Graph Theoretical Analysis of Functional Brain Networks: Test-Retest Evaluation on Short- and Long-Term Resting-State Functional MRI Data

Graph-based computational network analysis has proven a powerful tool to quantitatively characterize functional architectures of the brain. However, the test-retest (TRT) reliability of graph metrics of functional networks has not been systematically examined. Here, we investigated TRT reliability of topological metrics of functional brain networks derived from resting-state functional magnetic resonance imaging data. Specifically, we evaluated both short-term (<1 hour apart) and long-term (>5 months apart) TRT reliability for 12 global and 6 local nodal network metrics. We found that reliability of global network metrics was overall low, threshold-sensitive and dependent on several factors of scanning time interval (TI, long-term>short-term), network membership (NM, networks excluding negative correlations>networks including negative correlations) and network type (NT, binarized networks>weighted networks). The dependence was modulated by another factor of node definition (ND) strategy. The local nodal reliability exhibited large variability across nodal metrics and a spatially heterogeneous distribution. Nodal degree was the most reliable metric and varied the least across the factors above. Hub regions in association and limbic/paralimbic cortices showed moderate TRT reliability. Importantly, nodal reliability was robust to above-mentioned four factors. Simulation analysis revealed that global network metrics were extremely sensitive (but varying degrees) to noise in functional connectivity and weighted networks generated numerically more reliable results in compared with binarized networks. For nodal network metrics, they showed high resistance to noise in functional connectivity and no NT related differences were found in the resistance. These findings provide important implications on how to choose reliable analytical schemes and network metrics of interest

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe