A robust semi-parametric warping estimator of the survivor function with an application to two-group comparisons.

In this note, we develop a new and novel semi-parametric estimator of the survival curve that is comparable to the product-limit estimator under very relaxed assumptions. The estimator is based on a beta parametrization that warps the empirical distribution of the observed censored and uncensored data. The parameters are obtained using a pseudo-maximum likelihood approach adjusting the survival curve accounting for the censored observations. In the univariate setting, the new estimator tends to better extend the range of the survival estimation given a high degree of censoring. However, the key feature of this paper is that we develop a new two-group semi-parametric exact permutation test for comparing survival curves that is generally superior to the classic log-rank and Wilcoxon tests and provides the best global power across a variety of alternatives. The new test is readily extended to the k group setting.

Development, validation and clinical application of Pelvic Lymphadenectomy Assessment and Completion Evaluation: intraoperative assessment of lymph node dissection after robot-assisted radical cystectomy for bladder cancer.

OBJECTIVES: To develop a scoring tool, Pelvic Lymphadenectomy Appropriateness and Completion Evaluation (PLACE), to assess the intraoperative completeness and appropriateness of pelvic lymph node dissection (PLND) following robot-assisted radical cystectomy (RARC). PATIENTS, SUBJECTS AND METHODS: A panel of 11 open and robotic surgeons developed the content and structure of PLACE. The PLND template was divided into three zones. In all, 21 de-identified videos of bilateral robot-assisted PLNDs were assessed by the 11 experts using PLACE to determine inter-rater reliability. Lymph node (LN) clearance was defined as the proportion of cleared LNs from all PLACE zones. We investigated the correlation between LN clearance and LN count. Then, we compared the LN count of 18 prospective PLNDs using PLACE with our retrospective series performed using the extended template (No PLACE). RESULTS: A significant reliability was achieved for all PLACE zones among the 11 raters for the 21 bilateral PLND videos. The median (interquartile range) for LN clearance was 468 (431-545). There was a significant positive correlation between LN clearance and LN count (R2 = 0.70, P < 0.01). The PLACE group yielded similar LN counts when compared to the No PLACE group. CONCLUSIONS: Pelvic Lymphadenectomy Appropriateness and Completion Evaluation is a structured intraoperative scoring system that can be used intraoperatively to measure and quantify PLND for quality control and to facilitate training during RARC.

A Novel Approach to Testing for Average Bioequivalence Based on Modeling the Within-Period Dependence Structure.

Bioequivalence trials are commonly conducted to assess therapeutic equivalence between a generic and an innovator brand formulations. In such trials, drug concentrations are obtained repeatedly over time and are summarized using a metric such as the area under the concentration vs. time curve (AUC) for each subject. The usual practice is to then conduct two one-sided tests using these areas to evaluate for average bioequivalence. A major disadvantage of this approach is the loss of information encountered when ignoring the correlation structure between repeated measurements in the computation of areas. In this article, we propose a general linear model approach that incorporates the within-subject covariance structure for making inferences on mean areas. The model-based method can be seen to arise naturally from the reparameterization of the AUC as a linear combination of outcome means. We investigate and compare the inferential properties of our proposed method with the traditional two one-sided tests approach using Monte Carlo simulation studies. We also examine the properties of the method in the event of missing data. Simulations show that the proposed approach is a cost-effective, viable alternative to the traditional method with superior inferential properties. Inferential advantages are particularly apparent in the presence of missing data. To illustrate our approach, a real working example from an asthma study is utilized.

An examination of the relative impact of type I and type II error rates in phase II drug screening trial queues.

In this note, we highlight the fact that the choice of type I and type II error rates should not simply be set at traditional levels in the phase II clinical trial setting when considering the relative success rate of previous trials in a given disease setting. For diseases in which it is rare that a new compound is active, we argue that more stringent type I error rates in the phase II setting may be more important relative to relaxing the type II error rates. The paper itself is more of a 'thought' experiment on this topic such that specific clinical trial settings will require specific applications of this approach. This is due in part to the fact that the real-world setting is more complex relative to overall decision process in terms of moving from phase II to phase III trials than our basic illustrative model.