Novel biomarkers for pre-eclampsia detected using metabolomics and machine learning

Pre-eclampsia is a multi-system disorder of pregnancy with major maternal and perinatal implications. Emerging therapeutic strategies are most likely to be maximally effective if commenced weeks or even months prior to the clinical presentation of the disease. Although widespread plasma alterations precede the clinical onset of pre-eclampsia, no single plasma constituent has emerged as a sensitive or specific predictor of risk. Consequently, currently available methods of identifying the condition prior to clinical presentation are of limited clinical use. We have exploited genetic programming, a powerful data mining method, to identify patterns of metabolites that distinguish plasma from patients with pre-eclampsia from that taken from healthy, matched controls. High-resolution gas chromatography time-of-flight mass spectrometry (GC-tof-MS) was performed on 87 plasma samples from women with pre-eclampsia and 87 matched controls. Normalised peak intensity data were fed into the Genetic Programming (GP) system which was set up to produce a model that gave an output of 1 for patients and 0 for controls. The model was trained on 50% of the data generated and tested on a separate hold-out set of 50%. The model generated by GP from the GC-tof-MS data identified a metabolomic pattern that could be used to produce two simple rules that together discriminate pre-eclampsia from normal pregnant controls using just 3 of the metabolite peak variables, with a sensitivity of 100% and a specificity of 98%. Thus, pre-eclampsia can be diagnosed at the level of small-molecule metabolism in blood plasma. These findings justify a prospective assessment of metabolomic technology as a screening tool for pre-eclampsia, while identification of the metabolites involved may lead to an improved understanding of the aetiological basis of pre-eclampsia and thus the development of targeted therapies.