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PubMed2006

Joint National Cancer Institute-Food and Drug Administration workshop on research strategies, study designs, and statistical approaches to biomarker validation for cancer diagnosis and detection.

Cancer remains the second leading cause of death in the United States, in spite of tremendous advances made in therapeutic and diagnostic strategies. Successful cancer treatment depends on improved methods to detect cancers at early stages when they can be treated more effectively. Biomarkers for early detection of cancer enable screening of asymptomatic populations and thus play a critical role in cancer diagnosis. However, the approaches for validating biomarkers have yet to be addressed clearly. In an effort to delineate the ambiguities related to biomarker validation and related statistical considerations, the National Cancer Institute, in collaboration with the Food and Drug Administration, conducted a workshop in July 2004 entitled "Research Strategies, Study Designs, and Statistical Approaches to Biomarker Validation for Cancer Diagnosis and Detection." The main objective of this workshop was to review basic considerations underpinning the study designs, statistical methodologies, and novel approaches necessary to rapidly advance the clinical application of cancer biomarkers. The current commentary describes various aspects of statistical considerations and study designs for cancer biomarker validation discussed in this workshop.

Biomarkers, Tumor↗

PubMed1984

Computer interpretation of pediatric orthogonal electrocardiograms: statistical and deterministic classification methods.

Statistical multivariate and conventional deterministic methods of computerized interpretation of the electrocardiogram (ECG) were compared in the analysis of 1711 pediatric orthogonal ECGs validated by nonelectrocardiographic criteria on the basis of clinical and anatomic diagnoses. Among 642 children catheterized for the evaluation of congenital heart disease, there were 140 patients with left ventricular hypertrophy, 299 with right ventricular hypertrophy, and 203 with biventricular hypertrophy. A group of 1069 obviously healthy school children was studied as a control. The overall accuracy of multigroup ECG diagnosis was 85% and 79% for the statistical and deterministic methods, respectively. The diagnostic performances of both methods expressed in terms of sensitivity and predictive value were the highest for normal children and those with right ventricular hypertrophy and lowest for children with biventricular hypertrophy. The statistical method was more sensitive in the diagnosis of left ventricular hypertrophy (74% vs 64%), right ventricular hypertrophy (86% vs 83%), and biventricular hypertrophy (62% vs 50%). Mutual agreement for a correct diagnosis by the two methods was 83% for normal children and 82% for those with right ventricular hypertrophy but only 61% for children with left ventricular hypertrophy and 39% for those with biventricular hypertrophy. In conclusion, better classification results are obtained with statistical multivariate techniques as compared with conventional deterministic analysis, but both methods of ECG interpretation are complementary and their combination in the same electrocardiographic computer program can improve diagnostic accuracy.

Adolescent↗

PubMed2005

A hierarchical Bayesian model for learning nonlinear statistical regularities in nonstationary natural signals.

Capturing statistical regularities in complex, high-dimensional data is an important problem in machine learning and signal processing. Models such as principal component analysis (PCA) and independent component analysis (ICA) make few assumptions about the structure in the data and have good scaling properties, but they are limited to representing linear statistical regularities and assume that the distribution of the data is stationary. For many natural, complex signals, the latent variables often exhibit residual dependencies as well as nonstationary statistics. Here we present a hierarchical Bayesian model that is able to capture higher-order nonlinear structure and represent nonstationary data distributions. The model is a generalization of ICA in which the basis function coefficients are no longer assumed to be independent; instead, the dependencies in their magnitudes are captured by a set of density components. Each density component describes a common pattern of deviation from the marginal density of the pattern ensemble; in different combinations, they can describe nonstationary distributions. Adapting the model to image or audio data yields a nonlinear, distributed code for higher-order statistical regularities that reflect more abstract, invariant properties of the signal.

Bayes Theorem↗

PubMed2002

Ecological statistics of Gestalt laws for the perceptual organization of contours.

