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PubMed2006

A robust statistical procedure to discover expression biomarkers using microarray genomic expression data.

Microarray has become increasingly popular biotechnology in biological and medical researches, and has been widely applied in classification of treatment subtypes using expression patterns of biomarkers. We developed a statistical procedure to identify expression biomarkers for treatment subtype classification by constructing an F-statistic based on Henderson method III. Monte Carlo simulations were conducted to examine the robustness and efficiency of the proposed method. Simulation results showed that our method could provide satisfying power of identifying differentially expressed genes (DEGs) with false discovery rate (FDR) lower than the given type I error rate. In addition, we analyzed a leukemia dataset collected from 38 leukemia patients with 27 samples diagnosed as acute lymphoblastic leukemia (ALL) and 11 samples as acute myeloid leukemia (AML). We compared our results with those from the methods of significance analysis of microarray (SAM) and microarray analysis of variance (MAANOVA). Among these three methods, only expression biomarkers identified by our method can precisely identify the three human acute leukemia subtypes.

Biomarkers↗
PubMed2006

Robustness of surrogates of biodiversity in marine benthic communities.

The usefulness of surrogates to estimate complex variables describing community structure, such as the various components of biodiversity, is long established. Most attention has been given to surrogates of species richness and species diversity and has focused on identifying a subset of taxa as a surrogate of total community richness or diversity. In adopting a surrogate measure, it is assumed that the relationship between the surrogate(s) and total richness or diversity is consistent in both space and time. These assumptions are rarely examined explicitly. We examined the robustness of potential surrogates of familial richness and multivariate community structure for macrofauna communities inhabiting artificial kelp holdfasts by comparing among communities of dissimilar ages and among communities established at different times of the year. This is important because most benthic "landscapes" will be a mosaic of patches reflecting different intensities, frequencies, and timing of disturbances. The total abundance of organisms and familial richness of crustaceans or polychaetes were all good predictors of total familial richness (R2 > 0.68). In contrast, while the familial richness of other groups, such as mollusks and echinoderms, were well correlated with total familial richness for communities at an early stage of development, the strength of these relationships declined with community age. For multivariate community structure, carefully selected subsets of approximately 10% of the total taxa yielded similar patterns to the total suite of taxa, irrespective of the age of the community. Thus, useful surrogates of both familial richness and multivariate community structure can be identified for this type of community. However, the choice of technique for selecting surrogate taxa largely depends on the nature of the pilot data available, and careful selection is required to ensure that surrogates perform consistently across different-aged communities. While the specific taxa selected as surrogates will vary among different communities, and possibly even among similar communities at different sites, the techniques and the concepts we address are applicable to any community type.

Animals↗
PubMed2001

ArrayExplorer, a program in Visual Basic for robust and accurate filter cDNA array analysis.

Determining the dynamics in the global regulation of gene expression holds the promise of bringing a better understanding of the processes that govern physiological cell growth regulation and its disruption during the development of disease. The advent for cDNA arrays has created the possibility for the parallel analysis of expression of thousands of genes in a given cell population, simultaneously. The level of expression of a given set of genes within the studied tissue corresponds to the intensity of a labeled cDNA probe synthesized from the studied tissue RNA and bound specifically to the cDNAs of the genes spotted on the array. The accurate extraction of gene expression intensity values is essential for further data analysis and the interpretation of the obtained results. Here, we describe a new array image-processing software developed in Microsoft Visual Basic, the ArrayExplorer, which provides a user-friendly, multiple-window interface and a number of automatic and manual features that facilitate a reliable, robust, and accurate extraction of gene intensity values from filter-array images.

Biotechnology↗
PubMed2005

Inducible control of transgene expression with ecdysone receptor: gene switches with high sensitivity, robust expression, and reduced size.

