scholarly journals Overcoming bias in gene-set enrichment analyses of brain-wide transcriptomic data

Author(s):  
Ben D. Fulcher ◽  
Aurina Arnatkevičiūtė ◽  
Alex Fornito

The recent availability of whole-brain atlases of gene expression, which quantify the transcriptional activity of thousands of genes across many different brain regions, has opened new opportunities to understand how gene-expression patterns relate to spatially varying properties of brain structure and function. To aid interpretation of a given neural phenotype, gene-set enrichment analysis (GSEA) has become a standard statistical methodology to identify functionally related groups of genes, annotated using systems such as the Gene Ontology (GO), that are associated with a given phenotype. While GSEA has identified groups of genes related to diverse aspects of brain structure and function in mouse and human, here we show that these results are affected by substantial statistical biases. Quantifying the falsepositive rates of individual GO categories across an ensemble of random phenotypic maps, we found an average 875-fold inflation of significant findings relative to expectation in mouse, and a 582-fold inflation in human, with some categories being judged as significant for over 20% of random phenotypes. Concerningly, the probability of a GO category being reported as significant in the extant literature increases with its estimated false-positive rate, suggesting that published reports are strongly affected by the reporting of false-positive bias. We show that the bias is primarily driven by within-category gene–gene coexpression and spatial autocorrelation, which are not accounted for in conventional GSEA nulls, and we introduce flexible ensemble-based null models that can account for these effects. Testing a range of structural connectivity and cell density phenotypes in mouse and human, we demonstrate that many GO categories that would conventionally be judged as highly significant are in fact consistent with ensembles of random phenotypes. Our results highlight major pitfalls with applying standard GSEA to brain-wide transcriptomic data and outline solutions to this pervasive problem, which is made available as an open toolbox.

2001 ◽  
Vol 7 (3) ◽  
pp. 363-366
Author(s):  
L. Eisenberg

Thispaper describes the relation between genes at the molecular level and the brain at the organ level, and biological, social and environmental factors. The malleability of the brain and the effect of external factors and experience on influencing gene expression and brain structure and function are discussed.


2017 ◽  
Vol 49 (5S) ◽  
pp. 824 ◽  
Author(s):  
X. r. Tan ◽  
Ivan C. C. Low ◽  
Mary C. Stephenson ◽  
T. Kok ◽  
Heinrich W. Nolte ◽  
...  

2011 ◽  
Vol 32 (6) ◽  
pp. 814-822 ◽  
Author(s):  
Linda L. Chao ◽  
Linda Abadjian ◽  
Jennifer Hlavin ◽  
Deiter J. Meyerhoff ◽  
Michael W. Weiner

1997 ◽  
Vol 820 (1 Imaging Brain) ◽  
pp. 139-148 ◽  
Author(s):  
G. ALLAN JOHNSON ◽  
HELENE BENVENISTE ◽  
ROBERT T. ENGELHARDT ◽  
HUI QIU ◽  
LAURENCE W. HEDLUND

NeuroImage ◽  
2014 ◽  
Vol 89 ◽  
pp. 81-91 ◽  
Author(s):  
Silke Matura ◽  
David Prvulovic ◽  
Alina Jurcoane ◽  
Daniel Hartmann ◽  
Julia Miller ◽  
...  

2018 ◽  
Vol 50 (3) ◽  
pp. 2201-2210 ◽  
Author(s):  
Zhujing Shen ◽  
Peiyu Huang ◽  
Chao Wang ◽  
Wei Qian ◽  
Xiao Luo ◽  
...  

2010 ◽  
Vol 5 (4) ◽  
pp. 391-400 ◽  
Author(s):  
Denise C. Park ◽  
Chih-Mao Huang

There is clear evidence that sustained experiences may affect both brain structure and function. Thus, it is quite reasonable to posit that sustained exposure to a set of cultural experiences and behavioral practices will affect neural structure and function. The burgeoning field of cultural psychology has often demonstrated the subtle differences in the way individuals process information—differences that appear to be a product of cultural experiences. We review evidence that the collectivistic and individualistic biases of East Asian and Western cultures, respectively, affect neural structure and function. We conclude that there is limited evidence that cultural experiences affect brain structure and considerably more evidence that neural function is affected by culture, particularly activations in ventral visual cortex—areas associated with perceptual processing.


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