Sequential monitoring with conditional randomization tests

Sequential monitoring in clinical trials is often employed to allow for early stopping and other interim decisions, while maintaining the type I error rate. However, sequential monitoring is typically described only in the context of a population model. We describe a computational method to implement sequential monitoring in a randomization-based context. In particular, we discuss a new technique for the computation of approximate conditional tests following restricted randomization procedures and then apply this technique to approximate the joint distribution of sequentially computed conditional randomization tests. We also describe the computation of a randomization-based analog of the information fraction. We apply these techniques to a restricted randomization procedure, Efron's [Biometrika 58 (1971) 403--417] biased coin design. These techniques require derivation of certain conditional probabilities and conditional covariances of the randomization procedure. We employ combinatoric techniques to derive these for the biased coin design.Comment: Published in at http://dx.doi.org/10.1214/11-AOS941 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Handling Covariates in the Design of Clinical Trials

There has been a split in the statistics community about the need for taking covariates into account in the design phase of a clinical trial. There are many advocates of using stratification and covariate-adaptive randomization to promote balance on certain known covariates. However, balance does not always promote efficiency or ensure more patients are assigned to the better treatment. We describe these procedures, including model-based procedures, for incorporating covariates into the design of clinical trials, and give examples where balance, efficiency and ethical considerations may be in conflict. We advocate a new class of procedures, covariate-adjusted response-adaptive (CARA) randomization procedures that attempt to optimize both efficiency and ethical considerations, while maintaining randomization. We review all these procedures, present a few new simulation studies, and conclude with our philosophy.Comment: Published in at http://dx.doi.org/10.1214/08-STS269 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Exact properties of Efron's biased coin randomization procedure

Efron [Biometrika 58 (1971) 403--417] developed a restricted randomization procedure to promote balance between two treatment groups in a sequential clinical trial. He called this the biased coin design. He also introduced the concept of accidental bias, and investigated properties of the procedure with respect to both accidental and selection bias, balance, and randomization-based inference using the steady-state properties of the induced Markov chain. In this paper we revisit this procedure, and derive closed-form expressions for the exact properties of the measures derived asymptotically in Efron's paper. In particular, we derive the exact distribution of the treatment imbalance and the variance-covariance matrix of the treatment assignments. These results have application in the design and analysis of clinical trials, by providing exact formulas to determine the role of the coin's bias probability in the context of selection and accidental bias, balancing properties and randomization-based inference.Comment: Published in at http://dx.doi.org/10.1214/09-AOS758 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

X-ray transmission microscope development

We are developing a hard x-ray microscope for direct observation of solidification dynamics in metal alloys and metal matrix composites. The Fein-Focus Inc. x-ray source was delivered in September and found to perform better than expected. Confirmed resolution of better than 2 micrometers was obtained and magnifications up to 800X were measured. Nickel beads of 30 micrometer diameter were easily detected through 6mm of aluminum. X-ray metallography was performed on several specimens showing high resolution and clear definition of 3-dimensional structures. Prototype furnace installed and tested

X-ray transmission microscope development

This report covers the third 6 month period, from February 28, 1995 to August 31, 1995, under this contract. The main efforts during this period were the construction of the X-ray furnace, evaluation and selection of the CCD technology for the X-ray camera, solidification experiments with Al alloys and Al-zirconia composites in the prototype furnace, evaluation of specimens for the particle pushing flight experiment - PEPSI, measurements of emitted spectra from X-ray source, testing of the high resolution X-ray test targets, and the establishment of criteria for and selection of peripheral equipment. In addition to these tasks, two presentations were prepared in this period; one for the AIAA Microgravity Symposium and another for the Gordon Conference on Gravitational Effects in Pyisico-Chemical Systems

ERDO - a framework to select an appropriate randomization procedure for clinical trials

Background: Randomization is considered to be a key feature to protect against bias in randomized clinical trials. Randomization induces comparability with respect to known and unknown covariates, mitigates selection bias, and provides a basis for inference. Although various randomization procedures have been proposed, no single procedure performs uniformly best. In the design phase of a clinical trial, the scientist has to decide which randomization procedure to use, taking into account the practical setting of the trial with respect to the potential of bias. Less emphasis has been placed on this important design decision than on analysis, and less support has been available to guide the scientist in making this decision.Methods: We propose a framework that weights the properties of the randomization procedure with respect to practical needs of the research question to be answered by the clinical trial. In particular, the framework assesses the impact of chronological and selection bias on the probability of a type I error. The framework is applied to a case study with a 2-arm parallel group, single center randomized clinical trial with continuous endpoint, with no-interim analysis, 1:1 allocation and no adaptation in the randomization process.Results: In so doing, we derive scientific arguments for the selection of an appropriate randomization procedure and develop a template which is illustrated in parallel by a case study. Possible extensions are discussed.Conclusion: The proposed ERDO framework guides the investigator through a template for the choice of a randomization procedure, and provides easy to use tools for the assessment. The barriers for the thorough reporting and assessment of randomization procedures could be further reduced in the future when regulators and pharmaceutical companies employ similar, standardized frameworks for the choice of a randomization procedure