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1.
BMJ ; 367: l5205, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578187

RESUMO

OBJECTIVES: To determine how clinicians vary in their response to new guidance on existing or new interventions, by measuring the timing and magnitude of change at healthcare institutions. DESIGN: Automated change detection in longitudinal prescribing data. SETTING: Prescribing data in English primary care. PARTICIPANTS: English general practices. MAIN OUTCOME MEASURES: In each practice the following were measured: the timing of the largest changes, steepness of the change slope (change in proportion per month), and magnitude of the change for two example time series (expiry of the Cerazette patent in 2012, leading to cheaper generic desogestrel alternatives becoming available; and a change in antibiotic prescribing guidelines after 2014, favouring nitrofurantoin over trimethoprim for uncomplicated urinary tract infection (UTI)). RESULTS: Substantial heterogeneity was found between institutions in both timing and steepness of change. The range of time delay before a change was implemented was large (interquartile range 2-14 months (median 8) for Cerazette, and 5-29 months (18) for UTI). Substantial heterogeneity was also seen in slope following a detected change (interquartile range 2-28% absolute reduction per month (median 9%) for Cerazette, and 1-8% (2%) for UTI). When changes were implemented, the magnitude of change showed substantially less heterogeneity (interquartile range 44-85% (median 66%) for Cerazette and 28-47% (38%) for UTI). CONCLUSIONS: Substantial variation was observed in the speed with which individual NHS general practices responded to warranted changes in clinical practice. Changes in prescribing behaviour were detected automatically and robustly. Detection of structural breaks using indicator saturation methods opens up new opportunities to improve patient care through audit and feedback by moving away from cross sectional analyses, and automatically identifying institutions that respond rapidly, or slowly, to warranted changes in clinical practice.


Assuntos
Prescrições de Medicamentos/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Avaliação de Processos (Cuidados de Saúde)/métodos , Indicadores de Qualidade em Assistência à Saúde/estatística & dados numéricos , Medicina Estatal/estatística & dados numéricos , Anti-Infecciosos/uso terapêutico , Conjuntos de Dados como Assunto , Substituição de Medicamentos/estatística & dados numéricos , Medicamentos Genéricos/uso terapêutico , Inglaterra , Medicina Geral/organização & administração , Medicina Geral/normas , Medicina Geral/estatística & dados numéricos , Humanos , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/normas , Avaliação de Processos (Cuidados de Saúde)/estatística & dados numéricos , Medicina Estatal/normas , Fatores de Tempo , Infecções Urinárias/tratamento farmacológico
2.
N Engl J Med ; 381(7): 668-676, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31412182

RESUMO

Knowledge gained from observational cohort studies has dramatically advanced the prevention and treatment of diseases. Many of these cohorts, however, are small, lack diversity, or do not provide comprehensive phenotype data. The All of Us Research Program plans to enroll a diverse group of at least 1 million persons in the United States in order to accelerate biomedical research and improve health. The program aims to make the research results accessible to participants, and it is developing new approaches to generate, access, and make data broadly available to approved researchers. All of Us opened for enrollment in May 2018 and currently enrolls participants 18 years of age or older from a network of more than 340 recruitment sites. Elements of the program protocol include health questionnaires, electronic health records (EHRs), physical measurements, the use of digital health technology, and the collection and analysis of biospecimens. As of July 2019, more than 175,000 participants had contributed biospecimens. More than 80% of these participants are from groups that have been historically underrepresented in biomedical research. EHR data on more than 112,000 participants from 34 sites have been collected. The All of Us data repository should permit researchers to take into account individual differences in lifestyle, socioeconomic factors, environment, and biologic characteristics in order to advance precision diagnosis, prevention, and treatment.


