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Test of the decreased responsiveness hypothesis in retinitis pigmentosa.

Retinitis pigmentosa (RP) frequently leads to a decrease in cone system sensitivity. A number of alternative explanations have been proposed for this decrease. Based on the results of a psychophysical technique, the probe-flash paradigm, the authors suggest that a decrease in responsiveness of retinal elements can account for much of this loss. In this paper the decreased responsiveness hypothesis is tested by obtaining data at two levels of steady adaptation. The results of the study indicate that sensitivity loss is greater for the dark adapted than the light adapted state. The data rule out the decreased responsiveness hypothesis coupled with a simple model of adaptation. More complicated adaptation models cannot be excluded. The importance of considering models of adaptation when testing models of disease-related sensitivity loss is underscored.

Adult↗

Spouse support and myocardial infarction patient compliance.

This study investigated the relationship between spouse support and compliance of myocardial infarction patients. Data were obtained from a sample of 60 couples during home interviews with the husband at least three months following his infarction. The hypothesis tested was that there is a positive relationship between spouse support and compliance. Husband's self-reported compliance was obtained for each of 10 aspects of the regimen. A spouse support questionnaire completed by wives estimated the degree to which they engaged in behaviors theorized to be supportive. Demographic and illness variables were also obtained. The hypothesis was not supported. Moreover, compliance was not related to demographic or illness variables, although those subjects still engaged in a cardiac rehabilitation program had significantly higher compliance than those who had stopped attending.

Adult↗

A Bayesian approach to the transmission/disequilibrium test for binary traits.

The transmission/disequilibrium test (TDT) for binary traits is a powerful method for detecting linkage between a marker locus and a trait locus in the presence of allelic association. The TDT uses information on the parent-to-offspring transmission status of the associated allele at the marker locus to assess linkage or association in the presence of the other, using one affected offspring from each set of parents. For testing for linkage in the presence of association, more than one offspring per family can be used. However, without incorporating the correlation structure among offspring, it is not possible to correctly assess the association in the presence of linkage. In this presentation, we propose a Bayesian TDT method as a complementary alternative to the classical approach. In the hypothesis testing setup, given two competing hypotheses, the Bayes factor can be used to weigh the evidence in favor of one of them, thus allowing us to decide between the two hypotheses using established criteria. We compare the proposed Bayesian TDT with a competing frequentist-testing method with respect to power and type I error validity. If we know the mode of inheritance of the disease, then the joint and marginal posterior distributions for the recombination fraction (theta) and disequilibrium coefficient (delta) can be obtained via standard MCMC methods, which lead naturally to Bayesian credible intervals for both parameters.

Alleles↗

Nonparametric permutation tests for functional neuroimaging: a primer with examples.

Requiring only minimal assumptions for validity, nonparametric permutation testing provides a flexible and intuitive methodology for the statistical analysis of data from functional neuroimaging experiments, at some computational expense. Introduced into the functional neuroimaging literature by Holmes et al. ([1996]: J Cereb Blood Flow Metab 16:7-22), the permutation approach readily accounts for the multiple comparisons problem implicit in the standard voxel-by-voxel hypothesis testing framework. When the appropriate assumptions hold, the nonparametric permutation approach gives results similar to those obtained from a comparable Statistical Parametric Mapping approach using a general linear model with multiple comparisons corrections derived from random field theory. For analyses with low degrees of freedom, such as single subject PET/SPECT experiments or multi-subject PET/SPECT or fMRI designs assessed for population effects, the nonparametric approach employing a locally pooled (smoothed) variance estimate can outperform the comparable Statistical Parametric Mapping approach. Thus, these nonparametric techniques can be used to verify the validity of less computationally expensive parametric approaches. Although the theory and relative advantages of permutation approaches have been discussed by various authors, there has been no accessible explication of the method, and no freely distributed software implementing it. Consequently, there have been few practical applications of the technique. This article, and the accompanying MATLAB software, attempts to address these issues. The standard nonparametric randomization and permutation testing ideas are developed at an accessible level, using practical examples from functional neuroimaging, and the extensions for multiple comparisons described. Three worked examples from PET and fMRI are presented, with discussion, and comparisons with standard parametric approaches made where appropriate. Practical considerations are given throughout, and relevant statistical concepts are expounded in appendices.

