Towards personalized

medicine in Estonia

Erkki Leego

IT adviser

Estonian Genome Center,

University of Tartu

Biobanks

• Biobank – An organized collection of human biological

material and associated information stored for one or more research purposes

• Population biobank – The collection has a population basis

– To supply biological materials or data derived therefrom for multiple future research projects

– It contains biological materials and associated personal data

Genetic research

• Most complex diseases are caused by a large

number of combined effects from genes,

lifestyle, and the environment

• New discoveries and development of tools

depend on studies of large collections of well-

documented, up-to-date epidemiological and

clinical data accompanied by biological

material from individuals

Estonian Biobank

• Estonian Genome Center, University of Tartu

• A prospective, longitudinal, population biobank with health record and biological materials

• Established in 2000

• 52,000 gene donors recruited -5% of the adult population

• Supported directly by the government

• Estonian Human Genes Research Act

Population pyramid (50155 participants)

02680536080401072013400

0100200300400500600700

18

20

22

24

26

28

30

32

34

36

38

40

42

44

46

48

50

52

54

56

58

60

62

64

66

68

70

72

74

76

78

80

82

84

Count EGCUT

Ag

e

Female

EGCUT

Estonia 2007

0 2680 5360 8040 10720 13400

0 100 200 300 400 500 600 700

18

20

22

24

26

28

30

32

34

36

38

40

42

44

46

48

50

52

54

56

58

60

62

64

66

68

70

72

74

76

78

80

82

84

Count EGCUT

Male

EGCUT

Estonia 2007

Count Estonia Count Estonia

Data “infrastructure” for

research

• Good quality data collection – Biomedical data (DNA, plasma, WBC)

– Phenotype

– Genealogy

– Epidemiology data

– Genotypes

• Open to various research projects

• Well defined procedures for data release

• Usable next 30 years

Questionnaire of EGCUT

Personal data

Place of birth

Place of residence

Nationality

Education

Occupation

Genealogy

Parents

Children

Siblings

Grandparents

Health behavior

Smoking and alcohol

Personality inventory NEO-

PI-3

Physical activity

EQ-5D

Nutrition

Health self-assessment

Chronotype questionnaire

MCTQ

Diseases

Diagnosis

ICD – 10

Treatment

ATC

Psychiatry module

M.I.N.I. and SSP

Questions about diabetes

Questions

about c/v diseases

Objective data

Height & weight

Blood pressure

Pulse

Handedness

Waist

Hip

Diagnoses in the database (50155 participants)

64245

8928

3106

12677

10766

11833

19918

13833

40209

60778

39490

12585

37322

21170

3352

134

1405

3202

5710

1610

619

0 10000 20000 30000 40000 50000 60000 70000

Certain Infectious And Parasitic Diseases A00-B99

Neoplasms C00-D48

Diseases Of Blood And Blood-Forming Organs And Certain…

Endocrine, Nutritional And Metabolic Diseases E00-E90

Mental, Behavioural Disorders F00-F99

Diseases Of The Nervous System G00-G99

Diseases Of The Eye And Adnexa H00-H59

Diseases Of The Ear And Mastoid Process H60-H95

Diseases Of The Circulatory System I00-I99

Diseases Of The Respiratory System J00-J99

Diseases Of The Digestive System K00-K93

Diseases Of The Skin And Subcutaneous Tissue L00-L99

Diseases Of The Musculoskeletal System And Connective Tissue…

Diseases Of The Genitourinary System N00-N99

Pregnancy, Childbirth And The Puerperium O00-O99

Certain Conditions Originating In The Perinatal Period P00-P96

Congenital Malformations, Deformations, And Chromosomal…

Symptoms, Signs And Abnormal Clinical And Laboratory Findings,…

Injury, Poisoning And Certain Other Consequences Of External…

Factors Influencing Health Status And Contact With Health Services…

External Causes Of Morbidity And Mortality V01-Y98

•In average a participant has

reported 7.8 different diagnoses

•98.3% of participants have

reported at least one disease

Education: the Estonian population vs. EGCUT (50155 participants)