Assuntos
Bancos de Espécimes Biológicos , Pesquisa Biomédica , Estudos de Coortes , Conjuntos de Dados como Assunto , Registros Eletrônicos de Saúde , Inquéritos Epidemiológicos , Humanos , Estudos Observacionais como Assunto , Medicina de Precisão , Projetos de Pesquisa , Estados Unidos
3.
Genet Sel Evol ; 51(1): 44, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412777

RESUMO

BACKGROUND: Experimental intercrosses between outbred founder populations are powerful resources for mapping loci that contribute to complex traits i.e. quantitative trait loci (QTL). Here, we present an approach and its accompanying software for high-resolution reconstruction of founder mosaic genotypes in the intercross offspring from such populations using whole-genome high-coverage sequence data on founder individuals (~ 30×) and very low-coverage sequence data on intercross individuals (< 0.5×). Sets of founder-line informative markers were selected for each full-sib family and used to infer the founder mosaic genotypes of the intercross individuals. The application of this approach and the quality of the estimated genome-wide genotypes are illustrated in a large F2 pedigree between two divergently selected lines of chickens. RESULTS: We describe how we obtained whole-genome genotype data for hundreds of individuals in a cost- and time-efficient manner by using a Tn5-based library preparation protocol and an imputation algorithm that was optimized for this application. In total, 7.6 million markers segregated in this pedigree and, within each full-sib family, between 10.0 and 13.7% of these were fully informative, i.e. fixed for alternative alleles in the founders from the divergent lines, and were used for reconstruction of the offspring mosaic genotypes. The genotypes that were estimated based on the low-coverage sequence data were highly consistent (> 95% agreement) with those obtained using individual single nucleotide polymorphism (SNP) genotyping. The estimated resolution of the inferred recombination breakpoints was relatively high, with 50% of them being defined on regions shorter than 10 kb. CONCLUSIONS: A method and software for inferring founder mosaic genotypes in intercross offspring from low-coverage whole-genome sequencing in pedigrees from heterozygous founders are described. They provide high-quality, high-resolution genotypes in a time- and cost-efficient manner. The software is freely available at https://github.com/CarlborgGenomics/Stripes .


Assuntos
Galinhas/genética , Técnicas de Genotipagem , Sequenciamento Completo do Genoma , Animais , Cruzamento , Custos e Análise de Custo , Cruzamentos Genéticos , Conjuntos de Dados como Assunto , Feminino , Efeito Fundador , Técnicas de Genotipagem/economia , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Software , Sequenciamento Completo do Genoma/economia
4.
Br J Radiol ; 92(1102): 20190271, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31453720

RESUMO

OBJECTIVE: Radiomics pipelines have been developed to extract novel information from radiological images, which may help in phenotypic profiling of tumours that would correlate to prognosis. Here, we compared two publicly available pipelines for radiomics analyses on head and neck CT and MRI in nasopharynx cancer (NPC). METHODS AND MATERIALS: 100 biopsy-proven NPC cases stratified by T- and N-categories were enrolled in this study. Two radiomics pipeline, Moddicom (v. 0.51) and Pyradiomics (v. 2.1.2) were used to extract radiomics features of CT and MRI. Segmentation of primary gross tumour volume was performed using Velocity v. 4.0 by consensus agreement between three radiation oncologists. Intraclass correlation between common features of the two pipelines was analysed by Spearman's rank correlation. Unsupervised hierarchical clustering was used to determine association between radiomics features and clinical parameters. RESULTS: We observed a high proportion of correlated features in the CT data set, but not for MRI; 76.1% (51 of 67 common between Moddicom and Pyradiomics) of CT features and 28.6% (20 of 70 common) of MRI features were significantly correlated. Of these, 100% were shape-related for both CT and MRI, 100 and 23.5% were first-order-related, 61.9 and 19.0% were texture-related, respectively. This interpipeline heterogeneity affected the downstream clustering with known prognostic clinical parameters of cTN-status and GTVp. Nonetheless, shape features were the most reproducible predictors of clinical parameters among the different radiomics modules. CONCLUSION: Here, we highlighted significant heterogeneity between two publicly available radiomics pipelines that could affect the downstream association with prognostic clinical factors in NPC. ADVANCES IN KNOWLEDGE: The present study emphasized the broader importance of selecting stable radiomics features for disease phenotyping, and it is necessary prior to any investigation of multicentre imaging datasets to validate the stability of CT-related radiomics features for clinical prognostication.


