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Preview: American Journal of Epidemiology - Advance Access

American Journal of Epidemiology Advance Access

Published: Wed, 14 Feb 2018 00:00:00 GMT

Last Build Date: Wed, 14 Feb 2018 04:47:48 GMT


Congenital Abnormalities of the Male Reproductive System and Risk of Autism Spectrum Disorders

Wed, 14 Feb 2018 00:00:00 GMT

Androgens have an extensive influence on brain development in regions of the brain that are relevant for autism spectrum disorder (ASD), yet their etiological involvement remains unclear. Hypospadias (abnormal positioning of the urethral opening) and cryptorchidism (undescended testes) are 2 relatively common male birth defects that are strongly associated with prenatal androgen deficiencies. Having either disorder is a proxy indicator of atypical gestational androgen exposure, yet the association between these disorders and autism has not been extensively studied. We analyzed male singleton live births (n = 224,598) occurring from January 1, 1999, through December 31, 2013, in a large Israeli health-care organization. Boys with autism, cryptorchidism, and hypospadias were identified via International Classification of Diseases, Ninth Revision, codes, with further verification of autism case status by review of medical records. In multivariable-adjusted analyses, the odds ratio for ASD among boys with either condition was 1.62 (95% confidence interval (CI): 1.44, 1.82). The odds ratio for boys with cryptorchidism only was 1.55 (95% CI: 1.34, 1.78), and that for boys with hypospadias only was 1.65 (95% CI: 1.38, 1.98). ASD risk was not elevated among unaffected brothers of hypospadias or cryptorchidism cases, despite familial aggregation of all 3 conditions, providing some indication for the possibility of pregnancy-specific risk factors driving the observed associations. Results suggest that in-utero hypoandrogenicity could play a role in ASD etiology.

Invited Commentary: Male Reproductive System Congenital Malformations and the Risk of Autism Spectrum Disorder

Wed, 14 Feb 2018 00:00:00 GMT

Autism spectrum disorder (ASD) is a prevalent developmental disorder. Studies indicate that while ASD etiology has a genetic component, the risk is polygenic, with gene-environment interactions being likely. The prenatal period is a critical exposure window for nongenetic risk factors. Previous studies have found positive associations between congenital malformations (all types) and ASD; a few also found specific associations between genitourinary system malformations and ASD; and one study found an association between hypospadias and ASD. In the accompanying article, Rotem et al. (Am J Epidemiol. 2018;000(00):000–000) describe how they conducted a comprehensive analysis focusing on the shared risk of ASD with hypospadias or cryptorchidism, using existing data from a large Israeli health services system, which afforded several advantages because of the large sample size and low attrition of the patient population. The authors conducted a careful analysis, including sensitivity analyses, to account for risk factor and case misclassifications that might have occurred had they relied solely on preexisting diagnostic codes to define exposures and outcome. They observed positive associations between both hypospadias and cryptorchidism and ASD that were independent of numerous sociodemographic and pregnancy health factors. This study advances our understanding of ASD etiology and illustrates how existing data might be used to assess some ASD risk factors.

Exposure-lag-response in Longitudinal Studies: Application of Distributed Lag Non-linear Models in an Occupational Cohort

Tue, 13 Feb 2018 00:00:00 GMT

Prolonged exposures can have complex relationships with health outcomes, as timing, duration, and intensity of exposure are all potentially relevant. Summary measures such as cumulative exposure or average intensity of exposure may not fully capture these relationships. We applied penalized and unpenalized distributed lag non-linear models (DLNMs) with flexible exposure-response and lag-response functions in order to examine the association between crystalline silica exposure and mortality from lung cancer and non-malignant respiratory disease in a cohort study of 2,342 California diatomaceous earth workers, followed 1942-2011. We also assessed associations using simple measures of cumulative exposure assuming linear exposure-response and constant lag-response. Measures of association from DLNMs were generally higher than from simpler models. Rate ratios from penalized DLNMs corresponding to average daily exposures of 0.4 mg/m3 during lag years 31-50 prior to the age of observed cases were 1.47 (95% confidence interval (CI) 0.92, 2.35) for lung cancer and 1.80 (95% CI: 1.14, 2.85) for non-malignant respiratory disease. Rate ratios from the simpler models for the same exposure scenario were 1.15 (95% CI: 0.89-1.48) and 1.23 (95% CI: 1.03-1.46) respectively. Longitudinal cohort studies of prolonged exposures and chronic health outcomes should explore methods allowing for flexibility and non-linearities in the exposure-lag-response.