Maximin D-optimal designs for longitudinal mixed effects models

In this article, the optimal selection and allocation of time points in repeated measures experiments is considered. D-optimal cohort designs are computed numerically for the first- and second-degree polynomial models with random intercept, random slope, and first-order autoregressive serial correlations. Because the optimal designs are locally optimal, it is proposed to use a maximin criterion. It is shown that, for a large class of symmetric designs, the smallest relative efficiency over the model parameter space is substantial.     

Estimation of the spatial autocorrelation function: consequences of sampling dynamic populations in space and time

The estimation of spatial autocorrelation in spatially- and temporally-referenced data is fundamental to understanding an organism's population biology. I used four sets of census field data, and developed an idealized space-time dynamic system, to study the behavior of spatial autocorrelation estimates when a practical method of sampling is employed. Estimates were made using both a classical geostatistical approach and a recently developed non-parametric approach. In field data, the estimate of the local spatial autocorrelation (i.e. autocorrelation as the distance between pairs of sampling points approaches 0), was greatly affected by sample size, while the range of spatial dependence (i.e. the distance at which the autocorrelation becomes negligible) was fairly stable. Similar patterns were seen in the theoretical system, as well as greater variability in local spatial autocorrelation during the invasion stage of colonization. When sampling for the purposes of quantifying spatial patterns, improved estimates of spatial autocorrelation may be obtained by increasing the number of pairs of points that are close in space at the expense of attempting to cover the entire region of interest with equidistant sampling points. Also, results from the theoretical space-time system suggested that greater resolution in sampling may be required in newly establishing populations relative to those already established.     

A New Test for Cross-Over Clinical Trials with Order Effects

In cross-over designs for the comparison of two treatments, A and B, each patient receives both treatments in a randomized order. We will consider such design when the response of each patient is binary and propose a new test for treatment effect incorporating the information available from like pairs of response.     

A comparison of methods for adaptive treatment selection

Traditionally drug development is generally divided into three phases which have different aims and objectives. Recently so-called adaptive seamless designs that allow combination of the objectives of different development phases into a single trial have gained much interest. Adaptive trials combining treatment selection typical for Phase II and confirmation of efficacy as in Phase III are referred to as adaptive seamless Phase II/III designs and are considered in this paper. We compared four methods for adaptive treatment selection, namely the classical Dunnett test, an adaptive version of the Dunnett test based on the conditional error approach, the combination test approach, and an approach within the classical group-sequential framework. The latter two approaches have only recently been published. In a simulation study we found that no one method dominates the others in terms of power apart from the adaptive Dunnett test that dominates the classical Dunnett by construction. Furthermore, scenarios under which one approach outperforms others are described.     

Online Calculation of Efficient Designs for Multi‐Factor Models

A class of “incomplete” multivariate polynomial regression models on the q‐cube is considered. A simple algorithm for the determination of D‐optimal product designs is developed and illustrated by specific examples. The methods are implemented on an IBM compatible PC under MS‐DOS and provide an effective method for the numerical solution of an optimal design problem, which was unsolved in nearly all cases of practical interest.     

Robust and efficient design of experiments for the Monod model

In this paper the problem of designing experiments for the Monod model, which is frequently used in microbiology, is studied. The model is defined implicitly by a differential equation and has numerous applications in microbial growth kinetics, environmental research, pharmacokinetics, and plant physiology. The designs presented so far in the literature are local optimal designs, which depend sensitively on a preliminary guess of the unknown parameters, and are for this reason in many cases not robust with respect to their misspecification. Uniform designs and maximin optimal designs are considered as a strategy to obtain robust and efficient designs for parameter estimation. In particular, standardized maximin D- and E-optimal designs are determined and compared with uniform designs, which are usually applied in these microbiological models. It is demonstrated that maximin optimal designs are substantially more efficient than uniform designs. Parameter variances can be decreased by a factor of two by simply sampling at optimal times during the experiment. Moreover, the maximin optimal designs usually provide the possibility for the experimenter to check the model assumptions, because they have more support points than parameters in the Monod model.     

Robustness and Efficiency of D‐optimal Experimental Designs in a Growth Problem

To assess tree growth, for example in diameter, a forester typically measures the trees at regular time points. We call such designs equidistant. In this paper we look at the robustness and efficiency of several experimental designs, using the D‐optimality criterion, in a case study of diameter growth in cork oaks. We compare D‐optimal designs (unrestricted and replication‐free) with equidistant designs. We further compare designs in different experimental regions. Results indicate that the experimental region should be adequate to the problem, and that D‐optimal designs are substantially more efficient than equidistant designs, even under parameter mis‐specification.     

