BioSHaRE - UMCG Close out meeting 20160118

UMCG Close Out meeting
January 18th
, 2016
Het Schimmelpenninck Huys, Groningen

Agenda
AGENDA
16:15 Welcome - Ronald
16:20 BioSHaRE project and results overview - Lisette
16:40 Summary of WP1 - Coordination and management - Lisette
Summary of WP2 - Data repository and epidemiological/ clinical harmonization - Morris
Summary of WP3 - Epidemiology and Biostatistics for Biobank Harmonization/ Core Project statistics - Lisette
Summary of WP4 - Bioinformatics standardization/ harmonization for optimised information management - Morris
Summary of WP5 - Biospecimen harmonization/standardization / Healthy Obese Project - Bruce
Summary of WP7 - Societal and environmental risk factors for complex diseases / Environmental Core Project - Wilma
17:15 Beyond BioSHaRE - Ronald
Any other business

BioSHaRE project and results overview - Lisette
Mission
Organisation
Results
Our share in BioSHaRE

Mission
Development of harmonized measures and
standardized computing infrastructures enabling
the effective pooling of data to investigate common
complex diseases

Work Packages
1. Coordination and management Ronald Stolk
2. Data repository and epidemiological/ clinical harmonization (Hans Hillege)
Morris Swertz
3. Epidemiology and Biostatistics for Biobank Harmonization Paul Burton
4. Bioinformatics standardization/ harmonization for optimised information
management
Anthony Brookes
5. Biospecimen harmonization/standardization (Thomas Illig)
Melanie Waldenberger
6. Metabolomic and genetic risk factors for clustering of complex diseases Markus Perola
7. Societal and environmental risk factors for complex diseases Kristian Hveem
8. Strategic integration and coordination with major biobanking initiatives,
partnerships and dissemination
Jennifer Harris
9. Implementation & Roll-out Samuli Ripatti
Ethical, legal and social issues Bartha Knoppers

Core Projects
Statistical Methods for
Longitudinal
Harmonization
Data harmonisation and
federated analysis

Work Packages and Core Projects
1. Coordination and management Ronald Stolk
2. Data repository and epidemiological/ clinical harmonization (Hans Hillege)
Morris Swertz
3. Epidemiology and Biostatistics for Biobank Harmonization Paul Burton
4. Bioinformatics standardization/ harmonization for optimised information
management
Anthony Brookes
5. Biospecimen harmonization/standardization (Thomas Illig)
Melanie Waldenberger
6. Metabolomic and genetic risk factors for clustering of complex diseases Markus Perola
7. Societal and environmental risk factors for complex diseases Kristian Hveem
8. Strategic integration and coordination with major biobanking initiatives,
partnerships and dissemination
Jennifer Harris
9. Implementation & Roll-out Samuli Ripatti
Ethical, legal and social issues Bartha Knoppers

1
 LifeLines
 Prevention of REnal and Vascular
ENd-stage Disease (PREVEND)
 Estonian Genome Center
 Cooperative Health Research in the Region
of Augsburg, Southern Germany (KORA)
 Study of Health in Pomerania (SHIP)
 Microisolates in South Tyrol Study (MICROS)
 Collaborative Health Research in South Tyrol
Study (CHRIS)
 EPIC-Turin
 Cork and Kerry Diabetes and
Heart disease study
 National Child Development Study (NCDS)
 UK Biobank
The European Prospective Investigation
into Cancer and Nutrition (EPIC) Oxford
 Salford cohort
 The National FINRISK Study 2007 (FINRISK)
 Health 2000
 Nord-Trøndelag Health Study (HUNT)
Participating Biobanks

Overview of the studies participating in HOP
and ECP
Study name Country HOP ECP
Cartagene Canada X
Cooperative Health Research in South Tyrol Study (CHRIS) Italy X
EPIC-Oxford United Kingdom X
Estonian Genome Project of University of Tartu (EGCUT)
Biobank
Estonia X
FINRISK2007 (DILGOM and Health-2000) Finland X
Cooperative health research in the Region of Augsburg (KORA) Germany X
LifeLines Cohort Study & Biobank Netherlands X X
Microisolates in South Tyrol Study (MICROS) Italy X
Mitchelstown/ Cork and Kerry Diabetes and Heart Disease
Study Phase II
Ireland X
National Child Development Study (1958 Birth Cohort) United Kingdom X
Nord-Trøndelag Health Study (HUNT) Norway X X
Prevention of REnal and Vascular ENd-stage Disease
(PREVEND)
Netherlands X
Study of Health in Pomerania (SHIP) Germany X
UK Biobank (UKB) United Kingdom X

BioSHaRE Results
Deliverables
Foreground
Tools and methods
Data
Knowledge
Publications

Deliverables
A total of 53 deliverables, most of which are
available from our website

Tools and methods
BioSHaRE offers tools and methods for database
owners and researchers:
1. data description and presentation (database owner) and data search
(researcher);
2. data harmonisation across databases (researcher);
3. data analysis across databases (researcher);
4. contributor recognition(database owner and researcher);
5. standardisation of sample handling (database owner);
6. guidance and standards on ethical, legal and social implications (ELSI)
(database owner and researcher).

