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Ratio statistics of gene expression levels and applications to microarray data analysis.

MOTIVATION: Expression-based analysis for large families of genes has recently become possible owing to the development of cDNA microarrays, which allow simultaneous measurement of transcript levels for thousands of genes. For each spot on a microarray, signals in two channels must be extracted from their backgrounds. This requires algorithms to extract signals arising from tagged mRNA hybridized to arrayed cDNA locations and algorithms to determine the significance of signal ratios. RESULTS: This paper focuses on estimation of signal ratios from the two channels, and the significance of those ratios. The key issue is the determination of whether a ratio is significantly high or low in order to conclude whether the gene is upregulated or downregulated. The paper builds on an earlier study that involved a hypothesis test based on a ratio statistic under the supposition that the measured fluorescent intensities subsequent to image processing can be assumed to reflect the signal intensities. Here, a refined hypothesis test is considered in which the measured intensities forming the ratio are assumed to be combinations of signal and background. The new method involves a signal-to-noise ratio, and for a high signal-to-noise ratio the new test reduces (with close approximation) to the original test. The effect of low signal-to-noise ratio on the ratio statistics constitutes the main theme of the paper. Finally, and in this vein, a quality metric is formulated for spots. This measure can be used to decide whether or not a spot ratio should be deleted, or to adjust various measurements to reflect confidence in the quality of the measurement. CONTACT: e-dougherty@tamu.edu

Cell Line↗

Quantitative analysis of cuneate neurone responsiveness in the cat in association with reversible, partial deafferentation.

1. Partial deafferentation, based on peripheral nerve section or local anaesthetic blockade, has been reported to induce both immediate loss of responsiveness and/or immediate reorganization in receptive fields of neurones in the somatosensory system. In the present study, in anaesthetized cats, we have used a rapid, reversible deafferentation procedure based on cold block of the median nerve in order to evaluate quantitatively the response characteristics of cuneate neurones (n = 39) before, during and after partial deafferentation. 2. The first hypothesis tested was that cuneate neurones with input from ulnar or superficial radial nerve fields in the vicinity of the median nerve field should undergo, in association with median nerve blockade, an increased level of responsiveness to tactile stimuli within the ulnar or radial nerve zone, and an expansion of their cutaneous receptive fields. However, among eighteen cuneate neurones of this type, there was no evidence for any systematic enhancement of responsiveness nor, in at least sixteen of the eighteen neurones, any evidence for receptive field expansion. 3. The second hypothesis tested was that cuneate neurones whose input came from both the median nerve and another peripheral nerve source should undergo, in association with median nerve blockade, an increase in responsiveness to the remaining input and an expansion of the receptive field into the field of that remaining nerve source. However, in none of thirteen neurones of this type tested was there evidence of such a change. 4. The third hypothesis was that cuneate neurones whose control' receptive fields were within the median nerve zone of deafferentation should show an emergence of novel receptive fields and responsiveness from areas around the field of innervation of the median nerve. However, in none of eight neurones of this type was there evidence for such changes in adjacent skin areas. 5. In conclusion, with the use of cold block of the median nerve for partial deafferentation, the present study has confirmed previous findings of denervation-related loss of responsiveness in dorsal column nuclei neurones. The conflicting findings in studies of central nervous system plasticity indicate the need to understand better factors that do and do not lead to acute central changes.

Afferent Pathways↗

Cortico-striatal contributions to category learning: dissociating the verbal and implicit systems.

To better characterize the neuropsychological mechanisms of implicit and verbalizable category learning, the author studied weather prediction task (WPT) and information integration task (IIT) performance in patients with Parkinson's disease (PD) and healthy older and younger adults. Both older adults and patients with PD were impaired on the WPT, but only patients were impaired on the IIT, suggesting the 2 tasks rely on dissociable systems. Whereas the IIT appeared to rely on implicit processes, results suggest WPT classification depends on explicit processes. Awareness of underlying structure, hypothesis testing ability, and working memory capacity were all related to accuracy on the WPT but not the IIT. The variability commonly noted in WPT performance may reflect individual differences in hypothesis testing ability.

Adolescent↗

Sample size determination for establishing equivalence/noninferiority via ratio of two proportions in matched-pair design.

In this article, we propose approximate sample size formulas for establishing equivalence or noninferiority of two treatments in match-pairs design. Using the ratio of two proportions as the equivalence measure, we derive sample size formulas based on a score statistic for two types of analyses: hypothesis testing and confidence interval estimation. Depending on the purpose of a study, these formulas can be used to provide a sample size estimate that guarantees a prespecified power of a hypothesis test at a certain significance level or controls the width of a confidence interval with a certain confidence level. Our empirical results confirm that these score methods are reliable in terms of true size, coverage probability, and skewness. A liver scan detection study is used to illustrate the proposed methods.

