The Predictivity Concept
Peter Propping
Institute of Human Genetics
University of Bonn, Germany
CDBI Seminar on predictivity, genetic tests and insurance
Strasbourg, 3-4 December 2007
Gene-environment Interaction:
Heart
disease
PKU
Cancer
Cystic
fibrosis
Diabetes
Fragile X
Duchenne
muscular
dystrophy
Rheumatoid
arthritis
Schizophrenia
Multiple
sclerosis
Motor
vehicle
accident
Alzheimer
TB
Asthma
Obesity
Meningococcus
Autism
‘Totally’
Genetic
Struck
by
lightning
‘Totally’
Environmental
Source: Dr. Ron Zimmern, Oxford
The Human Genome
3,2 x 109 nucleotide pairs
not a “unique” sequence,
but appreciable interindividual variation
any two genomes:
99,9% DNA sequence identity,
thus, 0.1 % sequence differences (3 mio).
Any individual (diploid, i. e. two genomes):
6 mio differences to the reference genome.
Modes of inheritance
Autosomal dominant
?
Autosomal recessive
?
X-chromosomal
?
Two major groups of genetic diseases
Monogenic (= Mendelian) disorders
- monocausal
- clear relationship between genotype and phenotype
- about 2.000 disorders clarified
- most disorders are rare
- therapy mostly difficult
Genetically complex (multifactorial) disorders
- complicated genetic structure
- many of them common in the population
- may be influenced by exogenous factors
- therapy frequently possible
Conceptual distinction
-
Prognosis: statement about the future course of a past
or currently existing disorder
-
Prediction: probability of the onset of a disease
that has not yet occurred
Methods of prediction and prognosis in a proband
-
medical history
-
medical examinations
-
family history
-
predictive genetic diagnosis
-
prediction based on lifestyle
Prediction on the basis of medical examinations
Imaging techniques (CT, MRT, Ultrasound)
e.g. polycystic kidney disease
hereditary brain tumors, e.g. tuberous sclerosis
degenerative brain disorders
Electrocardiogram
e.g. hereditary disturbance of conductivity (long QT-syndrome)
Blood biochemistry
e.g. hypercholesterolemia
hyperlipidemia
Genetic diagnostics
in familial adenomatous polyposis (FAP)
60 y
I:1
36 y
II:1
I:2
34 y
II:2
34 y
II:3
10 y
III:1
58 y
II:4
8y
III:2
21 y
5y
III:3
Predictive diagnostics
in familial adenomatous polyposis (FAP)
60 y
I:1
36 y
II:1
I:2
34 y
II:2
34 y
II:3
10 y
III:1
58 y
II:4
8y
III:2
21 y
5y
III:3
Persons at risk for Lynch Syndrome
(Hereditary Nonpolyposis Colorectal Cancer, HNPCC)
?
?
CRC, 56y
CRC, 32y
HNPCC?
2y
30y
28y
Cumulative risk in carriers of a
mutation in the BRCA1 or BRCA2 gene
100
90
80
70
60
50
X
40
30
X
20
X
10
0
BRCA1 BrCa
BRCA2 BrCa
BRCA1 OvCa
BRCA2 OvCa
Gen.pop. BrCa
Gen.pop. OvCa
X
X
X
Meta-analysis, King et al., Science 2003
Examples for Hereditary disorders with late onset for
which predictive genetic diagnosis is possible
(autosomal-dominant)
Treatable:
Hereditary tumor syndromes:
breast/ovarian cancer
colorectal cancer
familial adenomatous polyposis
Polycystic kidney disease, type 1
Hereditary deafness, several late onset forms
Untreatable:
Huntington disease
Myotonic dystrophy
Alzheimer disease, autosomal-dominant forms
Spinocerebellar ataxia, several forms
Facio-scapulo-humeral muscular dystrophy
Retinitis pigmentosa, several late onset forms
Concordance rates in identical (monozygotic, MZ)
and fraternal (dizygotic, DZ) twins
%
MZ
Coronary heart disease
Hyperthyroidism
Neurodermitis
Diabetes mellitus I
Diabetes mellitus II
Lepra
Epilepsy („idiopathic“)
Schizophrenia – narrow definition
– wide definition
46
47
83
45
95
59
86
26
41
DZ
12
7
28
5
10
20
4
4-10
10-20
Genetic model of a complex (multifactorial) disease:
Hypertension as an example
„super-normal“
slightly
predisposed
slightly
increased
definitely
increased
severely ill
Relationship between genotype and phenotype in a
complex disease
-
Predictive value of a genotype
• Positive Predictive Value (PPV)
- Fraction of persons with a predisposing genotype who
will develop the disease
• Negative Predictive Value (NPV)
- Fraction of persons without the genotype who do not
have the disease
Positive Predictive Value (PPV):
Example: Crohn disease and association with NOD2 variant
NOD2 Genotype
Patients
Wildtype / Wildtype
Controls
227
248
Wildtype / Ins
57
23
Ins / Ins
20
1
Positive predictive value:
Homozygous
20
20
21
= 0,95
Heterozygous 57
57 = 0,71
80
Relationship between Genotype Frequency, Relative
Risk and Positive Predictive Value
Disease
Disease
Genotype
Frequency
COPD+
0,05
Pi ZZ
0,0005
20,0
99,1%
Narcolepsy
0,0005
DQB1*0602
homozygosity
0,021
10,5
0,4%
+COPD
Genotype
Frequency
= chronic obstructive pulmonary disease
Relative Risk
PPV
Predictability of affection status in the carrier of a
predisposing genotype
-
monogenic diseases
• up to 100% depending on penetrance
-
complex (multifactorial) diseases
• often low
• eventually higher after genotypic profiling
To what degree can multifactorial
disorders be predicted ?
Generally, the concordance rate of MZ twins is the
upper limit of prediction;
but:
only cross-sectional information taken into account,
no age correction possible;
global concordance rates give only average data, in
fact part of the cases higher degrees of heritability
may exist.
Screening approaches:
-
Genetic population screening
• newborn screening for treatable diseases
• e. g. preconceptual thalassemia screening on Sardinia and
Cyprus
• preconceptual screening in certain ethnic groups, e. g. for
Tay-Sachs in Jews
• cascade screening, e. g. for hypercholesterolemia in the
Netherlands
Screening approaches:
-
Ascertainment of persons at high risk through family history
• e. g. inherited breast/ovary cancer and Lynch syndrome
(HNPCC)
• population-based for preconceptual testing in recessive
diseases
The Future:
The “1000 Dollar Genome”
-
nightmare of informed consent
-
nightmare of interpretation