Data
The harmonisation process carried out in BioSHaRE
generated new data and data tools including:
1. A catalogue with metadata of the participating biobanks
2. Data schemas with the target variables (HOP, ECP)
3. Harmonisation algorithms (HOP)
4. Harmonised variables (stay at local servers, with respective biobanks)

Knowledge
The scientific knowledge, as well as the recommendations, best practices
and standards resulting from the project are reported in deliverables and
peer-reviewed publications.
BioSHaRE partners published nearly 100 scientific papers describing the
foreground produced in BioSHaRE.
The publications are listed and searchable by topic, author, year of
publication at our website (period 5 publications will be added before end
of Jan 2016)

Our share in BioSHaRE
Overall UMCG % realization %
Budget €11.998.152 €3.011.795 25 € 3.248.994 108
Person Months 1580 360 23 352 98
Deliverables 53 25 47
Publications 91 12 13
Workforce 178 31 17
female 87 15
male 91 16

SUMMARY OF WP1 - COORDINATION AND MANAGEMENT

Overview of work/ deliverables
WP n°
Delivera
ble N° Title
UMCG
involved
1 1 Copies of currently used ethical approvals and informed consent forms x
1 2 BioSHaRE website x
1 3 Periodic EC reports #1 x
1 7 Final EC report x
1 8 Catalogue of standardized data within European biobanks x

8 5 Final plan for the use and dissemination of foreground x
8 6 Report on Awareness and Wider Societal Implications x

Successes
 Amendment #1 and #2 to the Grant Agreement
 Midterm review
 Conference “LATEST TOOLS and SERVICES for DATA
SHARING”, July 28th
, 2015 in Milan, Italy
 Catalogue of tools and services for data sharing
 BioSHaRE Youtube channel, short intro movie,
instruction movies
 LinkedIn group Beyond BioSHaRE

SUMMARY WP2 - DATA REPOSITORY AND
EPIDEMIOLOGICAL/ CLINICAL HARMONIZATION
Chao Pang + (Joel Kuiper, Hans Hillege) + MOLGENIS team

WP n°
Deliver
able N° Title
UMCG
involved
2 1 Definition of a minimal datasets x
2 2 Validated phenotype systems x
2 3
DataSHaPER harmonization rules defined and integrated into
phenotype system
2 4 Data sharing protocols
2 5 Carry out a review of the requirements for the sharing of data

Goal: data harmonization for pooled analysis
PREVEND
Harmoniza on process
Which individual will develop
cardiovascular disease?
Example of research ques on
Pooled data
1. Defining the variables of
the target DataSchema
2. Matching biobank data
elements to the target
DataSchema
3. Generate algorithms to
convert data values to the
target DataSchema

Successes – Harmonization for HOP
10 studies, 7240 variables (Fortier, Doiron et al)

Successes - SORTA
System for Ontology-based Re-coding and Technical
Annotation of biomedical phenotype data
Pang et al, Database (Oxford), 2015, bav089

Successes - BiobankConnect
to rapidly connect data elements for pooled analysis
across biobanks using ontological and lexical indexing
Search for
‘History of hypertension’
Searching by system
Manual mapping:
‘CM ever had high
blood pressure’
Searching by expert
Rank is one in
57% and 10 in
96%!
Pang et al, 2014, JAMIA

Successes – BiobankConnect 2.0
for the automatic generation data integration
algorithms
Pang et al, Submitted

Successes – BiobankConnect 2.0
P r e v ie w
A lg o r it h m fo r ‘M e a s u r e d S t a n d in g H e ig h t ’
P re v ie w
A lg o r it h m f o r ‘H is t o r y o f H y p e r t e n s io n ’
a b

Remaining challenges
• Sustainability of the development
• Ease of deployment
• Prospective harmonization
• Adoption beyond bioshare
• Training!
• to get the world to also adopt rigorous harmonization methods
• Reduce duplicated efforts accross networks
• Bridge EU with other continents (and overcome politics)

