EURAC

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Istituto di biomedicina

Alessandro De Grandi

Genomica e ricerca traslazionale in oncologia

Trento 18.05.2019

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Institute for Biomedicine

• Translational Genomics

• Biology of Cardiac Health and Disease

• Mitochondria in Health and Disease

• Neurodegeneration Molecular and cellular Biology

Data Analysis

• Biomedical Informatics

• Biostatistics and Epidemiology

• Computational Genomics

• Computational Metabolomics Ethical, Legal and Social Implications

Group Structure

• Brain Health

• Cardiovascular Health

• Metabolic Health

• Ageing

• Precision Medicine and Health

Thematic Areas

Data Sources: Population and Patients

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Eurac Research

via Druso, 1 Bolzano

Amministrazione Trattamento dati

Istituto di biomedicina

via Galvani, 31 Bolzano

Ospedale di Bolzano Ospedale di Silandro

Coordinamento Ricerca biomedica

Trattamento campioni Analisi biochimiche Crioconservazione Raccolta dati e

campioni

Ospedale di Merano

Trattamento campioni Crioconservazione

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Population-based study to investigate

the molecular determinants

of common chronic conditions (& healthy life-style) , an typical of ageing population

(CVD, neurological and metabolic conditions)

Institute for Biomedicine

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Ospedale di Silandro:

single-site study

13 comuni

28,000 abitanti (adulti)

etá media 46 (18-93) 55% donne

13,393

partecipanti

(2011-2018)

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Baseline assessment

Questionnaires

Doctor diagnosed conditions;

Symptoms; Life style, drugs

Instrumental assessments

20‘ ECG, 20‘ BP, anthropometry,

bioimpedance, spiralography, olfaction

Biochemical parameters

>70

Ospedale di Merano Ospedale di Silandro

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CHRIS study: Questionnaires & Interview, Pedigrees, Biosignals

Cardiocirculatory system

MI; HF; cardiac arrhythmias Hypertension

Stroke; TIA Endocrine, nutritional and

metabolic diseases

Diabetes mellitus Disorders of thyroid gland Obesity and localized adiposity Genitourinary system Renal insufficiency

Nervous system:

extrapyramidal and movement disorders

Parkinson’s disease Essential Tremor Restless Leg Syndrome

Other diseases of the nervous system

Migraine

Sleep disorders; chronotype Pain including pain sensitivity Chronic pain

Psychiatric disorders

Anxiety Depression

Hypomania and mood

Cognition and autonomic function

Cognition impairment Autonomic dysfunction Disturbances of smell

Smoking ECRHS computer-assisted interview Diet

GA2LEN FFQ - paper, self-admin + optical scan

~100% response rate, ~100% item completeness derive nutrient intake

Physical activity IPAQ - computer-assisted, self-admin Childhood exposures Documented birth weight, malformations Pharmaceutical treatment Drug barcode scanner

HEALTHLIFE-STYLE & EXPOSURES

BIOSIGNALS

• 20 min resting ECG & continuous non-invasive arterial blood pressure

• Body composition monitoring

• Olfactory test

• Digitalized spirography → Tremor

• Pressure pain threshold (algometer)

• Family participation

• Reconstructed pedigrees

for 92% of participants

PEDIGREES

Current data release III (n=10518) available for analysis

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CHRIS study: Food frequency questionnaire (FFQ)

• Initial FFQ from 2011-2014

• Based on questionnaire used in previous large scale surveys (Winkler et al. Ernahrungswiss. 1998 37:234-41)

• FFQ from 2014-2018

• Modified version of the German and Italian FFQ of the

Global Allergy and Asthma European Network of Excellence (GA2LEN) study (Garcia-Larsen et al. Eur J Clin Nutr. 2011 65:750-6; doi:10.1038/ejcn.2011.15)

• Codebook Table 8.1 pg 394-455

• Derived estimates of nutrient intake (Codebook Table 8.2 pg 456-476)

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CHRIS study: Electrocardiogram (ECG) and Blood Pressure

• ECG performed with

custo cardio 200 from custo med

• ECG (10 sec)

• ECG (20 min)

• Synchronized with blood pressure measurement

• Continuous blood pressure (20min)

• Cnap monitor 500HD from CNSystems

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8 nurses/study assistants

10 participants/day

• Blood/urine

>70 standard blood/urine traits:

cholesterol & lipids; glycemia; kidney;

thyroid; coagulation; ...

