Rethinking Consistency Management in Real-time Collaborative Editing Systems

Networked computer systems offer much to support collaborative editing of shared documents among users. Increasing concurrent access to shared documents by allowing multiple users to contribute to and/or track changes to these shared documents is the goal of real-time collaborative editing systems (RTCES); yet concurrent access is either limited in existing systems that employ exclusive locking or concurrency control algorithms such as operational transformation (OT) may be employed to enable concurrent access. Unfortunately, such OT based schemes are costly with respect to communication and computation. Further, existing systems are often specialized in their functionality and require users to adopt new, unfamiliar software to enable collaboration. This research discusses our work in improving consistency management in RTCES. We have developed a set of deadlock-free multi-granular dynamic locking algorithms and data structures that maximize concurrent access to shared documents while minimizing communication cost. These algorithms provide a high level of service for concurrent access to the shared document and integrate merge-based or OT-based consistency maintenance policies locally among a subset of the users within a subsection of the document – thus reducing the communication costs in maintaining consistency. Additionally, we have developed client-server and P2P implementations of our hierarchical document management algorithms. Simulations results indicate that our approach achieves significant communication and computation cost savings. We have also developed a hierarchical reduction algorithm that can minimize the space required of RTCES, and this algorithm may be pipelined through our document tree. Further, we have developed an architecture that allows for a heterogeneous set of client editing software to connect with a heterogeneous set of server document repositories via Web services. This architecture supports our algorithms and does not require client or server technologies to be modified – thus it is able to accommodate existing, favored editing and repository tools. Finally, we have developed a prototype benchmark system of our architecture that is responsive to users’ actions and minimizes communication costs

At the intersection of medical geography and disease ecology: Mirko Grmek, Jacques May and the concept of pathocenosis

Environmental historians are not sufficiently aware of the extent to which mid twentieth-century thinkers turned to medical geography—originally a nineteenth-century area of study—in order to think through ideas of ecology, environment, and historical reasoning. This article outlines how the French–Croatian Mirko D. Grmek (Krapina, 1924–Paris, 2000), a major thinker of his generation in the history of medicine, used those ideas in his studies of historical epidemiology. During the 1960s, Grmek attempted to provide, in the context of the Annales School’s research program under the leadership of Fernand Braudel, a new theoretical framework for a world history of disease. Its development was inspired by several sources, most notably the French–American Jacques M. May (Paris 1896–Tunisia, 1975), who was then pioneering an opening up of medical geography and movement towards the concept of disease ecology. The cornerstone of Grmek’s “synthetic approach” to the field was the notion of “pathocenosis”. The diverse uses of this notion in the course of time—from his early agenda focused on a longue durée history of diseases in Western Antiquity to his last, relating to the new epidemiological threat of (re)emerging infectious diseases, specifically HIV/aids—enables us firstly, to note how concepts of ecology sat uneasily alongside those of medical geography; secondly, to assess the reach and limits of his theoretical contribution to historical epidemiology; and thirdly, to understand better the uneven fortunes of his concept of pathocenosis at the end of the twentieth and beginning of the twenty-first centuries.Peer reviewe

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that -80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAFPeer reviewe

Sex differences in oncogenic mutational processes

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi: https://doi.org/10.13039/501100002790Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Canada Foundation for Innovation (Fondation canadienne pour l'innovation); doi: https://doi.org/10.13039/501100000196Funder: Terry Fox Research Institute (Institut de Recherche Terry Fox); doi: https://doi.org/10.13039/501100004376Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Sex differences in oncogenic mutational processes

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.Peer reviewe