0 10 20 30

Education unknown

No elementary education

Elementary education

Basic education

Secondary education

Professional secondaryeducation

Higher education

Scientific degree

%

Estonian population EGCUT

Using data

• Today’s focus is on Genome Wide Association Studies (GWAS) – "Genetic variants in novel

pathways influence blood pressure and cardiovascular disease risk„

– "Complement Factor H Polymorphism in Age-Related Macular Degeneration"

– …

• Next focus on rich phenotype, including health behavior and sensor data

• Then personalized medicine solutions

Example. Coffee drinking habits

1: 2002-2005; 2: 2007-2008; 3: 2009-2010

Example of science project

• Genetic map of Europe (link)

Genetic „map“ of Estonia

-0,03

-0,02

-0,01

0

0,01

0,02

0,03

0,04

-0,02 -0,01 0 0,01 0,02 0,03

PC

2

PC1

Põhja-Eesti

Lõuna-Eesti

Põhja

Lõuna

Secure data handling

Courier

Filled questionnairesPersonal data, health data, genealogy data.

Consent. Transportation code. Information encrypted.

Consent (p

aper fo

rm).

Bio

logic

al s

am

ple

s.

Coding center

Memory stick

Consent forms. Questionnaires.

Receptionist

New barcode

High security area Access to database

Scientists

Health data. No identification

data.

Health data and identification

data

National Digital Health Record DB & registries

Operative database

Phenotype database

Data collector ISCommunication server

Laboratory ISCryo Preservation – MAPI

Coding center IS

Coding challenges

EXTERNAL DATABASESdata collecting

BIOSAMPLES DATAmanagement

PERSONAL-, GENEALOGY-, HEALTH DATA

Formatting for integration, deindentification

DKOOD

I U T L

I

HEALTH DATAdata collecting

I T

PHENOTYPESintegration, quality control,

analysis

U L

CODING CENTRE

H

GENOTYPESraw data, , quality control,

analysis

U L

PROJECT-BASED RESEARCH

L

CODE RELATIONS

U D L V

genotypes, fenotypes, biosamples, analysis

D V

BIOSAMPLES DATAanalysis

L

IKOOD UKOOD TKOOD LKOOD VKOOD

FOLLOW UPcoordination

D

FEEDBACKPERSONALIZED MEDICINE

genotypes, fenotypes, biosamples, analysis

DATA REALEASE

BIOSAMPLES DATAlogistics

LT

H

HKOOD

D V

D V

National Digital Health Record DB

Online access to database

Scientists

Health data. No identification

data

Phenotype database

Patient Portal National DHR

Cancer Registry

Citizen RegistryCauses of Death Registry

Participant

Participant

Participant

Participant

Participant

Participant

Participant

EGCUT databasePersonal health

information

Additional questions.

Timeline data

Updated phenotype

data

Participant

Data release

EGCUT IS 2011-2015

Primary care physician

...

Ver. 5.0

Public opinion and awareness of the EGCUT 2001-

2013

Illumina Genome Analyser

10 Gbit Network10 Gbit Network

EGCUT Network High Perfomance Computing Centre

10Gbit

Coding Centre

InfrastructureServers

DATABASESData Colletor

Phenotype DatabaseLaboratory IS

InfrastructureServers24 Core,

192GB RAM, 1,76TB HDD

System Storage

System Storage Tape Library 1,2PB storage

Coding

Centre IS

Analyser servers184 Core, 2048GB RAM

Backup Server

16 Core1,2TB HDD24GB RAM

EGCUT servers and storageApril 2013

· 15 servers

· Datastorage 1,1 PB harddrives

· 1,2 PB system storage tape library

MAPI

Hamilton ASMASM Store

ASM Server

Datastoragewith servers

1,1 PB HDD

19 2318 2217 2116 2011 159 13 10 148 123 71 5 2 6402498-B24

System x3650 M3

1 2

3 4

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

System x3650 M3

1 2

3 4

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

19 2318 2217 2116 2011 159 13 10 148 123 71 5 2 6402498-B24

Computing power

· 3260 processor core

· 8,2 TB RAM

OperativeDatabase

HPC Cluster „Aurumasin“

52 node,512 Core,

2,3TB RAM,

50TB HDD

HPC Cluster „Vedur“80 node,

2560 Core, 3,75TB RAM,

110TB HDD

Example of

personal genetic

information

Ref: https://www.23andme.com/you/

Risk dependence on age

• Men ages 0-79 • Men ages 40-49

What can I do?

