Met4Metab: Standardisation of targeted and untargeted metabolomic methods for clinical diagnosis

Metabolomics, which can measure hundreds of small molecules in blood or urine at once, is one of the most powerful tools for personalised medicine, yet its results are not comparable between laboratories and so cannot move from research into hospital laboratories. Met4Metab is building the metrological infrastructure to make metabolomics results traceable to the SI. For targeted methods it is developing robot-prepared calibration solutions containing more than 50 metabolites together, with reference measurement procedures; for untargeted methods, calibration strategies based on "beacon molecules" identified by machine learning, and three new matrix reference materials. Coordinated by PTB with 19 organisations, the project started in July 2026.

At a glance


Project number	25HLT04
Short name	Met4Metab
Programme	European Partnership on Metrology (co-financed by Horizon Europe and the Participating States), Health
Duration	July 2026 – June 2029 (36 months)
Coordinator	Gavin O’Connor, PTB (Germany)

Why it is needed

Healthcare is moving from a “one size fits all” approach towards personalised medicine tailored to each patient’s biology. This requires a holistic view of the biological processes in the body. Metabolomics studies the metabolome, the entirety of small biochemical molecules in cells, tissues and body fluids. A person’s metabolic state is an objective measure of their health and how it changes over hours, days and years. Mass spectrometry (MS) is already routinely used in clinical laboratories for steroids, vitamins and therapeutic drugs, and newborn screening is a tangible example of such methods entering clinical practice.

Targeted metabolomics methods measure tens to hundreds of metabolites at once, and untargeted methods hundreds to thousands. But differing measurement approaches, calibrations and evaluation methods make results hard to compare between studies, and untargeted results are rarely expressed in SI units. National metrology institutes have so far applied their reference methods to single metabolites or small groups; measurements at this scale exceed current capabilities. Meanwhile, the EU In Vitro Diagnostic Regulation (2017/746) requires manufacturers to show the metrological traceability of assigned values.

Objectives

Reference measurement systems for targeted metabolomics (WP1): Develop reference measurement procedures, including fully automated preparation of calibration standards, for characterising multiplexed (more than 50 measurands) metabolite standard solutions suitable as calibrators or reference materials under ISO 17511, ISO 15193, ISO 15194 and ISO 17034.
Standardisation of untargeted methods (WP2): Develop calibration strategies based on “beacon molecules” and internal standards, using chemoinformatics, data mining, machine learning and AI, to convert instrument signals into SI-traceable units.
Matrix reference materials (WP3): Prepare three matrix reference materials, regularly updated in collaboration with the Metabolomics Quality Assurance and Quality Control Consortium (mQACC).
Transfer to clinical use (WP4): With European clinical omics facilities and biobanks, ensure the calibration approaches help clinical laboratories meet ISO 15189, providing estimates of measurement uncertainty, repeatability and accuracy.
A sustainable European infrastructure (WP4 and WP5): With the European Metrology Network for Traceability in Laboratory Medicine (EMN TLM) and metabolomics societies, establish a sustainable European infrastructure for standardising metabolomics results.

Approach

Automated calibration standards

National metrology institutes usually assign reference values by isotope dilution mass spectrometry. This gives the smallest achievable uncertainty and direct traceability to the SI, but the gravimetric preparation of calibration solutions is manual and labour-intensive, so most institutes provide reference measurements for only one or a few similar measurands at a time. Met4Metab will develop and assess liquid-handling robots coupled with analytical balances to prepare multiplexed standard solutions of priority metabolites at biologically relevant concentrations, with a target relative expanded uncertainty below 3%, raising the number of measurands prepared simultaneously from 1 to 50.

Candidate metabolites include amino acids such as glutamine, tryptophan and kynurenic acid, phenylalanine and serine; central energy metabolites such as pyruvate, citrate and succinate; lipids such as sphingomyelins, ceramides and phosphatidylcholines; and compounds with specific clinical associations such as creatinine and choline. For metabolites without a traceable certified reference material, mass balance, peptide impurity corrected amino acid analysis (PICAA) and quantitative NMR (qNMR) will be evaluated for purity assessment.

Beacon molecules

Fully characterised matrix calibrators for thousands of measurands would exceed any single institute’s capacity and be impractical for routine use. Instead, the project aims to use machine learning to identify endogenous metabolites that are relatively stable within and between cohorts and use them as “beacon molecules”. Other metabolites will be linked to these beacons using chemoinformatics, and the effect of different calibration strategies on quantification accuracy will be investigated. The uncertainty may be larger, but the approach offers a practical route to traceability for institutes and clinical laboratories.

Reference materials and clinical validation

The most widely used long-term reference material in untargeted metabolomics is NIST’s human plasma SRM 1950. Relying on a single material risks losing harmonisation once it runs out. The project will develop three matrix reference materials supported by a dedicated web portal where users can share their results. The impact of calibration materials and methods on patient cohorts will be assessed, methods will be validated in an inter-laboratory ring trial, and the expected accuracy and uncertainty will be reported to regulators and stakeholders.

Work packages

Work package	Topic	Lead
WP1	Standardisation for targeted metabolomics	LGC
WP2	Calibration strategies for untargeted metabolomics	PTB
WP3	Quality control materials	BAM
WP4	Transfer of methods from research to clinical use	Vetmeduni
WP5	Creating impact	University of Liverpool
WP6	Management and coordination	PTB

TÜBİTAK UME takes part in WP1–WP4. Its experience in developing SI-traceable analytical methods by mass spectrometry, metabolite analysis and purity assessment of standards by qNMR will be used mainly in WP1.

Expected impact

The project aims to strengthen the capacity of European national metrology institutes to develop new reference measurement procedures, standard solution calibrators, matrix reference materials and computational workflows, accelerating the transfer of multiplexed metabolomics methods from research into the highly regulated clinical setting. Comparable, reliable results will also support personalised treatment, for example by helping to reveal sex-specific differences. Results will be shared through preprints, open data repositories (MetaboLights, Metabolomics Workbench) and open-source software, and training materials will be disseminated through mQACC and the Metabolomics Society.

Partners

National metrology and designated institutes: PTB (Germany, coordinator), BAM (Germany), FTMC (Lithuania), IAPR (Greece), LGC (United Kingdom), LNE (France), TÜBİTAK UME (Türkiye)
Universities and research organisations: CEA (France), Charité – Universitätsmedizin Berlin (Germany), Gebze Technical University (Türkiye), Helmholtz Centre for Infection Research HZI (Germany), ICAN (France), TU Braunschweig (Germany), University of Liverpool (United Kingdom), University of Lausanne (Switzerland), University of Veterinary Medicine Vienna (Austria), Helmholtz Zentrum München (Germany)
Industry and associated partners: Merck Life Science (Germany), NIST (United States)