Models for the analysis of C-reactive protein in statin trials

Elevation in C-reactive protein (CRP) is an independent risk factor for cardiovascular disease progression and levels are reduced by treatment with statins. However, on-treatment CRP, given baseline CRP and treatment, is not normally distributed and outliers exist even when transformations are applied. Although classical non-parametric tests address some of these issues, they do not enable straightforward inclusion of covariate information. The aims of this study were to produce a model that improved efficiency and accuracy of analysis of CRP data. Estimation of treatment effects and identification of outliers were addressed using controlled trials of rosuvastatin. The robust statistical technique of MM-estimation was used to fit models to data in the presence of outliers and was compared with least-squares estimation. To develop the model, appropriate transformations of the response and baseline variables were selected. The model was used to investigate how on-treatment CRP related to baseline CRP and estimated treatment effects with rosuvastatin. On comparing least-squares and MM-estimation, MM-estimation was superior to least-squares estimation in that parameter estimates were more efficient and outliers were clearly identified. Relative reductions in CRP were higher at higher baseline CRP levels. There was also evidence of a dose-response relationship between CRP reductions from baseline and rosuvastatin. Several large outliers were identified, although there did not appear to be any relationships between the incidence of outliers and treatments. In conclusion, using robust estimation to model CRP data is superior to least-squares estimation and non-parametric tests in terms of efficiency, outlier identification and the ability to include covariate information.     

Missing item imputation for quality-of-life instruments with application to asthma quality-of-life questionnaires

There has been increasing use of quality-of-life (QoL) instruments in drug development. Missing item values often occur in QoL data. A common approach to solve this problem is to impute the missing values before scoring. Several imputation procedures, such as imputing with the most correlated item and imputing with a row/column model or an item response model, have been proposed. We examine these procedures using data from two clinical trials, in which the original asthma quality-of-life questionnaire (AQLQ) and the miniAQLQ were used. We propose two modifications to existing procedures: truncating the imputed values to eliminate outliers and using the proportional odds model as the item response model for imputation. We also propose a novel imputation method based on a semi-parametric beta regression so that the imputed value is always in the correct range and illustrate how this approach can easily be implemented in commonly used statistical software. To compare these approaches, we deleted 5% of item values in the data according to three different missingness mechanisms, imputed them using these approaches and compared the imputed values with the true values. Our comparison showed that the row/column-model-based imputation with truncation generally performed better, whereas our new approach had better performance under a number scenarios.     

解析与重构：未注册驰名商标的法律保护

我国《商标法》依据注册与否,分别为注册和未注册驰名商标提供不同的法律保护,这在很大程度上将未注册驰名商标置于更加危险的境地。良好的商业信誉与广为知晓的知名度是所有驰名商标获得特殊保护的根本与基础。因此,我国《商标法》应改变目前以注册决定保护程度的做法,为未注册驰名商标实行跨类保护,赋予商标权和提供多种民事法律救济。     

Active‐controlled,non‐inferiority trials in oncology: arbitrary limits,infeasible sample sizes and uninformative data analysis. Is there another way?

In oncology, it may not always be possible to evaluate the efficacy of new medicines in placebo-controlled trials. Furthermore, while some newer, biologically targeted anti-cancer treatments may be expected to deliver therapeutic benefit in terms of better tolerability or improved symptom control, they may not always be expected to provide increased efficacy relative to existing therapies. This naturally leads to the use of active-control, non-inferiority trials to evaluate such treatments. In recent evaluations of anti-cancer treatments, the non-inferiority margin has often been defined in terms of demonstrating that at least 50% of the active control effect has been retained by the new drug using methods such as those described by Rothmann et al., Statistics in Medicine 2003; 22:239-264 and Wang and Hung Controlled Clinical Trials 2003; 24:147-155. However, this approach can lead to prohibitively large clinical trials and results in a tendency to dichotomize trial outcome as either 'success' or 'failure' and thus oversimplifies interpretation. With relatively modest modification, these methods can be used to define a stepwise approach to design and analysis. In the first design step, the trial is sized to show indirectly that the new drug would have beaten placebo; in the second analysis step, the probability that the new drug is superior to placebo is assessed and, if sufficiently high in the third and final step, the relative efficacy of the new drug to control is assessed on a continuum of effect retention via an 'effect retention likelihood plot'. This stepwise approach is likely to provide a more complete assessment of relative efficacy so that the value of new treatments can be better judged.     