Although numerous studies have measured the strength of visual grouping cues for controlled psychophysical stimuli, little is known about the statistical utility of these various cues for natural images. In this study, we conducted experiments in which human participants trace perceived contours in natural images. These contours are automatically mapped to sequences of discrete tangent elements detected in the image. By examining relational properties between pairs of successive tangents on these traced curves, and between randomly selected pairs of tangents, we are able to estimate the likelihood distributions required to construct an optimal Bayesian model for contour grouping. We employed this novel methodology to investigate the inferential power of three classical Gestalt cues for contour grouping: proximity, good continuation, and luminance similarity. The study yielded a number of important results: (1) these cues, when appropriately defined, are approximately uncorrelated, suggesting a simple factorial model for statistical inference; (2) moderate image-to-image variation of the statistics indicates the utility of general probabilistic models for perceptual organization; (3) these cues differ greatly in their inferential power, proximity being by far the most powerful; and (4) statistical modeling of the proximity cue indicates a scale-invariant power law in close agreement with prior psychophysics.

Form Perception↗

PubMed2004

Does human color constancy incorporate the statistical regularity of natural daylight?

The chromaticities of natural daylights cluster around the blackbody locus. We investigated whether the mechanisms that mediate human color constancy embody this statistical regularity of the natural environment, so that constancy is best when the illuminant change is one likely to occur. Observers viewed scenes displayed on a CRT-based stereoscope and adjusted a test patch embedded in the scene until it appeared achromatic. Scenes were rendered using physics-based graphics software (RADIANCE) coupled with custom extensions that ensured colorimetric accuracy. Across conditions, both the simulated illuminant and the simulated reflectance of scene objects were varied. Achromatic settings from paired conditions were used to compute a constancy index (CI) that characterizes the stability of object appearance across the two illuminants of the pair. Constancy indices were measured for four illuminant changes from a Neutral illuminant (CIE D65). Two of these changes (Blue and Yellow) were consistent with the statistics of daylight, whereas two (Green and Red) were not. The results indicate that constancy was least across the Red change, as one would expect for the statistics of natural daylight. Constancy for the Green direction, however, exceeded that for the Yellow illuminant change and was comparable to that for the Blue. This result is difficult to reconcile with the hypothesis that mechanisms of human constancy incorporate the statistics of daylights. Some possible reasons for the discrepancy are discussed.

Adult↗

PubMed2004

PyEvolve: a toolkit for statistical modelling of molecular evolution.

BACKGROUND: Examining the distribution of variation has proven an extremely profitable technique in the effort to identify sequences of biological significance. Most approaches in the field, however, evaluate only the conserved portions of sequences - ignoring the biological significance of sequence differences. A suite of sophisticated likelihood based statistical models from the field of molecular evolution provides the basis for extracting the information from the full distribution of sequence variation. The number of different problems to which phylogeny-based maximum likelihood calculations can be applied is extensive. Available software packages that can perform likelihood calculations suffer from a lack of flexibility and scalability, or employ error-prone approaches to model parameterisation. RESULTS: Here we describe the implementation of PyEvolve, a toolkit for the application of existing, and development of new, statistical methods for molecular evolution. We present the object architecture and design schema of PyEvolve, which includes an adaptable multi-level parallelisation schema. The approach for defining new methods is illustrated by implementing a novel dinucleotide model of substitution that includes a parameter for mutation of methylated CpG's, which required 8 lines of standard Python code to define. Benchmarking was performed using either a dinucleotide or codon substitution model applied to an alignment of BRCA1 sequences from 20 mammals, or a 10 species subset. Up to five-fold parallel performance gains over serial were recorded. Compared to leading alternative software, PyEvolve exhibited significantly better real world performance for parameter rich models with a large data set, reducing the time required for optimisation from approximately 10 days to approximately 6 hours. CONCLUSION: PyEvolve provides flexible functionality that can be used either for statistical modelling of molecular evolution, or the development of new methods in the field. The toolkit can be used interactively or by writing and executing scripts. The toolkit uses efficient processes for specifying the parameterisation of statistical models, and implements numerous optimisations that make highly parameter rich likelihood functions solvable within hours on multi-cpu hardware. PyEvolve can be readily adapted in response to changing computational demands and hardware configurations to maximise performance. PyEvolve is released under the GPL and can be downloaded from http://cbis.anu.edu.au/software.

Animals↗

PubMed2006

A method for computing the overall statistical significance of a treatment effect among a group of genes.