The ecdysone receptor (EcR)-based gene regulation system is a tool for controlling gene expression. To improve the sensitivity of this system, we evaluated many two-hybrid format synthetic gene constructs in which the GAL4 DNA binding domain was fused to the ligand binding domain of the Choristoneura fumiferana EcR mutant V390I/Y410E (GEvy), and various activation domains--VP16, p53, p65, or E2F-i--were fused to the EF domains of chimeric human RXR. These gene switches were assayed in NIH3T3 cells, HEK293 cells, and in mouse quadriceps in the presence of the nonsteroidal inducer RG-115819 or GS-E. All of the two-hybrid format constructs had no or very low background in the "off" condition and high luciferase reporter gene expression levels in "on" conditions. Extremely high sensitivity was achieved, with EC50 values in the subnanomolar range and with maximal induction at 10 nM RG-115819. Co-expression of both receptor genes with encephalomyocarditis virus (EMCV) or eIF4G internal ribosome entry site (IRES) sequences gave robust induction levels. To reduce the size of the switch construct, we tested single receptor formats, in which any of 14 different activation domains were fused to GEvy. We identified several switches with acceptable levels of basal and maximal induction levels. The gene switches described here provide receptor configuration options suitable for gene function studies, therapeutic protein production in cell culture, transgenic mouse models, and gene/cell therapy.

Animals↗
PubMed2005

A robust statistical method for detecting differentially expressed genes.

DNA microarray technology allows researchers to monitor the expressions of thousands of genes under different conditions, and to measure the levels of thousands of different DNA molecules at a given point in the life of an organism, tissue or cell. A wide variety of different diseases that are characterised by unregulated gene expression, DNA replication, cell division and cell death, can be detected early using microarrays. One of the major objectives of microarray experiments is to identify differentially expressed genes under various conditions. The detection of differential gene expression under two different conditions is very important in biological studies, and allows us to identify experimental variables that affect different biological processes. Most of the tests available in the literature are based on the assumption of normal distribution. However, the assumption of normality may not be true in real-life data, particularly with respect to microarray data.A test is proposed for the identification of differentially expressed genes in replicated microarray experiments conducted under two different conditions. The proposed test does not assume the distribution of the parent population; thus, the proposed test is strictly nonparametric in nature. We calculate the p-value and the asymptotic power function of the proposed test statistic. The proposed test statistic is compared with some of its competitors under normal, gamma and exponential population setup using the Monte Carlo simulation technique. The application of the proposed test statistic is presented using microarray data. The proposed test is robust and highly efficient when populations are non-normal.

Journal Article↗
PubMed2006

Robust statistical methods for hit selection in RNA interference high-throughput screening experiments.

RNA interference (RNAi) high-throughput screening (HTS) experiments carried out using large (>5000 short interfering [si]RNA) libraries generate a huge amount of data. In order to use these data to identify the most effective siRNAs tested, it is critical to adopt and develop appropriate statistical methods. To address the questions in hit selection of RNAi HTS, we proposed a quartile-based method which is robust to outliers, true hits and nonsymmetrical data. We compared it with the more traditional tests, mean +/- k standard deviation (SD) and median +/- 3 median of absolute deviation (MAD). The results suggested that the quartile-based method selected more hits than mean +/- k SD under the same preset error rate. The number of hits selected by median +/- k MAD was close to that by the quartile-based method. Further analysis suggested that the quartile-based method had the greatest power in detecting true hits, especially weak or moderate true hits. Our investigation also suggested that platewise analysis (determining effective siRNAs on a plate-by-plate basis) can adjust for systematic errors in different plates, while an experimentwise analysis, in which effective siRNAs are identified in an analysis of the entire experiment, cannot. However, experimentwise analysis may detect a cluster of true positive hits placed together in one or several plates, while platewise analysis may not. To display hit selection results, we designed a specific figure called a plate-well series plot. We thus suggest the following strategy for hit selection in RNAi HTS experiments. First, choose the quartile-based method, or median +/- k MAD, for identifying effective siRNAs. Second, perform the chosen method experimentwise on transformed/normalized data, such as percentage inhibition, to check the possibility of hit clusters. If a cluster of selected hits are observed, repeat the analysis based on untransformed data to determine whether the cluster is due to an artifact in the data. If no clusters of hits are observed, select hits by performing platewise analysis on transformed data. Third, adopt the plate-well series plot to visualize both the data and the hit selection results, as well as to check for artifacts.