Beyond BioSHaRE
The DataSchema harmonization protocol is taken forward in Maelstrom
organisation with applications including BBMRI-LPC
•see https://www.maelstrom-research.org/
The BiobankConnect/SORTA technology is being adopted in RD-Connect,
CORBEL/EXCELERATE, BBMRI-NL/ERIC as permanent application within the
MOLGENIS suite.
•See https://molgenis.org and http://molgenis.github.io
•See https://molgenis.org/sorta
•See https://biobankconnect.org
•See https://molgenis.org/connect
In particular: BioSHaRE tools flow into BBMRI projects

SUMMARY OF WP3 - EPIDEMIOLOGY AND BIOSTATISTICS
FOR BIOBANK HARMONIZATION/ CORE PROJECT STATISTICS

WP n°
Deliver
able N° Title
UMCG
involved
3 1 ESPRESSO-forte Study Simulation Platform completed
3 2 Working version of DataSHIELD completed
3 3
Complete analysis and report results of two case studies in
collaboration with WP9
3 4 Ethico-legal code of conduct for research
3 5 Implementation of model(s) in DataSHIELD for use in BioSHaRE x
3 6 Manuscript on model(s) for harmonizing longitudinal data x
3 7
Report on the social and epistemic implications of the DataSHIELD
methodology
3 8
Report on Social and epistemic implications of biobank standardisation
and harmonisation

Successes
D3.6 Implementation of model(s) in DataSHIELD for use in BioSHaRE
D3.7 Manuscript on model(s) for harmonizing longitudinal data

Major challenges
 Change in staff, Edwin leaving to Eindhoven
 No longitudinal data in BioSHaRE cohorts that are suitable to develop and test
statistics model and analyse across multiple cohorts

SUMMARY WP4 - BIOINFORMATICS STANDARDIZATION/
HARMONIZATION FOR OPTIMISED INFORMATION MANAGEMENT
(Joeri van der Velde), Fleur Kelpin + MOLGENIS team

WP n°
Deliver
able N° Title
UMCG
involved
4 1 Full scope data exchange format x
4 2 Final version modular database system x
4 3
Validated researcher digital IDs for control of data access, including
ELSI
4 4 Object models for experiment and molecular data x

Successes – Model & Exchange format
Observ-OM and Observ-TAB: Universal syntax
solutions for the integration, search, and exchange of
phenotype and genotype information
Adamusiak, et al, Swertz, 2012, Human Mutation

Successes – Model & Exchange format 2.0
Entity Model extensible (EMX)
g e n d e r s
e n t y n a m e la b e l d a t a T y p e re fEn t y d e scrip o n
p a e n t Id _ 1 id s t r in g Id e n fi e r o f t h e p a e n t
p a e n t S e x _ 1 g e n d e r c a t e g o r ic a l g e n d e r s P a e n t g e n d e r
p a e n t L e n g t h _ 1 h e ig h t d e c im a l H e ig h t w h ile s t a n d in g in m
p a e n t D is e a s e _ 1 d is e a s e x r e f d is e a s e s S e lf-r e p o r t e d d is e a s e
a r ib u t e s
Id h e ig h t ge n d e r d ise a se
1 1 8 5 .3 m a le T y p e 2 D ia b e t e s
2 1 7 9 .4 fe m a le C a r c in o m a
3 1 7 0 .0 fe m a le S t r o k e
4 1 9 2 .0 m a le H y p e r t e n s io n
p a e n t s
Co d e La b e l
1 m a le
2 fe m a le
N a m e Cla ssifica o n
T y p e 2 D ia b e t e s D is e a s e o n t o lo g y
T y p e 1 D ia b e t e s D is e a s e o n t o lo g y
C a r c in o m a D is e a s e o n t o lo g y
S t r o k e D is e a s e o n t o lo g y
H y p e r t e n s io n D is e a s e o n t o lo g y
P r o s t a t e c a n c e r D is e a s e o n t o lo g y
B r e a s t c a n c e r D is e a s e o n t o lo g y
… … … …
d is e a s e s
x re f
ca t e go rica l

Successes – Refactoring of MOLGENIS

Success – Refactoring of MOLGENIS

Successes – Upload in Excel
Participant Height Weight BMI ..
LL_123041 176 68 25 ..
LL_123042 163 62 23 ..
LL_123043 188 75 25 ..
LL_123044 180 60 23 ..
LL_123045 165 106 32 ..
.. .. .. .. ..
Attributes
name description unit dataType
Participant Indivdual observed ref Patient
Height Height standing up by nurse cm decimal
Weight Weight on digital floor scale by nurse kg decimal
BMI Body Mass Index kg/cm^2 decimal
.. .. .. ..
(d)
(b)Entities
name description ..
Study 1 Lifelines base
collection
(a)