BACKGROUND: In studies that use DNA arrays to assess changes in gene expression, our goal is to evaluate the statistical significance of treatments on sets of genes. Genes can be grouped by a molecular function, a biological process, or a cellular component, e.g., gene ontology (GO) terms. The meaning of an affected GO group is often clearer than interpretations arising from a list of the statistically significant genes. RESULTS: Computer simulations demonstrated that correlations among genes invalidate many statistical methods that are commonly used to assign significance to GO terms. Ignoring these correlations overstates the statistical significance. Meta-analysis methods for combining p-values were modified to adjust for correlation. One of these methods is elaborated in the context of a comparison between two treatments. The form of the correlation adjustment depends upon the alternative hypothesis. CONCLUSION: Reliable corrections for the effect of correlations among genes on the significance level of a GO term can be constructed for an alternative hypothesis where all transcripts in the GO term increase (decrease) in response to treatment. For general alternatives, which allow some transcripts to increase and others to decrease, the bias of naïve significance calculations can be greatly decreased although not eliminated.

Biometry↗

PubMed2006

Investigation of geo-spatial hotspots for the occurrence of tuberculosis in Almora district, India, using GIS and spatial scan statistic.

BACKGROUND: The World Health Organization has declared tuberculosis a global emergency in 1993. It has been estimated that one third of the world population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. The emergence of TB/HIV co-infection poses an additional challenge for the control of tuberculosis throughout the world. The World Health Organization is supporting many developing countries to eradicate tuberculosis. It is an agony that one fifth of the tuberculosis patients worldwide are in India. The eradication of tuberculosis is the greatest public health challenge for this developing country. The aim of the present population based study on Mycobacterium tuberculosis is to test a large set of tuberculosis cases for the presence of statistically significant geographical clusters. A spatial scan statistic is used to identify purely spatial and space-time clusters of tuberculosis. RESULTS: Significant (p < 0.05 for primary clusters and p < 0.1 for secondary clusters) high rate spatial and space-time clusters were identified in three areas of the district. CONCLUSION: There is sufficient evidence about the existence of statistically significant tuberculosis clusters in Almora district of Uttaranchal, India. The spatial scan statistics methodology used in this study has a potential use in surveillance of tuberculosis for detecting the true clusters of the disease.

Cluster Analysis↗

PubMed1992

Statistical power and the Rorschach: 1975-1991.

The Rorschach Inkblot Test has been the source of long-standing controversies as to its nature and its psychometric properties. Consistent with behavioral science research in general, the concept of statistical power has been entirely ignored by Rorschach researchers. The concept of power is introduced and discussed, and a power survey of the Rorschach literature published between 1975 and 1991 in the Journal of Personality Assessment, Journal of Consulting and Clinical Psychology, Journal of Abnormal Psychology, Journal of Clinical Psychology, Journal of Personality, Psychological Bulletin, American Journal of Psychiatry, and Journal of Personality and Social Psychology was undertaken. Power was calculated for 2,300 statistical tests in 158 journal articles. Power to detect small, medium, and large effect sizes was .13, .56, and .85, respectively. Similar to the findings in other power surveys conducted on behavioral science research, we concluded that Rorschach research is underpowered to detect the differences under investigation. This undoubtedly contributes to the inconsistency of research findings which has been a source of controversy and criticism over the decades. It appears that research conducted according to the Comprehensive System for the Rorschach is more powerful. Recommendations are offered for improving power and strengthening the design sensitivity of Rorschach research, including increasing sample sizes, use of parametric statistics, reduction of error variance, more accurate reporting of findings, and editorial policies reflecting concern about the magnitude of relationships beyond an exclusive focus on levels of statistical significance.

Journal Article↗

PubMed2003

U.S. Government statistics on the World Wide Web.

The U.S. Government produces and provides massive amounts of statistics. Government initiatives have made much of the statistical information emanating from its various federal agencies, departments, and offices digitally accessible on the Internet. Assisting users in locating specific statistics can be one of the most challenging duties librarians have. This article provides a guide to government sources that will help librarians locate health statistics for researchers, health professionals, health consumers, and others. Some selected sites may be an endpoint of the search, and others may offer a solid beginning to a complex answer. Links are also provided to gateway Web sites, where a search strategy utilizing some of the tips discovered while compiling this list can be used to help promote successful outcomes. As always, it is recommended to use evaluative criteria to assess information quality as well as integrity of the data.