Brain↗

Biogeographic origins of goannas (Varanidae): a molecular perspective.

This project aims to clarify the phylogenetic relationships among the extant species of Varanus in order to elucidate the origins of Varanidae, using DNA sequences. Results obtained for a minimum of 662 nucleotides of 12S rRNA sequence data from each of 21 extant species of Varanus indicate that the Australian varanids form a single monophyletic clade and also suggest that within the Australian varanids, members of the subgenus Odatria (pygmy monitors) may from a clade separate from those in the subgenus Varanus (large monitors). The Asian species appear to be sister taxa to the Australian species, while the two African species investigated were most divergent, suggesting that the Varanidae are not Gondwanic in origin. Hypothesis testing analyses were performed and involved constraining the 12S sequence data according to previously described topologies and testing the difference using parametric and nonparametric statistics. The phylogeny generated using 12S sequence data was statistically different from previously described morphological trees, while there was some support for topologies based on chomosomal and immunological datasets. Overall, our results suggest that the Australian species may be derived from an Asian source and are, therefore, in agreement with the hypothesis based on the fossil record suggesting that Varanidae may be Asian in origin.

Animals↗

Testing the accelerator hypothesis: body size, beta-cell function, and age at onset of type 1 (autoimmune) diabetes.

OBJECTIVE: The "accelerator hypothesis" predicts that fatness is associated with an earlier age at onset of type 1 diabetes. We tested the hypothesis using data from the SEARCH for Diabetes in Youth study. RESEARCH DESIGN AND METHODS: Subjects were 449 youth aged <20 years at diagnosis who had positive results for diabetes antibodies measured 3-12 months after diagnosis (mean 7.6 months). The relationships between age at diagnosis and fatness were examined using BMI as measured at the SEARCH visit and reported birth weight, both expressed as SD scores (SDSs). RESULTS: Univariately, BMI SDS was not related to age at diagnosis. In multiple linear regression, adjusted for potential confounders, a significant interaction was found between BMI SDS and fasting C-peptide (FCP) on onset age (P < 0.0001). This interaction remained unchanged after additionally controlling for number and titers of diabetes antibodies. An inverse association between BMI and age at diagnosis was present only among subjects with FCP levels below the median (<0.5 ng/ml) (regression coefficient -7.9, P = 0.003). A decrease of 1 SDS in birth weight (639 g) was also associated with an approximately 5-month earlier age at diagnosis (P = 0.008), independent of sex, race/ethnicity, current BMI, FCP, and number of diabetes antibodies. CONCLUSIONS: Increasing BMI is associated with younger age at diagnosis of type 1 diabetes only among those U.S. youth with reduced beta-cell function. The intrauterine environment may also be an important determinant of age at onset of type 1 diabetes.

Adolescent↗

Cerebellar limb ataxia: abnormal control of self-generated and external forces.

Our work has been focused on understanding the mechanism of movement abnormalities associated with cerebellar ataxia. The hypothesis tested is that the cerebellum acts to modulate muscle activity across multiple joints in anticipation of the mechanical interaction torques generated by one's own movement and by external forces. Individuals with cerebellar damage were studied in two sets of experiments. In the first experiment, we studied how cerebellar subjects' movement changed when interaction torques were present, and then reduced via mechanically constraining movement to a single joint. Consistent with the hypothesis, it was found that cerebellar endpoint errors were greatly improved when interaction torques were reduced. We also found that cerebellar deficits in the unconstrained condition were not explained by a general failure of torque timing or magnitude scaling. This supports the idea that the cerebellum plays a specific and important role in adjusting for the dynamics of one's own body movements. In the second experiment, we studied how well cerebellar subjects could adapt arm movements to external loads. Cerebellar subjects were tested as they adapted a catching movement to balls of different weight. It was found that they were slow or unable to adapt through practice and did not show evidence of storage of the adaptation. This suggests that the cerebellum is needed for rapid adaptations for loads in movement. Given these findings, we think that the cerebellum is important in anticipating and adjusting for the mechanical demands of movement though trial-and-error practice.

Analysis of Variance↗

Microcomputer programs for complex epidemiologic procedures. II. Test for equality and trend of adjusted rates.

