HarmonizATforms · Defining the antithrombin measurand: role of proteoforms in harmonisation of diagnostic tests in thrombosis
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-05-01 → 2021-04-30
- EU contribution
- €187,572
- Participants
- 1
- Scheme
- MSCA-IF-EF-RI
Lines connect the coordinator with its partners.
Results in brief
Defining the antithrombin measurand: role of proteoforms in harmonisation of diagnostic tests in thrombosis
Proteins are complex molecules that may exist in multiple molecular forms. Thus far, most clinical chemistry tests target all of the molecular forms, without differentiating the actual ones present in an individual. This holds true for the underappreciated antithrombin (AT) activity test as well. Antithrombin exists in many molecular forms, caused by >350 known genetic variants, as well as heterogeneity in protein glycosylation. Both of these are known to affect AT activity in various ways, resulting in variable phenotypes associated with AT deficiency. However, these phenotypes cannot be distinguished using current activity tests. This results in insufficient clinical sensitivity of the test, an improperly defined target population, and sometimes inconclusive results. Alternative tests that can distinguish molecular forms of AT are needed to provide more clinical insight. To conclude, within this project we developed an alternative test that allows for characterization of AT at the molecular level, and validated the method analytically according to current clinical chemistry practice. We now aim to further assess whether our method can aid in harmonization of current AT tests, but more importantly, will also assess whether our test provides increased clinical sensitivity and/or could identify subgroups of patients with AT deficiency that might benefit from specific therapy.
Data: CORDIS, © European Union
Project objective
Current medical tests for antithrombin deficiency generally measure the overall activity, being blind for the actual proteoforms of AT that contribute to the test. To ensure accurate test results, a traceability chain needs to be in place, which requires the accurate definition of the exact analyte to be measured. I hypothesize that an in-depth understanding of the pathological molecular proteoforms of antithrombin (AT) will allow for the identification of clinically relevant proteoforms and enable test harmonization, resulting in a test with a well-defined clinical outcome that are actionable by clinicians. Mass spectrometry (MS) is an emerging technique in the field of clinical chemistry, which is well suited for the detection of proteoform characteristics and outperforms testing methods based on immunoassays. Therefore my aims are 1. To develop a mass spectrometry based test for the quantification of individual characteristics of molecular proteoforms of AT. 2. Analytically validate the developed method according to clinical chemistry procedures, and 3. Assess the role of MS based test for the standardization of AT tests. I am a passionate scientist with a strong background in the development of MS-based tests for proteins. I plan to perform the project in collaboration with my supervisor, who has large experience in medical test development and the ECAT foundation, who is specialized in proficiency testing of AT and test harmonization. This project will allow me to obtain skills and experience to oversee and develop a clinical test from biomarker discover to test evaluation and implementation, specifically in the niche of thrombosis and haemostasis, as well as the transferable skills required to eventually establish my own independent research group.
Original text from CORDIS.
Participants
- ACADEMISCH ZIEKENHUIS LEIDEN · LeidenCoordinatorNetherlands
Links
Data: CORDIS, © European Union