Successes – Data explorer
47

Successes – Integrate R
48
http://molgenis.org/ase

Challenge 4
Insight /
action?
Insight /
action?
DNA /
phenotype
DNA /
phenotype
50

Challenge 4DNA /
phenotype
DNA /
phenotype
Population
genomic
variants
Insight /
action?
Insight /
action?
Clinical
symptoms
& diseases
Biochem-
ical
pathways
Imputation
Patho-
genicity
predictions
Model
organism
knockouts
Actionable
genes
Known
pathogenic
& benign
variants
Allele
specific
expression
Tissue
specific
expression
Pedigree
analysis
Protein
conser-
vation
Age, onset,
heritability
modes
GWAS and
QTL
studies
Conseq-
uence
51

Upload VCF file
Successes – OMX (‘omics’) for loading,
browsing and annotating genomics data
=
Open source at http://github.com/molgenis/molgenis

Success – Federated analysis using Opal,
DataShield and Mica (Ferretti et al)

Success – Federated genomics in OmicsConnect
and CafeVariome (with Brookes et al)

Successes – OmicsConnect visual data
integration (Brookes et al)

Major challenges
• Scale of genomic data
• Deployment / maintenance cost
• Too many projects now 
• Data warehouse/research portal
• Data integration / biobankconnect
• Biobank catalogues for NL, ERIC, RD
• Genomics data interpretation for UMCG, VKGL, etc

Beyond BioSHaRE
BioSHaRE has given a major boost to Opal, DataSHield, MOLGENIS, Café
Variome, GWAS central, ea
Part of many projects, e.g. MOLGENIS is in RD-connect, CORBEL, BBMRI + 25
other installations.
In particular: BioSHaRE tools flow into BBMRI projects

SUMMARY OF WP5 - BIOSPECIMEN
HARMONIZATION/STANDARDIZATION / HEALTHY OBESE
PROJECT

WP n°
Deliver
able N° Title
UMCG
involved
5 1
Evidence-based minimal standards for important samples types and
measurement techniques
5 2
SOPs for standardisation of sample collection, sample pre-treatment and
sample analysis
5 3
Temperature effects of preparing and thawing samples on different
analyses techniques
5 4
SOPs for shipment of samples and laboratory analyses of inflammatory
markers from different biobanks x
5 5 ELSI standards for the use of biospecimen from multiple biobanks
5 6
Scientific report on harmonization and standardization of prospective
phenotypes for future research x
5 7
Scientific paper on GWA / GWI studies on obesity, healthy obesity and
associated comorbidity x
5 8
Scientific paper on health outcome (cardiovascular diabetes domain) for
Healthy Obese phenotypes x
5 9
Scientific paper on the use and utility of inflammatory markers in Healthy
Obese individuals x

Successes
New collaboration and friendships
We are still alive after these 5 years
There are some publications

HOP DataSchema update:
Now at 98 variables (Phases 1 – prevalence of HO, and
phase 2 - risk factors of HO)
10 studies have their data on Opal servers:
NCDS (n= 7,210)
Prevend (n=8,592)
LifeLines (n=90,920)
Mitchelstown (n=2,047)
Finrisk (n=5,024)
45 harmonized variables validated and available for
analyses on DataSHIELD for 10 studies:
Healthy Obese, MetS (strict and moderate criteria)
8 Physical measures: blood pressure, height/weight, BMI, hip/waist size
10 lab/biochem measures: gluc, HDL, trig, TSC, creatinin, hsCRP, mALb,
LDL, Renal Function (Cockcroft Gault Glomerular filtration rate)
Medication intake and disease history (cardio-vascular, diabetes)
Data harmonization work
 Kora (n=3,080)
 MICROS (1,060)
 CHRIS (n=1,583)
 HUNT (n=78,968)
 SHIP (n=4,308)

No publications other than baseline paper

Present list of accepted phase 1-2-3 studies comprises:
Total/LDL-chol and statin use E Reischl
Methodology & harmonization phase 1 variables D Doiron
published by Emerging Themes Epidemiology
Interrelation of smoking and MS S Slagter
Individual components metabolic syndrome B Wolffenbuttel
Type 2 diabetes across Europe M
Wendker
Genetics of HOP M.L. Nuotio
Additional genetic analysis 'Manchester'
BP, hypertension & use of medication none
Gender differences in obesity none
HOP phenotype extension B Wolffenbuttel
HOP Additional phase 1 papers
No preliminary manuscripts yet

HR-QOL harmonization difficult

Physical activity less difficult ??