Humans↗

PubMed2004

On the chi-square approximation to the exact distribution of goodness-of-fit statistics in multinomial models with composite hypotheses.

Multinomial models are increasingly being used in psychology, and this use always requires estimating model parameters and testing goodness of fit with a composite null hypothesis. Goodness of fit is customarily tested with recourse to the asymptotic approximation to the distribution of the statistics. An assessment of the quality of this approximation requires a comparison with the exact distribution, but how to compute this exact distribution when parameters are estimated from the data appears never to have been defined precisely. The main goal of this paper is to compare two different approaches to defining this exact distribution. One of the approaches uses the marginal distribution and is, therefore, independent of the data; the other approach uses the conditional distribution of the statistics given the estimated parameters and, therefore, is data-dependent. We carried out a thorough study involving various parameter estimation methods and goodness-of-fit statistics, all of them members of the general class of power-divergence measures. Included in the study were multinomial models with three to five cells and up to three parameters. Our results indicate that the asymptotic distribution is rarely a good approximation to the exact marginal distribution of the statistics, whereas it is a good approximation to the exact conditional distribution only when the vector of expected frequencies is interior to the sample space of the multinomial distribution.

Binomial Distribution↗

PubMed2006

Adaptive detection mechanisms in globally statistically nonstationary-oriented noise.

Studies have shown that human observers can adapt their detection strategies on the basis of the statistical properties of noisy backgrounds. One common property of such studies is that the backgrounds studied are (or are assumed to be) statistically stationary. Less is known about how humans detect signals in the more complex setting of nonstationary backgrounds. We investigated detection performance in the presence of a globally nonstationary oriented noise background. We controlled for noise-correlation effects by considering a stationary background with a power spectrum matched to the average spectrum of the nonstationary process. Performance of a nonadaptive linear filter that was unable to make use of differences in local statistics yielded constant performance in both the stationary and the nonstationary backgrounds. In contrast, performance of an ideal observer that uses local noise statistics yielded substantially higher (140%) detectability with the nonstationary backgrounds than the stationary ones. Human observers showed significantly higher (33%) detection performance in the nonstationary backgrounds, suggesting that they can adapt their detection mechanisms to the local orientation properties.

Journal Article↗

PubMed2006

Assessment of the statistics of the Strehl ratio: predictions of central limit theorem analysis.

For a beam propagating through turbulence, the statistics of the Strehl ratio are determined by recognizing that the real and imaginary parts of the on-axis far-field pattern can be represented as the sum of many contributions from the aperture. With this in mind, the central limit theorem (CLT) can be used to develop the statistics of the real and imaginary parts of the optical field, which through the appropriate mathematical manipulations as described here can then be used to develop the probability distribution of the far-field irradiance. The results obtained in this way (which we call the CLT theory or analysis) provide an analytic expression that agrees with the results of detailed wave-optics simulations. This provides an approach by which the statistics of the Strehl ratio can be rapidly determined. A key feature of this work is that the analytic results depend on the values of a few relevant turbulence parameters that include r0,fG, and sigma2(l). Therefore, a measurement of these parameters at various sites of interest allows us to rapidly assess the detailed nature of the statistical fluctuations of the far-field irradiance that will be experienced at these locations.

Journal Article↗

PubMed2004

ISSR-based clustering of cultivated flax germplasm is statistically correlated to thousand seed mass.

Inter-simple sequence repeat (ISSR)-polymerase chain reaction (PCR) polymorphism was generated to provide useful markers for assessment of genetic diversity within flax germplasm collections. We used nine previously selected anchored ISSR primers for fingerprinting of 53 flax cultivars or genotypes and obtained 62 scorable bands, from which 45 bands (72.6%) were polymorphic. An efficient separation of 53 flax accessions into four groups and eight subgroups was achieved using unweighted pair group method with arithmetic means (UPGMA) clustering procedure based on genetic similarity expressed by the Jaccard similarity coefficient (JSC). Clustering procedure within both groups and subgroups successfully produced smaller homogenous clusters, whereas clustering between the main four groups of flax accessions displayed only a continuous decrease of similarity with a weak clustering effect. Statistical significance of grouping and subgrouping within a cluster dendrogram was estimated by calculation of the error flag and cophenetic correlation parameter for each branch. Principal coordinates (PCO) analysis mostly confirmed the separation by UPGMA clustering. We observed a statistically significant correlation between the number of total vs polymorphic bands in ISSR patterns. A one-way analysis of variance (ANOVA) test confirmed statistically significant differences in the average thousand seed mass (TSM) between eight subclusters of flax accessions from an ISSR-PCR-based UPGMA dendrogram, which indicate statistical correlation between flax ISSR polymorphism (the structure of ISSR-based clustering) TSM.

