MSI-CE-MS: A High Throughput Metabolomics Platform for Large-scale Epidemiological Studies

A high throughput metabolomics protocol based on multiplexed separations coupled to mass spectrometry is implemented for large-scale epidemiological studies. We outline a standardized data workflow for characterization of the maternal serum metabolome in a diverse population of pregnant women.

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There is growing interest in applying metabolomics in nutritional sciences and clinical medicine notably in the context of population health and chronic disease prevention. For example, metabolomic studies of dietary exposures during pregnancy (i.e., maternal metabolome) offer unique insights into fetal development that impact childhood health outcomes later in life. Yet, there have been few metabolomic studies applied to ethnically diverse populations of pregnant women, which is needed for the validation of generalizable biomarkers of habitual diet.

Conventional instrumental platforms in metabolomics that rely on liquid chromatography-mass spectrometry and nuclear magnetic resonance face significant barriers when applied to large-scale epidemiological studies. These limitations include low sample throughput, high operating costs, poor sensitivity and/or limited metabolome coverage. Moreover, nontargeted metabolite profiling strategies require complicated data processing that are prone to bias especially when identifying unknown metabolites of clinical significance. As a result, higher throughput instrumental platforms in metabolomics are required when analyzing volume-restricted biobanked specimens.

Our group has introduced a multiplexed platform for metabolomics based on multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS), where seven or more samples are introduced in series and analyzed within a single run. This approach boosts sample throughput without added infrastructure costs while also improving data fidelity with stringent quality control. However, MSI-CE-MS has yet been applied in a large-scale metabolomics project to demonstrate its robustness given long-term signal drift and inter-batch variations in longitudinal studies.

For the first time, our protocol is implemented in a multiethnic birth cohort study involving more than a thousand pregnant women from across Canada when using a standardized data workflow for serum metabolite authentication with effective batch adjustment. Acceptable intermediate precision was achieved for a diverse array of polar/ionic serum metabolites over a 7-month period with metabolite reference intervals for Canadian women in their second trimester of pregnancy. This protocol opens the door towards more routine and cost effective assessment of dietary exposures as required for evidence-based public policies that support maternal and childhood health.

Shanmuganathan, M., Krozen, Z., Gill, B. et al. The maternal serum metabolome by multisegment injection-capillary electrophoresis-mass spectrometry: a high-throughput platform and standardized data workflow for large-scale epidemiological studies. Nat Protoc (2021) DOI: 10.1038/s41596-020-00475-0

Philip Britz-McKibbin

Professor, McMaster University

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