Modeling blood metabolite homeostatic levels reduces sample heterogeneity across cohorts.

Blood metabolite levels are affected by numerous factors, including preanalytical factors such as collection methods and geographical sites. These perturbations have caused deleterious consequences for many metabolomics studies and represent a major challenge in the metabolomics field. It is important to understand these factors and develop models to reduce their perturbations. However, to date, the lack of suitable mathematical models for blood metabolite levels under homeostasis has hindered progress. In this study, we develop quantitative models of blood metabolite levels in healthy adults based on multisite sample cohorts that mimic the current challenge. Five cohorts of samples obtained across four geographically distinct sites were investigated, focusing on approximately 50 metabolites that were quantified using 1H NMR spectroscopy. More than one-third of the variation in these metabolite profiles is due to cross-cohort variation. A dramatic reduction in the variation of metabolite levels (90%), especially their site-to-site variation (95%), was achieved by modeling each metabolite using demographic and clinical factors and especially other metabolites, as observed in the top principal components. The results also reveal that several metabolites contribute disproportionately to such variation, which could be explained by their association with biological pathways including biosynthesis and degradation. The study demonstrates an intriguing network effect of metabolites that can be utilized to better define homeostatic metabolite levels, which may have implications for improved health monitoring. As an example of the potential utility of the approach, we show that modeling gender-related metabolic differences retains the interesting variance while reducing unwanted (site-related) variance.

Novel empirical likelihood inference for the mean difference with right-censored data.

This paper focuses on comparing two means and finding a confidence interval for the difference of two means with right-censored data using the empirical likelihood method combined with the independent and identically distributed random functions representation. In the literature, some early researchers proposed empirical link-based confidence intervals for the mean difference based on right-censored data using the synthetic data approach. However, their empirical log-likelihood ratio statistic has a scaled chi-squared distribution. To avoid the estimation of the scale parameter in constructing confidence intervals, we propose an empirical likelihood method based on the independent and identically distributed representation of Kaplan-Meier weights involved in the empirical likelihood ratio. We obtain the standard chi-squared distribution. We also apply the adjusted empirical likelihood to improve coverage accuracy for small samples. In addition, we investigate a new empirical likelihood method, the mean empirical likelihood, within the framework of our study. The performances of all the empirical likelihood methods are compared via extensive simulations. The proposed empirical likelihood-based confidence interval has better coverage accuracy than those from existing methods. Finally, our findings are illustrated with a real data set.