Ancestery and relatives

• Ancestery

• DNA relatives

Towards more

personalized

medicine

Calculating personal genetic

risks

Person

DNA

Personal disease risks

Personal variants

Database of known risk markers

Conditions for feedback

• Treatable health conditions with genetic

factors

– Melanoma

– Prostate cancer

– Type I and II Diabetes

– Lupus

– Age-Related Macular Degeneration

– Iron Overload/Hemochromatosis

Pharmacogenomics

• How genetic makeup affects an individual’s

response to drugs

• Aim is to ensure maximum efficacy with

minimal adverse effects

• Drugs and drug combinations can be

optimized for each individual's unique genetic

makeup

• Reduces cost of healthcare

New devices for self monitoring

• ECG adaptor for

smartphone

• Blood clucose sensors

• Sleep monitoring

• Ultrasound device Vscan

Ref: E. Topol. http://www.ted.com/talks/eric_topol_the_wireless_future_of_medicine.html

Challenges and issues

• Awareness doctors and patients

• New technologies and data empower patient with more possibilities to manage own health

• Ethical issues – Right to know and right not to know

– Treatable and non-treatable conditions

• Not enough knowledge about associations between DNA variants and diseases

• Large work-load to keep database of known risk markers updated

Estonia’s unique

starting point

Estonian E-services

• 99% of bank transfers are performed electronically

• 94% of income tax declarations made via the e-Tax Board

• 24% of votes were cast over the internet on 2011

• 62% persons have completed the e-census 2012

• 2000: Launch of e-Tax Board

• 2000: Launch of m-Parking

• 2002 : Introduction of national electronic ID-Card

• 2005: i-Voting was introduced

• 2007: Introduction of m-ID

• 2007: Launch of e-Police system

• 2008: Launch of e-Health system

• 2010: Launch of e-Prescription

• 2012: e-census

Tools and enablers of

information exchange

• One universal national identification code – Registries and databases use same code to uniquely

identify persons

• National PKI infrastructure

• The Estonian ID card – Smartcard with two digital certificates

• National Data Exchange Layer X-Road

• Obligatory national data security framework

• High public acceptance and trust – No public incidents or misuses (10 years)

Estonian information system

PHARMACIES AND

FAMILY DOCTORS

2009

X-Road, ID-card, State IS Service Register

HE

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11

NATION- WIDE

HEALTH

INFORMATION

EXCHANGE PLATFORM

2008 december

PRESCRIPTION

CENTRE

2010 january

PATIENT PORTAL

2009

X-ROAD

GATEWAY

SERVICE

2009

The Estonian ID card

• The ID card is a mandatory ID document for all Estonian residents from the age of 15

• Enables secure digital authentication and signing

• A digital signature has the same legal consequences as a hand-written signature

• Does not have any additional information – No bank account, no health information etc.

• Active cards: 1 209 594 (13.09.2013) – Estonian Population 1 286 540 (01.01.2013)

– Estonia has been issuing electronic ID cards from January 1st 2002

Public Key Infrastructure PKI

• PKI or the public key infrastructure enables secure digital authentication and signing

• The infrastructure also allows forwarding data by using an encrypting key pair: a public encryption key and a private decryption key

• In Estonia, this technology is used in relation with electronic identity (ID card, mobile ID, digital ID)

• Certification Service and Time-stamping Service provider is non-governmetal

Data Exchange Layer X-Road

• Technical and organizational environment, which enables secure Internet-based data exchange between the state’s information systems

Conclusions

• Estonia has great potential to implement state

level personalized medicine solutions

– Genetic research with 5% of population genetic

and continuously updated phenotype information

– Nation wide Health Information Exchange platform

– 10 years of experience of national level e-services

(PKI, X-Road, ID-card, security framework)

– High level public trust and acceptance

Thank you!

Erkki Leego

www.geenivaramu.ee

Erkki.Leego@ut.ee