The microcomputer program presented in Part I of this series (M. H. Dong, Comput. Biomed. Res. 22, 349 (1989)) is useful for computing adjusted excess rates. That program, however, does not provide a means for a quantitative analysis of the adjusted rates computed for the categories of a risk factor. At times it is crucial for us to determine whether after adjustment a factor exerts a dose-response effect that is statistically significant. Recently a hypothesis test for analyzing such an effect has been reported. The test is based on score statistics obtained directly from a product model assumed for the excess rate. The objective of this second part is to continue to make available a microcomputer program that has been written to implement the computation of these score statistics, which likewise entails a complex and lengthy iterative procedure. In this communication the test is described and the application of the microcomputer program is illustrated.

Biometry↗

Organisms in nature as a central focus for biology.

Theories summarize science, tell us what to measure when we test hypotheses, and help us study nature better. Nevertheless, organisms themselves embody genetics, development, morphology, physiology and behavior, and they are the units of populations, communities and ecosystems. Biologists seek to understand organisms, their diversification and environmental relationships--not theories and experiments per se--and discoveries of new organisms and new facts about organisms reset the research cycles of hypothesis testing that underlie conceptually progressive science. I argue here that recent disagreements about the fate of natural history are thus more apparent than real and should not distract us from addressing important issues. The conservation of biodiversity requires factual knowledge of particular organisms, yet we know little or nothing about most species, and organismal diversity is often poorly represented in biological education. Accordingly, I urge those who are especially concerned with teaching and conservation to seek increased financial and curricular support for descriptive natural history, which is so fundamental to many of the applied facets of biology.

Journal Article↗

Quantitative electroencephalography (QEEG) and neuropsychological syndrome analysis.

The ideographic, syndrome analysis and the nomothetic, standardized test battery approaches to neuropsychological assessment are compared and contrasted within the context of advances in noninvasive technology readily available for use within the examiner's office. By demonstrating the relative strengths and benefits of syndrome analysis, it is suggested that this approach provides a thorough and efficient method of neuropsychological assessment. Subsequently, the utility of an a priori hypothesis testing process approach as a critical technique in syndrome analysis will be supported. It will be proposed that QEEG procedures provide a useful method for further substantiating conclusions generated from a syndrome analysis approach to neuropsychological assessment. Two cases are described demonstrating the utility and flexibility of the QEEG as a confirmatory test of localization following syndrome analysis. In summary, the contributions that neuropsychologists make to the understanding of brain-behavior relationships may be strengthened by combining neuropsychological and neurophysiological assessment methods.

Adult↗

Selecting a contingency table in a population-based association study: allele frequency or positivity?

In population-based association studies, the significance of the association between a candidate gene and a disease is usually examined by a simple chi 2 test. Such studies require a 2 x 2 contingency table made up of either allele frequencies or positivities in affected and control groups. In order to investigate the influence of each 2 x 2 table on the power of the chi 2 test, P values were calculated for two penetrance models (multiplicative and additive). When the value of penetrance was small and not markedly different among genotypes, a large difference in the power of the chi 2 test was observed between the two tables. In a multiplicative model, the allele frequency table was superior to the positivity table for detecting significance. In contrast, in an additive model, the positivity table was most suitable. Selecting a contingency table was especially important for detecting true association, when the required significance level was corrected to avoid the problem of multiple hypothesis testing. The chi 2 test, therefore, should be performed for both tables to identify a susceptible gene with a low penetrance, even when no significant difference is observed in one table.

Alleles↗

Modeling breastmilk infectivity in HIV-1 infected mothers.

Estimation of breastmilk infectivity in HIV-1 infected mothers is difficult because transmission can occur while the fetus is in utero, during delivery, or through breastfeeding. Since transmission can only be detected through periodic testing, however, it may be impossible to determine the actual mode of transmission in any individual child. In this article we develop a model to estimate breastmilk infectivity, along with the probabilities of in-utero and intrapartum transmission. In addition, the model allows separate estimation of early and late breastmilk infectivity, and individual variation in maternal infectivity. Methods for hypothesis testing of binary risk factors and a method for assessing goodness of fit are also described. Data from a randomized trial of breastfeeding versus formula feeding among HIV-1 infected mothers in Nairobi, Kenya, are used to illustrate the methods.

Adult↗

The optimal discovery procedure for large-scale significance testing, with applications to comparative microarray experiments.

