OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

Objective To evaluate the effects of branched-chain amino acids-enriched early parenteral and enteral nutrition on the liver function and serum aminograms in cirrhotic rats after partial hepatectomy. Methods In this prospective randomized controlled study, 24 cirrhotic rats, induced by thioacetamide, were randomized into three groups: enteral nutrition (EN) group, EN + branched-chain amino acid (BCAA) group, and parenteral nutrition (PN) + BCAA group. After receiving partial hepatectomy, rats in all three groups were nutritionally supported with equal amount of calorie and nitrogen contents from the 1st postoperative day ( PO day 1 ) to PO day 5. On PO day 6, parameters including body weight, liver functions, prealbumin, transferring, and serum aminograms were measured or determined, and the level of liver albumin mRNA was detected by reversal transcription-polymerase chain reaction and morphological examinations such as HE staining and immunohistochemical staining, which were assessed by index of Ki67 protein index. Results Body weight was significantly decreased in all three groups on PO day 6 (P ＜0.05 ). Compared with EN + BCAA group, serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase after partial hepatectomy were significantly higher in PN + BCAA group (P ＜0.05 ). Serum alkaline phosphatase level was significantly higher in PN + BCAA group than in EN group ( P ＜0. 05). The level of prealbumin was significantly lower in PN + BCAA group when compared with EN group or EN +BCAA group ( both P ＜ 0. 05 ), although no such significant difference was noted in terms of transferrin ( P ＞0. 05 ). The levels of leucine and isoleucine elevated while those of tyrosine, phenylalanine, arginine and tryptophan declined in PN + BCAA group or EN + BCAA group when compared with EN group ( P ＜ 0. 05 ). Aminograms were not significantly different between EN + BCAA group and PN + BCAA group ( P ＞ 0. 05 ). Levels of total amino acid and aromatic amino acid (AAA) were significantly lower while BCAA and ratio between BCAA and AAA (BCAA/AAA) were significantly higher in PN + BCAA group or EN + BCAA group than in EN group (P ＜ 0. 05 ).Significantly lower level of albumin mRNA and index of Ki67 were observed in PN + BCAA group than in EN group or EN + BCAA group (P ＜ 0.05 ) on PO day 6. Conclusions BCAA-enriched EN or PN reverses amino acid disequilibrium and restores BCAA/AAA in cirrhotic rats after partial hepatectomy. Compared with PN, EN is superior in improving postoperative liver function, promoting protein synthesis, and speed up tissue regeneration in the postoperative liver. However, it still can not restore serum albumin in a short term.