Within Metabolomic Diagnostics, a world-class research team is fully dedicated to one single goal: the development of novel clinical tests which can improve women’s health. To achieve this goal, our researchers are engaging in a wide and diverse variety of internal research and collaborative research projects, like:
- The development of several novel analytical technologies to enable the robust analysis of novel “biomarkers”. For instance, during our journey of creating PrePsia™, it became clear that we needed a way to assess dozens of putative biomarkers at the same time, in order to find the most performant combination(s). Therefore, our research team developed MetDxSCOUT™, a translational metabolomics pipeline to do exactly this.
- The development of a dedicated bioinformatics pipeline to identify the most predictive combinations of biomarkers; this we do in close collaboration with our partner SQU4RE {hyperlink}
- The formulation of novel paradigms for performance evaluations of clinical tests as well as novel road maps for bringing novel clinical tests to the market. We share our thoughts with the global research community to support advancements in the development of novel clinical tests worldwide [future link to PPV/NPV paper; future link to TRL white paper by Charles]
- The collaboration in large scale international translational research projects whereby pregnant women, research midwifes, clinicians, clinical trialists, statisticians, database and software developers, …; and our company are joining forces to verify the biomarker potential of newly discovered biomarkers relating to women’s health issues. We enjoy partaking in these multi-expertise, multi-team projects as it allows for stimulating synergisms, and effective leverage of our in-house expertise. A great example of such a collaboration is IMPROvED, a pan-European multi-centre phase IIa clinical study which aims to determine whether prototype predictive assays and algorithms for pre-eclampsia prediction, as developed by Metabolomic Diagnostics, translate to the clinical environment.
- Health economics modelling studies to quantify the health and societal benefits of our novel tests. We also use this information to improve our product offerings and to demonstrate to stake holders how and why our novel tests will help in improving women’s health as well as in getting better value for money for health care systems.
MetDxSCOUT™
In line with recent insights that many of the big pregnancy conditions are syndromic in nature, and therefore their prediction and/or diagnosis will draw from biomarker combinations rather than single markers, we put in place a mass spectrometry-based translational metabolomics pipeline, MetDxSCOUT™. Using targeted mass spectrometry, we are capable to develop highly multiplexed assays for metabolites (and proteins) to verify multiplex biomarker potential in clinical study samples.
Our research team took a holistic approach when it conceived MetDxSCOUT™: they developed a library of methods to analyse a library of metabolite biomarkers relevant to the prediction of pre-eclampsia. A lot of the method technology underpinning our biomarker analyses uses instruments of Agilent Technologies. They actively support us in achieving our goals both with instruments and expertise.
The technical pipeline is using a robotics liquid handling platform to prepare 96 blood samples simultaneously (so called 96-well format); whereby the extraction of metabolites can be done in a variety of alternative ways depending on their type and/or concentration in blood.
Upon extraction, the metabolite mixtures, constituting 1000s of metabolites, are separated using a method called liquid chromatography, or LC. The aim of this step is to separate similar metabolites from each other as well as to simplify the mixture when it is presented to the mass spectrometer. Since, we know what metabolites we want to analyse, i.e., our library of candidates, we use so-called triple quadrupole mass spectrometers, or QqQ-MS. These mass spectrometers allow for the sensitive and specific analyses of complex mixtures of known compounds. Again, our research team developed a set of different LC-QqQ-MS methods to ensure all metabolites of interest can be analysed.
MetDxSCOUT™ is construed as such that batches of 96 samples are analysed using the LC-QqQ-MS system in less than 24h. As a result, data on large sample collections can be generated in short times. Currently there are >70 putative metabolite biomarkers for preeclampsia in the MetDxSCOUT™ library; of which 40+ can be robustly quantified (relative) in a minimal blood sample volume. The quantification strategy applied in MetDxSCOUT™ is Stable Isotope Dilution mass spectrometry.
It is important to note that MetDxSCOUT™ is designed to only require minimal amounts of blood (plasma, serum) for the analysis of the panel of MetDxSCOUT™ metabolites. As such MetDxSCOUT™ is highly suitable to assess the levels of metabolite biomarkers in biobanked biospecimens, which are often unique, precious and valuable research resources.
Whilst MetDxSCOUT historically focused mainly on preeclampsia-related metabolite markers, we are current expanding the MetDxSCOUT metabolite library to include markers for other pregnancy complications. Assays for putative metabolite biomarkers for preterm birth are currently being developed.
Integral part of MetDxSCOUT is a suite of customized bioinformatics tools and statistical analyses which gives us a very rich and multi-facetted view on our biomarker data. This collection of tools was largely developed by our partner SQU4RE.
At a technical level, these bioinformatics and statistical tools enable us to design very robust research studies, monitor the quality of our data, and to expose any unaccounted for experimental or other bias, if such would be present.
When it comes to translational biomarker research, we established a unique data mining methodology to give us an extremely information-rich view on our data. Moreover, we embedded the possibility to mine for biomarker panels whilst accounting for different view points. As such MetDxSCOUT™ supports the development of bespoke tests (as relevant to certain health care systems, for syndromic outcomes. Moreover, by expanding the MetDxSCOUT library with novel putative biomarkers, test performances can be improved over time.
PrePsia™ is testament to the value-creation abilities of MetDxSCOUT™.
In addition, as MetDxSCOUT, constitutes an open-ended metabolite biomarker library, it has the appeal it can evaluate novel markers, which are for instance discovered by other researchers in this space, together with a library of other markers of interest. Since the discovery of a golden bullet, ie., a single highly performant marker, is highly unlikely for syndromic diseases, evaluation of a novel marker as part of an existing library opens the possibility to assess whether a marker can synergistically add to another biomarker / biomarker combination.
As such MetDxSCOUT offers the possibility to collaborate with other researchers and/or tech transfer offices of academic institutes to create additional value and utility for novel putative biomarkers relevant to women’s health issues. under scrutiny). If this is of interest to you, don’t hesitate to contact us at XYZ@metabolomicdiagnostics.com
Robust Early Pregnancy Prediction of Later Preeclampsia Using Metabolomic Biomarkers
Paper Abstract
Preeclampsia is a pregnancy-specific syndrome that causes substantial maternal and fetal morbidity and mortality. The etiology is incompletely understood, and there is no clinically useful screening test. Current metabolomic technologies have allowed the establishment of metabolic signatures of preeclampsia in early pregnancy. Here, a 2-phase discovery/validation metabolic profiling study was performed. In the discovery phase, a nested case-control study was designed, using samples obtained at 15 weeks’ gestation from 60 women who subsequently developed preeclampsia and 60 controls taking part in the prospective Screening for Pregnancy Endpoints cohort study. Controls were proportionally population matched for age, ethnicity, and body mass index at booking. Plasma samples were analyzed using ultra performance liquid chromatography-mass spectrometry. A multivariate predictive model combining 14 metabolites gave an odds ratio for developing preeclampsia of 36 (95% CI: 12 to 108), with an area under the receiver operator characteristic curve of 0.94. These findings were then validated using an independent case-control study on plasma obtained at 15_1 weeks from 39 women who subsequently developed preeclampsia and 40 similarly matched controls from a participating center in a different country. The same 14 metabolites produced an odds ratio of 23 (95% CI: 7 to 73) with an area under receiver operator characteristic curve of 0.92. The finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of preeclampsia offers insight into disease pathogenesis and offers the tantalizing promise of a robust presymptomatic screening test.
The full paper is available here