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As técnicas mais difundidas em análise de sobrevivência supõem independência entre as observações. No entanto, em muitos problemas práticos esta suposição não é adequada, pela própria natureza dos dados. Uma maneira de abordar o problema é a utilização de modelos multiníveis, que são desenvolvidos para dados com estrutura hierárquica. Nestes modelos, a inclusão de coeficientes aleatórios faz com que o modelo possa incorporar dependências entre observações. Neste trabalho, foram estudados modelos de sobrevivência multiníveis em que os coeficientes apresentam distribuição normal, considerando-se uma abordagem paramétrica (modelos exponencial e Weibull) e uma abordagem baseada no modelo de regressão do Cox. A estimação estudada baseia-se na metodologia desenvolvida para modelos lineares generalizados. São apresentados dois métodos de estimação, que foram utilizados para analisar três conjuntos de dados. Além disso, é utilizado o método bootstrap para verificação de hipóteses de interesse sobre os parâmetrosIn survival analysis, the methodology usually considered assume independence among the observations. Nevertheless, it is not uncommon that such assumption is not adequate. In order to incorporate the dependence in the model, one may use multilevel models. These models were developed to analyze data with hierachical structure. The main difference between multilevel models and the usual approach is the use of random coefficients in the former. In this work, we consider multilevel models in survival analysis in which the random coefficients are normally distributed. We focus on parametric models, especifically the exponential and the Weibull distributions. We also consider the semiparametric approach based on the Cox proportional hazards model. The estimation of parameters is based on mixed generalized linear models. We present two different estimation methods, which are used to analyze three data sets. In addition, the bootstrap is used in order to get some insight on hypothesis testin

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Em experimentos clínicos, muitas vezes é importante incluir o bem estar (tanto físico quanto emocional) dos pacientes na análise, além do tempo de sobrevivência. O tempo de sobrevivência ajustado pela qualidade de vida é uma medida que tem a vantagem de englobar informação a respeito da sobrevida e também da qualidade de vida dos pacientes. Este trabalho aborda a questão da estimação da esperança do tempo de sobrevivência ajustado pela qualidade de vida, baseada em modelos multi-estado para os tempos de permanência. São propostos estimadores para essa esperança em duas situações. No primeiro caso, considera-se que os tempos de permanência em cada estado são variáveis aleatórias independentes e identicamente distribuídas e, na segunda abordagem, a suposição de que os tempos de permanência são identicamente distribuídos é retirada. Em todas situações, considera-se tanto a modelagem paramétrica, baseada na distribuição exponencial, quanto a semiparamétrica. Foi feito também um estudo de simulação para avaliar o desempenho dos estimadores propostos, com a aplicação do Jackknife para estimação da variância.not availabl

Cutpoint selection for discretizing a continuous covariate for generalized estimating equations

We consider consider the problem of dichotomizing a continuous covariate when performing a regression analysis based on a generalized estimation approach. The problem involves estimation of the cutpoint for the covariate and testing the hypothesis that the binary covariate constructed from the continuous covariate has a significant impact on the outcome. Due to the multiple testing used to find the optimal cutpoint, we need to make an adjustment to the usual significance test to preserve the type-I error rates. We illustrate the techniques on one data set of patients given unrelated hematopoietic stem cell transplantation. Here the question is whether the CD34 cell dose given to patient affects the outcome of the transplant and what is the smallest cell dose which is needed for good outcomes. (C) 2010 Elsevier BM. All rights reserved.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP, Brazil[2007/02823-3]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)National Cancer Institute (NCI/NIH)[R01 CA54706-14]National Cancer Institute (NCI/NIH

Cutpoint selection for discretizing a continuous covariate for generalized estimating equations

We consider the problem of dichotomizing a continuous covariate when performing a regression analysis based on a generalized estimation approach. The problem involves estimation of the cutpoint for the covariate and testing the hypothesis that the binary covariate constructed from the continuous covariate has a significant impact on the outcome. Due to the multiple testing used to find the optimal cutpoint, we need to make an adjustment to the usual significance test to preserve the type-I error rates. We illustrate the techniques on one data set of patients given unrelated hematopoietic stem cell transplantation. Here the question is whether the CD34 cell dose given to patient affects the outcome of the transplant and what is the smallest cell dose which is needed for good outcomes.Dichotomized outcomes Generalized estimating equations Generalized linear model Pseudo-values Survival analysis

Estimation of the mean quality-adjusted survival using a multistate model for the sojourn times

In clinical trials, it may be of interest taking into account physical and emotional well-being in addition to survival when comparing treatments. Quality-adjusted survival time has the advantage of incorporating information about both survival time and quality-of-life. In this paper, we discuss the estimation of the expected value of the quality-adjusted survival, based on multistate models for the sojourn times in health states. Semiparametric and parametric (with exponential distribution) approaches are considered. A simulation study is presented to evaluate the performance of the proposed estimator and the jackknife resampling method is used to compute bias and variance of the estimator. (C) 2007 Elsevier B.V. All rights reserved

Premature atrial and ventricular complexes in outpatients referred from a primary care facility.