Biopsy↗

Statistical phylogeography: methods of evaluating and minimizing inference errors.

Nested clade phylogeographical analysis (NCPA) has become a common tool in intraspecific phylogeography. To evaluate the validity of its inferences, NCPA was applied to actual data sets with 150 strong a priori expectations, the majority of which had not been analysed previously by NCPA. NCPA did well overall, but it sometimes failed to detect an expected event and less commonly resulted in a false positive. An examination of these errors suggested some alterations in the NCPA inference key, and these modifications reduce the incidence of false positives at the cost of a slight reduction in power. Moreover, NCPA does equally well in inferring events regardless of the presence or absence of other, unrelated events. A reanalysis of some recent computer simulations that are seemingly discordant with these results revealed that NCPA performed appropriately in these simulated samples and was not prone to a high rate of false positives under sampling assumptions that typify real data sets. NCPA makes a posteriori use of an explicit inference key for biological interpretation after statistical hypothesis testing. Alternatives to NCPA that claim that biological inference emerges directly from statistical testing are shown in fact to use an a priori inference key, albeit implicitly. It is argued that the a priori and a posteriori approaches to intraspecific phylogeography are complementary, not contradictory. Finally, cross-validation using multiple DNA regions is shown to be a powerful method of minimizing inference errors. A likelihood ratio hypothesis testing framework has been developed that allows testing of phylogeographical hypotheses, extends NCPA to testing specific hypotheses not within the formal inference key (such as the out-of-Africa replacement hypothesis of recent human evolution) and integrates intra- and interspecific phylogeographical inference.

Computer Simulation↗

Perceptual and linguistic interactions in speeded classification: tests of the semantic coding hypothesis.

We tested the semantic coding hypothesis, which states that cross-modal interactions observed in speeded classification tasks arise after perceptual information is recoded into an abstract format common to perceptual and linguistic systems. Using a speeded classification task, we first confirmed the presence of congruence interactions between auditory pitch and visual lightness and observed Garner-type interference with nonlinguistic (perceptual) stimuli (low-frequency and high-frequency tones, black and white squares). Subsequently, we found that modifying the visual stimuli by (a) making them lexical (related words) or (b) reducing their compactness or figural 'goodness' altered congruence effects and Garner interference. The results are consistent with the semantic coding hypothesis, but only in part, and suggest the need for additional assumptions regarding the role of perceptual organization in cross-modal dimensional interactions.

Female↗

Analysis of statistical outliers with application to whole effluent toxicity testing.

In this analysis, low-value outliers were detected in five data sets obtained from laboratory records. The effect of removing the outliers by three methods data rejection (asymmetrical and symmetrical trimming and Winsorization) revealed that all three methods slightly increased the mean and reduced the variance of the data sets. These opposing effects on the results of a hypothesis test of means were examined in the context of passing or failing a regulatory requirement significant difference between effluent concentration and a control. Analysis by statistical resampling of one data set showed that while all data rejection methods reduced the level of Type II error in a hypothesis test of no difference in reproduction between a test concentration and a regulatory limit, asymmetrical trimming was the best in this regard.

Analysis of Variance↗

Testing the hypothesis of the relationships between laterality and ability according to Annett's right-shift theory: findings in an epidemiological sample of young adults.

In a large epidemiological sample of young adults, predictions of the right-shift (RS) theory of Annett that cognitive abilities will vary with right-left hand skill were tested. Presenting a theory of a genetic balanced polymorphism with heterozygote advantage for laterality and ability, Annett & Manning (1989, 1990a) and Annett (1993c) claimed that probands at the right end of the R-L hand skill continuum would show lower general intelligence in IQ testing and that specific verbal abilities and educational success would be lower at both extremes of the R-L distribution, taking the form of an inverted U. Most of these predictions could not be confirmed by our study. In particular, our data contrast with the important and specific prediction of the RS theory that strong dextrals will be the most disfavoured group. In our sample, probands at the left end of the R-L continuum had significantly lower scores in spelling and educational success and showed a tendency to have lower non-verbal IQ scores, while strong dextrals tended to have average or even marginally higher ability scores. The effects, however, are small and decrease when controlling for other variables. Implications of these empirical findings for the right-shift theory are discussed.

Achievement↗

Applications of binary segmentation to the estimation of quantal response curves and spatial intensity.

This paper explores the use of binary segmentation procedures in two applications. The first application is concerned with the estimation of nonparametric quantal response curves. With Bernoulli data and an assumed monotone increasing curve, this gives rise a change-point model where the change points are determined using a sequence of nested hypothesis tests of whether a change point exists. The second application concerns cluster identification and inference for spatial data where the shape of the clusters and the number of clusters is unknown. The procedure involves a sequence of nested hypothesis tests of a single cluster versus a pair of distinct clusters. Examples of both applications are provided.

