Stratification of population in NHANES 2009–2014 based on exposure pattern of lead, cadmium, mercury, and arsenic and their association with cardiovascular, renal and respiratory outcomes

Environmental exposure to toxic metals is an important risk factor to human health. Traditional methods have examined associations between a health endpoint and exposure to heavy metals by either univariate or multiple regression. In the setting of ubiquitous heterogeneous environmental exposures, statistical methods that incorporate mixed exposures are increasingly relevant and may provide new insight into the association between metal exposure and important cardiovascular, renal and respiratory outcomes. The objective of this study was to classify the population of National Health and Nutrition Examination Survey (NHANES) into different exposure subgroups using modern unsupervised clustering methods based on lead, cadmium, mercury, and arsenic measured in urine or whole blood, and to assess the association between the identified exposure groups and twelve important health endpoints. We analyzed a sub-cohort of 9662 subjects participating in the 6 cycles (2003–2004 to 2013–2014) of NHANES study. The urine levels of 3 heavy metals (total arsenic, lead, cadmium) and blood levels of 3 heavy metals (lead, cadmium and mercury) were analyzed using a two-step approach. In the first step, we stratified the population into subgroups using unsupervised clustering (k-medoids) based on levels of metals either in urine or in blood. Then, we examine the association between 12 health endpoints and identified exposure subgroups while controlling for age, sex, race/ethnicity, education, smoking status, BMI, and urinary creatinine. The k-medoids algorithm clustered NHANES population into 2 groups based on either blood or urinary levels of heavy metals. The concentrations of all the three heavy metals were significantly different between the identified groups in blood (p < 2.2e−16) or in urine (p = 0). The group with higher concentrations was defined as the “high-exposure” group, while the group with lower concentrations was defined as “low-exposure” group. Association analysis with health outcomes suggested that the high-exposure group according to either blood or urinary metal levels had significantly higher total mortality (1.63–1.64 times higher, p < 0.0001), mortality caused by malignant neoplasms (2.05–2.62 times higher, p < 0.0002), Gamma-glutamyl transferase (GGT) (1.03–1.05 times higher, p < 0.0001). In addition, the high-exposure group based on blood levels was also significantly associated with SBP, death related to hypertension, heart disease and chronic lower respiratory disease, while the high-exposure group based on urinary concentrations had higher mortality related to nephritis. We proposed an unsupervised clustering method to stratify the population into high- and low-exposure groups based on the co-exposure of heavy metals. The high-exposure groups, characterized by higher metal concentrations, had significant higher GGT, SBP, DBP, and mortality rates suggesting the detrimental effects of exposure to these heavy metals. The stratification of the NHANES population based on exposure patterns provides an informative method to study the impact of metal exposures on health outcomes.