Cluster Analysis↗

PubMed1974

Concerning the statistical procedures enumerated by Gentile et al.: another perspective.

The thrust of this paper is to bring to the attention of operant researchers statistical procedures that are appropriate for correlated data. In addition to specifying these statistical procedures consideration is given to the question of using individual comparison statistics rather than omnibus F tests. Specifically, it is recommended that a more powerful test of the experimental hypotheses can be obtained by performing Bonferroni t statistics rather than analysis of variance F tests.

Journal Article↗

PubMed1998

Evaluating cluster alarms: a space-time scan statistic and brain cancer in Los Alamos, New Mexico.

OBJECTIVES: This article presents a space-time scan statistic, useful for evaluating space-time cluster alarms, and illustrates the method on a recent brain cancer cluster alarms in Los Alamos, NM. METHODS: The space-time scan statistic accounts for the preselection bias and multiple testing inherent in a cluster alarm. Confounders and time trends can be adjusted for. RESULTS: The observed excess of brain cancer in Los Alamos was not statistically significant. CONCLUSIONS: The space-time scan statistic is useful as a screening tool for evaluating which cluster alarms merit further investigation and which clusters are probably chance occurrences.

Brain Neoplasms↗

PubMed2004

Statistical significance threshold criteria for analysis of microarray gene expression data.

The methodological advancement in microarray data analysis on the basis of false discovery rate (FDR) control, such as the q-value plots, allows the investigator to examine the FDR from several perspectives. However, when FDR control at the "customary" levels 0.01, 0.05, or 0.1 does not provide fruitful findings, there is little guidance for making the trade off between the significance threshold and the FDR level by sound statistical or biological considerations. Thus, meaningful statistical significance criteria that complement the existing FDR methods for large-scale multiple tests are desirable. Three statistical significance criteria, the profile information criterion, the total error proportion, and the guide-gene driven selection, are developed in this research. The first two are general significance threshold criteria for large-scale multiple tests; the profile information criterion is related to the recent theoretical studies of the connection between FDR control and minimax estimation, and the total error proportion is closely related to the asymptotic properties of FDR control in terms of the total error risk. The guide-gene driven selection is an approach to combining statistical significance and the existing biological knowledge of the study at hand. Error properties of these criteria are investigated theoretically and by simulation. The proposed methods are illustrated and compared using an example of genomic screening for novel Arf gene targets. Operating characteristics of q-value and the proposed significance threshold criteria are investigated and compared in a simulation study that employs a model mimicking a gene regulatory pathway. A guideline for using these criteria is provided. Splus/R code is available from the corresponding author upon request.

Journal Article↗

PubMed1982

The depth of the lingual fossa in permanent maxillary incisors of East Greenland Eskimos. I. Statistical distribution and fluctuating dental asymmetry.

Maxillary incisor lingual fossa depth was measured in East Greenland Eskimos. It was shown that the statistical distribution for the trait may vary from population to population, from tooth type to tooth type and between the sexes. Examination of statistical distribution should be a part of studies giving detailed statistical analysis of trait. The statistical distribution is probably compatible with a hypothesis of polygenic inheritance. The correlations across the midline were higher for I1 than for I2, and I1 to I2 correlations were lower than across midline correlations for both I1 and I2. It was shown that the degree of fluctuating asymmetry may vary from one dental trait to another. For lingual fossa depth no population variation in fluctuating asymmetry could be demonstrated, in spite of obvious differences in environmental conditions for the populations compared. No sex differences in fluctuating asymmetry were found.

Female↗