Andrey Rzhetsky; Steven C. Bagley; Kanix Wang; Christopher S. Lyttle; Edwin H. Cook, Jr; Russ B. Altman; Robert D. Gibbons

“ Following similar logic, in addition to causing birth defects, environmental toxins, such as pesticides [34] , [35] can substantially weaken the human immune system, especially in men, which results in more frequent infections. (The rates of female viral infections were highly correlated with male viral infections; these can serve a somewhat weaker fixed effect predictor, data not shown.) ”

“ The model parameters were estimated using a joint statistical inference as follows. Most of the parameters (44 out of 50) were real-valued coefficients representing regression weights of individual factors, such as average income in county, percentage of ethnic groups, per cent of urban and poor population, see Table 1. The factors that are a priori suspected to be relevant to disease incidence and are deliberately included into the model, are referred to in the mixed effect model formalism as the fixed effects. ”

“ Both ASD and ID showed significant gender-specific incidence effects, with males affected more frequently than females; this was more extreme for ASD (Table 1 and Figure 3) . Using ethnicity variables to account for genetic heterogeneity of the US population, corrected for socioeconomic factors, such as the mean county-specific income, we found the incidence of the two diseases significantly varied across ethnic groups (Table 1) , with Pacific Islanders, for example, having significantly lower risk for both diseases. ”

“ Similarly, for ID, the average rate over the whole country is 0.024% per any male, 0.025% per any female. The maximum per county per person rate reached 0.9% and 0.58% for males and females, respectively. Furthermore, for males, the rates of ASD and ID at the county level were weakly but significantly correlated (Pearson product-moment correlation 0.0589, p = 0.00101) , while for females the correlation was much stronger (0.197, p<2.26×10−16) . The estimated Poisson rates of incidence produced by model-based inference are shown in Figure 2. ”

“ This database spans the years 2003 to 2010 and consists of approved commercial health insurance claims for between 17.5 and 45.2 million people annually, with linkage across years, yielding a total of approximately 105 million patient records. (Note that, consistent with low prevalence of both phenotypes, only a small proportion of individuals described in this enormous dataset were diagnosed with either ASD or ID.) This national database contains information contributed by well over 100 insurance carriers and large self-insuring companies. ”

“ Maternal occupation and the risk of major birth defects: a follow-up analysis from the National Birth Defects Prevention Study. Int J Hyg Environ Health 216: 317–323226951061 2 Brent RL (2004) Environmental causes of human congenital malformations: the pediatrician's role in dealing with these complex clinical problems caused by a multiplicity of environmental and genetic factors. ”

“ AU – autism spectrum disorders; ID – intellectual disabilities; AmInd – proportion of American Indians; Asian – proportion of Asians; WHisp – White Hispanics; W – White non-Hispanic; BHisp – black Hispnics; B – black non-Hispaic; Pacific – Pacific Islanders; Insured – proportion of insured; Poor – proportion of poor; Urban – proportion of urban; CongMrepM – congenital malformations excluding malformations of genitals in males; ConGenM – congenital malformations of genitals in males; Viral_M – viral infections affecting males; ASD – inclusion of Autism Spectrum Disorders ”

“ Prenatal exposure to di-n-butyl phthalate induces anorectal malformations in male rat offspring. Toxicology 290: 322–32622027561↑ Lawson CC, Schnorr TM, Whelan EA, Deddens JA, Dankovic DA, et al. (2004) Paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and birth outcomes of offspring: birth weight, preterm delivery, and birth defects. ”

“ While these variables produced statistically significant fixed-effect coefficients, they did not affect the relationship between the outcome variable and the compound environmental predictor variables as would be expected if these added variables were true confounders.The authors are grateful to David Blair, Christiann Frazier, Ravinesh Kumar, Diane Lauderdale, Rita Rzhetsky, and Kevin White for numerous comments that significantly improved the manuscript.
References ↑ Croen LA, Grether JK, Hoogstrate J, Selvin S (2002) The changing prevalence of autism in California. ”