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PubMed2006

Cation and anion diversity in [M(dithiooxalate)2]2- salts: structure robustness in crystal synthesis.

A series of crystalline salts based on the [M(dto)2]2- (dto = 1,2-dithiooxalate, M = Ni, Pt, Cu) dianion with hydrogen-bond donor cations have been synthesised following a molecular tectonics approach. The chelating M(dto)[dot dot dot]HN supramolecular synthon has been exploited in a systematic study of its robustness. The effects of competition between hydrogen-bond acceptors, of the shape and functionality of the cations and of varying the metal in the anion are discussed. The preparation and structural characterisation of the new crystalline phases [4,4'-H(2)bipy][Pt(dto)2] (2), [HNC5H4CO2H-4]2[Pt(dto)2] (5), [HNC5H4CO2H-3]2[Pt(dto)2] (6), [HNC5H4CH2CO2H-4]2[Ni(dto)2] (7), [HNC(5)H(4)CH(2)CO(2)H-3]2[Ni(dto)2] (8), [HNC5H4CONH2-4]2[Ni(dto)2] (9), [HNC5H4CHNOH-4]2[Ni(dto)2] (10), [HNC5H4CHNOH-3]2[Ni(dto)2] (11), [4,4'-H2bipip][Ni(dto)2] (12), [H2NC5H9CO2H-4]2[Pt(dto)2] (12), [H2NC5H9CO2H-4]2[Cu(dto)2] (14), [H2NC5H9CO2H-3]2[Ni(dto)2][H2O]2 (15), [H2NC5H9CO2H-3]2[Pt(dto)2][H2O]2 (16), [H2NC5H9CO2H-3]2[Cu(dto)2][H2O]2 (17), [H(Me)NC5H9CO2H-4]2[Ni(dto)2][H2O]2 (18) is reported. The charge-assisted NH[dot dot dot]dto synthon is formed in each of compounds 1-20, and is apparently much more robust than the conventional synthons used (such as the carboxylic acid dimer), which have a much lower rate of occurrence. The NH[dot dot dot]dto synthon may be generalised to 3- and 4-pyridinium species and 3- and 4-piperidinium derivatives. In the latter cases branching of the hydrogen-bond networks through the NH2 groups arises. The robustness of the NH...dto synthon allows structures of the form [NH cation]2[M(dto)2] to be regarded as being formed by the packing of neutral supermolecules. Cases of isomorphism (as in 16-18) and latent polymorphism (e.g. in 4 and 6) are noted.

Journal Article↗
PubMed1999

A statistically robust variance-components approach for quantitative trait linkage analysis.

Previously we showed (Wang, Guerra & Cohen 1998) that a statistically robust version of the Haseman & Elston (1972) sib-pair method greatly increased power to detect linkage in the presence of outliers. In this paper we report on M-estimation to accommodate outliers in the variance-components approach to linkage analysis developed by Amos (1994). Simulations show that in the presence of outliers the robust variance-components approach provides substantially greater power, more precise estimation of heritabilities, and better false-positive rates than the original Gaussian based approach. In the absence of outliers the performance of the robust variance-components approach is similar to that of the Gaussian based approach. For illustration we apply the method to two well characterized lipoprotein systems.

Alleles↗
PubMed2006

Evolutionary design on a budget: robustness and optimality of bacteriophage T7.

Exploring how biological systems have been 'designed' by evolution to achieve robust behaviours is now a subject of increasing research effort. Yet, it still remains unclear how environmental factors may contribute to this process. This issue is addressed by employing a detailed computer model for the intracellular growth of phage T7. More than 150 000 in silico T7 mutants were generated and the rates and efficiencies of their growth in two host environments, namely, a realistic environment that offered finite host resources for the synthesis of phage functions and a hypothetical environment where the phage was supplied infinite host resources, were evaluated. Results revealed two key properties of phage T7. First, T7 growth was overall robust with respect to perturbations in its parameters, but fragile with respect to changes in the ordering of its genetic elements. Secondly, the wild-type T7 had close to optimal fitness in the finite environment. Furthermore, a strong correlation was found between fitness and growth efficiency in the finite environment. The results underscore the potential importance of the environment in shaping robust design of a biological system. In particular, the strong correlation between fitness and growth efficiency suggests that T7 may have evolved to maximise its growth rate by minimising waste of finite resources.

Bacteriophage T7↗
PubMed2003

Phase resetting effects for robust cycles between chaotic sets.

