Predicting the HER2 status of breast cancer from basic histopathology data: an analysis of 1500 breast cancers as part of the HER2000 International Study

The tests that are currently available for the measurement of overexpression of the human epidermal growth factor-2 (HER2) in breast cancer have shown considerable problems in accuracy and interlaboratory reproducibility. Although these problems are partly alleviated by the use of validated, standardised 'kits', there may be considerable cost involved in their use. Prior to testing it may therefore be an advantage to be able to predict from basic pathology data whether a cancer is likely to overexpress HER2. In this study, we have correlated pathology features of cancers with the frequency of HER2 overexpression assessed by immunohistochemistry (IHC) using HercepTest (Dako). In addition, fluorescence in situ hybridisation (FISH) has been used to re-test the equivocal cancers and interobserver variation in assessing HER2 overexpression has been examined by a slide circulation scheme. Of the 1536 cancers, 1144 (74.5%) did not overexpress HER2. Unequivocal overexpression (3+ by IHC) was seen in 186 cancers (12%) and an equivocal result (2+ by IHC) was seen in 206 cancers (13%). Of the 156 IHC 3+ cancers for which complete data was available, 149 (95.5%) were ductal NST and 152 (97%) were histological grade 2 or 3. Only 1 of 124 infiltrating lobular carcinomas (0.8%) showed HER2 overexpression. None of the 49 'special types' of carcinoma showed HER2 overexpression. Re-testing by FISH of a proportion of the IHC 2+ cancers showed that only 25 (23%) of those assessable exhibited HER2 gene amplification, but 46 of the 47 IHC 3+ cancers (98%) were confirmed as showing gene amplification. Circulating slides for the assessment of HER2 score showed a moderate level of agreement between pathologists (kappa 0.4). As a result of this study we would advocate consideration of a triage approach to HER-2 testing. Infiltrating lobular and special types of carcinoma may not need to be routinely tested at presentation nor may grade 1 NST carcinomas in which only 1.4% have been shown to overexpress HER2. Testing of these carcinomas may be performed when HER2 status is required to assist in therapeutic or other clinical/prognostic decision-making. The highest yield of HER2 overexpressing carcinomas is seen in the grade 3 NST subgroup in which 24% are positive by IHC. (C) 2003 Elsevier Science Ltd. All rights reserved.

Capillaries within compartments: Microvascular interpretation of dynamic positron emission tomography data

Measurement of exchange of substances between blood and tissue has been a long-lasting challenge to physiologists, and considerable theoretical and experimental accomplishments were achieved before the development of the positron emission tomography (PET). Today, when modeling data from modern PET scanners, little use is made of earlier microvascular research in the compartmental models, which have become the standard model by which the vast majority of dynamic PET data are analysed. However, modern PET scanners provide data with a sufficient temporal resolution and good counting statistics to allow estimation of parameters in models with more physiological realism. We explore the standard compartmental model and find that incorporation of blood flow leads to paradoxes, such as kinetic rate constants being time-dependent, and tracers being cleared from a capillary faster than they can be supplied by blood flow. The inability of the standard model to incorporate blood flow consequently raises a need for models that include more physiology, and we develop microvascular models which remove the inconsistencies. The microvascular models can be regarded as a revision of the input function. Whereas the standard model uses the organ inlet concentration as the concentration throughout the vascular compartment, we consider models that make use of spatial averaging of the concentrations in the capillary volume, which is what the PET scanner actually registers. The microvascular models are developed for both single- and multi-capillary systems and include effects of non-exchanging vessels. They are suitable for analysing dynamic PET data from any capillary bed using either intravascular or diffusible tracers, in terms of physiological parameters which include regional blood flow. (C) 2003 Elsevier Ltd. All rights reserved.

An EM-based Semi-Parametric Mixture Model Approach to the Regression Analysis of Competing-Risks Data

We consider a mixture model approach to the regression analysis of competing-risks data. Attention is focused on inference concerning the effects of factors on both the probability of occurrence and the hazard rate conditional on each of the failure types. These two quantities are specified in the mixture model using the logistic model and the proportional hazards model, respectively. We propose a semi-parametric mixture method to estimate the logistic and regression coefficients jointly, whereby the component-baseline hazard functions are completely unspecified. Estimation is based on maximum likelihood on the basis of the full likelihood, implemented via an expectation-conditional maximization (ECM) algorithm. Simulation studies are performed to compare the performance of the proposed semi-parametric method with a fully parametric mixture approach. The results show that when the component-baseline hazard is monotonic increasing, the semi-parametric and fully parametric mixture approaches are comparable for mildly and moderately censored samples. When the component-baseline hazard is not monotonic increasing, the semi-parametric method consistently provides less biased estimates than a fully parametric approach and is comparable in efficiency in the estimation of the parameters for all levels of censoring. The methods are illustrated using a real data set of prostate cancer patients treated with different dosages of the drug diethylstilbestrol. Copyright (C) 2003 John Wiley Sons, Ltd.

