2024-10-01 Biomarkers Europe 2024, Basel, Alain van Gool.pdf

Lecture for professionals in pharma, diagnostics and academia on the translation of omics biomarker innovations in clinic to drive personalized healthcare. As case study, our work in multiple myeloma was described, where we developed a 1000x-more sensitive proteomic biomarker for monitoring minimal residual disease.

1. TranslationalOmicsInnovationsToDrive
PersonalizedHealth(care)
Biomarkers Europe 2024
1 October 2024
Prof. Alain van Gool
Professor PersonalizedHealthcare
DepartmentHuman Genetics
RadboudumcTechnology Centers
Netherlands X-omicsInitiative
EATRIS BiomarkerPlatform
Radboud Healthy Data Programme
Sectorplan Data-driveninnovation

2. to have a significant impact on health and
healthcare

3. •Academichospital(1 of 7 in Netherlands)
•Specialist hospital+ Medicalfacultyof Radboud University
•13.000 employees; 3.500 students; 1,4 B euro/year
•Coretasks:
•Patientcare, research, education
•3 institutes:
•PatientCare Institute
•Research InstituteforMedicalInnovation
•Radboud Health Academy
•11 clinicalcenters, 39 departments
•Eg Center forDiagnostics& Advice 6 departments
•Dept. Human Genetics 1200 employees
•Dept. Pathology Focus totranslate research toinnovationtopatientcare (ISO15189)
•Dept. Radiology Research groupsandresearch programs
•Dept. Laboratorymedicine Translationaltechnologies
•Dept. Pharmacy Close interactionwithcliniciansandpatients
•Dept. Medicalmicrobiology Translationis fast; samedepartment/group/scientist
to have a significant impact on health and
healthcare

4. 4 Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
www.radboudumc.nl/research/ technologycenters

5. Department Human Genetics
Specialized in rare diseases
•Research
•disease mechanisms
•omics technologies
•Innovation
•new biomarkers, new methods
•Patient care
•diagnostics (ISO15189)
•genetic counseling
•Education
•translational medicine, omics, biomarkers,
clinical mechanisms
•Research support
•RTC genomics, mass spectrometry, stem cells
Translating science to impact
Biomarkers
Products Technology Readiness Levels

6. The Netherlands X-omics Initiative
National RoadmapLarge ScaleResearch Infrastructure
2018-2029
40M euro, partiallyfundedbyNWO
Objectives:
1.Advance X-omics technologiesfar beyond
state-of-the-art
2.Realizea genuinelyintegratedX-omics
infrastructurein NL
3.Developanddemonstrateimpact of robustX-
omicsanalysis
Coordinator:
Alain van Gool
X-omics.nl

7. Data Stewardship
& Integration (WP2)
Multi-omics
technologies (WP1)
Genomics
Epigenetics
Transcriptomics
Proteomics
Metabolomics
Quality Assessment
(WP3)
Data GenerationData

Curation
Quality AssessmentData Variability
Multi-omics Toolbox
Academia & Industry
Pilot Access
•SOPs
•Guidelines for best practices
•Reference materials
•Quality parameters
•Data analytical tools
•Criteria for reference values
•Troubleshooting guidelines
•Repository of multi-omics data
An open access WEB
resource, containing:
Enable high-quality research in PM, including
accelerating the implementation of accurate
patient stratification and treatment management
Emanuela Oldoni
EATRIS scientific
programmemanager
flagshipproject

8. 8 Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Clinical multi-omics data to drive personalized healthcare
Personalizedanalysis
Genomics
Metabolomics
Glycomics
Glycoproteomics
DeepLearning/ AI
Integrateddiagnostics
System biology
Diagnosis of (new)
diseasemechanisms
Transcriptomics
Proteomics
Epigenetics
Cellomics
…-omics
Development andmonitoring
of (new) personalized
therapies

9. 9 Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Multi-omics discovery (example 1)
•127 healthy blood donors from
Czech biobank (sex-balanced, 21 –
61 yrs)
•Multi-omics profiling at EATRIS
facilities across Europe
•Quality Control and first analyses
were performed locally
•Integrated multi-omics data analysis
by joint bioinformatics team from
EATRIS sites across Europe
•Research questions:
•Relative level and variability of
omics components in healthy
subjects
•Basis for precision medicine

10. 10Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Multi-omics discovery (example 1)
Concept conclusions:
•Different variationsin analytesamongindividualsin eachomicslevel
•Identifieda yetundiagnosedKlinefelter individual(XXY)
•Re-discoveredepigeneticpatternforbiologicalaging
•Deeperdata analysis ongoing
{de Visser et al, unpublished 2024}

