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Original Investigation |

Association of Peripheral Blood Levels of Brain-Derived Neurotrophic Factor With Autism Spectrum Disorder in Children A Systematic Review and Meta-analysis ONLINE FIRST

Xiao-Yan Qin, MD1,2; Jin-Chao Feng, PhD1; Chang Cao, BS1; Huan-Tong Wu, BS1; Y. Peng Loh, PhD3; Yong Cheng, PhD3
[+] Author Affiliations
1Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing
2Beijing Engineering Research Center of Food Environment and Health, Minzu University of China, Beijing
3Section on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
JAMA Pediatr. Published online September 19, 2016. doi:10.1001/jamapediatrics.2016.1626
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Importance  Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) may be implicated in the developmental outcomes of children with autism spectrum disorder (ASD).

Objective  To use meta-analysis to determine whether children with ASD have altered peripheral blood levels of BDNF.

Data Source  A systematic search of PubMed, PsycINFO, and Web of Science was performed for English-language literature through February 7, 2016. The search terms included brain-derived neurotrophic factor or BDNF in combination with autism, without year restriction. Two additional records were retrieved after a review of the reference lists of selected articles.

Study Selection  Studies were included if they provided data on peripheral blood levels of BDNF in children with ASD and healthy control children. Studies that included adults or with overlapping samples were excluded.

Data Extraction and Synthesis  Data were extracted by 2 independent observers from 19 included studies. Data were pooled using a random-effects model with Comprehensive Meta-analysis software.

Main Outcomes and Measures  Blood levels of BDNF in children with ASD compared with healthy controls. Altered levels of BDNF were hypothesized to be related to ASD.

Results  This meta-analysis included 19 studies with 2896 unique participants. Random-effects meta-analysis of all 19 studies showed that children with ASD had significantly increased peripheral blood levels of BDNF compared with healthy controls (Hedges g, 0.490; 95% CI, 0.185-0.794; P = .002). Subgroup analyses in 4 studies revealed that neonates diagnosed with ASD later in life had no association with blood levels of BDNF (Hedges g, 0.384; 95% CI, −0.244 to 1.011; P = .23), whereas children in the nonneonate ASD group (15 studies) demonstrated significantly increased BDNF levels compared with healthy controls (Hedges g, 0.524; 95% CI, 0.206 to 0.842; P = .001). Further analysis showed that children in the nonneonate ASD group had increased BDNF levels in serum (10 studies) (Hedges g, 0.564; 95% CI, 0.168 to 0.960; P = .005) but not in plasma (5 studies) (Hedges g, 0.436; 95% CI, −0.176 to 1.048; P = .16). Meta-regression analyses revealed that sample size had a moderating effect on the outcome of the meta-analysis in the nonneonate group. In addition, no publication bias was found in the meta-analysis.

Conclusions and Relevance  Children with ASD have increased peripheral blood levels of BDNF, strengthening the clinical evidence of an abnormal neurotrophic factor profile in this population.

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Figures

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Figure 1.
PRISMA Flowchart of the Literature Search

BDNF indicates brain-derived neurotrophic factor.

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Figure 2.
Forest Plot for Random-Effects Meta-analysis

Differences in blood levels of brain-derived neurotrophic factor are shown between children with autism spectrum disorder (ASD) and healthy controls. The sizes of the squares are proportional to study weights. Diamond marker indicates pooled effect size.

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Figure 3.
Forest Plot for Subgroup Analysis Stratified by Study Design

Pooled results compare blood levels of brain-derived neurotrophic factor between children with autism spectrum disorder (ASD) and healthy controls. Study design is stratified into neonate and nonneonate studies. The sizes of the squares are proportional to study weights. Diamond markers indicate pooled effect sizes.

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Figure 4.
Forest Plot for Subgroup Analysis Stratified by Sample Source

Pooled results compare blood levels of brain-derived neurotrophic factor between children with autism spectrum disorder (ASD) and healthy controls. Sample source is stratified into serum and plasma samples in the nonneonate group. The sizes of the squares are proportional to study weights. Diamond markers indicate pooled effect sizes.

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Figure 5.
Funnel Plot of Precision by Hedges g Statistics

Publication bias in studies comparing brain-derived neurotrophic factor levels between children with autism spectrum disorder and healthy controls. The plots describe the effect size (Hedges g statisic) of studies against their precision (inverse of SE). Data markers indicate individual studies. Diamond marker indicates pooled effect.

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