Median and 90th percentile of False Discovery Rates (FDR) in order left-to-right of threshold value and number of statistically significant results for all three groups (C, BD, and SZ).

<p>The Y-axis is an estimate of the percentage of false positives. High-ranked miRNA (at the left) have a low rate of false positives, while lower-ranked miRNA (moving toward the right) have higher rates of false positives.</p

Student’s t-test comparison of qPCR Delta-CT.

<p>miR-29c expression is significantly increased in BD samples, and miR-497 in SZ samples.</p><p>BD =  bipolar disorder; SZ =  schizophrenia.</p

Analyzed human prefrontal cortices (BA9).

<p>SZ =  schizophrenia; BD =  bipolar disorder; C =  controls.</p><p>BB =  Braak and Braak.</p><p>L =  Luminex; P =  qPCR.</p

SAM test of <i>Luminex</i> miRNA expression data for all 3 examined groups of cases: SZ, BD, and C.

<p>The list of 198 miRNAs were narrowed from 312 microRNA using a linear regression model and subsequently ranked by z-score test statistics. Local FDR evaluates false discoveries by assigning samples to random groups to test for statistical significance by chance. The relevance of FDR is determined using q-values, an analog of the p-value. The 21 top-ranked miRNAs have a q-value equal to 0%, meaning that it is highly unlikely for this miRNAs to be expressed differentially by chance among the three groups examined.</p><p>SZ =  schizophrenia; BD =  bipolar disorder; C =  controls.</p

Misclassification rate analysis.

<p>(A) Controls (red) have the most variable miRNA expression. The expression data have less variability in BD (green) and the least in SZ (blue; misclassification rate  = 0), resulting in stronger predictive power within their respective clinical groups.</p

Covariate effects of medications on highly-ranked miRNAs in SAM (top-21 in Table 2 and top-12 in Table 3).

<p>Covariate effects of medications on highly-ranked miRNAs in SAM (top-21 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048814#pone-0048814-t002" target="_blank">Table 2</a> and top-12 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048814#pone-0048814-t003" target="_blank">Table 3</a>).</p

In comparison to controls, the expression of miR-29c and miR-497 is significantly increased in BD and SZ samples, respectively.

<p>Average exosomal RNA extracted from BA9 cortices of BD samples show a 2.77 fold increase of miR-29c in comparison to controls (A). SZ samples reveal 2.35 fold increase of miR-497 when compared to controls (B). Error bars indicate S.E.M.</p

Characterization of exosome-containing pellets from human brain tissue.

<p>Electron microscopy of exosomal extractions from BA9 cortices demonstrates the presence of microvesicles (∼70–100 nm in diameter). Upon immuno-gold labeling procedure with antibodies against CD63 (A; additional negative staining highlights membrane of the vesicle) and GAPDH (B), the microvesicles reveal the presence of exosome-associated antigens. Bars indicate 100 nm. Comparison of exosomal extraction procedure products from BA9 cortices and H4 cell-culture reveals similar outcomes in Western blot. Supernatant of BA9 exosome-containing pellets (lane 1), supernatant of H4 exosome-containing pellets (lane 2), BA9 exosome-containing pellets reconstituted in PBS (lane 3), and of H4 exosome-containing pellets reconstituted in PBS (lane 4), show robust presence of exosomal marker flotillin-2 in the pellets, but not in the supernatants (C).</p

Hierarchical clustering analysis of top 21 ranked miRNAs from FDR analysis.

<p>Correlation coefficient (cc) was generated to assess the relationship between the expression values of each sample and the rest of the samples (see Methods). The coefficient is 1 if their expression profiles are highly similar and 0 if their expression profiles are highly divergent. The clustering graph is built so that the samples with similar expression patterns are clustered at the bottom while more differential patterns are at the top of the graph.</p

Classes (A–G) encompassing the medications in Table 4.

<p>SZ =  schizophrenia; BD =  bipolar disorder.</p