Cluster Analysis↗
PubMed2003

Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial.

OBJECTIVE: To assess the ability of the 4-week healing rate to predict complete healing over a 12-week period in a large prospective multicenter trial of diabetic patients with foot ulceration. RESEARCH DESIGN AND METHODS: We examined the change in ulcer area over a 4-week period as a predictor of wound healing within 12 weeks in patients who were seen weekly in a prospective, randomized controlled trial. RESULTS: Wound area measurements at baseline and after 4 weeks were performed in 203 patients. The midpoint between the percentage area reduction from baseline at 4 weeks in patients healed versus those not healed at 12 weeks was found to be 53%. Subjects with a reduction in ulcer area greater than the 4-week median had a 12-week healing rate of 58%, whereas those with reduction in ulcer area less than the 4-week median had a healing rate of only 9% (P < 0.01). The absolute change in ulcer area at 4 weeks was significantly greater in healers versus nonhealers (1.5 vs. 0.8 cm(2), P < 0.02). The percent change in wound area at 4 weeks in those who healed was 82% (95% CI 70-94), whereas in those who failed to heal, the percent change in wound area was 25% (15-35; P < 0.001). CONCLUSIONS: The percent change in foot ulcer area after 4 weeks of observation is a robust predictor of healing at 12 weeks. This simple tool may serve as a pivotal clinical decision point in the care of diabetic foot ulcers for early identification of patients who may not respond to standard care and may need additional treatment.

Diabetic Foot↗
PubMed2001

Robustness of the two-dimensional structure of recognition of facial expression: evidence under different intensities of emotionality.

Many studies have indicated that recognition of facial expression is geometrically represented in terms of two underlying bipolar dimensions, pleasure-displeasure and the intensity of arousal. A psychological space defined by these two dimensions has been found under particular conditions using prototype faces: however, the question arises whether this two-dimensional psychological space is also an accurate representation for faces with lower emotional intensity. To test this we prepared four different conditions of emotional intensity (100%, 75%, 50%, and 25% of emotionality) for six basic facial expressions using morphing. Participants (29 for the 100%, 30 for 75%, 35 for 50%, and 34 for the 25% condition) in each condition rated the facial stimuli on a 6-point scale of "not at all" and "very much so". Multidimensional scaling for each condition clearly indicated a two-dimensional representation and multiple correlations showed significant similarity across conditions (p < .001). This shows that the two-dimensional representation of recognition of facial expression is robust.

Adult↗
PubMed1996

Does the MMPI PTSD-PK scale measure robustness?

Research evaluating the diagnostic value of the MMPI PK scale for determining Posttraumatic Stress Disorder has been consistently positive. Various cut-off points have been suggested, depending on the population studied. The current study, involving a select group of police candidates from middle-sized midwestern towns, suggests that low PK scores may represent robustness. These subjects as a group made low use of health and mental health services and obtained very low PK scores (T = 41), although they made average scores on the clinical scales.

Female↗
PubMed1996

Robustness of taxometric analysis with skewed indicators: II. A Monte Carlo study of the MAXCOV procedure.

A small Monte Carlo study was conducted to determine whether MAXCOV analysis, a taxometric method for testing between discrete ("taxonic") and continuous models of latent variables, is robust when indicators of the latent variable are skewed. Analysis of constructed data sets containing three levels of skew indicated that the MAXCOV procedure is unlikely to yield spurious findings of taxonicity even when skewness is considerable. However, care must be taken to distinguish low base-rate taxonic variables from skewed nontaxonic variables.

Humans↗
PubMed2001

A robust method for the analysis of experiments with ordered treatment levels.

A robust approach for the analysis of experiments with ordered treatment levels is presented as an alternative to existing approaches such as the parametric Abelson-Tukey test for monotone alternatives and the nonparametric Terpstra-Jonckheere test. The method integrates the familiar Spearman rank-order correlation with bootstrap routines to provide magnitude of association measures, p values, and confidence intervals for magnitude of association measures. The advantages of this method relative to five alternative approaches are pointed out.