Assuntos
Imagem por Ressonância Magnética , Tomografia Computadorizada Multidetectores , Carcinoma Nasofaríngeo/diagnóstico por imagem , Neoplasias Nasofaríngeas/diagnóstico por imagem , Adulto , Algoritmos , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Fenótipo , Prognóstico , Radioterapia de Intensidade Modulada
5.
Genet Sel Evol ; 51(1): 34, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262251

RESUMO

BACKGROUND: Milk quality in dairy cattle is routinely assessed via analysis of mid-infrared (MIR) spectra; this approach can also be used to predict the milk's cheese-making properties (CMP) and composition. When this method of high-throughput phenotyping is combined with efficient imputations of whole-genome sequence data from cows' genotyping data, it provides a unique and powerful framework with which to carry out genomic analyses. The goal of this study was to use this approach to identify genes and gene networks associated with milk CMP and composition in the Montbéliarde breed. RESULTS: Milk cheese yields, coagulation traits, milk pH and contents of proteins, fatty acids, minerals, citrate, and lactose were predicted from MIR spectra. Thirty-six phenotypes from primiparous Montbéliarde cows (1,442,371 test-day records from 189,817 cows) were adjusted for non-genetic effects and averaged per cow. 50 K genotypes, which were available for a subset of 19,586 cows, were imputed at the sequence level using Run6 of the 1000 Bull Genomes Project (comprising 2333 animals). The individual effects of 8.5 million variants were evaluated in a genome-wide association study (GWAS) which led to the detection of 59 QTL regions, most of which had highly significant effects on CMP and milk composition. The results of the GWAS were further subjected to an association weight matrix and the partial correlation and information theory approach and we identified a set of 736 co-associated genes. Among these, the well-known caseins, PAEP and DGAT1, together with dozens of other genes such as SLC37A1, ALPL, MGST1, SEL1L3, GPT, BRI3BP, SCD, GPAT4, FASN, and ANKH, explained from 12 to 30% of the phenotypic variance of CMP traits. We were further able to identify metabolic pathways (e.g., phosphate and phospholipid metabolism and inorganic anion transport) and key regulator genes, such as PPARA, ASXL3, and bta-mir-200c that are functionally linked to milk composition. CONCLUSIONS: By using an approach that integrated GWAS with network and pathway analyses at the whole-genome sequence level, we propose candidate variants that explain a substantial proportion of the phenotypic variance of CMP traits and could thus be included in genomic evaluation models to improve milk CMP in Montbéliarde cows.


Assuntos
Bovinos/genética , Queijo , Estudo de Associação Genômica Ampla/veterinária , Leite/química , Animais , Simulação por Computador , Conjuntos de Dados como Assunto , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Masculino , Locos de Características Quantitativas , Sequenciamento Completo do Genoma/veterinária
6.
Genome Biol ; 20(1): 138, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300005

RESUMO

Methylation datasets are affected by innumerable sources of variability, both biological (cell-type composition, genetics) and technical (batch effects). Here, we propose a reference-free method based on sparse canonical correlation analysis to separate the biological from technical sources of variability. We show through simulations and real data that our method, CONFINED, is not only more accurate than the state-of-the-art reference-free methods for capturing known, replicable biological variability, but it is also considerably more robust to dataset-specific technical variability than previous approaches. CONFINED is available as an R package as detailed at https://github.com/cozygene/CONFINED .


