Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability.

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

doi:10.1371/journal.pcbi.1003518

Abstract

Many factors affect the risks for neurodevelopmental maladies such as autism spectrum disorders (ASD) and intellectual disability (ID). To compare environmental, phenotypic, socioeconomic and state-policy factors in a unified geospatial framework, we analyzed the spatial incidence patterns of ASD and ID using an insurance claims dataset covering nearly one third of the US population. Following epidemiologic evidence, we used the rate of congenital malformations of the reproductive system as a surrogate for environmental exposure of parents to unmeasured developmental risk factors, including toxins. Adjusted for gender, ethnic, socioeconomic, and geopolitical factors, the ASD incidence rates were strongly linked to population-normalized rates of congenital malformations of the reproductive system in males (an increase in ASD incidence by 283% for every percent increase in incidence of malformations, 95% CI: [91%, 576%], p<6×10−5). Such congenital malformations were barely significant for ID (94% increase, 95% CI: [1%, 250%], p = 0.0384). Other congenital malformations in males (excluding those affecting the reproductive system) appeared to significantly affect both phenotypes: 31.8% ASD rate increase (CI: [12%, 52%], p<6×10−5), and 43% ID rate increase (CI: [23%, 67%], p<6×10−5). Furthermore, the state-mandated rigor of diagnosis of ASD by a pediatrician or clinician for consideration in the special education system was predictive of a considerable decrease in ASD and ID incidence rates (98.6%, CI: [28%, 99.99%], p = 0.02475 and 99% CI: [68%, 99.99%], p = 0.00637 respectively). Thus, the observed spatial variability of both ID and ASD rates is associated with environmental and state-level regulatory factors; the magnitude of influence of compound environmental predictors was approximately three times greater than that of state-level incentives. The estimated county-level random effects exhibited marked spatial clustering, strongly indicating existence of as yet unidentified localized factors driving apparent disease incidence. Finally, we found that 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).

Highlights

Autism spectrum disorders (ASD) are a collection of chronic, complex neuropsychiatric diseases with well-characterized comorbidities and increasing apparent prevalence [1]
We analyzed the strength of disparate factors on the apparent incidence rates of autism spectrum disorders (ASD) and intellectual disability (ID) by computationally interrogating insurance claims for approximately one third of the US population, using a bivariate-response, three-level, mixed-effects Poisson regression model with 50 free parameters, 44 of which correspond to the fixed effects of known factors while the remaining 6 account for the variance and covariance among the random effects
By analyzing the spatial incidence patterns of autism and intellectual disability drawn from insurance claims for nearly one third of the total US population, we found strong statistical evidence that environmental factors drive the apparent spatial heterogeneity of both phenotypes while economic incentives and population structure appear to have relatively large albeit weaker effects

Summary

Introduction

Autism spectrum disorders (ASD) are a collection of chronic, complex neuropsychiatric diseases with well-characterized comorbidities and increasing apparent prevalence [1]. With few and limited effective treatments and considerable financial burden, its etiology remains a scientific puzzle. Evidence suggests that autism is highly heritable and clustered within families; much scientific attention has been dedicated to the discovery of predisposing genetic factors [2,3,4,5,6,7]. There are numerous factors that could affect or distort the observed variation in temporal and spatial disease prevalence: evolving diagnostic criteria, socioeconomic, legal, and cultural incentives for diagnosis [8], changing environmental exposures, and the accumulation of genetic burden in the growing human population. The relative importance of all these putative causal factors and confounders on ASD prevalence, the nature of interactions between contributing factors, and the underlying biological mechanisms, remain unclear

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Results

Conclusion