Cluster Analysis↗

Indefinite survival of human skin allografts in patients with long-term immunosuppression.

The transplantation of a sufficient quantity of good quality skin is of great clinical importance. Severe burn patients lack adequate skin donor sites to cover their wounds with autografts. Patients with severe injuries and burns of areas such as the entire face are presently reconstructed with multiple full- or split-thickness skin grafts. The final result is a patchwork appearance of skin with inferior qualities to normal full-thickness facial skin. Before structures such as hands should be transplanted, each individual tissue component should be evaluated to determine whether the tissue will survive and function with immunosuppression. Skin is obviously an important part of the hand. One hypothesis tested is the ability of transplanted human skin to survive indefinitely with long-term immunosuppression. The early detection of rejection of transplanted organs is paramount in reversing the rejection phenomena and hence saving the transplanted organ. Another hypothesis tested is the ability of a synchronously placed, same-donor, same-recipient skin graft to be used to detect rejection of a transplanted organ. As the skin and kidney from the same donor have similar antigens and the transplantation of both these tissues is to the same recipient and immunological system, it is hypothesized that there will be a correlation of rejection between the transplanted skin and the transplanted organ. To test the above hypotheses a small skin graft was placed on renal transplant patients synchronously with renal transplantation. The skin allografts were followed by direct observation and biopsy at regular intervals and at the time of suspected rejection. The patients were treated with the usual renal transplant immunosuppressant drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗

Inferences on standardized mean difference: the generalized variable approach.

The standardized mean difference has been widely used as the most common index of effect magnitude in many applied fields. In this paper, we propose a novel approach using the concept of generalized variable for the confidence interval estimation and hypothesis testing of standardized mean difference. Furthermore, we extend this approach to compare standardized mean differences between two studies or between two strata. Simulation results demonstrate that the proposed approach can provide confidence intervals with excellent coverage properties and can perform hypothesis testing with satisfactory type-I error control.

Confidence Intervals↗

Sample size computations for PK/PD population models.

We describe an accurate, yet simple and fast sample size computation method for hypothesis testing in population PK/PD studies. We use a first order approximation to the nonlinear mixed effects model and chi-square distributed Wald statistic to compute the minimum sample size to achieve given degree of power in rejecting a null hypothesis in population PK/PD studies. The method is an extension of Rochon's sample size computation method for repeated measurement experiments. We compute sample sizes for PK and PK/PD models with different conditions, and use Monte Carlo simulation to show that the computed sample size retrieves the required power. We also show the effect of different sampling strategies, such as minimal, i.e., as many observations per individual as parameters in the model, and intensive on sample size. The proposed sample size computation method can produce estimates of minimum sample size to achieve the desired power in hypothesis testing in a greatly reduced time than currently available simulation-based methods. The method is rapid and efficient for sample size computation in population PK/PD study using nonlinear mixed effect models. The method is general and can accommodate any type of hierarchical models. Simulation results suggest that intensive sampling allows the reduction of the number of patients enrolled in a clinical study.

Algorithms↗

Comparison of correlated receiver operating characteristic curves derived from repeated diagnostic test data.

RATIONAL AND OBJECTIVES: It is common to administer the same diagnostic test more than once to the same set of patients. The purpose of this study was to develop two statistical methods for estimating and comparing correlated receiver operating characteristic (ROC) curves for data derived from repeated diagnostic tests. MATERIAL AND METHODS: Parametric and semiparametric transformation models were developed. These estimation methods were illustrated with data from 72 pigmented lesions suspected of being malignant melanoma. A diagnostic scoring system based on asymmetry, border irregularity, color variation, and diameter was used repeatedly, with or without a dermoscope. Statistical hypothesis tests were conducted to evaluate whether a dermoscope improved the clarity of the lesion features in the scoring system. The resulting ROC curves were constructed, along with characteristics and summary measures. RESULTS: The areas under the ROC curves were 0.885 (parametric method) and 0.893 (semiparametric method) without the dermoscope, and 0.916 (parametric) and 0.912 (semiparametric) with the dermoscope. The statistical hypothesis tests did not yield statistically significant differences between the underlying ROC curves for either estimation method. CONCLUSION: The two transformation models yielded similar results for estimation and comparison of the ROC curves. Although a dermoscope did not add extra information, the scoring system was accurate for diagnosing malignant melanoma.

Diagnosis, Differential↗

Pilot testing the Readiness Estimate and Deployability Index Revised for Air Force Nurses.