Analysis of Variance↗
PubMed1994

Validation of parameters for assessing Obscure Auditory Dysfunction--robustness of determinants of OAD status across samples and test methods.

About 5% of those presenting at an ENT clinic with ear or hearing complaints are found to have normal pure-tone thresholds. Many of this group complain specifically of difficulties understanding speech in background noise. We have termed this complaint 'Obscure Auditory Dysfunction' (OAD). Previous research on OAD (Saunders and Haggard, 1992) on a sample of 50 patients and 50 matched controls showed that 83% of the deviance (binary variance) in membership of group (OAD/control) could be explained by four variables, with three underlying factors. These four variables are performance threshold in noise for speech; discrepancy between this and a self-adjusted signal-to-noise ratio value (i.e. a measure of auditory confidence); dichotic listening performance; and performance on a psychoacoustic test, the threshold for detecting a tone in a spectrally notched noise. This paper reports a study on a further 59 new OAD patients and 64 unmatched controls, using the tests in the form present in the test package, plus certain others. For routine practice, slightly differing implementations of the auditory test techniques were used. Compared to the earlier sample, the new sample had poorer measures of speech reception threshold in noise and they considered themselves more handicapped by their OAD state; however there was no significant difference between the two samples on the other performance variables. Overall, the results demonstrate the robustness of the conclusions reached from the previous study, as the test-variable determinants of OAD status (i.e. case-control differences) were similar. The items on the OAD interview questionnaire which had shown significant differences between OADs and controls were also similar for the two OAD samples, giving a consistent picture of patient profile. These were: difficulties learning to read or write as a child (which relates to dichotic listening scores); adult ear problems; and tinnitus (which relate to the psychoacoustic scores). This necessary replication confirms the validity of the three-factor model of OAD status and the utility of the clinical test package based upon it.

Adolescent↗
PubMed2005

A robust solution for dealing with environmental changes in intercepting moving balls.

The authors tested whether a simple model based on the cancellation of the rate of change in bearing angle could account for the behavioral adaptations produced when individuals intercept moving balls while walking. In Experiment 1, the place of arrival of the ball and the angle of approach were varied. In accord with the model, velocity regulations were earlier and more pronounced the larger the angle of approach. In Experiment 2, ball speed unexpectedly changed during a trial, once again highlighting participants' functional velocity adaptations. A direct test of the model on the basis of each individual trial (N = 256) revealed that, on average, 70% of the total variance could be explained. Together, those results confirm the usefulness of such a robust strategy in the control of interceptive tasks.

Adaptation, Psychological↗
PubMed2001

Robust tracking and posture description for laboratory rodents using active shape models.

We are in the process of developing an automated image analysis system, which uses deformable models of shape, learned from image examples, to interpret video images of rodents. Active shape models provide a compact description of the shape of the animal in a way that enables the postures the differentiate various behaviors to be distinguished. They also model the image profile across the shape boundary. We show how these features allow automatic, robust segmentation of the explicit object of interest. Rather than just detecting movement or changes from background in the image, the system can focus on objects that are of the correct shape and appearance. The modeling of the image profiles also allows the system to distinguish between the actual animal and image artifacts. We show how these techniques are being extended to extract postural information, which can then be integrated with positional data to produce a model of behavior.

Animals↗
PubMed2003

QMLE: fast, robust, and efficient estimation of distribution functions based on quantiles.

Quantile maximum likelihood (QML) is an estimation technique, proposed by Heathcote, Brown, and Mewhort (2002), that provides robust and efficient estimates of distribution parameters, typically for response time data, in sample sizes as small as 40 observations. In view of the computational difficulty inherent in implementing QML, we provide open-source Fortran 90 code that calculates QML estimates for parameters of the ex-Gaussian distribution, as well as standard maximum likelihood estimates. We show that parameter estimates from QML are asymptotically unbiased and normally distributed. Our software provides asymptotically correct standard error and parameter intercorrelation estimates, as well as producing the outputs required for constructing quantile-quantile plots. The code is parallelizable and can easily be modified to estimate parameters from other distributions. Compiled binaries, as well as the source code, example analysis files, and a detailed manual, are available for free on the Internet.

