Optimal transport for automatic alignment of untargeted metabolomic data.

Untargeted metabolomic profiling through liquid chromatography-mass spectrometry (LC-MS) measures a vast array of metabolites within biospecimens, advancing drug development, disease diagnosis, and risk prediction. However, the low throughput of LC-MS poses a major challenge for biomarker discovery, annotation, and experimental comparison, necessitating the merging of multiple datasets. Current data pooling methods encounter practical limitations due to their vulnerability to data variations and hyperparameter dependence. Here, we introduce GromovMatcher, a flexible and user-friendly algorithm that automatically combines LC-MS datasets using optimal transport. By capitalizing on feature intensity correlation structures, GromovMatcher delivers superior alignment accuracy and robustness compared to existing approaches. This algorithm scales to thousands of features requiring minimal hyperparameter tuning. Manually curated datasets for validating alignment algorithms are limited in the field of untargeted metabolomics, and hence we develop a dataset split procedure to generate pairs of validation datasets to test the alignments produced by GromovMatcher and other methods. Applying our method to experimental patient studies of liver and pancreatic cancer, we discover shared metabolic features related to patient alcohol intake, demonstrating how GromovMatcher facilitates the search for biomarkers associated with lifestyle risk factors linked to several cancer types.

Inferring causal networks of dynamical systems through transient dynamics and perturbation.

Inferring causal relations from time series measurements is an ill-posed mathematical problem, where typically an infinite number of potential solutions can reproduce the given data. We explore in depth a strategy to disambiguate between possible underlying causal networks by perturbing the network, where the forcings are either targeted or applied at random. The resulting transient dynamics provide the critical information necessary to infer causality. Two methods are shown to provide accurate causal reconstructions: Granger causality (GC) with perturbations, and our proposed perturbation cascade inference (PCI). Perturbed GC is capable of inferring smaller networks under low coupling strength regimes. Our proposed PCI method demonstrated consistently strong performance in inferring causal relations for small (2-5 node) and large (10-20 node) networks, with both linear and nonlinear dynamics. Thus, the ability to apply a large and diverse set of perturbations to the network is critical for successfully and accurately determining causal relations and disambiguating between various viable networks.