Massively parallel sequencing technology and the associated rapidly decreasing sequencing costs have enabled systemic analyses of somatic mutations in large cohorts of cancer cases. Here we introduce a comprehensive mutational analysis pipeline that uses standardized sequence-based inputs along with multiple types of clinical data to establish correlations among mutation sites, affected genes and pathways, and to ultimately separate the commonly abundant passenger mutations from the truly significant events. In other words, we aim to determine the Mutational Significance in Cancer (MuSiC) for these large data sets. The integration of analytical operations in the MuSiC framework is widely applicable to a broad set of tumor types and offers the benefits of automation as well as standardization. Herein, we describe the computational structure and statistical underpinnings of the MuSiC pipeline and demonstrate its performance using 316 ovarian cancer samples from the TCGA ovarian cancer project. MuSiC correctly confirms many expected results, and identifies several potentially novel avenues for discovery.
PURPOSE Precision oncology depends on the matching of tumor variants to relevant knowledge describing the clinical significance of those variants. We recently developed the Clinical Interpretations for Variants in Cancer (CIViC; civicdb.org ) crowd-sourced, expert-moderated, and open-access knowledgebase. CIViC provides a structured framework for evaluating genomic variants of various types (eg, fusions, single-nucleotide variants) for their therapeutic, prognostic, predisposing, diagnostic, or functional utility. CIViC has a documented application programming interface for accessing CIViC records: assertions, evidence, variants, and genes. Third-party tools that analyze or access the contents of this knowledgebase programmatically must leverage this application programming interface, often reimplementing redundant functionality in the pursuit of common analysis tasks that are beyond the scope of the CIViC Web application. METHODS To address this limitation, we developed CIViCpy ( civicpy.org ), a software development kit for extracting and analyzing the contents of the CIViC knowledgebase. CIViCpy enables users to query CIViC content as dynamic objects in Python. We assess the viability of CIViCpy as a tool for advancing individualized patient care by using it to systematically match CIViC evidence to observed variants in patient cancer samples. RESULTS We used CIViCpy to evaluate variants from 59,437 sequenced tumors of the American Association for Cancer Research Project GENIE data set. We demonstrate that CIViCpy enables annotation of > 1,200 variants per second, resulting in precise variant matches to CIViC level A (professional guideline) or B (clinical trial) evidence for 38.6% of tumors. CONCLUSION The clinical interpretation of genomic variants in cancers requires high-throughput tools for interoperability and analysis of variant interpretation knowledge. These needs are met by CIViCpy, a software development kit for downstream applications and rapid analysis. CIViCpy is fully documented, open-source, and available free online.
Locke considers miracles to be crucial in establishing the credibility and reasonableness of Christian faith and revelation. The performance of miracles, he argues, is vital in establishing the "credit of the proposer" who makes any claim to providing a divine revelation. He accords reason a pivotal role in distinguishing spurious from genuine claims to divine revelation, including miracles. According to Locke, genuine miracles contain the hallmark of the divine such that pretend revelations become intuitively obvious. This paper argues that serious tensions exist in Locke's position regarding miracles, which impact on the reasonableness of the assent to Christianity which he presumes they provide.
It is a testimony to the enduring importance of Thomas Kuhn's The Structure of Scientific Revolutions that, 30 years on, its doctrines of normal science and paradigm, incommensurability and revolution continue to challenge metascien tists and stimulate vigorous debate. Critique has mainly come from philosophers and historians; by and large, interested sociologists have embraced Kuhn. Un justifiably so, this article argues, bringing to light a serious difficulty or "anom aly" in his account of the social side of science. Contrary to what he claims, scientific knowledge is not the achievement of organic communities. It is con structed in "trans-epistemic arenas" by diverse participants, laypeople, and specialists. Accepting "community" is a flawed concept in the sociology of science, and in appreciating the major role Kuhn assigned it, the Kuhnian system looks less robust than it did before.
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