Nonparametric Evaluation of Repeated Measurement Designs by Point-Symmetry Testing

It is suggested to use simultaneous point-symmetry tests in evaluating trivariate repeated measurement designs nonparametrically. With k =3 treatments being applied to each of N individuals in randomized sequence, pairs of treatments are compared as to 3 variables or incremental sign patterns. It is shown that unifold trivariate tests preserve more information than do multifold univariate tests. The method is illustrated by an example from psychophysiological research.     

Contextual constraints on codon pair usage: structural and biological implications

Complementary DNA sequence data of 278 protein coding genes from prokaryotic systems have been analysed at the level of near neighbour codon pairs. Our analysis points out that constraints exist even at the level of near neighbour codon pairs. These constraints are in addition to those which arise due to relative levels of tRNA. Codon pairs, which in the data base have different occurrence values from their expected values, neither have common secondary structure nor do have better stabilization due to high base stacking. Our study points out that there are strong interaction between constituent codons in these codon pairs. These strongly interacting codon pairs, we suggest, are involved in the formation of three dimensional structural elements of cDNA/mRNA and interact with ribosome and thus modulate translation.     

Stoichiometry of lac repressor binding to nonspecific DNA: three different complexes form

The stoichiometry of lac repressor binding to nonspecific DNA was investigated by three different techniques. Four molecules of the fluorescent probe 5,5'-bis(8-anilino-1-naphthalenesulfonate) [bis(ANS)] bind to each repressor subunit with an average dissociation constant of 20 microM. Nonspecific DNA displaces most of this bound bis(ANS), reducing the fluorescence. Titrations of repressor with nonspecific DNA monitored with high [bis(ANS)] (5-15 microM) had end points at 8 base pairs per repressor. Lower [bis(ANS)] (0.1-1 microM) resulted in end points at either 15 or 26 base pairs per repressor, depending on the ionic strength. These end points correspond to complexes containing approximately one, two, or four repressors per 28 base pairs. Boundary sedimentation velocity experiments with saturating amounts of repressor revealed that five repressors can bind to 28 base pairs. By monitoring the circular dichroism as DNA was added to repressor, the sequential appearance of complexes containing approximately four, two, and one repressors per 28 base pairs was observed. The inability of repressor cores or iodinated repressor to bind to complexes containing one or two repressors per 28 base pairs implies that all of the repressors directly contact the DNA in the complex containing four repressors per 28 base pairs. It is proposed that while two subunits of each repressor contact the DNA in complexes containing one or two repressors per 28 base pairs, only one subunit of each repressor contacts the DNA in the complex with four repressors per 28 base pairs. These results suggest a novel mechanism for the one-dimensional diffusion of repressor along DNA.     

Excited states and energy transfer among DNA bases in double helices.

The study of excited states and energy transfer in DNA double helices has recently gained new interest connected to the development of computational techniques and that of femtosecond spectroscopy. The present article points out contentious questions regarding the nature of the excited states and the occurrence of energy transfer and shows how they are currently approached. Using as example the polymer poly(dA) . poly(dT), composed of about 2000 adenine-thymine pairs, a model is proposed on the basis of time-resolved measurements (fluorescence decays, fluorescence anisotropy decays and fluorescence spectra, obtained with femtosecond resolution), associated to steady-state spectra. According to this qualitative model, excitation at 267 nm populates excited states that are delocalized over a few bases (excitons). Ultrafast internal conversion directs the excited state population to the lower part of the exciton band giving rise to fluorescence. Questions needing further investigations, both theoretical and experimental, are underlined with particular emphasis on delicate points related to the complexity and the plasticity of these systems.     

Contextual Constraints on Codon Pair Usage: Structural and Biological Implications

Abstract

Complementary DNA sequence data of 278 protein coding genes from prokaryotic systems have been analysed at the level of near neighbour codon pairs. Our analysis points out that constraints exist even at the level of near neighbour codon pairs. These constraints are in addition to those which arise due to relative levels of tRNA. Codon pairs, which in the data base have different occurrence values from their expected values, neither have common secondary structure nor do have better stabilization due to high base stacking. Our study points out that there are strong interactions between constituent codons in these codon pairs. These strongly interacting codon pairs, we suggest, are involved in the formation of three dimensional structural elements of cDNA/mRNA and interact with ribosome and thus modulate translation.     

The use of multiple mass spectral line pairs for enhanced precision in isotope enrichment studies of 15N-labeled amino acids

A method for enhancing the precision in the calculation of isotope enrichment for 15N-labeled amino acids is presented. The method utilizes multiple line pairs for the calculation of isotope enrichment. Using multiple line pairs allows the evaluation of calibration curves for nonlinear behavior and permits differentiation among sites containing more than one labeled nitrogen. The increase in precision is related to the number of isotopically shifted line pairs used in calculating the isotopic enrichment and varies with the amino acid of interest.     