In the presence of symmetries or invariant subspaces, attractors in dynamical systems can become very complicated, owing to the interaction with the invariant subspaces. This gives rise to a number of new phenomena, including that of robust attractors showing chaotic itinerancy. At the simplest level this is an attracting heteroclinic cycle between equilibria, but cycles between more general invariant sets are also possible. In this paper we introduce and discuss an instructive example of an ordinary differential equation where one can observe and analyze robust cycling behavior. By design, we can show that there is a robust cycle between invariant sets that may be chaotic saddles (whose internal dynamics correspond to a Rössler system), and/or saddle equilibria. For this model, we distinguish between cycling that includes phase resetting connections (where there is only one connecting trajectory) and more general non(phase) resetting cases, where there may be an infinite number (even a continuum) of connections. In the nonresetting case there is a question of connection selection: which connections are observed for typical attracted trajectories? We discuss the instability of this cycling to resonances of Lyapunov exponents and relate this to a conjecture that phase resetting cycles typically lead to stable periodic orbits at instability, whereas more general cases may give rise to "stuck on" cycling. Finally, we discuss how the presence of positive Lyapunov exponents of the chaotic saddle mean that we need to be very careful in interpreting numerical simulations where the return times become long; this can critically influence the simulation of phase resetting and connection selection.

Journal Article↗
PubMed2002

Robustness of circadian rhythms with respect to molecular noise.

We use a core molecular model capable of generating circadian rhythms to assess the robustness of circadian oscillations with respect to molecular noise. The model is based on the negative feedback exerted by a regulatory protein on the expression of its gene. Such a negative regulatory mechanism underlies circadian oscillations of the PER protein in Drosophila and of the FRQ protein in Neurospora. The model incorporates gene transcription into mRNA, translation of mRNA into protein, reversible phosphorylation leading to degradation of the regulatory protein, transport of the latter into the nucleus, and repression of gene expression by the nuclear form of the protein. To assess the effect of molecular noise, we perform stochastic simulations after decomposing the deterministic model into elementary reaction steps. The oscillations predicted by the stochastic simulations agree with those obtained with the deterministic version of the model. We show that robust circadian oscillations can occur already with a limited number of mRNA and protein molecules, in the range of tens and hundreds, respectively. Entrainment by light/dark cycles and cooperativity in repression enhance the robustness of circadian oscillations with respect to molecular noise.

Animals↗
PubMed1998

The role of robustness and changeability on the origin and evolution of genetic codes.

We propose that an essential factor on the origin of genetic codes is a balanced accomplishment of robustness and changeability, two antithetical, but fundamental, properties for the survival and evolution of organisms. These measures are defined as the intrinsic properties of genetic codes. An evaluation of these properties explains the structural regularity of genetic codes, estimates the order of codon reassignment in deviant codes, and predicts the most probable deviant codes that exist. The enumeration of genetic codes that could have evolved from the standard genetic code under the selection pressure on robustness and changeability strongly limits the freedom of codon reassignments. The codon reassignments of all currently known deviant genetic codes belong to this predicted evolutionary path, and they generally give the highest improvements on robustness and changeability.

Amino Acids↗
PubMed2003

Allosteric interactions and bifunctionality make the response of glutamine synthetase cascade system of Escherichia coli robust and ultrasensitive.

Glutamine synthetase (GS) regulation in Escherichia coli by reversible covalent modification cycles is a prototype of signal transduction by enzyme cascades. Such enzyme cascades are known to exhibit ultrasensitive response to primary stimuli and act as signal integration systems. Here, we have quantified GS bicyclic cascade based on steady state analysis by evaluating Hill coefficient. We demonstrate that adenylylation of GS with glutamine as input is insensitive to total enzyme concentrations of GS, uridylyltransferase/uridylyl-removing enzyme, regulatory protein PII, and adenylyltransferase/adenylyl-removing enzyme. This robust response of GS adenylylation is also observed for change in system parameters. From numerical analyses, we show that the robust ultrasensitive response of bicyclic cascade is because of allosteric interactions of glutamine and 2-ketoglutarate, bifunctionality of converter enzymes, and closed loop bicyclic cascade structure. By system level quantification of the GS bicyclic cascade, we conclude that such a robust response may help the cell in adapting to different carbon and nitrogen status.

Allosteric Regulation↗
PubMed1994

Recovered-memory therapy and robust repression: influence and pseudomemories.

