The Predictivity Concept

Peter ProppingInstitute of Human Genetics

University of Bonn, Germany

CDBI Seminar on predictivity, genetic tests and insurance

Strasbourg, 3-4 December 2007

Source: Dr. Ron Zimmern, Oxford

Gene-environment Interaction:

Cystic fibrosis

Fragile XDuchenne muscular dystrophy

Heart disease

PKU

Cancer

Diabetes

Multiple sclerosis

Schizophrenia

Asthma TBObesity

Alzheimer

Autism

MeningococcusStruck

bylightning

Motor vehicle

accident

Rheumatoid arthritis

‘Totally’ Genetic

‘Totally’Environmental

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 sclerosisdegenerative brain disorders

Electrocardiogram- e.g. hereditary disturbance of conductivity (long QT-syndrome)

Blood biochemistry- e.g. hypercholesterolemia

hyperlipidemia

I:1

60 y

I:2

58 y

II:1

36 y

II:2

34 y

II:4

21 y

II:3

34 y

III:1

10 y

III:2

8 y

III:3

5 y

Genetic diagnostics in familial adenomatous polyposis (FAP)

I:1

60 y

I:2

58 y

II:1

36 y

II:2

34 y

II:4

21 y

II:3

34 y

III:1

10 y

III:2

8 y

III:3

5 y

Predictive diagnostics in familial adenomatous polyposis (FAP)

CRC, 56y

CRC, 32yHNPCC?

30y 28y

? ?

2y

Persons at risk for Lynch Syndrome

(Hereditary Nonpolyposis Colorectal Cancer, HNPCC)

Cumulative risk in carriers of amutation in the BRCA1 or BRCA2 gene

Meta-analysis, King et al., Science 2003

BRCA1 BrCa

BRCA2 BrCa

BRCA1 OvCa

BRCA2 OvCa

Gen.pop. BrCa

Gen.pop. OvCa

X

0

10

20

30

40

50

60

70

80

90

100

0 30 40 50 60 70 80

X

X

XXX

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 polyposisPolycystic kidney disease, type 1Hereditary deafness, several late onset forms

Untreatable:Huntington diseaseMyotonic dystrophyAlzheimer disease, autosomal-dominant formsSpinocerebellar ataxia, several formsFacio-scapulo-humeral muscular dystrophyRetinitis pigmentosa, several late onset forms

Concordance rates in identical (monozygotic, MZ) and fraternal (dizygotic, DZ) twins

%

MZ DZ

Coronary heart disease 46 12

Hyperthyroidism 47 7

Neurodermitis 83 28

Diabetes mellitus I 45 5

Diabetes mellitus II 95 10

Lepra 59 20

Epilepsy („idiopathic“) 86 4

Schizophrenia – narrow definition 26 4-10

– wide definition 41 10-20

Genetic model of a complex (multifactorial) disease:

Hypertension as an example

„„super-normal“super-normal“ slightly slightly predisposedpredisposed

slightly slightly increased increased

definitely definitely increasedincreased

severely illseverely 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 Controls

Wildtype / Wildtype 227 248

Wildtype / Ins 57 23

Ins / Ins 20 1

Positive predictive value:

Homozygous 20 = 0,95

Heterozygous 57 = 0,71

2021

5780

Relationship between Genotype Frequency, Relative Risk and Positive Predictive Value

Disease Disease Genotype Genotype Relative Risk PPVFrequency Frequency

COPD+ 0,05 Pi ZZ 0,0005 20,0 99,1%

Narcolepsy 0,0005 DQB1*0602 0,021 10,5 0,4%homozygosity

+COPD = chronic obstructive pulmonary disease

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