Effect of changing data collection parameters on statistical motor unit number estimates

The effect of number of samples and selection of data for analysis on the calculation of surface motor unit potential (SMUP) size in the statistical method of motor unit number estimates (MUNE) was determined in 10 normal subjects and 10 with amyotrophic lateral sclerosis (ALS). We recorded 500 sequential compound muscle action potentials (CMAPs) at three different stable stimulus intensities (10–50% of maximal CMAP). Estimated mean SMUP sizes were calculated using Poisson statistical assumptions from the variance of 500 sequential CMAP obtained at each stimulus intensity. The results with the 500 data points were compared with smaller subsets from the same data set. The results using a range of 50–80% of the 500 data points were compared with the full 500. The effect of restricting analysis to data between 5–20% of the CMAP and to standard deviation limits was also assessed. No differences in mean SMUP size were found with stimulus intensity or use of different ranges of data. Consistency was improved with a greater sample number. Data within 5% of CMAP size gave both increased consistency and reduced mean SMUP size in many subjects, but excluded valid responses present at that stimulus intensity. These changes were more prominent in ALS patients in whom the presence of isolated SMUP responses was a striking difference from normal subjects. Noise, spurious data, and large SMUP limited the Poisson assumptions. When these factors are considered, consistent statistical MUNE can be calculated from a continuous sequence of data points. A 2 to 2.5 SD or 10% window are reasonable methods of limiting data for analysis. Muscle Nerve 27: 320–331, 2003

Model-based clustering in gene expression microarrays: An application to breast cancer data

In microarray studies, the application of clustering techniques is often used to derive meaningful insights into the data. In the past, hierarchical methods have been the primary clustering tool employed to perform this task. The hierarchical algorithms have been mainly applied heuristically to these cluster analysis problems. Further, a major limitation of these methods is their inability to determine the number of clusters. Thus there is a need for a model-based approach to these. clustering problems. To this end, McLachlan et al. [7] developed a mixture model-based algorithm (EMMIX-GENE) for the clustering of tissue samples. To further investigate the EMMIX-GENE procedure as a model-based -approach, we present a case study involving the application of EMMIX-GENE to the breast cancer data as studied recently in van 't Veer et al. [10]. Our analysis considers the problem of clustering the tissue samples on the basis of the genes which is a non-standard problem because the number of genes greatly exceed the number of tissue samples. We demonstrate how EMMIX-GENE can be useful in reducing the initial set of genes down to a more computationally manageable size. The results from this analysis also emphasise the difficulty associated with the task of separating two tissue groups on the basis of a particular subset of genes. These results also shed light on why supervised methods have such a high misallocation error rate for the breast cancer data.

Zygosity Diagnosis in the Absence of Genotypic Data: An Approach Using Latent Class Analysis

For zygosity diagnosis in the absence of genotypic data, or in the recruitment phase of a twin study where only single twins from same-sex pairs are being screened, or to provide a test for sample duplication leading to the false identification of a dizygotic pair as monozygotic, the appropriate analysis of respondents' answers to questions about zygosity is critical. Using data from a young adult Australian twin cohort (N = 2094 complete pairs and 519 singleton twins from same-sex pairs with complete responses to all zygosity items), we show that application of latent class analysis (LCA), fitting a 2-class model, yields results that show good concordance with traditional methods of zygosity diagnosis, but with certain important advantages. These include the ability, in many cases, to assign zygosity with specified probability on the basis of responses of a single informant (advantageous when one zygosity type is being oversampled); and the ability to quantify the probability of misassignment of zygosity, allowing prioritization of cases for genotyping as well as identification of cases of probable laboratory error. Out of 242 twins (from 121 like-sex pairs) where genotypic data were available for zygosity confirmation, only a single case was identified of incorrect zygosity assignment by the latent class algorithm. Zygosity assignment for that single case was identified by the LCA as uncertain (probability of being a monozygotic twin only 76%), and the co-twin's responses clearly identified the pair as dizygotic (probability of being dizygotic 100%). In the absence of genotypic data, or as a safeguard against sample duplication, application of LCA for zygosity assignment or confirmation is strongly recommended.

