M.Spraul, H.Schäfer, C.Cannet, F.Fang

Bruker BioSpin Biobank Webinar 2018

The IVDr Concept and its Use in Biobanks,View on Personalized Metabolic Profiles

The IVDr Concept

IVDr= In Vitro Diagnostic Research

IVDr:

Offering a completely standardized push button concept based on the IVDrPlatform and its embedded solutions for Clinical and Translational Research allowing:

- integration of results from different user groups all over the world, forminga sofar unthinkable reservoir of completely compatible spectral data andanalysis results

- Speed up translation to future diagnostic methods, be it for personalizedmedicine or populationwide studies on phenotypes and associated riskfactors.

- Development of future diagnostic routines with unmatched specificity andsensitivity

- Enabling tools for quantification of a large number of compound

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IVDr-Platform +Tools3

The IVDr Platform concept

External Partner 1

Cardiovascular

Diseases

In progress

External Partner 2

Prostate Cancer in

progress

External Partner 3

Obesity/Diabetes

Metabolic Syndrome

In progress

External developments in

R&D Ecosystem

IVDr-Platform and Standardization : Allows to combine solutions, developed byBruker BioSpin and/or external partners

• FoodScreener

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e.g. Addressing CVD risk worldwide

Note: Bodyfluid spectral databases only make sense, when data

implemented are run identically (SOPs)

Currently > 65 groups worldwide operate under Bruker NMR SOPs

Data

Analysis

Operation based on complete standardization

guarantees unrestricted exchangeability of

data worldwide

Innovation with Integrity

Longitudinal NMR Reproducibilityringtest on 11 IVDr platforms in 5 organizations on lipoprotein analysisDoi: 10.1021/acs.analchem.8b02412

NCEP Criteria for Lipid and Lipoprotein Testing

Instrument specific variance in QC samples

5 Lipoprotein Ringtest

Biobanks and NMR

NMR can provide added

value to biobanks:

Extensive QC ofIncoming samples

Offer metadata

Selected spectra

from inventory

Support Clinical trials

with spectra instead

of aliquots to

measure

Build compatible

spectra inventory

To other biobanks ww

Build compatible Spectra base withPhenome centers

QC processGenerates NMRData for storage in the biobank

Add AnalysisResults to spectraAnd metadata: e.g.Urine Quant. LipoproteinSubclass Analysis

Sort outAliquots withLow quality

Support developmentOf new diagnosticroutines

NMR for Biobanks

Gain new funding possibilities

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Biobank WorkflowB.I.Methods – Spectrum – B.I.BioBankTool– QC results

B.I.Methods

B.I.

BioBank

Tool

7 NMR for Biobanks

Biobank QC in Plasma/Serum and Urine

Criteria Plasma/Serum Criteria Urine

Matrix Identity Test Matrix Identity Test

Matrix Integrity Test Matrix Integrity Test

Matrix Contamination Test Matrix ContaminationTest

NMR preparation NMR preparation

NMR measurement NMR measurement

Medication Test

Protein Background Test

Test for further indicative parameters

8 NMR for Biobanks

B.I.BioBankToolQC report urineProtein Background

Protein in Urine can have different reasons:

• Kidney damage

• Diabetes

• High blood pressure

• Eating too much protein supplements

• Fever

• Stress

• Preeclampsia

Can be compared to metadata

Visualization of protein backgroundDistribution In 13.000 urine spectraused for validation

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Biobank Input

Quality Control by NMR

Examples

10 NMR for Biobanks

Also Citrate Plasma, Heparine Plasma

Matrix Identity Test MatrixContaminationTests

Biobank QC passed successfullyTransfer of spectrum into BiobankTransfer of quantification data into Biobank

B.I.QUANT-UR

B.I.QUANT-PSB.I.LISA

NMR for Biobanks11

Classical Organization of a Clinical Trialgenerating cohorts:NMR can provide a better way

Group organizingClinical Trial

Groups and Biobanks participating

In Clinical Trial

?

NMR for Biobanks12

Reduce the number of samples to be generated for a clinical trial by adding metadata selected Biobank NMR spectra instead of samples

Group organizingClinical Trial

providing andmeasuring Samples

Groups and Biobanksparticipating

In Clinical TrialProviding samples

NMR Spectra

NMR Spectra NMR Spectra

NMR for Biobanks13

• Some results with relevance for precisionmedicine and precision nutrition

Back to precision medicine

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Person specific self-referencing fingerprints allowHealth assessment from metabolic trajectories

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40

60

80

time

‚Invariant‘

How to solve high urine variabilityUse several snap shots per person!

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Several spectra per person allow the definitionof an invariant metabolic profile per person

22 Volunteers (25-50J.)

40 Samples / person

3 Month collection

- Strip off daily

variation

- Identification of

invariant patterns

original

invariant

Bertini, I. et al., PNAS Feb. 5, 2008

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Person prediction accuracy depending onhealth status, recovery and permanentchanges

DOi : 10.1021/acs.jproteom.5b0275

AS and BV had relocation

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Persons with strong deviations:explanations

AG female 2 pregnancies, in 2014 breastfeeding,

profile changes in lactose, glycine up (reported for

pregnancy and lactating phase)

back to high recognition rate in 2015

AW Male prolonged antibiotic treatment

secondary lactose intolerance in 2014

withdraw fresh dairy from diet, gut microbiom changes

trigonelline, hippuric acid and Hydroxyisobutyrate,

ascorbic acid down, longterm stress

2015 dairy resumed, no antibiotics

Back to high recognition rate 2015

BD 2 pregnancies, not lactating at collections

2014 Total thyroid removal due to cancer,

thyroidal hormon treatment afterwards

permanent distortion of metabolic profile

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Control sample Donor had cardiovascular event 3 days after blood collection

Use Lipoprotein subclass analysis tooptimize treatment on a personalized basis

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Use longitudinal NMR based screening to select and optimize treatment in PKU on a personal basis compared to healthy and disease cohort

Classification model:PCA-DA

Projection of the scores of the patients treated with sapropterindihydrochloride(Kuvan®) treatment (n=12) to the classification model

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Summary

1. NMR supports biobanking by comprehensive quality control

2. NMR can add important information to be stored in biobanks, spectra, analysis results

like quantification of small molecule metabolites and lipoprotein subclass analysis

3. NMR can help to reduce cost and time in clinical trials by using spectra/analysis from various

biobanks instead of generation of new samples

4. NMR can differentiate persons by their invariant metabolic profile

5. NMR can follow invariant personal metabolic profiles and show early deviations

6. NMR can show resiliance/permanent change of the personalized metabolic profile after

disease events

7. NMR can be used to identify best treatment and optimize it, revealing dose response

differences

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Thank you

• M.Nauck et al Greifswald University Hospital Germany

• F.Trefz, J.Okun, G.Hofmann Heidelberg Hospital PediatricsGermany

• J.Nicholson, J.Lindon, E.Holmes, B.Jimenez Imperial College London UK

• C.Luchinat et al CERM, Florence Italy

• S.Aygen INFAI, Cologne Germany

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