11. 11Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Multi-omics discovery (example 2)
Concept conclusions:
•Identified3 cases wheresamples wereincorrectlyannotated
•Different variationsin analytesamongiPSCin eachomicslevel
•Deeperdata analysis ongoing
{de Visser et al, unpublished 2024}
•3 Rare diseases
•CHD2, NANS, DM1
•Patient-derived induced
pluripotent stem cells
•Multi-omics profiling at
EATRIS and X-omics facilities
•Research questions:
•iPSC reproducibility
•Disease-specific
mechanisms

12. 12Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Some of our recent clinical omics innovations
Automatedmetabolomics-based
screening of Genetic Metabolic
Disorders in ISO15189 diagnostics
Hoegenet al, Metabolites2021
Intensity
AI-basedfacial phenotypicrecognitionof
rare geneticdiseases
Dingemans et al, Nature Genetics 2023
Plasma glycoproteomics delivers high-
specificity disease biomarkers
Wessels et al, J Adv Res 2023

13. 13Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Some of our recent clinical omics innovations
Revio 1 installed April 5
th
, 2023
Revio 2 installed Dec 14
th
, 2023
Revio 3+4: installed May 2024
Nature Genetics 2004, 2006, 2010, 2015
New England Journal of Medicine 2012
Nature 2014; Nature Review Genetics 2016
American Journal of Human Genetics 2003,
2015, 2016, 2017, 2018, 2020
Increasediagnosticyieldin rare diseaseby
HiFilong readsequencing
Currentstate: 62% positive
diagnosis

14. 14Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Personalized healthcare in Multiple Myeloma
•2
nd
most common
hematological malignancy
•Monoclonal plasma cells in
bone marrow that secrete a
monoclonal (M) protein
•Treatment by chemotherapy,
steroids and specific drugs
•Disease often comes back
(relapse)
•Sensitive monitoring needed
for early relapse detection =
Minimal Residual Disease
(MRD) monitoring
{Cancer Facts & Figures 2021, ACS
Kumaret al. Lancet Oncology2016}
The story of today:

15. 15Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Lack of sensitive and easy detection of Minimal Residual Disease
Sampling errorcaused
bytumor
heterogeneity
Cumbersomeandinvasive
procedure
for repetitivemonitoring
•Diagnostic test blood M-protein by gel
electrophoresis
(Serum protein electrophoresis, SPEP)
•Current tests for MRD:
•Isolate bone marrow
•Analysis stromal cells by Flow Cytometry or Genomics
(PCR, NGS)
Healthy
Multiple
myeloma

16. 16Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Insufficientsensitivity of currentM-proteindiagnostics
0.001
0.01
0.1
1
10
100
0 200 400 600 800 1000 1200 1400
[M protein] (g/L)
Sampling day
Maintenance
therapy
Earlier relapse detection: A more sensitive, easy, longitudinal method is needed
Limit of Detection gel-based method (SPEP)
?
?
?
?
?
Uncertainty !!!

17. 17Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Variableregion:
patient-& MM specific
(VDJ-rearrangements)
Constant region:
non-specific
Use plasma proteomics to monitor MRD in Multiple Myeloma
Steps:
•Verifyeachpatienthas uniqueM protein(COMPASS database)
•First assay: PRM MS withSIL peptidesas standards
•SensitivedetectionM proteinfromarchivedSPEP gels
•Equalperformance MS-MRD (plasma) withNGS (bonemarrow)
•Test suitabilityMS-MRD fordynamicmonitoring MM patients
•Second assay: DIA MS withSILuMABas standard
Approach:
Direct measurementof rearrangedregion
of theM-proteinbytargetedproteomicsin
plasma samples (= MS MRD methode)
•Higherspecificity
•Highersensitivity
http://www.barcode.co.uk/make/ciaxcom.php?t=http://www.barcode.co.uk/make/ciaxcom.php?t=
{Langerhorst et al, Clin Chem 2021}
{Noori, Zajecet al, HemaSphere, 2022}
{Langerhorst, Noori et al, Clin Chem, 2021}
(selectedas Top Story byClinChem)
{Langerhorst, Nooriet al, ClinChem, 2021}
{Noori, Wijnandset al. Blood Cancer J 2023}

18. 18Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
MS-MRD longitudinal follow-up
Limit of Detection gel-based method (SPEP)
Limit of Detection mass spec-based method (MS-MRD)
0.001
0.01
0.1
1
10
100
0 200 400 600 800 1000 1200 1400
[M protein] (g/L)
Sampling day
Maintenance
therapy
1000x !
Conclusions:
•Feasible in 100% of included patients
•More sensitive than bone marrow-based MRD
•Early relapse detection: >1 year earlier
compared to gel-basedmethod(M-spike)
http://debedwantsspecialist.nl/wp-content/uploads/vergrootglas.png
http://www.barcode.co.uk/make/ciaxcom.php?t=http://www.barcode.co.uk/make/ciaxcom.php?t=
•ClinicalChemistry Science and Innovation Award 2022
•College of Medical Immunologists Joos Kerckhaert Award 2022
‘pioneering MS-work on personalized cancer diagnostics’

