Modified 3+3 design for phase I clinical trials

Phase I clinical trial is mainly designed to determine the maximum tolerated dose (MTD) of a new drug. Optimization of phase I trial design is crucial to minimize the number of enrolled patients exposed to unsafe dose levels and to provide reliable information to the later phases of clinical trials. Although it has been criticized about its inefficient MTD estimation, nowadays the traditional 3+3 method remains dominant in practice due to its simplicity and conservative estimation. There are many new designs that have been proven to generate more credible MTD estimation, such as the Continual Reassessment Method (CRM). Despite its accepted better performance, the CRM design is still not widely used in real trials. There are several factors that contribute to the difficulties of CRM adaption in practice. First, CRM is not widely accepted by the regulatory agencies such as FDA in terms of safety. It is considered to be less conservative and tend to expose more patients above the MTD level than the traditional design. Second, CRM is relatively complex and not intuitive for the clinicians to fully understand. Third, the CRM method take much more time and need statistical experts and computer programs throughout the trial. The current situation is that the clinicians still tend to follow the trial process that they are comfortable with. This situation is not likely to change in the near future. Based on this situation, we have the motivation to improve the accuracy of MTD selection while follow the procedure of the traditional design to maintain simplicity. We found that in 3+3 method, the dose transition and the MTD determination are relatively independent. Thus we proposed to separate the two stages. The dose transition rule remained the same as 3+3 method. After getting the toxicity information from the dose transition stage, we combined the isotonic transformation to ensure the monotonic increasing order before selecting the optimal MTD. To compare the operating characteristics of the proposed isotonic method and the other designs, we carried out 10,000 simulation trials under different dose setting scenarios to compare the design characteristics of the isotonic modified method with standard 3+3 method, CRM, biased coin design (BC) and k-in-a-row design (KIAW). The isotonic modified method improved MTD estimation of the standard 3+3 in 39 out of 40 scenarios. The improvement is much greater when the target is 0.3 other than 0.25. The modified design is also competitive when comparing with other selected methods. A CRM method performed better in general but was not as stable as the isotonic method throughout the different dose settings. The results demonstrated that our proposed isotonic modified method is not only easily conducted using the same procedure as 3+3 but also outperforms the conventional 3+3 design. It can also be applied to determine MTD for any given TTL. These features make the isotonic modified method of practical value in phase I clinical trials.^

Computer analysis and design of concrete shell roofs

This paper is a preliminary version of Chapter 3 of a State-of-the-Art Report by the IASS Working Group 5: Concrete Shell Roofs. The intention of this chapter is to set forth for those who intend to design concrete shell roofs information and advice about the selection, verification and utilization of commercial computer tools for analysis and design tasks.The computer analysis and design steps for a concrete shell roof are described. Advice follows on the aspects to be considered in the application of commercial finite element (FE)computer programs to concrete shell analysis, starting with recommendations on how novices can gain confidence and competence in the use of software. To establish vocabulary and provide background references, brief surveys are presented of, first,element types and formulations for shells and, second, challenges presented by advanced analyses of shells. The final section of the chapter indicates what capabilities to seek in selecting commercial FE software for the analysis and design of concrete shell roofs. Brief concluding remarks summarize advice regarding judicious use of computer analysis in design practice.

Characteristic enrichment of DNA repeats in different genomes

Using computer programs developed for this purpose, we searched for various repeated sequences including inverted, direct tandem, and homopurine–homopyrimidine mirror repeats in various prokaryotes, eukaryotes, and an archaebacterium. Comparison of observed frequencies with expectations revealed that in bacterial genomes and organelles the frequency of different repeats is either random or enriched for inverted and/or direct tandem repeats. By contrast, in all eukaryotic genomes studied, we observed an overrepresentation of all repeats, especially homopurine–homopyrimidine mirror repeats. Analysis of the genomic distribution of all abundant repeats showed that they are virtually excluded from coding sequences. Unexpectedly, the frequencies of abundant repeats normalized for their expectations were almost perfect exponential functions of their size, and for a given repeat this function was indistinguishable between different genomes.

A high-resolution annotated physical map of the human chromosome 13q12-13 region containing the breast cancer susceptibility locus BRCA2.

Various types of physical mapping data were assembled by developing a set of computer programs (Integrated Mapping Package) to derive a detailed, annotated map of a 4-Mb region of human chromosome 13 that includes the BRCA2 locus. The final assembly consists of a yeast artificial chromosome (YAC) contig with 42 members spanning the 13q12-13 region and aligned contigs of 399 cosmids established by cross-hybridization between the cosmids, which were selected from a chromosome 13-specific cosmid library using inter-Alu PCR probes from the YACs. The end sequences of 60 cosmids spaced nearly evenly across the map were used to generate sequence-tagged sites (STSs), which were mapped to the YACs by PCR. A contig framework was generated by STS content mapping, and the map was assembled on this scaffold. Additional annotation was provided by 72 expressed sequences and 10 genetic markers that were positioned on the map by hybridization to cosmids.

User's manual for the CAL-3D user convenience package. Volume II - program listings. Final technical report.

National Highway Traffic Safety Administration, Washington, D.C.

Vehicle fog lighting: an analytical evaluation. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

A user's guide to ISRP : the Interactive Survey Reduction Program /

"November 1984."

Driver-vehicle effectiveness model. Volume II: appendices. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Traffic safety demonstration program modeling system. Volume IV: appendices.

National Highway Traffic Safety Administration, Washington, D.C.

Guardrail/vehicle dynamic interaction. Final report.

Federal Highway Administration, Washington, D.C.

Tools for embedded computing systems software.

"Preprint for a workshop sponsored by NASA Langley Research Center, Hampton, Virginia, and the American Institute of Aeronautics and Astronautics, New York, and held in Hampton, Virginia, November 7-8, 1978."

Sensitivity analysis of vehicle design attributes that affect vehicle response in critical accident situations - part 1: user's manual. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

PROMETHEUS 2 - a user oriented program for human crash dynamics. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Contact-impact problems. Volume 2 - programmer's manual. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Sensitivity analysis of vehicle design attributes that affect vehicle response in critical accident situations - part II: technical report. Final report.

National Highway Traffic Safety Administration, Washington, D.C.