A new topological method to measure protein structure similarity

A method for the quantitative evaluation of structural similarity between protein pairs is developed that makes use of a Delaunay-based topological mapping. The result of the mapping is a three-dimensional array which is representative of the global structural topology and whose elements can be used to construe an integral scoring scheme. This scoring scheme was tested for its dependence on the protein length difference in a pairwise comparison, its ability to provide a reasonable means for structural similarity comparison within a family of structural neighbors of similar length, and its sensitivity to the differences in protein conformation. It is shown that such a topological evaluation of similarity is capable of providing insight into these points of interest. Protein structure comparison using the method is computationally efficient and the topological scores, although providing different information about protein similarity, correlate well with the distance root-mean-square deviation values calculated by rigid-body structural alignment.     

A Stochastic Algorithm for Selecting of Defining Contrasts in Two-Level Experiments

Franklin and Bailey (1977) provided an algorithm for construction of fractional factorial designs for estimating a user specified set of factorial effects. Their algorithm is based on a backtrack procedure. This is computer intensive when the number of factors is not small. We propose a stochastic search method called SEF (sequential elimination of factors) algorithm. The SEF algorithm is a simple modification of the exhaustive approach of the Franklin-Bailey algorithm since defining contrasts for the design of interest are chosen stochastically rather than choosing them in a systematic and exhaustive manner. Our experience shows the probability of success of obtaining a required design to be sufficiently large to make this a practical approach. The success probability may be expected to be rather small if the required design is close to a saturated design. We suggest the use of this stochastic alternative particularly when the number of factors is large. This can offer substantial savings in computing time relative to an exhaustive approach. Moreover, if the SEF algorithm fails to produce a design even after several attempts, one can always revert back to the Franklin-Bailey approach.     

Specific contacts between the FLP protein of the yeast 2-micron plasmid and its recombination site

Contact points between the FLP protein of the yeast 2-micron plasmid and its recombination site have been defined. Important features of the region previously defined as the minimal recombination site in vitro include a pair of 13-base pair inverted repeats separated by an 8-base pair spacer. The two FLP protein-binding sites within this region are 12 base pairs in length. In each case they include the internal 11 base pairs of one of the 13-base pair repeats, as well as the adjacent base pair within the spacer. The internal 6 base pairs within the spacer are not involved in binding or recognition by FLP protein. When the size of the spacer is increased or decreased by one base pair, the distance between the cleavage points is also increased or decreased correspondingly by one base pair. Points of cleavage are unaffected by changes in the spacer sequence. Specific contact points involving purine residues, identified by methylation protection and recombination interference experiments, are located in both the major and minor grooves of the DNA. Additional contact points between FLP protein and phosphate groups in the phosphate-deoxyribose backbone are clustered near the cleavage sites.     

On Construction of Some Augmented Block Designs

Augmented block designs are frequently used in practice. In this paper procedures of construction of some types of augmented block designs are discussed using the concept of efficiency-balance and partially efficiency-balance.     

Principal Predictors and Efficiency in Small Second-Order Designs

Linear parametric functions affected by deleting or augmenting sets of design points are identified explicitly using principal components of the predictive dispersion at those points, offering fresh insight and significant computational savings. Leverages from regression diagnostics are seen to determine efficiencies due to augmenting or deleting single points. Eight small second-order designs are studied in detail with supporting numerical displays. Comparisons are drawn to other approaches from the literature.     

Pose estimation in automated visual inspection using genetic algorithm

In this paper, we propose a genetic algorithm based approach to determine the pose of an object in Automated Visual Inspection having three degrees of freedom. We have investigated the effect of noise at 20 dB SNR and also mismatch resulting from incorrect correspondences between the object space points and the image space points, on the estimation of pose parameters. The maximum error in translation parameters is less than 0.45 cm and rotational error is less than 0.2 degree at 20 dB SNR. The error in parameter estimation is insignificant upto 7 pairs of mismatched points out of 24 points in object space and the results skyrockets when 8 or more pairs of points are mismatched. We have compared our result with that obtained by least square technique and it shows that GA based method outperform the gradient based technique when the number of vertices of the object to be inspected is small. These results have clearly established the robustness of GA in estimating the pose of an object with small number of vertices in automated visual inspection.     

Nucleotide sequences at the ends of the mercury resistance transposon, Tn501.

The nucleotide sequences at the ends of the mercury-resistance transposon, Tn501, have been determined. The terminal sequences are inverted repeated sequences 38 nucleotide pairs in length, which differ in 3 nucleotide pairs. The transposon is flanked by directly repeated sequences of 5 nucleotide pairs, originating from a single pentanucleotide sequence in the recipient replicon. There is no obvious homology between recipient replicons at the site of insertion of the transposon. The structures of the ends of Tn501 are compared with those of other transposons and insertion sequences. The use of Tn501 to locate an EcoRI site within a genetically defined sequence of interest is discussed.