Browsing by Author "Duggan, Gavin"

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    Maternal Metabolism and Pregnancy: Predicting Pregnancy Outcomes Using Metabolomic Assessment
    (2024-10-31) Han, Ying Chieh; Shearer, Jane; Slater, Donna; Manske, Sarah; Duggan, Gavin
    Despite the significant health risks preterm birth poses to both mothers and babies, assessing the risk remains challenging due to its heterogeneous nature. Common risk factors, such as personal health history or lifestyle habits, have had some success in identifying at-risk mothers. However, their effectiveness is limited in asymptomatic and niche populations that lack distinct, identifiable preterm traits. Recent efforts have shifted toward exploring metabolic biomarkers for preterm prediction, aiming to capture the metabolic changes occurring during gestation. Nevertheless, most targeted compounds in these studies have been chosen based on their association with other underlying conditions, such as obesity or uterine disorders. With advancements in computational methods, particularly in machine learning, prediction models based on high-dimensional data have emerged as a promising new approach. This project aims to explore metabolic signatures associated with preterm birth by leveraging machine learning and untargeted metabolomics. We analyzed third-trimester serum samples from primigravid participants—first-time mothers—enrolled in the All Our Families (AOF) Cohort. Significant reductions in acylcarnitines and amino acid derivatives were identified, with various acylcarnitines, particularly butenylcarnitine, notably reduced in preterm mothers. These metabolites proved effective in predicting preterm birth, as shown by receiver operating characteristic (ROC) analysis. Next, we compared the performance of six different machine learning models in predicting preterm birth across a broader population from the AOF cohort, using Shapley Additive Explanations (SHAP) analysis to evaluate feature importance. We also assessed the impact of resampling techniques, such as bootstrapping. Linear models, including PLS-DA and linear logistic regression, demonstrated moderate predictive performance, while non-linear models like XGBoost and artificial neural networks (ANN) showed a slight advantage. Bootstrapping improved model accuracy and predictive strength, with varying degrees of enhancement across different models. Among the models tested, the bootstrap-resampled XGBoost model was the top performer in predicting preterm birth. SHAP analysis consistently identified acylcarnitines as the most significant class of metabolites in preterm prediction, with kynurenic acid also emerging as a contributing metabolite in several models following bootstrapping. The observed alterations in acylcarnitines suggest possible disruptions in lipid transport and energy metabolism in preterm mothers. The modeling results underscored the complexity of preterm prediction, while resampling techniques proved effective in mitigating the overtraining and low-variance challenges posed by the small sample size. This project introduces a novel approach to predicting preterm birth based on a combination of metabolites. As preterm birth continues to present significant risks to fetal health, the development of newer and more effective prediction models could improve maternal and fetal outcomes.
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    Multivariate NMR analysis of human disease models
    (2013-02-01) Duggan, Gavin; Vogel, Hans; Weljie, Aalim
    In the late 1990s, the field of metabolic profiling evolved into metabolomics following the general move towards systems biology and other omics techniques. Using sensitive, analytical platforms such as NMR, metabolomics aims to gather an unbiased, broad perspective of the active biochemistry in biofluids. The result was an explosive growth in the data available to study short term physiological effects, followed perforce by the application of multivariate pattern-recognition techniques to aid in its interpretation. Given the sensitive and comprehensive nature of the technique, it quickly became apparent that any number of artifactual or spurious relationships appear in the results. To alleviate those concerns, a variety of improved experimental designs, analytical techniques, and validation paradigms can be applied. Starting with a basic experimental design, the aim of this work is to explore the ability of properly validated metabolomics to provide useful information about the metabolic shifts seen in established animal models of insulin resistance, a human disease with increasing medical significance. Different two-factor experimental designs are used to refine the results of this early study, validate the resulting hypothesis and reinforce its interpretation. Having seen significant differences in ostensibly identical batches of animals in the first three experiments, further analysis of the differences are performed. Techniques for comparing batch models, as a form of multivariate hypothesis validation, are evaluated and the ability of statistical techniques to predict or ameiliorate these “batch effects” is studied. Finally, a rat model of vitamin C deficiency, another condition with ongoing pathological implications in the third world, is studied using the same metabolomic techniques. The identified metabolic shifts are subjected to a complete pathway analysis, the context of which provides a potentially interesting insight into the regulation of an important human oxidative damage control mechanism.