Centroid estimation in discrete high-dimensional spaces with applications in biology.

Maximum likelihood estimators and other direct optimization-based estimators dominated statistical estimation and prediction for decades. Yet, the principled foundations supporting their dominance do not apply to the discrete high-dimensional inference problems of the 21st century. As it is well known, statistical decision theory shows that maximum likelihood and related estimators use data only to identify the single most probable solution. Accordingly, unless this one solution so dominates the immense ensemble of all solutions that its probability is near one, there is no principled reason to expect such an estimator to be representative of the posterior-weighted ensemble of solutions, and thus represent inferences drawn from the data. We employ statistical decision theory to find more representative estimators, centroid estimators, in a general high-dimensional discrete setting by using a family of loss functions with penalties that increase with the number of differences in components. We show that centroid estimates are obtained by maximizing the marginal probabilities of the solution components for unconstrained ensembles and for an important class of problems, including sequence alignment and the prediction of RNA secondary structure, whose ensembles contain exclusivity constraints. Three genomics examples are described that show that these estimators substantially improve predictions of ground-truth reference sets.

Complete and Sustained Response with a Doublet Chemotherapy Protocol in an 81-Year-Old Patient with Metastatic Breast Cancer.

Metastatic breast cancer (MBC) entails an overall 5-year survival of approximately 25%. The choice of therapy is influenced by expression of the HER2 gene and hormone receptors, by a disease-free interval, and by age. The use of paclitaxel combined with gemcitabine (doublet protocol) has shown efficacy as first-line treatment for MBC in either initial or maintenance therapy when compared to monotherapy with paclitaxel. There is evidence showing that the doublet protocol is a good alternative to maintenance therapy in women under 50 years old. Nevertheless, there is a lack of information concerning individuals above that age. We report the case of an 81-year-old patient presenting with recurrence of MBC, with lung and skin metastases both positive for hormone receptor and negative for HER2. We implemented a therapy based on the combination of gemcitabine and paclitaxel for 12 cycles, when complete response was achieved. Currently, 16 months after this achievement, the patient is receiving maintenance treatment under the doublet protocol, presenting acceptable parameters of toxicity since the beginning of treatment, which shows satisfactory tolerability and management of chemotherapy in an elderly patient. We suggest that the maintenance treatment protocol with a doublet might be an alternative with a satisfactory response in patients with MBC.

A Bayesian hierarchical gene model on latent genotypes for genome-wide association studies.

The primary goal of genome-wide association studies is to determine which genetic markers are associated with genetic traits, most commonly human diseases. As a result of the "large p, small n" nature of genome-wide association study data sets, and especially because of the collinearity due to linkage disequilibrium, multivariate regression results in an ill-posed problem. To overcome these obstacles, we propose preprocessing single-nucleotide polymorphisms to adjust for linkage disequilibrium, and a novel Bayesian statistical model that exploits a hierarchical structure between single-nucleotide polymorphisms and genes. We obtain posterior samples using a hybrid Metropolis-within-Gibbs sampler, and further conduct inference on single-nucleotide polymorphism and gene associations using centroid estimation. Finally, we illustrate the proposed model and estimation procedure and discuss results obtained on the data provided for the Genetic Analysis Workshop 18.

Exon expression profiling reveals stimulus-mediated exon use in neural cells.

BACKGROUND: Neuronal cells respond to changes in intracellular calcium ([Ca2+]i) by affecting both the abundance and architecture of specific mRNAs. Although calcium-induced transcription and transcript variation have both been recognized as important sources of gene regulation, the interplay between these two phenomena has not been evaluated on a genome-wide scale. RESULTS: Here, we show that exon-centric microarrays can be used to resolve the [Ca2+]i-modulated gene expression response into transcript-level and exon-level regulation. Global assessments of affected transcripts reveal modulation within distinct functional gene categories. We find that transcripts containing calcium-modulated exons exhibit enrichment for calcium ion binding, calmodulin binding, plasma membrane associated, and metabolic proteins. Additionally, we uncover instances of regulated exon use in potassium channels, neuroendocrine secretory proteins and metabolic enzymes, and demonstrate that regulated changes in exon expression give rise to distinct transcript variants. CONCLUSION: Our findings connect extracellular stimuli to specific exon behavior, and suggest that changes in transcript and exon abundance are reflective of a coordinated gene expression response to elevated [Ca2+]i. The technology we describe here lends itself readily to the resolution of stimulus-induced gene expression at both the transcript and exon levels.

Efeito da inclinaçäo lateral da cabeça sobre a acuidade visual de pacientes astigmatas corrigidos com óculos / Effects of the lateral head tilting on the visual acuity of astigmata patients corrected with glasses

Vinte e oito pacientes com astigmatismo elevado e corrigidos com óculos tiveram sua acuidade visual avaliada na posiçäo primária do olhar, com a cabeça ereta e inclinada lateralmente para a esquerda e para a direita, formando um ângulo de 60 graus com uma linha vertical (cabeça-pés). A reduçäo da acuidade visual ao inclinar a cabeça ocorreu em vinte e sete pacientes (93,1 por cento), comprovando a existência de uma torçäo reflexa, que desloca os olhos do eixo da lente cilíndrica.