The Readiness Estimate and Deployability Index Revised for Air Force Nurses (READI-R-AFN) was derived from modifications of Reineck's Readiness Instrument. Reliability and validity of the READI-R-AFN was estimated on completed questionnaires of 181 active duty Air Force nurses. The READI-R-AFN was evaluated based on item analysis, internal consistency (alpha coefficient, >0.70), confirmatory factor analysis with structural equation modeling, and hypothesis testing. The findings were supported by Flannery's model of stress resistance. There was evidence of reliability and validity of the 83-item READI-R-AFN based on internal consistency (alpha, 0.80-0.96), structural equation modeling, and hypothesis testing. The original hypothesized six dimensions were retained.

Adult↗

The implicit benefit of learning without errors.

Two studies examined whether the number of errors made in learning a motor skill, golf putting, differentially influences the adoption of a selective (explicit) or unselective (implicit) learning mode. Errorful learners were expected to adopt an explicit, hypothesis-testing strategy to correct errors during learning, thereby accruing a pool of verbalizable rules and exhibiting performance breakdown under dual-task conditions, characteristic of a selective mode of learning. Reducing errors during learning was predicted to minimize the involvement of explicit hypothesis testing leading to the adoption of an unselective mode of learning, distinguished by few verbalizable rules and robust performance under secondary task loading. Both studies supported these predictions. The golf putting performance of errorless learners in both studies was unaffected by the imposition of a secondary task load, whereas the performance of errorful learners deteriorated. Reducing errors during learning limited the number of error-correcting hypotheses tested by the learner, thereby reducing the contribution of explicit processing to skill acquisition. It was concluded that the reduction of errors during learning encourages the use of implicit, unselective learning processes, which confer insusceptibility to performance breakdown under distraction.

Adult↗

Wisconsin's environmental public health tracking network: information systems design for childhood cancer surveillance.

In this article we describe the development of an information system for environmental childhood cancer surveillance. The Wisconsin Cancer Registry annually receives more than 25,000 incident case reports. Approximately 269 cases per year involve children. Over time, there has been considerable community interest in understanding the role the environment plays as a cause of these cancer cases. Wisconsin's Public Health Information Network (WI-PHIN) is a robust web portal integrating both Health Alert Network and National Electronic Disease Surveillance System components. WI-PHIN is the information technology platform for all public health surveillance programs. Functions include the secure, automated exchange of cancer case data between public health-based and hospital-based cancer registrars; web-based supplemental data entry for environmental exposure confirmation and hypothesis testing; automated data analysis, visualization, and exposure-outcome record linkage; directories of public health and clinical personnel for role-based access control of sensitive surveillance information; public health information dissemination and alerting; and information technology security and critical infrastructure protection. For hypothesis generation, cancer case data are sent electronically to WI-PHIN and populate the integrated data repository. Environmental data are linked and the exposure-disease relationships are explored using statistical tools for ecologic exposure risk assessment. For hypothesis testing, case-control interviews collect exposure histories, including parental employment and residential histories. This information technology approach can thus serve as the basis for building a comprehensive system to assess environmental cancer etiology.

Automation↗

Statistical analysis of the extreme values of stress time series from the Portevin-Le Châtelier effect.

In an effort to understand the deterministic vs stochastic character of the Portevin-Le Châtelier (PLC) phenomenon, we investigate the structure of the underlying mechanism that generates the stick-slip patterns of stress over time. The stress time series is reduced to a series of successive pairs of minimum and maximum values representing the stick-slip patterns and a statistical analysis by means of hypothesis testing is applied to it. The null hypothesis of least deterministic structure is that the time series of extreme values is a bounded random walk of alternating direction (BRWAD); that is, besides the constraint of succession of minima to maxima bounded at a predefined range there are no other correlations in the data. To implement the test we use surrogate data generated by a model consistent with a BRWAD type process, which also uses the statistics of the original data to best mimic them. The proposed hypothesis testing is found to perform properly on simulated data from stochastic and deterministic systems. For the PLC time series, the null hypothesis is rejected at a high level of confidence giving evidence for some deterministic structure in the succession of the extreme stress values. This result allows for further statistical analysis including also the time aspect of the stick-slip patterns.

Journal Article↗

Some remarks on the indoor radon distribution in a country.

From the point of view of indoor radon activity concentrations, a country is characterized correctly by two parameters (GM and GSD) of a lognormal distribution if and only if hypothesis tests do not reject the distribution of the local radon activity concentrations as a lognormal one. The authors introduce a way to obtain an empirical distribution using a stratum system covering almost the whole country and in each stratum the lognormal model is acceptable according to hypothesis tests. The sample for the analysis is provided by the measurement of radon level in 15,619 Hungarian homes.

Air Pollutants, Radioactive↗