Assuntos
Artefatos , Metilação de DNA , Variação Genética , Software , Conjuntos de Dados como Assunto
7.
J Clin Pathol ; 72(9): 573-578, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31300532

RESUMO

The International Collaboration on Cancer Reporting (ICCR) has developed a suite of detailed datasets for international implementation. These datasets are based on the reporting protocols developed by the Royal College of Pathologists (UK), The Royal College of Pathologists of Australasia and the College of American Pathologists, with modifications undertaken by international expert groups appointed according to ICCR protocols. The dataset for the reporting of renal biopsy for tumour is designed to provide a structured reporting template containing minimum data recording key elements suitable for international use. In formulating the dataset, the ICCR panel incorporated recommendations from the 2012 Vancouver Consensus Conference of the International Society of Urological Pathology (ISUP) and the 2016 edition of the WHO Bluebook on tumours of the urinary and male genital systems. Reporting elements were divided into Required (Core) and Recommended (Non-core) components of the report. Required elements are as follows: specimen laterality, histological tumour type, WHO/ISUP histological tumour grade, sarcomatoid morphology, rhabdoid morphology, necrosis, lymphovascular invasion and coexisting pathology in non-neoplastic kidney. Recommended reporting elements are as follows: operative procedure, tumour site(s), histological tumour subtype and details of ancillary studies. In particular, it is noted that fluorescence in situ hybridisation studies may assist in diagnosing translocation renal cell carcinoma (RCC) and in distinguishing oncocytoma and eosinophilic chromophobe RCC. It is anticipated that the implementation of this dataset into routine clinical practice will facilitate uniformity of pathology reporting worldwide. This, in turn, should have a positive impact on patient treatment and the quality of demographic information held by cancer registries.


Assuntos
Biópsia/normas , Confiabilidade dos Dados , Bases de Dados Factuais/normas , Conjuntos de Dados como Assunto/normas , Cooperação Internacional , Neoplasias Renais/patologia , Consenso , Comportamento Cooperativo , Guias como Assunto/normas , Humanos , Neoplasias Renais/epidemiologia , Neoplasias Renais/cirurgia , Gradação de Tumores/normas , Nefrectomia/normas , Valor Preditivo dos Testes
8.
Nat Commun ; 10(1): 3101, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308377

RESUMO

The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.


Assuntos
Adenocarcinoma/genética , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/genética , Perfilação da Expressão Gênica/métodos , Medicina de Precisão/métodos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Progressão da Doença , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Instabilidade Genômica , Humanos , Aprendizado de Máquina , Modelos Genéticos , Família Multigênica/efeitos dos fármacos , Taxa de Mutação , Polimorfismo de Nucleotídeo Único
9.
Nat Commun ; 10(1): 3069, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337762

RESUMO

While rich medical, behavioral, and socio-demographic data are key to modern data-driven research, their collection and use raise legitimate privacy concerns. Anonymizing datasets through de-identification and sampling before sharing them has been the main tool used to address those concerns. We here propose a generative copula-based method that can accurately estimate the likelihood of a specific person to be correctly re-identified, even in a heavily incomplete dataset. On 210 populations, our method obtains AUC scores for predicting individual uniqueness ranging from 0.84 to 0.97, with low false-discovery rate. Using our model, we find that 99.98% of Americans would be correctly re-identified in any dataset using 15 demographic attributes. Our results suggest that even heavily sampled anonymized datasets are unlikely to satisfy the modern standards for anonymization set forth by GDPR and seriously challenge the technical and legal adequacy of the de-identification release-and-forget model.


Assuntos
Análise de Dados , Anonimização de Dados , Informações Pessoalmente Identificáveis , Conjuntos de Dados como Assunto , Funções Verossimilhança , Distribuição Normal
10.
Cancer Sci ; 110(9): 2734-2747, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278886

