Lecture to outline the added value of intergrating genomics with proteomics, glycomics and metabolomics to create novel personalized diagnostics and drive personalised healthcare.

1. Integration of ‘omics data
towards integrated
personalized diagnostics
Alain van Gool
Professor Personalized Healthcare
Head Translational Metabolic Laboratory
Belfast, 28 Nov 2017
1st European Alliance for Personalised Medicine Congress

2. https://www.youtube.com/watch?v=yhLbuX0H7rg (search TML on Youtube)
2 Alain van Gool, EAPM, Belfast, 28 Nov 2017

3. www.radboudumc.nl

4. Our ambition to X-Omics in Personalized Healthcare’
• Personalized diagnosis
• Personalized therapy
= Personalized healthcare
+
• Patient participation
X-Omics
4 Alain van Gool, EAPM, Belfast, 28 Nov 2017

5. X-omics in (functional) genome diagnostics
Agilent V4  V5
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(n=1,533)
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(n=4,213)
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(n=5,964)
Q1-Q2 2016
(n=3,543)
#clinicalexomes/month
Outsourcing to BGI
Agilent V4
Hiseq2000 Hiseq
2000 
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Human Genetics Nijmegen (Lisenka Vissers, Marcel Nelen, Han Brunner et al)
5 Alain van Gool, EAPM, Belfast, 28 Nov 2017

6. Added value of WES
Total number of patients
with a possible diagnosis: 41
Diagnostic yield WES in retrospective ID cohort (n=150)
Whole Exome Sequencing testing
Total number of tests: 150 (x3)
Average #tests/patient: 1
Genetic cause identified: 44
Standard GENETIC testing
Total number of tests: 810
Average #tests/patient: 5.4 (1-28)
Genetic cause identified: 11
Human Genetics Nijmegen (Lisenka Vissers, Marcel Nelen, Han Brunner et al)
6 Alain van Gool, EAPM, Belfast, 28 Nov 2017

8. Our functional Omics platforms
Research Biomarkers Diagnostics
Translational Metabolic Laboratory (www.youtube.com/watch?v=yhLbuX0H7rg)
Targeted proteomics
Glycopeptidomics
500
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m/z
5 10 15 20 25 30 35 40 Time [min]
Metabolomics
400
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m/z
10 20 30 40 50 60 Time [min]
Bottom-up proteomics
Glycomics
Top-down proteomics
8 Alain van Gool, EAPM, Belfast, 28 Nov 2017

9. 9 Alain van Gool, EAPM, Belfast, 28 Nov 2017
Uric acid
Human
samples
Plasma, CSF (urine)
Controls vs. patient
QTOF Mass Spectrometry
- Reverse phase liquid chromatography
- Positive and negative mode
- Features
XCMS
Alignment
Peak comparison
> 10,000 Features
Xanthine
Whole Exome Sequencing
Leo Kluijtmans,
Ron Wevers
Genomics & Metabolomics

10. 10 Alain van Gool, EAPM, Belfast, 28 Nov 2017
Genomics & Glycomics
SLC8A6
GlycoModelC
ontrol(n=40)
SLC
10A
7-C
D
G
(n=4)
O
therC
D
G
-II(n=21)
-150
-100
-50
0
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P33
P32
P17
P39
Modelvalues
99 patients; 47 without known gene defect
- Glycomics profiling on 99
- Intact transferrin glycoprofiling on 99
- Whole Exome Sequencing for 32 cases
PGM1: New Eng J Med 2014
Man1B1: Brain 2014
More subtle changes: here
(manuscript in prep)

11. Moving to Genomics & Glycoproteomics
Gene
Protein
N-Glycosylation
11 Alain van Gool, EAPM, Belfast, 28 Nov 2017

12. Comprehensive glycopeptide profiling workflow
• Mass spectrometry analysis of glycoproteins in human plasma
• 1/20 microliter analysis: detection of 1.000.000 signals in one scan (1,4 Gb)
• ~40.000 peptides of which >80% contain sugar modification
• Potential to screen patients and identify new biomarkers
500
1000
1500
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m/z
5 10 15 20 25 30 35 40 Time [min]
Proof of principle study:
Biomarkers !?
{Hans Wessels, Dirk Lefeber}
12 Alain van Gool, EAPM, Belfast, 28 Nov 2017

13. Comprehensive glycopeptide profiling workflow
{Hans Wessels, Anouk Suppers,
Dirk Lefeber, Monique van Scherpenzeel}

14. Performance Glycopeptide profiling versus Glycomics
GlycomicsGlycopeptide
profiling
14 Alain van Gool, EAPM, Belfast, 28 Nov 2017

15. Basis for Personalized Medicine
{Dirk Lefeber, Monique van Scherpenzeel}
• Rare disease: liver disease and dilated cardiomyopathy (5-20 years)
• Specific sugar loss of serum transferrin identified via glycoproteomics
• Genetic defect in glycosylation enzyme (PGM1) identified via exome sequencing
• Outcome 1: Explanation of disease
• Outcome 2: Dietary intervention as succesful personalized therapy
• Outcome 3: Glycoprofile of intact transferrin protein (80 kDa) applied as diagnostic test
15 Alain van Gool, EAPM, Belfast, 28 Nov 2017

16. Progress further through collaboration
(local)
(European)
(national)
(global)
16 Alain van Gool, EAPM, Belfast, 28 Nov 2017

17. Collaboration towards Good Biomarker Practices
{van Gool et al, Nature Reviews Drug Discovery, Apr 2017}
COST action CA16113
http://clinimark.eu
17 Alain van Gool, EAPM, Belfast, 28 Nov 2017

18. Collaboration towards a Netherlands X-omics Initiative
www.x-omics.nl
18 Alain van Gool, EAPM, Belfast, 28 Nov 2017

19. Collaboration towards nationwide programs
Health-RI conference
Utrecht
8th Dec 2017
19 Alain van Gool, EAPM, Belfast, 28 Nov 2017
health-ri.org

20. Acknowledgements
Hans Wessels Jolein Gloerich
Roel Tans Esther Willems
Maurice van Dael Jenneke Keizer
Dirk Lefeber Monique van
Scherpenzeel
Leo Kluijtmans Ron Wevers
Marcel Verbeek Lucien Engelen
Jan Kremer Bas Bloem
Nathalie Bovy Paul Smits
the Radboudumc Technology Centers
and many others
Jan van der Greef Ben van Ommen
Ivana Bobeldijk Hans Princen
Lars Verschuren Marjan van Erk
Suzan Wopereis Heleen Wortelboer
Wessel Kraaij Ronald Mooi
Peter van Dijken Cyrille Krul
and many others
Ruben Kok Barend Mons
Jaap Heringa Merlijn van Rijswijk and
many others
Anton Ussi Florence Bietrix
Laura Bermejo Andreas Scherer
Sulev Koks Marian Hajduch
Giovanni Migliaccio
and many others
20 Alain van Gool, ODDP, Amsterdam 24 Nov 2017
Collaborators/funders
CarTarDis
alain.vangool@radboudumc.nl
www.linkedIn.com
www.slideshare.net/alainvangool