Systematic characterization of mutations in yeast acetohydroxyacid synthase: Interpretation of herbicide-resistance data

Acetohydroxyacid synthase (AHAS, EC 4.1.3.18) catalyses the first step in branched-chain amino acid biosynthesis and is the target for sulfonylurea and imidazolinone herbicides, which act as potent and specific inhibitors. Mutants of the enzyme have been identified that are resistant to particular herbicides. However, the selectivity of these mutants towards various sulfonylureas and imidazolinones has not been determined systematically. Now that the structure of the yeast enzyme is known, both in the absence and presence of a bound herbicide, a detailed understanding of the molecular interactions between the enzyme and its inhibitors becomes possible. Here we construct 10 active mutants of yeast AHAS, purify the enzymes and determine their sensitivity to six sulfonylureas and three imidazolinones. An additional three active mutants were constructed with a view to increasing imidazolinone sensitivity. These three variants were purified and tested for their sensitivity to the imidazolinones only. Substantial differences are observed in the sensitivity of the 13 mutants to the various inhibitors and these differences are interpreted in terms of the structure of the herbicide-binding site on the enzyme.

The developmental activities of elite ice hockey players

The purpose of this study was to analyze the development of four 20 year-old elite hockey players through an in-depth examination of their sporting activities. The theoretical framework of deliberate practice (Ericsson, Krampe, & Tesch-Römer, 1993) and the notion of deliberate play (Côté, 1999) served as the theoretical foundations. Interviews were conducted to provide a longitudinal and detailed account of each participant's involvement in various sporting activities. The interviewer asked questions about the conditions and sporting activities for each year of development. The data obtained were validated through independent interviews conducted with three parents of three different athletes. The results were consistent with Côté's (1999) three stages of development in sport: the sampling (age 6-12), specializing (age 13-15), and investment (age 16+) years.

Data Mart para apoio ?? capacita????o em gest??o de pol??ticas p??blicas voltado para uma Escola de Administra????o P??blica

Este trabalho consiste num estudo de caso que se destina ao desenvolvimento de um Data Mart que possibilite a Escola Nacional de Administra????o P??blica ??? ENAP conhecer o perfil e o panorama geral da situa????o funcional dos servidores p??blicos federais que se capacitaram na Escola nos ??ltimos 7 anos. O aplicativo foi desenvolvido cruzando o banco de dados do sistema gerenciador dos cursos ministrados pela ENAP, onde est??o armazenadas informa????es sobre os alunos capacitados, os cursos realizados, os resultados alcan??ados, o perfil dos docentes e demais informa????es relativas ??s atividades da Escola, com os dados gerados pelo Sistema Integrado de Administra????o de Recursos Humanos ??? SIAPE, cuja extra????o de dados foi direcionada para os registros sobre a situa????o funcional, cargos, carreiras, fun????es, ??rg??os e alguns dados pessoais dos alunos, servidores p??blicos federais que se encontram registrados no SIAPE

Comprometimento no trabalho de gestores p??blicos em uma autarquia estadual no Brasil

O objetivo deste artigo ?? compreender a percep????o dos gestores, que atuam com o planejamento estrat??gico de uma organiza????o p??blica, sobre o construto de comprometimento no trabalho, bem como a influ??ncia dessa percep????o em suas pr??ticas cotidianas de gest??o. Para tanto, realizou-se, inicialmente, pesquisa bibliogr??fica focando quest??es relacionadas ao sentido e natureza do construto, bem como sobre os estudos realizados sobre o tema do comprometimento no contexto da administra????o p??blica. Em seguida, foram coletados dados com gestores mediante entrevista com roteiro semiestruturado, os quais foram analisados por meio da t??cnica de an??lise de conte??do. As evid??ncias indicam que os gestores associam o v??nculo ao trabalho a quest??es atitudinais e de inten????es comportamentais e que suas pr??ticas cotidianas s??o influenciadas pela percep????o de comprometimento dos indiv??duos, admitindo que as decis??es tomadas, motivadas por essa percep????o, podem trazer consequ??ncias negativas tanto para a organiza????o quanto para o indiv??duo.