19. 19Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Reproducibility
y = 1.0199x - 0.2117
R² = 0.9389
Inter-institute variationIntra-assay variation Inter-assay variation
(DIA MS usingSILuMABas off-the-shelfcalibrator) {Wijnands, Langerhorst et al. CCLM 2023}
(instrumental variation)
20x same sample →
all CVs below 15%
(sample prep variation)
3 individual measurements (5 replicates) →
In line with FDA guidelines
all longitudinal samples of 15 patients
measured by 2 institutes →
R² = 0.9389

20. 20Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
0.001
0.01
0.1
1
10
100
0 500 1000 1500 2000
[M
-
protein] (g/L)
Sampling day
Maintenance
therapy
0.001
0.01
0.1
1
10
100
0 200 400 600 8001000
[M
-
protein
] (mg/L)
Sampling day
Maintenance
therapy
0.0001
0.001
0.01
0.1
1
10
100
0 200 400 600 800 1000120014001600
[M
-
protein
] (g/L)
Sampling day
Maintenance
therapy
•41 Patients tested (IFM cohort)
•Different profiles found (ranging from relapse to further decrease). Why?
MS-MRD longitudinal follow-up
•Follow-up project: test 160 patients (HOVON cohort)
•Collect longitudinal multimodal data (disease state, M protein, clinchem, metadata)
•Applydeeplearningalgorithmstodeduceprofiles, explain, simulateandpredict
•Exploretheapplicationin monitoring efficacyin clinicaltrials of MM drugs
•Scaleup MS-MRD assay toISO15189

21. 21Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Multidisciplinary collaboration
Hans Jacobs
Charissa Wijnands
Dennis Trede
Gary Kruppa
Lennard Pfennig
Markus Lubeck
Niels Goedecke
Oliver Raether
Pierre-Olivier Schmit
Sven Brehmer
Tharan Srikumar
Pierre Sonigo
Vincent Bonifay
Caroline Rouge
Somayya Noori
Martijn van Duijn
Theo Luider Aurore Perrot
Cyrille Touzeau
Helene Caillon
Jill Corre
Philippe Moreau
Thomas Dejoie
Bruker-Radboudumc
Joint Center for
TranslationalOmics
Pieter Langerhorst
Anastasia Tzatsa
GadArmony
Hans Wessels
JoleinGloerich

22. 22Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Data re-use will be increasingly important
{Wilkinson et al,
Nature Scientific Data, 2016}
•Data capture
•Data stewardship (FAIR)
Good data stewardship will enable open/community science and
faster breakthroughs in personalized health(care)

23. 23Biomarkers Europe 2024, Basel, 1 Oct 2024. Alain van Gool
Data interoperabilityis key
Resource
Description
Framework
(RDF)
If data are interoperable … … analytics provide new knowledge
Research data should be FAIR and AI-ready

24. Radboud program
Radboud AI events
reveal
connect
improve
apply
Research data &
infrastructures
Application in
health & medical
practices
AI model
development
sustainable & scalable
Localstrategicinitiative
2023-2028; 21M euro
FundedbyReinier Post Foundation,
Radboud University, Radboudumc
Radboud Healthy Data coreteam
Strengtheningour
data & AI
infrastructureandculture
@Radboud campus
toboost
translationalresearch
in health andhealthcare
Radboud University campus

25. Acknowledgements
Charissa Wijnands
Anastasia Tzasta
Pieter Langerhorst
Hans Wessels
Jolein Gloerich
Dirk Lefeber
Purva Kulkarni
Gadi Armony
Richard Rodenburg
Bert van den Heuvel
and others
Marcel Nelen
Albert Heck
Thomas Hankemeier
Peter Bram ‘t Hoen
Daniella Kasteel
Jessie Smits
and others
erasmusmclogo
Collaborators/funders
Helger Ijntema
Alexander Hoischen
Lisenka Vissers
Christian Gillisen
Janneke Weiss
[email protected]
www.radboudumc.nl/en/people/alain-van-gool
www.slideshare.net/alainvangool
Dapha Habets
Irene Keularts
Marek Noga
and others
Gary Kruppa
Dennis Trede
Klaus Lindpaintner
Pierre-Olivier Schmit
and others
Emanuela Oldoni
Laura Garcia Bermejo
Andreas Scherer
Florence Bietrix
Eliis Keidong
Toni Andreu
and others
Hans Jacobs
Peter-Bram ‘t Hoen
Anna Niehues
Xiaofeng Liao
Casper de Visser
Junda Huang
Translational Metabolic Laboratory
Human Genetics Nijmegen
Center for Molecular and Biomolecular Informatics