Genomics and Metabolomics

• Questionnaires/Interview

• Biosignals

CHRIS study: Biobank & Clinical Chemistry

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Biobank → more -omics

• 10,500 genotyped samples (soon 13,300)

• mtDNA copy number (n = 10,500)

• whole-exome sequence data (n = 3600)

• metabolomics (n=5000)

• oral microbiome (n=2000, coming soon) samples

• serum hepcin, STFR (n=5000)

• steroids (n=1500)

• and other biomarkers ongoing

Fraction Aliquots ul °C

Serum 15 220 –80

EDTA Plasma 10 220 –80

Citrate Plasma 10 220 –80

EDTA buffy coat

RNA later 4 490 –80

Citrate buffy

coat+DMSO 1 900 -190

Citrate whole

blood 3 1000 -190

Urine 15 220 -80

> 800.000 cryo-vials

60 cryo-vials for each participant

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CHRIS study: Metabolomics p180 kit

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Pattaro et al. Nat Commun 2016 7:10023 doi:10.1038/ncomms10023

Rainer et BMC Genomics. 2018 19(1):491 doi: 10.1186/s12864-018-4876-6.

Weichenberger et al. Bioinformatics.

2018

doi:10.1093/bioinformatics/bty541

Sekula et al. J Am Soc Nephrol 2018 doi:10.1681/ASN.2016010098

Computational Genomics Biostatistics

Data Analysis

Genome-wide association studies (GWAS) GWAS meta-analysis within consortia

Causality

Mendelian Randomization

Familial aggregation analysis Network models

Identify Biological Processes Gene Prioritization

Bioinformatics

Genotype imputation

Das et al. Nature genetics, 2016, 48:1284-1287 doi:10.1038/ng.3656

Computational Metabolomics

Processing large scale metabolomics data

doi:10.18129/B9.bioc.xcm s

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Bioinformatics & Big data (Omics) mining

Biobanking & ELSI

Advanced Human Cell Models

Electrophysiology &

Biological Imaging Genetic Epidemiology

and Biostatistics

Hear t

Brain He althy Ageing

Metabolis m

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Cell Models

Neuronal cultures

Cardiac cell models

Native Alpha- Synuclein Aggregation Model

Imaging and synaptic reconstruction

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• Follow-up time: max 8 years

• Closed cohort: recall all baseline participants

• Repeat [meaningful] baseline assessments

• Expand objective [instrumental] assessments

• Biobank again

CHRIS study: Perspectives 2011-2024

CHRIS follow-up

(2019-2023)

N= 10 500

Subproject 2

Targeted subprojects

Subproject 1

• < questions

• + quantitative data

• + clinical data

• Link Electronic Health Records

Subproject 3

Testing ground for Precision Health

Solutions

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Baseline assessment

Questionnaires

Doctor diagnosed conditions;

Symptoms; Life style, drugs

Instrumental assessments

20‘ ECG, 20‘ BP, anthropometry, bioimpedance, spiralography, olfaction

Biochemical parameters

>60

• WHR

• Carotid ultrasound

• Vascular assessment

• Pain sensitivity

• Tremor

• Retina imaging and eye phenotyping

• Hearing

• Knee ultrasound

• Hand grip strenght

• Spirometry

• Physical activity

• ?DEXA

(osteoporosis)

Linkage to

Electronic health records (passive follow-up)

Remote phenotyping

smartphone

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VERSUS

Development of general regulation for the biobank Access policy for the biobank

Public access policy

Application to appointed board for access Clear evaluation criteria

Access to CHRIS Data and Sample External Internal

Basata su

• Fondi pubblici

• Libera partecipazione

biobanca bioteca

Accessibilità a dati e campioni

http://www.eurac.edu/en/research/health/biomed/projects/Pages/default.aspx

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Peter P. Pramstaller, Andrew Hicks, Francisco Domingues, Alessandra Rossini, Cristian Pattaro, Christian Fuchsberger, Deborah Mascalzoni, Johannes Reiner, Irene Pichler, Mattia Volta,

Egger Clemens, Chiara Cantaloni, Alessandro De Grandi