Causal Discovery in High-dimensional, Multicollinear Datasets.

As the cost of high-throughput genomic sequencing technology declines, its application in clinical research becomes increasingly popular. The collected datasets often contain tens or hundreds of thousands of biological features that need to be mined to extract meaningful information. One area of particular interest is discovering underlying causal mechanisms of disease outcomes. Over the past few decades, causal discovery algorithms have been developed and expanded to infer such relationships. However, these algorithms suffer from the curse of dimensionality and multicollinearity. A recently introduced, non-orthogonal, general empirical Bayes approach to matrix factorization has been demonstrated to successfully infer latent factors with interpretable structures from observed variables. We hypothesize that applying this strategy to causal discovery algorithms can solve both the high dimensionality and collinearity problems, inherent to most biomedical datasets. We evaluate this strategy on simulated data and apply it to two real-world datasets. In a breast cancer dataset, we identified important survival-associated latent factors and biologically meaningful enriched pathways within factors related to important clinical features. In a SARS-CoV-2 dataset, we were able to predict whether a patient (1) had Covid-19 and (2) would enter the ICU. Furthermore, we were able to associate factors with known Covid-19 related biological pathways.

Lipidomic signatures align with inflammatory patterns and outcomes in critical illness.

Alterations in lipid metabolism have the potential to be markers as well as drivers of pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. The previously reported survival benefit of early thawed plasma administration was associated with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers in causal modelling. Phosphatidylethanolamines (PE) were elevated in patients with persistent critical illness and PE levels were prognostic for worse outcomes not only in trauma but also severe COVID-19 patients. Here we show selective rise in systemic PE as a common prognostic feature of critical illness.