements
Prof. Jan Aerts (bio-informatics)
Prof. Pascal Borry (medical ethics)
Prof. Koen Devriendt (human genetics)
Prof. Kris Dierickx (medical ethics)
Prof. Gert Matthijs (human genetics)
Prof. Yves Moreau (bio-informatics)
Prof. Erik Schokkaert (economics)
Prof. Ann Swillen (educational psychology)
Prof. Hilde Van Esch (human genetics)
Mevr. Griet Verhenneman (ICT-law)
Prof. Joris Vermeesch (human genetics)
http://www.kuleuven.be/metaforum/page.php?FILE=wg_text&ID=14&TID=3&LAN=E