Probabilistic machine learning and artificial intelligence.

How can a machine learn from experience? Probabilistic modelling provides a framework for understanding what learning is, and has therefore emerged as one of the principal theoretical and practical approaches for designing machines that learn from data acquired through experience. The probabilistic framework, which describes how to represent and manipulate uncertainty about models and predictions, has a central role in scientific data analysis, machine learning, robotics, cognitive science and artificial intelligence. This Review provides an introduction to this framework, and discusses some of the state-of-the-art advances in the field, namely, probabilistic programming, Bayesian optimization, data compression and automatic model discovery.The author acknowledges an EPSRC grant EP/I036575/1, the DARPA PPAML programme, a Google Focused Research Award for the Automatic Statistician and support from Microsoft Research.This is the author accepted manuscript. The final version is available from NPG at http://www.nature.com/nature/journal/v521/n7553/full/nature14541.html#abstract

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

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era

Evolução das desigualdades sociais em saúde entre idosos e adultos brasileiros: um estudo baseado na Pesquisa Nacional por Amostra de Domicílios (PNAD 1998, 2003) Health inequality trends among Brazilian adults and old-aged: a study based on the National Household Sample Survey (PNAD 1998, 2003)

O objetivo deste trabalho foi verificar se as desigualdades sociais em saúde de adultos (20-64 anos) e idosos (> 65 anos) brasileiros se alteraram entre 1998 e 2003. O estudo foi realizado em uma amostra de 203.455 e 239.700 participantes da PNAD 1998 e 2003, respectivamente. As condições de saúde e função física, uso de serviços de saúde e filiação a plano de saúde daqueles pertencentes ao quintil inferior da distribuição da renda domiciliar per capita foram comparadas às daqueles com renda mais alta, utilizando-se métodos multivariados de análise. Os resultados mostraram que nos dois anos considerados, os indivíduos no estrato mais baixo de renda apresentavam piores condições de saúde, pior função física e menor uso de serviços de saúde, tanto na faixa etária de 20-64 quanto na de > 65 anos de idade. As forças das associações entre renda domiciliar per capita, condições de saúde e uso de serviços de saúde não se modificaram entre 1998 e 2003, indicando que não houve alterações nas desigualdades sociais em saúde no período estudado. A persistência dessas desigualdades aponta para a ineficiência de políticas, nos últimos cinco anos, que as reduzissem.<br>The aim of this study was to verify whether health inequalities among Brazilian adults (20-64 years) and old-aged (> 65 years) have changed from 1998 to 2003. The study was conducted in samples of 203.455 and 239.700 participants of the National Household Sample Survey in 1998 and 2003 respectively. The health characteristics of those in the lower quintile of the per capita family income were compared to those with higher income by means of multivariate analysis methods. The characteristics considered in this study were health conditions and physical functioning, use of medical and dental services and health plan affiliation. The results from both years showed poorer health conditions, poorer physical functioning and less use of medical and dental services among those with lower per capita family income in both age groups, 20-64 and > 65 years. The associations between per capita family income, health status and use of health services were similar in 1998 and 2003, indicating that health inequalities have not changed in the period under study. The persistence of these inequalities shows the inefficiency of public policies in the last five years to reduce such inequalities