Data Interpretation, Statistical↗
PubMed2006

Measures of sensitivity based on a single hit rate and false alarm rate: the accuracy, precision, and robustness of d', Az, and A'.

Signal detection theory offers several indexes of sensitivity (d', Az, and A') that are appropriate for two-choice discrimination when data consist of one hit rate and one false alarm rate per condition. These measures require simplifying assumptions about how target and lure evidence is distributed. We examine three statistical properties of these indexes: accuracy (good agreement between the parameter and the sampling distribution mean), precision (small variance of the sampling distribution), and robustness (small influence of violated assumptions on accuracy). We draw several conclusions from the results. First, a variety of parameters (sample size, degree of discriminability, and magnitude of hits and false alarms) influence statistical bias in these indexes. Comparing conditions that differ in these parameters entails discrepancies that can be reduced by increasing N. Second, unequal variance of the evidence distributions produces significant bias that cannot be reduced by increasing N-a serious drawback to the use of these sensitivity indexes when variance is unknown. Finally, their relative statistical performances suggest that Az is preferable to A'.

Humans↗
PubMed2002

Regeneration of natural antibody repertoire after massive ablation of lymphoid system: robust selection mechanisms preserve antigen binding specificities.

Natural Abs (NAbs) are Igs present in the serum and body fluids of healthy vertebrate animals, without any previous intentional immunization. NAbs often exhibit autoreactivity but also play an essential role in immunity, being a first line of defense against infectious microorganisms. We have previously analyzed the natural serum IgM Ab repertoire of normal mice, characterizing their reactivity with hundreds/thousands of self Ags; a significant similarity among different individuals was observed, and it was found that many reactivities of NAbs stably kept during adulthood were established early in life, implicating that period as a critical time window in the physiology of NAb repertoire selection. In the work reported here, experiments were conducted to address the role of normal lymphocyte ontogeny to the formation and stability of adult NAb repertoire. The massive destruction of the lymphoid system was promoted in adult mice with gamma-irradiation, and regeneration of hemopoietic tissues was granted by bone marrow or fetal liver inoculum. NAb repertoire regeneration was followed for 60 days after gamma-irradiation in bone marrow or fetal liver chimeric animals. The analysis of serum IgM reactivity with hundreds/thousands of self Ags showed that the NAb repertoire regenerated most of its original format after massive destruction of lymphoid compartments, characterizing autoreactive repertoire selection as a robust biological process. The data also show that regeneration of the NAb repertoire occurred similarly in fetal liver and bone marrow chimeras, although the latter animals poorly reconstituted their CD5(+) B1 cell compartment, suggesting that B1 cells are not essential for natural Ab regeneration.

Aging↗
PubMed2003

Cutting edge: MHC class II-restricted peptides containing the inflammation-associated marker 3-nitrotyrosine evade central tolerance and elicit a robust cell-mediated immune response.

Nitrotyrosine is widely recognized as a surrogate marker of up-regulated inducible NO synthase expression at sites of inflammation. However, the potential immunogenicity of autologous proteins containing nitrotyrosine has not previously been investigated. Herein, we used the I-E(K)-restricted T cell epitope of pigeon/moth cytochrome c (PCC/MCC(88-103)) to assess the ability of T cells to recognize ligands containing nitrotyrosine. Substitution of the single tyrosine (Y97) in PCC/MCC(88-103) with nitrotyrosine abrogates recognition by the MCC(88-103)-specific T cell hybridoma 2B4. CBA (H2(K)) mice immunized with MCC(88-103) or nitrated MCC(88-103) peptides produce T cell responses that are mutually exclusive. Transgenic mice that constitutively express PCC under the control of an MHC class I promoter are tolerant toward immunization with MCC(88-103), but exhibited a robust immune response against nitrated MCC(88-103). Analysis of T cell hybridomas specific for nitrated-MCC(88-103) indicated that subtle differences in TCR VDJ gene usage are sufficient to allow nitrotyrosine-specific T cells to escape the processes of central tolerance.

Amino Acid Sequence↗