This article develops a local partial likelihood technique to estimate the timedependent coefficients in Cox's regression model. The basic idea is a simple extension of the local linear fitting technique used in the scatterplot smoothing. The coefficients are estimated locally based on the partial likelihood in a window around each time point. Multiple time-dependent covariates are incorporated in the local partial likelihood procedure. The procedure is useful as a diagnostic tool and can be used in uncovering time-dependencies or departure from the proportional hazards model. The programming involved in the local partial likelihood estimation is relatively simple and it can be modified with few efforts from the existing programs for the proportional hazards model. The asymptotic properties of the resulting estimator are established and compared with those from the local constant fitting. A consistent estimator of the asymptotic variance is also proposed. The approach is illustrated by a real data set from the study of gastric cancer patients and a simulation study is also presented.

This research integrates theory building, technology design, and design-based research to address a central challenge pertaining to collective inquiry and knowledge building: how can studentdriven, ever-deepening inquiry processes become socially organized and pedagogically supported in a community? Different from supporting inquiry using pre-designed structures, we propose reflective structuration as a social and temporal mechanism by which members of a community co-construct/re-construct shared inquiry structures to shape and guide their ongoing knowledge building processes. Idea Thread Mapper (ITM) was designed to help students and their teacher monitor emergent directions and co-organize the unfolding inquiry processes over time. A study was conducted in two upper primary school classrooms that investigated electricity with the support of ITM. Qualitative analyses of classroom videos and observational data documented the formation and elaboration of shared inquiry structures. Content analysis of the online discourse and student reflective summaries showed that in the classroom with reflective structuration, students made more active and connected contributions to their online discourse, leading to deeper and more coherent scientific understandings.3

The efficacy of an HIV vaccine to prevent infection is likely to depend on the genetic variation of the exposing virus. This paper addresses the problem of using data on the HIV sequences that infect vaccine efficacy trial participants to (1) test for vaccine efficacy more powerfully than procedures that ignore the sequence data and (2) evaluate the dependence of vaccine efficacy on the divergence of infecting HIV strains from the HIV strain that is contained in the vaccine. Because hundreds of amino acid sites in each HIV genome are sequenced, it is natural to treat the genetic divergence as a continuous mark variable that accompanies each failure (infection) time. Problems (1) and (2) can then be approached by testing whether the ratio of the mark-specific hazard functions for the vaccine and placebo groups is unity or independent of the mark. We develop nonparametric and semiparametric tests for these null hypotheses and nonparametric techniques for estimating the mark-specific relative risks. The asymptotic properties of the procedures are established. In addition, the methods are studied in simulations and are applied to HIV genetic sequence data collected in the first HIV vaccine efficacy trial.

For time-to-event data with finitely many competing risks, the proportional hazards model has been a popular tool for relating the cause-specific outcomes to covariates [Prentice et al. Biometrics 34 (1978) 541–554]. This article studies an extension of this approach to allow a continuum of competing risks, in which the cause of failure is replaced by a continuous mark only observed at the failure time. We develop inference for the proportional hazards model in which the regression parameters depend nonparametrically on the mark and the baseline hazard depends nonparametrically on both time and mark. This work is motivated by the need to assess HIV vaccine efficacy, while taking into account the genetic divergence of infecting HIV viruses in trial participants from the HIV strain that is contained in the vaccine, and adjusting for covariate effects. Mark-specific vaccine efficacy is expressed in terms of one of the regression functions in the mark-specific proportional hazards model. The new approach is evaluated in simulations and applied to the first HIV vaccine efficacy trial.

In this paper, we consider a semiparametric time-varying coefficients regression model where the influences of some covariates vary non-parametrically with time while the effects of the remaining covariates follow certain parametric functions of time. The weighted least squares type estimators for the unknown parameters of the parametric coefficient functions as well as the estimators for the non-parametric coefficient functions are developed. We show that the kernel smoothing that avoids modelling of the sampling times is asymptotically more efficient than a single nearest neighbour smoothing that depends on the estimation of the sampling model. The asymptotic optimal bandwidth is also derived. A hypothesis testing procedure is proposed to test whether some covariate effects follow certain parametric forms. Simulation studies are conducted to compare the finite sample performances of the kernel neighbourhood smoothing and the single nearest neighbour smoothing and to check the empirical sizes and powers of the proposed testing procedures. An application to a data set from an AIDS clinical trial study is provided for illustration. Copyright 2005 Board of the Foundation of the Scandinavian Journal of Statistics..

An objective of randomized placebo-controlled preventive HIV vaccine efficacy trials is to assess the relationship between the vaccine effect to prevent infection and the genetic distance of the exposing HIV to the HIV strain represented in the vaccine construct. Motivated by this objective, recently a mark-specific proportional hazards model with a continuum of competing risks has been studied, where the genetic distance of the transmitting strain is the continuous `mark' defined and observable only in failures. A high percentage of genetic marks of interest may be missing for a variety of reasons, predominantly due to rapid evolution of HIV sequences after transmission before a blood sample is drawn from which HIV sequences are measured. This research investigates the stratified mark-specific proportional hazards model with missing marks where the baseline functions may vary with strata. We develop two consistent estimation approaches, the first based on the inverse probability weighted complete-case (IPW) technique, and the second based on augmenting the IPW estimator by incorporating auxiliary information predictive of the mark. We investigate the asymptotic properties and finite-sample performance of the two estimators, and show that the augmented IPW estimator, which satisfies a double robustness property, is more efficient.

Histone deacetylases (HDACs), as epigenetic modifiers, are essential for gene transcriptional activities. The alternation of HDACs expression, mutation and/or inappropriate recruitments has been discovered in a broad range of tumors contributing to the tumorigenesis through a serial of biological pathways. HDACs, therefore, are characterized as promising cancer therapeutic targets, and their inhibitors are under rapid development. Here, we discuss HDAC inhibitors in terms of their functional mechanism establishing the anti-tumor effects and potential clinical applications including the synergistic effects in combinational treatment.

Background: Ischemic cardiovascular diseases, particularly acute myocardial infarction (MI) is one of the leading cause of mortality worldwide. Indoleamine 2, 3-dioxygenase 1 (IDO) catalyzes one rate-limiting step of L-Tryptophan (Trp) metabolism, and emerges as an important regulator of many pathological conditions. We hypothesized that IDO could play a key role to locally regulate cardiac homeostasis after MI. Methods: Cardiac repair was analyzed in mice harboring specific endothelial or smooth muscle cells or cardiomyocyte or myeloid cell deficiency of IDO and challenged with acute myocardial infarction. Results: We show that Kynurenine (Kyn) generation through IDO is markedly induced after MI in mice. Total genetic deletion or pharmacological inhibition of IDO limits cardiac injury and cardiac dysfunction after MI. Distinct loss of function of IDO in smooth muscle cells, inflammatory cells, or cardiomyocytes does not impact cardiac function and remodeling in infarcted mice. In sharp contrast, mice harboring endothelial cell-specific deletion of IDO show an improvement of cardiac function, as well as cardiomyocyte contractility and reduction in adverse ventricular remodeling. In vivo Kyn supplementation in IDO-deficient mice abrogates the protective effects of IDO deletion. Notably, Kyn precipitates cardiomyocyte apoptosis through reactive oxygen species production in an aryl hydrocarbon receptor-dependent mechanism. Conclusions: These data suggest that IDO could constitute a new therapeutic target during acute MI.