RESUMO

Lung cancer has the highest morbidity and mortality among all cancers. Discovery of early diagnostic and prognostic biomarkers of lung cancer can greatly facilitate the survival rate and reduce its mortality. In our study, by analyzing Gene Expression Omnibus and Oncomine databases, we found a novel potential oncogene uridine-cytidine kinase 2 (UCK2), which was overexpressed in lung tumor tissues compared to adjacent nontumor tissues or normal lung. Then we confirmed this finding in clinical samples. Specifically, UCK2 was identified as highly expressed in stage IA lung cancer with a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). We also found that high UCK2 expression was related to poorer clinicopathological features, such as higher T stage and N stage and higher probability of early recurrence. Furthermore, we found that patients with high UCK2 expression had poorer first progression survival and overall survival than patients with low UCK2 expression. Univariate and multivariate Cox regression analyses showed that UCK2 was an independent risk factor related with worse DFS and OS. By gene set enrichment analysis, tumor-associated biological processes and signaling pathways were enriched in the UCK2 overexpression group, which indicated that UCK2 might play a vital role in lung cancer. Furthermore, in cytology experiments, we found that knockdown of UCK2 could suppress the proliferation and migration of lung cancer cells. In conclusion, our study indicated that UCK2 might be a potential early diagnostic and prognostic biomarker for lung cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/diagnóstico , Uridina Quinase/metabolismo , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Feminino , Técnicas de Silenciamento de Genes , Humanos , Pulmão/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Uridina Quinase/genética
11.
Cancer Sci ; 110(9): 2905-2923, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31335995

RESUMO

The aim of the present study is to construct a competitive endogenous RNA (ceRNA) regulatory network by using differentially expressed long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in patients with hepatocellular carcinoma (HCC), and to construct a prognostic model for predicting overall survival (OS) of HCC patients. Differentially expressed lncRNAs, miRNAs, and mRNAs were explored between HCC tissues and normal liver tissues. A prognostic model was built for predicting OS of HCC patients and receiver operating characteristic curves were used to evaluate the performance of the prognostic model. There were 455 differentially expressed lncRNAs, 181 differentially expressed miRNAs, and 5035 differentially expressed mRNAs. A ceRNA regulatory network was constructed based on 43 lncRNAs, 37 miRNAs, and 105 mRNAs. Eight mRNA biomarkers (H2AFX, SQSTM1, ITM2A, PFKP, TPD52L1, ACSL4, STRN3, and CPEB3) were identified as independent risk factors by multivariate Cox regression and were used to develop a prognostic model for OS. The C-indexes in the model group were 0.776 (95% confidence interval [CI], 0.730-0.822), 0.745 (95% CI, 0.699-0.791), and 0.789 (95% CI, 0.743-0.835) for 1-, 3-, and 5-year OS, respectively. The current study revealed potential molecular biological regulation pathways and prognostic biomarkers by the ceRNA regulatory network. A prognostic model based on prognostic mRNAs in the ceRNA network might be helpful to predict the individual mortality risk for HCC patients. The individual mortality risk calculator can be used by visiting the following URL: https://zhangzhiqiao.shinyapps.io/Smart_cancer_predictive_system_HCC/.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , RNA Mensageiro/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Nomogramas , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética
12.
Cancer Sci ; 110(9): 2941-2959, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31343810

RESUMO

A sensitive and specific diagnosis biomarker, in principle scalable to most cancer types, is needed to reduce the prevalent cancer mortality. Meanwhile, the investigation of diagnosis determinants of a biomarker will facilitate the interpretation of its screening results in clinic. Here we design a large-scale (1558 enrollments), multicenter (multiple hospitals), and cross-validation (two datasets) clinic study to validate plasma Hsp90α quantified by ELISA as a pan-cancer biomarker. ROC curve shows the optimum diagnostic cutoff is 69.19 ng/mL in discriminating various cancer patients from all controls (AUC 0.895, sensitivity 81.33% and specificity 81.65% in test cohort; AUC 0.893, sensitivity 81.72% and specificity 81.03% in validation cohort). Similar results are noted in detecting early-stage cancer patients. Plasma Hsp90α maintains also broad-spectrum for cancer subtypes, especially with 91.78% sensitivity and 91.96% specificity in patients with AFP-limited liver cancer. In addition, we demonstrate levels of plasma Hsp90α are determined by ADAM10 expression, which will affect Hsp90α content in exosomes. Furthermore, Western blotting and PRM-based quantitative proteomics identify that partial false ELISA-negative patients secret high levels of plasma Hsp90α. Mechanism analysis reveal that TGFß-PKCγ gene signature defines a distinct pool of hyperphosphorylated Hsp90α at Theronine residue. In clinic, a mechanistically relevant population of false ELISA-negative patients express also higher levels of PKCγ. In sum, plasma Hsp90α is a novel pan-cancer diagnosis biomarker, and cancer diagnosis with plasma Hsp90α is particularly effective in those patients with high expression of ADAM10, but may be insufficient to detect the patients with low ADAM10 and those with hyperphosphorylated Hsp90α.


