Background Numerous studies have identified the potential risk factors and biomarkers for autism spectrum disorder (ASD). We aim to study the strength and validity of the suggested environmental risk factors or biomarkers of ASD. Methods We conducted an umbrella review and systematically appraised the relevant meta-analyses of observational studies (PROSPERO registration: CRD42018091704). We searched PubMed, Embase, and Cochrane Database of Systematic Reviews from inception to 10/17/2018 and screened the reference list of relevant articles. We obtained the summary effect, 95% confidence interval (CI), heterogeneity, and 95% prediction intervals. We examined small study effects and excess significance. We performed analyses under credibility ceilings. Findings A total of 46 eligible articles yielded data on 67 environmental risk factors (cases=544212, population=81708787) and 52 biomarkers (cases=15614, controls=15417). Evidence of association was convincing for greater maternal age (RR=1•31, 95% CI=1•18 to 1•45), maternal chronic hypertension (OR=1•48, 95% CI=1•29 to 1•70), maternal gestational hypertension (OR=1•37, 95% CI=1•21 to 1•54), maternal overweight (RR=1•28, 95% CI=1•19 to 1•36), preeclampsia (RR=1•32, 95% CI=1•20 to 1•45), pre-pregnancy maternal antidepressant exposure (RR=1•48, 95% CI=1•29 to 1•71), and selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy (OR=1•84, 95% CI=1•60 to 2•11). Only two associations, maternal overweight and SSRI during pregnancy, retained high level of evidence under subset sensitivity analyses. Evidence from biomarkers was limited. Interpretation Convincing evidence suggests that maternal factors such as age and features of metabolic syndrome are associated with risk of ASD. SSRI use during pregnancy was also convincingly associated with risk of ASD when exposed and non-exposed groups were compared. However, there is a possibility that the association is affected by other confounding factors, considering that pre-pregnancy maternal antidepressant exposure was also convincingly associated with higher risk of ASD. Findings from prior studies suggest that one possible confounding factor is underlying maternal psychiatric disorders.

Background Many potential environmental risk and protective factors, and peripheral biomarkers for ADHD have been investigated, but their consistency and magnitude are unclear. We aimed to systematically appraise the published evidence of association between potential risk factors, protective factors, or peripheral biomarkers, and ADHD. MethodsWe did an umbrella review of meta-analyses. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews from inception to Oct 31, 2019, and screened the references of relevant articles. We included systematic reviews providing meta-analyses of observational studies that examined associations of potential environmental risk factors, protective factors, or peripheral biomarkers with diagnosis of ADHD. We included meta-analyses using categorical ADHD diagnosis criteria according to DSM, or hyperkinetic disorder according to ICD, and accepted less rigorous criteria such as self-reports. We excluded articles that did not examine environmental risk factors, protective factors, or peripheral biomarkers of ADHD; articles that did not include a meta-analysis; and articles that did not present enough data for re-analysis. We excluded non-human studies, primary studies, genetic studies, and conference abstracts. We calculated the summary effect estimates (odds ratio [OR], relative risk [RR], and weighted mean difference [WMD]), 95% CI, heterogeneity I2 statistic, 95% prediction interval, small study effects, and excess significance biases. We did analyses under credibility ceilings, and assessed the quality of the meta-analyses with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). This study is registered with PROSPERO, number CRD42019145032. Findings We identified 1839 articles, of which 35 were eligible for inclusion. These 35 articles yielded 63 meta-analyses encompassing 40 environmental risk factors and protective factors (median cases 16 850, median population 91 954) and 23 peripheral biomarkers (median cases 175, median control 187).

Manuscript word count: 4455 words 4 5 Funding 1 None. 2 3

Lithium carbonate is a widely used drug for affective disorders. It may effect calcium metabolism and alter parathyroid physiology by causing hypersecretion of parathyroid hormone. Patients treated with this medication might therefore be predisposed to osteoporosis. The purpose of this study was to evaluate the effect of either short- or long-term lithium carbonate therapy on parameters of bone metabolism. Parathyroid function and indices of bone metabolism were assessed in 23 patients treated for affective disorders. 10 patients were treated for 0.4-1.0 year (Group 1), and 13 patients were treated for more than 3 years (Group 2). In all subjects, bone mineral density measurements in the hip and lumbar spine regions were performed using dual energy X-ray absorptiometry. Serum thyroid hormone, PTH, LH, testosterone and urine OH-proline, free cortisol, calcium and phosphate excretion were measured. The two groups were well matched for sex, weight, calcium intake, lithium levels and smoking habits, although Group 2 was slightly older. No differences between the two groups were noted in either bone mineral density or other parameters that were assessed. Urinary OH-proline was elevated similarly in both groups. Our results did not detect any effect on bone density after short- or long-term lithium carbonate therapy, although the data does suggest an increase in bone turnover associated with this treatment. Thus, short- or long-term treatment with lithium is not associated with increased risk for osteoporosis.

This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk; however, genuine associations should be carefully verified and understood.