A subset of the psychotherapists practicing trauma-focused therapy predicate their treatment on the existence of a newly claimed, powerful form of repression that differs from repression as used in the psychoanalytic tradition and from amnesia in any of its recognized forms. Recovered-memory specialists assist patients to supposedly retrieve vast quantities of information (e.g., utterly new dramatic life histories) that were allegedly unavailable to consciousness for years or decades. We refer to the hypothesized mental mechanism as "robust repression" and call attention to the absence of evidence documenting its validity and to the differences between it and other mental mechanisms and memory features. No recovered-memory practitioner has ever published a full specification of the attributes of this mechanism. That is, the properties it would have to have for the narratives developed during therapy to be historically accurate to any significant degree. This article reports a specification of the properties of the robust repression mechanism based on interviews with current and former patients, practitioners' writings, and reports to researchers and clinicians. The spread of reliance on the robust repression mechanism over the past 20 years through portions of the clinical community is traced. While involved in therapy, patients of recovered-memory practitioners come to believe that they have either instantly repressed large numbers of discrete events or simultaneously repressed all information about abuse they may have endured for as long as a decade.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2006

Two-stage fuzzy-stochastic robust programming: a hybrid model for regional air quality management.

In this study, a hybrid two-stage fuzzy-stochastic robust programming (TFSRP) model is developed and applied to the planning of an air-quality management system. As an extension of existing fuzzy-robust programming and two-stage stochastic programming methods, the TFSRP can explicitly address complexities and uncertainties of the study system without unrealistic simplifications. Uncertain parameters can be expressed as probability density and/or fuzzy membership functions, such that robustness of the optimization efforts can be enhanced. Moreover, economic penalties as corrective measures against any infeasibilities arising from the uncertainties are taken into account. This method can, thus, provide a linkage to predefined policies determined by authorities that have to be respected when a modeling effort is undertaken. In its solution algorithm, the fuzzy decision space can be delimited through specification of the uncertainties using dimensional enlargement of the original fuzzy constraints. The developed model is applied to a case study of regional air quality management. The results indicate that reasonable solutions have been obtained. The solutions can be used for further generating pollution-mitigation alternatives with minimized system costs and for providing a more solid support for sound environmental decisions.

Air Pollutants, Occupational↗
PubMed2006

A robust approach to IMRT optimization.

Managing uncertainty is a major challenge in radiation therapy treatment planning, including uncertainty induced by intrafraction motion, which is particularly important for tumours in the thorax and abdomen. Common methods to account for motion are to introduce a margin or to convolve the static dose distribution with a motion probability density function. Unlike previous work in this area, our development does not assume that the patient breathes according to a fixed distribution, nor is the patient required to breathe the same way throughout the treatment. Despite this generality, we create a robust optimization framework starting from the convolution method that is robust to fluctuations in breathing motion, yet spares healthy tissue better than a margin solution. We describe how to generate the data for our model using breathing motion data and we test our model on a computer phantom using data from real patients. In our numerical results, the robust solution delivers approximately 38% less dose to the healthy tissue than the margin solution, while providing the same level of protection against breathing uncertainty.

Algorithms↗
PubMed2003

Robust cluster analysis of microarray gene expression data with the number of clusters determined biologically.

MOTIVATION: The success of each method of cluster analysis depends on how well its underlying model describes the patterns of expression. Outlier-resistant and distribution-insensitive clustering of genes are robust against violations of model assumptions. RESULTS: A measure of dissimilarity that combines advantages of the Euclidean distance and the correlation coefficient is introduced. The measure can be made robust using a rank order correlation coefficient. A robust graphical method of summarizing the results of cluster analysis and a biological method of determining the number of clusters are also presented. These methods are applied to a public data set, showing that rank-based methods perform better than log-based methods. AVAILABILITY: Software is available from http://www.davidbickel.com.

Algorithms↗
PubMed2005

Robust classification modeling on microarray data using misclassification penalized posterior.

