February 27, 2013

Record 1 of 5.

Click Here to View Full Record

Title:

Small-sample behavior of novel phase I cancer trial designs

Author Full Names:

Oron, Assaf P.; Hoff, Peter D.

Source:

CLINICAL TRIALS, 10 (1):63-80; 10.1177/1740774512469311 FEB 2013

Abstract:

Background Novel dose-finding designs for Phase I cancer clinical trials, using estimation to assign the best estimated Maximum Tolerated Dose (MTD) at each point in the experiment, most prominently via Bayesian techniques, have been widely discussed and promoted since 1990.
Purpose To examine the small-sample behavior of these 'Bayesian Phase I' designs, and also of non-Bayesian designs sharing the same main 'Long-Memory' traits of using likelihood estimation and assigning the estimated MTD to the next patient.
Methods Data from several recently published experiments are presented and discussed, and Long-Memory designs' operating principles are explained. Simulation studies compare the small-sample behavior of Long-Memory designs with short-memory 'Up-and-Down' designs.
Results In simulation, Long-Memory and Up-and-Down designs achieved similar success rates in finding the MTD. However, for all Long-Memory designs examined, the number n* of cohorts treated at the true MTD was highly variable between simulated experiments drawn from the same toxicity-threshold distribution. Further investigation using the same set of thresholds in permuted order indicates that this Long-Memory behavior is driven by sensitivity to the order in which participants enter the experiment. This sensitivity is related to Long-Memory designs' 'winner-takes-all' dose-assignment rule, which grants the early cohorts a disproportionately large influence, and causes many experiments to settle early on a specific dose. Additionally for the Bayesian Long-Memory designs, the prior-predictive distribution over the dose levels has a substantial impact upon MTD-finding performance, long into the experiment.
Limitations While the numerical evidence for Long-Memory designs' order sensitivity is broad, and plausible explanations for it are provided, we do not present a theoretical proof of the phenomenon.
Conclusions Method developers, analysts, and practitioners should be aware of Long-Memory designs' order sensitivity and related phenomena. In particular, they should be informed that settling on a single dose does not guarantee that this dose is the MTD. Presently, Up-and-Down designs offer a simpler and more robust alternative for the sample sizes of 10-40 patients used in most Phase I trials. Future designs might benefit from combining the two approaches. We also suggest that the field's paradigm change from dose-selection to dose-estimation. Clinical Trials 2013; 10: 63-80. http://ctj.sagepub.com

Record 2 of 5.

Click Here to View Full Record

Title:

Small-sample behavior of novel phase I designs: Rejoinder

Author Full Names:

Oron, Assaf P.; Hoff, Peter D.

Source:

CLINICAL TRIALS, 10 (1):88-89; 10.1177/1740774512470766 FEB 2013

Record 3 of 5.

Click Here to View Full Record

Title:

Basilar Tip Aneurysms: A Microsurgical and Endovascular Contemporary Series of 100 Patients

Author Full Names:

Sekhar, Laligam N.; Tariq, Farzana; Morton, Ryan P.; Ghodke, Basavaraj; Hallam, Daniel K.; Barber, Jason; Kim, Louis J.

Source:

NEUROSURGERY, 72 (2):284-298; 10.1227/NEU.0b013e3182797952 FEB 2013

Abstract:

BACKGROUND: Endovascular therapy has largely replaced microsurgical clipping for the treatment of basilar tip aneurysms.
OBJECTIVE: We describe the variables our center evaluates when choosing to clip or coil basilar tip aneurysms and our outcomes. Four case illustrations are presented.
METHODS: All patients with ruptured or unruptured basilar tip aneurysms from 2005 to April 2012 were examined. The patients were treated by 2 interventional neuroradiologists and 2 dually trained neurosurgeons.
RESULTS: There were 63 ruptured (clipped 38%, coiled 62%) and 37 unruptured (clipped 35%, coiled 65%) aneurysms in this 100-patient study. Seventy percent of the patients with ruptured aneurysms and 92% of the patients with unruptured aneurysms had a good outcome (modified Rankin scale 0-2) at 3 months. For ruptured aneurysms, there was a statistically significant difference in clipping and coiling with respect to age and treatment modality (clip 48.8 years, coil 57.6 years). Patients in the coiled group had higher dome-to-neck (1.3 vs 1.1) (P = .01) and aspect ratios (1.6 vs 1.2) (P = .007). In the ruptured coiling group, 69.5% achieved a Raymond 1 radiographic outcome, 28% Raymond 2, and 2.5% Raymond 3. Eleven (17.4%) patients required re-treatment, and 3 (4.4%) patients were re-treated more than twice. Coiling of unruptured aneurysms resulted in 75% Raymond 1. There were no residual lesions for unruptured clipped aneurysms. There were no differences in outcome between! clipping and coiling in the ruptured and unruptured group.
CONCLUSION: In our current management of basilar tip aneurysms, the majority can be treated via endovascular means, albeit with the expectation of a higher percentage of residual lesions and recurrences. Microsurgery is still appropriate for aneurysms with complex neck morphologies and in young patients desiring a more durable treatment.

Record 4 of 5.

Click Here to View Full Record

Title:

A system for exact and approximate genetic linkage analysis of SNP data in large pedigrees

Author Full Names:

Silberstein, Mark; Weissbrod, Omer; Otten, Lars; Tzemach, Anna; Anisenia, Andrei; Shtark, Oren; Tuberg, Dvir; Galfrin, Eddie; Gannon, Irena; Shalata, Adel; Borochowitz, Zvi U.; Dechter, Rina; Thompson, Elizabeth; Geiger, Dan

Source:

BIOINFORMATICS, 29 (2):197-205; 10.1093/bioinformatics/bts658 JAN 15 2013

Abstract:

Motivation: The use of dense single nucleotide polymorphism (SNP) data in genetic linkage analysis of large pedigrees is impeded by significant technical, methodological and computational challenges. Here we describe Superlink-Online SNP, a new powerful online system that streamlines the linkage analysis of SNP data. It features a fully integrated flexible processing workflow comprising both well-known and novel data analysis tools, including SNP clustering, erroneous data filtering, exact and approximate LOD calculations and maximum-likelihood haplotyping. The system draws its power from thousands of CPUs, performing data analysis tasks orders of magnitude faster than a single computer. By providing an intuitive interface to sophisticated state-of-the-art analysis tools coupled with high computing capacity, Superlink-Online SNP helps geneticists unleash the potential of SNP data for detecting disease genes.
Results: Computations performed by Superlink-Online SNP are automatically parallelized using novel paradigms, and executed on unlimited number of private or public CPUs. One novel service is large-scale approximate Markov Chain-Monte Carlo (MCMC) analysis. The accuracy of the results is reliably estimated by running the same computation on multiple CPUs and evaluating the Gelman-Rubin Score to set aside unreliable results. Another service within the workflow is a novel parallelized exact algorithm for inferring maximum-likelihood haplotyping. The reported system enables genetic analyses that were previously infeasible. We demonstrate the system capabilities through a study of a large complex pedigree affected with metabolic syndrome.

Record 5 of 5.

Click Here to View Full Record

Title:

Introduction to the Special Issue on Sparsity and Regularization Methods

Author Full Names:

Wellner, Jon; Zhang, Tong

Source:

STATISTICAL SCIENCE, 27 (4):447-449; 10.1214/12-STS409 NOV 2012