Identifying the most successful dose (MSD) in dose-finding studies in cancer

For a dose finding study in cancer, the most successful dose (MSD), among a group of available doses, is that dose at which the overall success rate is the highest. This rate is the product of the rate of seeing non-toxicities together with the rate of tumor response. A successful dose finding trial in this context is one where we manage to identify the MSD in an efficient manner. In practice we may also need to consider algorithms for identifying the MSD which can incorporate certain restrictions, the most common restriction maintaining the estimated toxicity rate alone below some maximum rate. In this case the MSD may correspond to a different level than that for the unconstrained MSD and, in providing a final recommendation, it is important to underline that it is subject to the given constraint. We work with the approach described in O'Quigley et al. [Biometrics 2001; 57(4):1018-1029]. The focus of that work was dose finding in HIV where both information on toxicity and efficacy were almost immediately available. Recent cancer studies are beginning to fall under this same heading where, as before, toxicity can be quickly evaluated and, in addition, we can rely on biological markers or other measures of tumor response. Mindful of the particular context of cancer, our purpose here is to consider the methodology developed by O'Quigley et al. and its practical implementation. We also carry out a study on the doubly under-parameterized model, developed by O'Quigley et al. but not     

Fathering With Multiple Partners: Links to Children's Well‐Being in Early Childhood

The claim that multiple partner fertility may pose a risk of adverse outcomes for children has not been tested. We test this argument using a sample of 4,027 resident fathers and children from the Fragile Families and Child Well‐being Survey by examining the pathways through which fathers' multipartnered fertility is associated with children's externalizing behaviors and physical health status at 36 months. Path analyses indicate that multiple partner fertility exerted both a significant direct and indirect effect through paternal depression to influence children's externalizing behaviors. Fathers' multiple partner fertility also exerted a significant indirect effect through one mediator—father involvement—to influence children's physical health. This evidence suggests that the disruptions brought about by multipartnered fertility are important for understanding child well‐being.     

Promoting Fathers' Engagement With Children: Preventive Interventions for Low‐Income Families

Few programs to enhance fathers' engagement with children have been systematically evaluated, especially for low‐income minority populations. In this study, 289 couples from primarily low‐income Mexican American and European American families were randomly assigned to one of three conditions and followed for 18 months: 16‐week groups for fathers, 16‐week groups for couples, or a 1‐time informational meeting. Compared with families in the low‐dose comparison condition, intervention families showed positive effects on fathers' engagement with their children, couple relationship quality, and children's problem behaviors. Participants in couples' groups showed more consistent, longer term positive effects than those in fathers‐only groups. Intervention effects were similar across family structures, income levels, and ethnicities. Implications of the results for current family policy debates are discussed.     

Stepfamily Formation: Implications for Adolescent Ties to Mothers,Nonresident Fathers,and Stepfathers

This study examines how the entrance of a stepfather influences adolescent ties to mothers and nonresident fathers and how prior ties to each biological parent influence the development of stepfather‐stepchild ties. Data come from 1,753 adolescents in the National Longitudinal Study of Adolescent Health who lived with a single mother in Wave 1 who remained single, cohabited, or married by Wave 2, approximately 1 year later. Stepfamily formation had little consequence for adolescent‐nonresident father ties. Adolescent‐mother closeness, however, declined when cohabiting, but not married, stepfathers entered the household. Close ties to married stepfathers were more likely to develop when adolescents were closer to their mothers before stepfather entry. Prior ties to nonresident fathers were unrelated to stepfather‐stepchild ties.     

Women's “Justification” of Domestic Violence in Egypt

We explored the influences of women's social learning, marital resources and constraints, and exposure to norms about women's family roles on their views about wife hitting or beating among 5,450 participants in the 2005 Egypt Demographic and Health Survey. One half justified wife hitting or beating for some reason. Women from rural areas who were exposed to domestic violence more often justified such acts. Dependent wives whose husbands had more schooling, were blood relatives, and were coresident more often justified such acts. In settings where women tended to marry at older ages, women less often justified such acts. Women's resources and constraints in marriage accounted for the largest share of the variability in their attitudes about domestic violence against women.