The WP5 inflammatory project timeline
Nov 13, 2014: results presented
Dec 2011: protocol submission
Jan 2012: protocol approval
April 2014: additional samples sent
May 2013: samples sent
June 2013: samples analyzed
May 2014: samples analyzed
2012
2013
2014
Sept 9, 2014: final phenotypes available

Overall conclusion of the WP5 inflammatory
project
This project showed every flaw that can ever occur in scientific research:
delay in delivery of samples
human factor in picking wrong samples, loosing valid assay and overall
validity of results
one specific TNFa ELISA kit which has very low quality
It also showed:
excellent sample stability when inflammatory marker hsCRP is measured
after 4 years of storage at -80C
no major differences in reproducibility when 'complexity' of sample is
taken into account

Server down, researcher depressed

Major challenges
Updating the DATA-Shield / Data-SHIELD software
until it really becomes a mature environment

Beyond BioSHaRE
indicate if and how the work is being used and continued in other projects
WE DO HOPE SO …
The imposed LifeLines 'policy' of max. two papers per project
makes this however a very expensive issue, for some of my
projects this turns out 100.000 Euro per paper !

SUMMARY OF WP7 - SOCIETAL AND ENVIRONMENTAL RISK
FACTORS FOR COMPLEX DISEASES / ENVIRONMENTAL CORE
PROJECT

WP n°
Deliver
able N° Title
UMCG
involved
7 1 ELSI guidance on the specific issues
7 2 Georeferencing of individual cohort data
7 3 Integrated EU GIS toolkit
7 4 Working version of EnviroSHaPER completed
7 5 Complex lifestyle and risk factor variables harmonized x
7 6
Scientific paper on the relation between the harmonized complex
variables and risk factors and specific health outcomes x
7 7
Scientific report on harmonization of life habits/behaviors, physical and
social environment, and socio-economic status variables x

Successes
European noise model and user friendly interface to facilitate the
application of this model across other cohorts.
Assigned harmonised air pollution and noise exposure variables to four
key European cohorts, across 3 countries, for use in the BioSHaRE ECP
analyses, and in subsequent analyses by other researchers in the
community.

Cohorts
UK
Biobank
UK Biobank - 500,000
participants, recruited 2006-
2010 from across UK
EPIC-Oxford - 57,000
participants, recruited 1993-
1999 from across UK
HUNT - 50,000 participants,
recruited 1984-1986 from the
Nord-Trøndelag County,
Norway
Lifelines - 95,000 participants,
recruited 2007-2013 from the
Groningen, Friesland, Drenthe
regions of the Netherlands

Successes
European noise model and user friendly interface to facilitate the
application of this model across other cohorts.
Assigned harmonised air pollution and noise exposure variables to
four key European cohorts, across 3 countries, for use in the
BioSHaRE ECP analyses, and in subsequent analyses by other
researchers in the community.
Retrospective harmonisation of the key variables required to
undertake the main analyses.
Made recommendations to support the prospective
harmonization of common somatic symptoms.
Published papers (6) and disseminated output at National and
International conferences (14); 2 finalised PhD projects.

My PhD thesis
Main findings
-Differential health impact of urbanity
according to disease
-Road traffic noise and increased
heart rate
-Noise annoyance and common
somatic symptoms
-No evidence for relations between
noise and increased blood pressure;
noise and somatic symptoms; air
pollution and depression

Major challenges
Obtaining cohort data
Data access time consuming, complex, non standardised
Harmonisation
Assigning ‘harmonised’ environmental exposures (e.g. no
ESCAPE data for HUNT)
Harmonisation not possible for a number of target
variables
Loss of detailed data
Analysis (e.g. via DataSHIELD)
Heterogeneous and clustered data

Beyond BioSHaRE
Some BioSHaRE projects are still ongoing:
Samuel Cai: Associations between road traffic noise, air pollution and
cardiorespiratory health
Kirsti Kvaloy: Effects of road traffic noise and air pollution on diabetes in
European cohorts: a harmonized approach in the BioSHaRE project
New projects with BioSHaRE data/tools:
Dany Doiron: Associations between air pollution and respiratory heath in
large European cohorts
UMCG: Genome-wide interaction study of gene-by-air pollution exposure
interactions in relation to lung function levels in LifeLines

BioSHaRE - UMCG Close out meeting 20160118

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