MOTIVATION: Genome-wide microarray data are often used in challenging classification problems of clinically relevant subtypes of human diseases. However, the identification of a parsimonious robust prediction model that performs consistently well on future independent data has not been successful due to the biased model selection from an extremely large number of candidate models during the classification model search and construction. Furthermore, common criteria of prediction model performance, such as classification error rates, do not provide a sensitive measure for evaluating performance of such astronomic competing models. Also, even though several different classification approaches have been utilized to tackle such classification problems, no direct comparison on these methods have been made. RESULTS: We introduce a novel measure for assessing the performance of a prediction model, the misclassification-penalized posterior (MiPP), the sum of the posterior classification probabilities penalized by the number of incorrectly classified samples. Using MiPP, we implement a forward step-wise cross-validated procedure to find our optimal prediction models with different numbers of features on a training set. Our final robust classification model and its dimension are determined based on a completely independent test dataset. This MiPP-based classification modeling approach enables us to identify the most parsimonious robust prediction models only with two or three features on well-known microarray datasets. These models show superior performance to other models in the literature that often have more than 40-100 features in their model construction. AVAILABILITY: Our MiPP software program is available at the Bioconductor website (http://www.bioconductor.org).

Algorithms↗
PubMed2001

Column robustness case study for a liquid chromatographic method validated in compliance with ICH, VICH, and GMP guidelines.

This article presents a case study in dealing with robustness investigations and attempts by our analytical laboratory to address these issues without sacrificing valuable time in revamping the method validation prior to submission. A liquid chromatographic method is developed for the analysis of a novel triazinetrione anticoccidial product. The method effectively separates the active pharmaceutical ingredient (API), impurities, and preservatives in the API and product formulation. For much of the validation, the method holds up to the rigorous guidelines of the International Conference of Harmonization, the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products, and the Good Manufacturing Practices. However, in analyzing a base-degraded sample one of the impurity peaks yields inconsistent retention times (RTs) during a series of injections. When switching the system to another analytical column from the same supplier, this impurity peak elutes at a different retention window and the remaining peaks in the chromatographic profile remain essentially the same. This RT variation of a single peak in the chromatographic profile is observed with additional columns from the same supplier and from different manufacturing lots. This suitability problem is not encountered with the columns used in the method development stage. The method no longer meets the robustness criteria established for pharmaceutical methods. An investigation is commenced and it is discovered that with the addition of tetrabutylammonium hydroxide to the mobile phases, the impurity peak gives a consistent RT in relation to the active peak. The peak shows comparable RTs relative to that of the API peak with columns of different silica lots and bond lots. All peaks, including the aforementioned impurity peak, are well-resolved under the revised high-performance liquid chromatographic conditions. This temporary solution enables continued submission work for FDA, but the robustness of this method is still a concern. After further investigation, it is determined that inhomogeneity of the active sites on the column's stationary phase is the likely culprit. Fortunately, a new column is found to be more suitable for this method and a column qualification study is initiated.

Journal Article↗
PubMed1994

The robustness of recombination frequency estimates in intercrosses with dominant markers.

The robustness of the maximum likelihood estimates of recombination frequencies has been investigated in double intercrosses with complete dominance at both loci. The robustness was investigated with respect to bias in the recombination frequency estimates due to: (1) limited sample sizes, (2) heterogeneity in recombination frequencies between sexes or among meioses and (3) factors that distort the segregation-misclassification or differential viability. In the coupling phase, the recombination frequency estimates are quite robust with respect to most of the investigated factors. Potentially, the most serious cause of a bias is misclassifications, which tend to increase the recombination frequency estimates. In the repulsion phase, misclassifications are particularly serious, leading to extreme discrepancies between true and observed values. In addition, limited sample size and sex differences in recombination can also bias recombination frequency estimates in repulsion. These effects may pose serious problem in genetic mapping with random amplified polymorphic DNA (RAPD) markers.

Animals↗
PubMed1995

The log-linear relationship between sexual isolation and sequence divergence in Bacillus transformation is robust.

The relationship between sexual isolation and sequence divergence in Bacillus transformation was previously shown to be log linear. In the present study, we have shown that this relationship is robust with respect to naturally occurring genetic variation among recipient strains of Bacillus subtilis and B. mojavensis. Naturally occurring restriction endonuclease activity was shown not to affect this relationship. Also, seven out of eight recombination mutants tested for their sensitivity to sequence divergence have shown the same relationship between sequence divergence and sexual isolation; a mutant for recH was more sensitive to sequence divergence, suggesting that the product of this gene may be involved in resolution of mismatches in heterogamic transformation. We have also shown that the relationship between sexual isolation and sequence divergence is robust with respect to variation in the conditions of transformation, including variation in the length of donor DNA, the concentration of donor DNA, and intracellular competition between donor-derived and recipient-derived DNA. The robustness of the relationship between sexual isolation and sequence divergence among naturally occurring strains and across transformation conditions allows us to predict the eventual outcome of sequence divergence among B. subtilis and its closest relatives.