Assuntos
Biomarcadores Tumorais/sangue , Proteínas de Choque Térmico HSP90/sangue , Neoplasias/diagnóstico , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Adolescente , Adulto , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Criança , Pré-Escolar , Conjuntos de Dados como Assunto , Ensaio de Imunoadsorção Enzimática , Exossomos/metabolismo , Reações Falso-Negativas , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , Fosforilação , Estudos Prospectivos , Curva ROC , Treonina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
13.
Nat Commun ; 10(1): 3009, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285442

RESUMO

Quantitative genetics theory predicts that X-chromosome dosage compensation (DC) will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of DC in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and 1600 gene expression traits from a sample of 2000 individuals as well as across-tissue gene expression from the GTEx resource. We find approximately twice as much X-linked genetic variation across the UK Biobank traits in males (mean h2SNP = 0.63%) compared to females (mean h2SNP = 0.30%), confirming the predicted DC effect. Our DC estimates for complex traits and gene expression are consistent with a small proportion of genes escaping X-inactivation in a trait- and tissue-dependent manner. Finally, we highlight examples of biologically relevant X-linked heterogeneity between the sexes that bias DC estimates if unaccounted for.


Assuntos
Genes Ligados ao Cromossomo X/genética , Loci Gênicos/genética , Variação Genética/genética , Herança Multifatorial/genética , Inativação do Cromossomo X/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Modelos Genéticos , Fenótipo , Fatores Sexuais
14.
Nature ; 571(7765): 393-397, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31316195

RESUMO

Existing estimates of sea surface temperatures (SSTs) indicate that, during the early twentieth century, the North Atlantic and northeast Pacific oceans warmed by twice the global average, whereas the northwest Pacific Ocean cooled by an amount equal to the global average1-4. Such a heterogeneous pattern suggests first-order contributions from regional variations in forcing or in ocean-atmosphere heat fluxes5,6. These older SST estimates are, however, derived from measurements of water temperatures in ship-board buckets, and must be corrected for substantial biases7-9. Here we show that correcting for offsets among groups of bucket measurements leads to SST variations that correlate better with nearby land temperatures and are more homogeneous in their pattern of warming. Offsets are identified by systematically comparing nearby SST observations among different groups10. Correcting for offsets in German measurements decreases warming rates in the North Atlantic, whereas correcting for Japanese measurement offsets leads to increased and more uniform warming in the North Pacific. Japanese measurement offsets in the 1930s primarily result from records having been truncated to whole degrees Celsius when the records were digitized in the 1960s. These findings underscore the fact that historical SST records reflect both physical and social dimensions in data collection, and suggest that further opportunities exist for improving the accuracy of historical SST records9,11.