BACKGROUND:Premature complexes are common electrocardiographic findings in daily clinical practice that require further evaluation. Investigation may sometimes be complex and expensive. The aim of our study was to analyze variables associated with premature beats identified in outpatients referred from a primary care facility. MATERIALS AND METHODS:We performed a cross-sectional study of 407 outpatients (aged 55.8±11years; 56% women) who were followed by general practitioners and were referred for resting 12-lead electrocardiograms for a routine clinical follow-up. After signing informed consent, patients answered a questionnaire and underwent physical examinations, laboratory diagnostics, transthoracic echocardiograms and 24-hour Holter monitoring to evaluate for the presence of premature complexes. After the univariate analyses, logistic regression analyses were performed with adjustment for age, sex, and cardiovascular diseases. RESULTS:Premature complexes distribution revealed that they were frequent but with low density. Premature atrial complexes (≥ 4/hours) were associated with age (Odds Ratio (OD) = 1.030, Confidence Interval (CI) 95% = 1.002 ─ 1.059, p = 0.029), brain natriuretic peptide (BNP) levels > 20mg/dL (OR = 4.489, 95%CI = 1.918 ─ 10.507, p = 0.0005), intraventricular blocks (OR = 4.184, 95%CI = 1.816 ─ 9.406, p = 0.0005) and left atrial diameter (OR = 1.065, 95%CI = 1.001 ─ 1.134, p = 0.046). Premature ventricular complexes (≥ 5/hour) were related to age (OR = 1.032, 95%CI = 1.010 ─ 1.054, p = 0.004), the use of calcium channel blockers (OR = 2.248, 95%CI = 1.019 ─ 4.954, p = 0.045), HDL-cholesterol levels (OR = 0.971, 95%CI = 0.951 ─ 0.992, p = 0.007), BNP levels > 20mg/dL (OR = 2.079, 95%CI = 0.991 ─ 0.998, p = 0.033), heart rate (OR = 1.019, 95%CI = 1.001 ─ 1.038, p = 0.041), left ventricular hypertrophy (OR = 2.292, 95%CI = 1.402 ─ 3.746, p = 0.001) and left ventricular ejection fraction (OR = 0.938, 95%CI = 0.900 ─ 0.978, p = 0.002). CONCLUSIONS:Premature complexes had low density and were associated with BNP levels > 20mg/dL, lower levels of HDL-cholesterol, left atrial enlargement and ventricular hypertrophy. The identification of premature complexes on 24-hour Holter monitor recordings of outpatients in a primary public healthcare setting was associated with uncontrolled cardiovascular risk factors that may be addressed with medical advice and therapy in a primary care setting

The impact of atrial fibrillation and long-term oral anticoagulant use on all-cause and cardiovascular mortality:A 12-year evaluation of the prospective Brazilian Study of Stroke Mortality and Morbidity

BackgroundAtrial fibrillation is a predictor of poor prognosis after stroke.AimsTo evaluate atrial fibrillation and all-cause and cardiovascular mortality in a stroke cohort with low socioeconomic status, taking into consideration oral anticoagulant use during 12-year follow-up.MethodsAll-cause mortality was analyzed by Kaplan-Meier survival curve and Cox regression models to estimate hazard ratios and 95% confidence intervals (95% CI). For specific mortality causes, cumulative incidence functions were computed. A logit link function was used to calculate odds ratios (OR) with 95% CIs. Full models were adjusted by age, sex, oral anticoagulant use (as a time-dependent variable) and cardiovascular risk factors.ResultsOf 1121 ischemic stroke participants, 17.8% had atrial fibrillation. Overall, 654 deaths (58.3%) were observed. Survival rate was lower (median days, interquartile range-IQR) among those with atrial fibrillation (531, IQR: 46-2039) vs. non-atrial fibrillation (1808, IQR: 334-3301), p-log rank p = 0.002) and stroke mortality (oral anticoagulant time-dependent effect ≥ 6 months: multivariable OR, 0.09; 95% CI: 0.01-0.65, p-value = 0.02), but not cardiovascular mortality.ConclusionsAmong individuals with low socioeconomic status, atrial fibrillation was an independent predictor of poor survival, increasing all-cause and cardiovascular mortality risk. Long-term oral anticoagulant use was associated with a markedly reduced risk of all-cause and stroke mortality

Impact of polio vaccines (oral polio vaccine - OPV or inactivated polio vaccine - IPV) on rotavirus vaccine-associated intussusception

Although safe, rotavirus vaccines have been associated with increased intussusception risk. In Brazil, after the oral human rotavirus vaccine (OHRV) introduction in the childhood immunization, in 2006, increased intussusception risk was identified after the second OHRV dose, whereas in other countries, higher risk was associated to the first vaccine dose. It was hypothesized that the concomitant use of oral poliovirus vaccine (OPV) in Brazil might explain this difference. In 2012, the inactivated polio vaccine (IPV) was adopted in the first two doses of Brazilian childhood immunization schedule, creating an opportunity to study the subject. Our objective was analyzing the impact of polio vaccines on rotavirus-associated intussusception. We used surveillance data on intussusception in infants living in São Paulo State. Two periods were considered: an OPV-period (March 2006 to June 2012) and an IPV-period (October 2012 to December 2017). The period from June to September 2012 were considered as transition. Self-controlled case series analysis with event-dependent exposure was performed, considering two risk periods (7 and 21 days post-vaccination). We identified 325 intussusception cases in infants reported to the surveillance systems during the study period. The statistical analysis included 221 cases that occurred within 60 days after vaccination. Overall, a higher intussusception risk was observed in the first week after vaccination for both the first (Relative Incidence [RI] = 4.3, 95%CI 2.8–6.5, p < .001) and second vaccine doses (RI = 4.2, 95%CI 2.7–6.4; p < .001). There were no statistically significant differences in intussusception risk according to the rotavirus vaccine dose and the polio vaccine (OPV or IPV) administered concomitantly