Systematic evaluation of environmental and behavioural factors associated with all-cause mortality in the United States national health and nutrition examination survey

Abstract

Background: Environmental and behavioural factors are thought to contribute to all-cause mortality. Here, we develop a method to systematically screen and validate the potential independent contributions to all-cause mortality of 249 environmental and behavioural factors in the National Health and Nutrition Examination Survey (NHANES).

Methods: We used Cox proportional hazards regression to associate 249 factors with all-cause mortality while adjusting for sociodemographic factors on data in the 1999-2000 and 2001-02 surveys (median 5.5 follow-up years). We controlled for multiple comparisons with the false discovery rate (FDR) and validated significant findings in the 2003-04 survey (median 2.8 follow-up years). We selected 249 factors from a set of all possible factors based on their presence in both the 1999-2002 and 2003-04 surveys and linkage with at least 20 deceased participants. We evaluated the correlation pattern of validated factors and built a multivariable model to identify their independent contribution to mortality.

Results: We identified seven environmental and behavioural factors associated with all-cause mortality, including serum and urinary cadmium, serum lycopene levels, smoking (3-level factor) and physical activity. In a multivariable model, only physical activity, past smoking, smoking in participant's home and lycopene were independently associated with mortality. These three factors explained 2.1% of the variance of all-cause mortality after adjusting for demographic and socio-economic factors.

Conclusions: Our association study suggests that, of the set of 249 factors in NHANES, physical activity, smoking, serum lycopene and serum/urinary cadmium are associated with all-cause mortality as identified in previous studies and after controlling for multiple hypotheses and validation in an independent survey. Whereas other NHANES factors may be associated with mortality, they may require larger cohorts with longer time of follow-up to detect. It is possible to use a systematic association study to prioritize risk factors for further investigation.

Keywords: All-cause mortality; behaviour; environment-wide association study; exposure.

Figure 1

Methodology to scan for environmental and behavioural factors associated with mortality. (A) Summary of environmental and behavioural variables in three independent NHANES surveys (1999–2000, 2001–02, 2003–04). (B) Training (combined 1999–2000 and 2001–02 surveys) and testing survey information. (C) Associating each 249 variables with all-cause mortality (SES, socio-economic status estimate, quintile of income/poverty ratio). (D) Empirical false discovery rate (FDR) estimation in training surveys. (E) Proportional hazards assumption verification. (F) Tentative validation (P <0.05 in testing surveys). (G) Estimation of variance explained by tentatively validated factors with independent contribution and interaction with demographic variables

Figure 2

Volcano plot of 249 environmental and behavioural factor associations with all-cause mortality in training step (all black points). Red horizontal line denotes FDR-adjusted level of statistical significance (FDR = 5%, P-value = 0.0003). Red points show the standard demographic and socio-economic factors considered for adjustments. For SES: SES_0: 1st quantile of SES, SES_1: 2nd quantile of SES, SES_2: 3rd quantile of SES, SES_3: 4th quantile of SES; SES HR are relative to highest quintile of SES. For education: education_hs: high school education, education_less_hs: less than high school education, education HR relative to greater than hig -school education. For occupation: occupation_blue_semi: semi blue c-ollar, occupation_blue_high: high blue-collar, occupation_white_semi: semi white-collar, occupation_never: never worked. Filled black markers denote validated factors. –log10(P-value) for physical activity and age are annotated in parentheses, since they are extreme. Y-axis is discontinuous to accommodate higher –log10(P-values) for physical activity and age

Figure 3

Pairwise correlations of factors with FDR <5% in the training set and of the standard demographic and socio-economic factors used for adjustments