Assuntos
Conjuntos de Dados como Assunto/normas , Aquecimento Global/estatística & dados numéricos , Água do Mar/análise , Temperatura Ambiente , Ar/análise , Oceano Atlântico , Conjuntos de Dados como Assunto/história , Mapeamento Geográfico , Alemanha , Aquecimento Global/história , História do Século XX , Japão , Oceano Pacífico , Reprodutibilidade dos Testes
17.
Nat Commun ; 10(1): 2569, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189880

RESUMO

Synonymous mutations have been viewed as silent mutations, since they only affect the DNA and mRNA, but not the amino acid sequence of the resulting protein. Nonetheless, recent studies suggest their significant impact on splicing, RNA stability, RNA folding, translation or co-translational protein folding. Hence, we compile 659194 synonymous mutations found in human cancer and characterize their properties. We provide the user-friendly, comprehensive resource for synonymous mutations in cancer, SynMICdb ( http://SynMICdb.dkfz.de ), which also contains orthogonal information about gene annotation, recurrence, mutation loads, cancer association, conservation, alternative events, impact on mRNA structure and a SynMICdb score. Notably, synonymous and missense mutations are depleted at the 5'-end of the coding sequence as well as at the ends of internal exons independent of mutational signatures. For patient-derived synonymous mutations in the oncogene KRAS, we indicate that single point mutations can have a relevant impact on expression as well as on mRNA secondary structure.


Assuntos
Bases de Dados de Ácidos Nucleicos , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias/genética , Mutação Silenciosa/genética , Conjuntos de Dados como Assunto , Humanos , Mutação de Sentido Incorreto/genética , Mutação Puntual/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Dobramento de RNA/genética , Processamento de RNA/genética , RNA Mensageiro/química , RNA Mensageiro/genética
18.
Nat Commun ; 10(1): 2736, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227718

RESUMO

Reconstruction and annotation of volume electron microscopy data sets of brain tissue is challenging but can reveal invaluable information about neuronal circuits. Significant progress has recently been made in automated neuron reconstruction as well as automated detection of synapses. However, methods for automating the morphological analysis of nanometer-resolution reconstructions are less established, despite the diversity of possible applications. Here, we introduce cellular morphology neural networks (CMNs), based on multi-view projections sampled from automatically reconstructed cellular fragments of arbitrary size and shape. Using unsupervised training, we infer morphology embeddings (Neuron2vec) of neuron reconstructions and train CMNs to identify glia cells in a supervised classification paradigm, which are then used to resolve neuron reconstruction errors. Finally, we demonstrate that CMNs can be used to identify subcellular compartments and the cell types of neuron reconstructions.


Assuntos
Encéfalo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais (Computação) , Neurônios/citologia , Sinapses , Algoritmos , Animais , Encéfalo/citologia , Conjuntos de Dados como Assunto , Estudos de Viabilidade , Masculino , Microscopia Eletrônica , Passeriformes
19.
Nat Commun ; 10(1): 2760, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235787

RESUMO

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.


Assuntos
Redes Reguladoras de Genes/genética , Insuficiência Cardíaca/genética , Miócitos Cardíacos/patologia , Fosfoproteínas Fosfatases/metabolismo , Animais , Benzenoacetamidas , Células Cultivadas , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fosfoproteínas Fosfatases/genética , Cultura Primária de Células , Piridinas , Locos de Características Quantitativas/genética , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA/métodos
20.
Forensic Sci Int ; 301: 91-100, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31153110

RESUMO

Writer characterization from images of handwriting has remained an important research problem in the handwriting recognition community that finds applications in forensics, paleography and neuropsychology. This paper presents a study to evaluate the effectiveness of an implicit shape codebook technique to recognize writer from digitized images of handwriting. The technique relies on identifying the key points in handwriting and clustering the patches around these key points to generate an implicit shape codebook. A writer is then characterized by the probability distribution of producing the codebook patterns. Experiments are carried out in text-dependent as well text-independent mode using the standard BFL and CVL databases of handwriting images. Promising identification and verification performance is reported in a number of interesting experimental scenarios.


Assuntos
Identificação Biométrica/métodos , Ciências Forenses/métodos , Escrita Manual , Conjuntos de Dados como Assunto , Humanos , Modelos Estatísticos , Máquina de Vetores de Suporte
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