Abono Perman??ncia em uma institui????o federal de ensino superior: aplica????o e desdobramentos

A preocupa????o principal deste artigo ?? descrever a implementa????o do Abono Perman??ncia em uma Institui????o Federal de Ensino Superior e as implica????es que o mesmo acarretou a seus servidores e ?? pr??pria institui????o. O objetivo pretendido aqui n??o est?? em exaurir o assunto ent??o tratado, mas mostrar o quanto este pode ser importante, partindo do pressuposto de seu significado intr??nseco na motiva????o para o trabalho. O principal interessado no assunto ?? o servidor p??blico e este pode usufruir desse benef??cio dado sua idade para aposentar. Trata-se de uma pesquisa descritiva, cuja coleta foi atrav??s de entrevistas semi-estruturadas e individuais com funcion??rios que trabalham diretamente com os processos de Abono Perman??ncia, e tamb??m atrav??s de an??lise de documentos e observa????o direta dos sistemas gerenciais de processos administrativos da institui????o. Este estudo contribui nas discuss??es sobre benef??cios sociais na Gest??o de Pessoas e a utiliza????o desses recursos na Administra????o P??blica. Pode-se concluir que o Abono Perman??ncia traz diversas contribui????es como, por exemplo, a motiva????o pessoal em continuar trabalhando, por??m, apresenta algumas limita????es no pr??prio incentivo ao benef??cio, que pode n??o ser interessante em determinados tetos salariais.

A Proposta de Acolhimento: sua formula????o e implementa????o nas unidades de aten????o prim??ria do Sistema ??nico de Sa??de no Munic??pio de Belo Horizonte

A proposta de acolhimento teve por objetivo garantir o acesso ??s Unidades de Aten????o Prim??ria do Sistema ??nico de Sa??de (SUS) em Belo Horizonte, Minas Gerais. Este trabalho analisa e tenta compreender a not??vel dist??ncia entre a proposi????o e a execu????o da proposta neste munic??pio. Usando contribui????es te??ricas do campo tem??tico das pol??ticas p??blicas na an??lise do contexto pol??tico-administrativo em que se desenvolveu a proposta, e utilizando as informa????es obtidas na pesquisa de campo com os principais idealizadores da proposta e alguns trabalhadores e usu??rios, foram identificadas, na sua formula????o e implanta????o, informa????es que ajudam a entender a dist??ncia observada.

O uso da ren??ncia fiscal na ??rea de museus

O objetivo desse artigo ?? investigar como a ren??ncia fiscal ?? utilizada na ??rea de museus. A fundamenta????o te??rica faz breve apresenta????o da literatura sobre implementa????o e descreve o uso da ren??ncia fiscal na ??rea de museus mediante an??lise de seis vari??veis: incentivos, autonomia, informa????o, apoio institucional, apoio social e etapas e tempo. A metodologia utilizada foi a an??lise documental e entrevistas. A an??lise foi feita com ajuda do programa NVIVO9. As principais conclus??es s??o que embora haja incentivos e autonomia em graus suficientes para permitir boa implementa????o via ren??ncia fiscal, h?? quest??es informacionais e referentes ??s etapas e tempo que dificultam sua implementa????o. Al??m disso, a ren??ncia fiscal ?? concentradora, desigual e apresenta baixa participa????o de empresas do setor privado. Esses problemas parecem diminuir a capacidade de a implementa????o de museus mediante o uso da ren??ncia fiscal alcan??ar os efeitos almejados.

Nova gest??o p??blica e motiva????o no servi??o p??blico: a carreira de EPPGG como alternativa para as disfun????es burocr??ticas

Este artigo visa compreender at?? que ponto as pr??ticas gerenciais incorporam as dimens??es da satisfa????o e motiva????o no trabalho de servidores p??blicos na atualidade. Aborda os modelos de administra????o burocr??tica e gerencial, exp??e as disfun????es do modelo ideal da burocracia weberiana, apresenta a motiva????o para o trabalho e suas implica????es, e evidencia a carreira de Especialista em Pol??ticas P??blicas e Gest??o Governamental (EPPGG) no intuito de apresentar uma alternativa poss??vel de proporcionar satisfa????o e motiva????o no trabalho, por meio do enriquecimento do cargo. A metodologia consta de uma pesquisa qualitativa, na qual se fez uso de entrevistas semiestruturadas aplicadas junto a tr??s EPPGG. Utilizou-se da an??lise de conte??do com uso da t??cnica de categoriza????o para a an??lise os dados. Os resultados demonstraram a satisfa????o e motiva????o dos gestores, a preval??ncia da administra????o burocr??tica com fortes ind??cios da administra????o gerencial e aus??ncia de disfun????es burocr??ticas. Evidenciaram que o modelo da nova gest??o p??blica, uma vez implantado conforme descrito na teoria, pode combater disfun????es burocr??ticas e contribuir para a satisfa????o e motiva????o dos servidores p??blicos. Destaca-se a relev??ncia de estudos posteriores, visto que foram apontadas diversidades de condi????es de trabalho de ??rg??o para ??rg??o e dificuldades enfrentadas no in??cio da carreira.