Intra- and Inter-Individual Variance of Gene Expression in Clinical Studies

Abstract

Background Variance in microarray studies has been widely discussed as a critical topic on the identification of differentially expressed genes; however, few studies have addressed the influence of estimating variance. Methodology/Principal Findings To break intra- and inter-individual variance in clinical studies down to three levels–technical, anatomic, and individual–we designed experiments and algorithms to investigate three forms of variances. As a case study, a group of “inter-individual variable genes” were identified to exemplify the influence of underestimated variance on the statistical and biological aspects in identification of differentially expressed genes. Our results showed that inadequate estimation of variance inevitably led to the inclusion of non-statistically significant genes into those listed as significant, thereby interfering with the correct prediction of biological functions. Applying a higher cutoff value of fold changes in the selection of significant genes reduces/eliminates the effects of underestimated variance. Conclusions/Significance Our data demonstrated that correct variance evaluation is critical in selecting significant genes. If the degree of variance is underestimated, “noisy” genes are falsely identified as differentially expressed genes. These genes are the noise associated with biological interpretation, reducing the biological significance of the gene set. Our results also indicate that applying a higher number of fold change as the selection criteria reduces/eliminates the differences between distinct estimations of variance.

Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

“…The varied and incomplete penetrance suggests a potential role of other genetic/environmental factors in the disease onset in DCM related titinopathy. It was shown by Cheng et al that levels of genes’ expression can vary even among individuals of the same family and in this way influence the penetrance of mutation [19]. Furthermore, manifestation of clinical symptoms of pathogenic mutations is more likely to appear with increasing age of individual which, again, was showed for HCM and MYBPC3 mutations [20] or Emery-Dreifuss muscular dystrophy and LMNA [21].…”

Extremely Low-Frequency Electromagnetic Fields Cause G1 Phase Arrest through the Activation of the ATM-Chk2-p21 Pathway

“…Further details regarding the fabrication of cDNA microarrays and loop-design statistics are available in previous reports [21]–[23].…”

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…Humans are characterized by marked inter-individual differences in the expression levels of their genes (Stranger et al 2007; Skelly et al 2009; Cowley et al 2009; Cheng et al 2012). Since gene expression is controlled by a combination of cis - and trans -acting regulatory factors, one means by which heritable differences in gene expression may be mediated is through polymorphism either of trans -acting regulatory (transcription) factors or of the cis -acting target sequences to which they bind.…”