Bacillus↗
PubMed2002

Artifact robustness, inter- and intraindividual baseline stability, and rational EEG parameter selection.

BACKGROUND: Artifact robustness (i.e., size of deviation of an electroencephalographic parameter value from baseline caused by artifacts) and baseline stability (i.e., consistency of median baseline values) of electroencephalographic parameters profoundly influence electroencephalography-based pharmacodynamic parameter estimation and the usefulness of the processed electroencephalogram as measure of the arousal state of the central nervous system (depth of anesthesia). In this study, the authors compared the artifact robustness and the interindividual and intraindividual baseline stability of several univariate descriptors of the electroencephalogram (Shannon entropy, approximate entropy, spectral edge frequency 95, delta ratio, and canonical univariate parameter). METHODS: Electroencephalographic data of 16 healthy volunteers before and after administration of an intravenous bolus of propofol (2 mg/kg body weight) were analyzed. Each volunteer was studied twice. The baseline electroencephalogram was recorded for a median of 18 min before drug administration. For each electroencephalographic descriptor, the authors calculated the following: (1) baseline variability (= (median baseline - median effect) [i.e., signal]/SD baseline [i.e., noise]) without artifact rejection; (2) baseline variability with artifact rejection; and (3) baseline stability within and between individuals (= (median baseline - median effect) averaged over all volunteers/SD of all median baselines). RESULTS: Without artifact rejection, Shannon entropy and canonical univariate parameter displayed the highest signal-to-noise ratio. After artifact rejection, approximate entropy, Shannon entropy, and the canonical univariate parameter displayed the highest signal-to-noise ratio. Baseline stability within and between individuals was highest for approximate entropy. CONCLUSIONS: With regard to robustness against artifacts, the electroencephalographic entropy parameters and the canonical univariate parameter were superior to spectral edge frequency 95 and delta ratio. Electroencephalographic approximate entropy displayed the best interindividual and intraindividual baseline stability.

Adult↗
PubMed1996

Robustness of computerized identification of masses in digitized mammograms. A preliminary assessment.

RATIONALE AND OBJECTIVES: The authors assess the robustness of a computer-aided diagnosis (CAD) scheme with five rule-based stages to identify regions suspicious for mass in digitized mammograms. METHODS: With a database of 428 mammograms, 234 of which had not been analyzed by this scheme before, the authors evaluated the performance robustness of their CAD scheme. The following four issues were investigated to assess the variability of the scheme's performance due to: (1) the maximum permissible number of "masses" detected at each stage; (2) exclusion of selected individual rule-based stages; (3) added image noise; and (4) repeated digitizations of the same image. RESULTS: Enabling the CAD scheme to select a maximum of two suspicious mass regions at any one stage increased sensitivity by as much as 4% (from 93% to 97%), but it increased the false-positive detection rate by as much as 1.2 per image (from 1.7 to 2.9). Eliminating any individual stage decreased sensitivity by as much as 6%, but this reduced the false-positive detection rate by as much as 0.4 per image (from 1.7 to 1.3). The addition of reasonable noise levels decreased sensitivity by as much as 4% without substantially affecting the false-positive detections. Repeated digitizations of selected images demonstrated a scheme sensitivity of 93% +/- 1.8% with more than a 90% overlap of the false-positive regions. CONCLUSIONS: The results of this preliminary study clearly indicate that this scheme is reasonably robust to the variables investigated here.

Breast Neoplasms↗
PubMed2004

Duplicate genes and robustness to transient gene knock-downs in Caenorhabditis elegans.

We examine robustness to mutations in the nematode worm Caenorhabditis elegans and the role of single-copy and duplicate genes in it. We do so by integrating complete genome sequence and microarray gene expression data with results from a genome-scale study using RNA interference (RNAi) to temporarily eliminate the functions of more than 16000 worm genes. We found that 89% of single-copy and 96% of duplicate genes show no detectable phenotypic effect in an RNAi knock-down experiment. We find that mutational robustness is greatest for closely related gene duplicates, large gene families and similarly expressed genes. We discuss the different causes of mutational robustness in single-copy and duplicate genes, as well as its evolutionary origin.

Animals↗