As much of the focus of genetics and molecular biology has shifted toward the systems level, it has become increasingly important to accurately extract biologically relevant signal from thousands of related measurements. The common property among these high-dimensional biological studies is that the measured features have a rich and largely unknown underlying structure. One example of much recent interest is identifying differentially expressed genes in comparative microarray experiments. We propose a new approach aimed at optimally performing many hypothesis tests in a high-dimensional study. This approach estimates the optimal discovery procedure (ODP), which has recently been introduced and theoretically shown to optimally perform multiple significance tests. Whereas existing procedures essentially use data from only one feature at a time, the ODP approach uses the relevant information from the entire data set when testing each feature. In particular, we propose a generally applicable estimate of the ODP for identifying differentially expressed genes in microarray experiments. This microarray method consistently shows favorable performance over five highly used existing methods. For example, in testing for differential expression between two breast cancer tumor types, the ODP provides increases from 72% to 185% in the number of genes called significant at a false discovery rate of 3%. Our proposed microarray method is freely available to academic users in the open-source, point-and-click EDGE software package.

Apoptosis Regulatory Proteins↗

Mixed-model segregation analysis of schizophrenia in the Lindelius Swedish pedigrees.

To test if familial transmission of schizophrenia is consistent with a model of monogenic inheritance with a multifactorial background, a mixed-model segregation analysis was applied to Swedish pedigrees consisting of 270 probands in 263 nuclear families. Results of the best-fitting mixed-model solutions are consistent with multifactorial transmission and no major gene. However, numerical instabilities prevented formal hypothesis testing, so an irrefutable genetic mechanism remains unidentified. Alternative research strategies that exploit recent advances in molecular genetics are discussed.

Female↗

Stability of the Hungarian National BCG Reference Preparations. Trend of viability during 4-7 years storage at +4 degrees C.

The stability of the viability of the Hungarian BCG Reference Preparations (Vaccine Bch. Nos: 265, 456, 505) was tested according to the recommendation of the World Health Organization. The BCG viable units of the vaccines were estimated from the colony counts determined on solid medium. The control data of the BCG viable units expressing the stability in 10(6)/ml values were analysed up to 7 years in a three-step statistical model applying unbiased parameter estimates, valid hypothesis test and multiple comparison. The presented model verifying the stability of the reference preparations ensures the reliability of the assays to accept or reject the viability at controlling routine BCG vaccines in comparison with the reference preparations.

BCG Vaccine↗

Molecular phylogeny of the marmots (Rodentia: Sciuridae): tests of evolutionary and biogeographic hypotheses.

There are 14 species of marmots distributed across the Holarctic, and despite extensive systematic study, their phylogenetic relationships remain largely unresolved. In particular, comprehensive studies have been lacking. A well-supported phylogeny is needed to place the numerous ecological and behavioral studies on marmots in an evolutionary context. To address this situation, we obtained complete cytochrome (cyt) b sequences for 13 of the species and a partial sequence for the 14th. We applied a statistical approach to both phylogeny estimation and hypothesis testing, using parsimony and maximum likelihood-based methods. We conducted statistical tests on a suite of previously proposed hypotheses of phylogenetic relationships and biogeographic histories. The cyt b data strongly support the monophyly of Marmota and a western montane clade in the Nearctic. Although some other scenarios cannot be rejected, the results are consistent with an initial diversification in North America, followed by an invasion and subsequent rapid diversification in the Palearctic. These analyses reject the two major competing hypotheses of M. broweri's phylogenetic relationships--namely, that it is the sister species to M. camtschatica of eastern Siberia, and that it is related closely to M. caligata of the Nearctic. The Alaskan distribution of M. broweri is best explained as a reinvasion from the Palearctic, but a Nearctic origin can not be rejected. Several other conventionally recognized species groups can also be rejected. Social evolution has been homoplastic, with large colonial systems evolving in two groups convergently. The cyt b data do not provide unambiguous resolution of several basal nodes in the Palearctic radiation, leaving some aspects of pelage and karyotypic evolution equivocal.

Animals↗

Testing a molecular clock without an outgroup: derivations of induced priors on branch-length restrictions in a Bayesian framework.

We propose a Bayesian method for testing molecular clock hypotheses for use with aligned sequence data from multiple taxa. Our method utilizes a nonreversible nucleotide substitution model to avoid the necessity of specifying either a known tree relating the taxa or an outgroup for rooting the tree. We employ reversible jump Markov chain Monte Carlo to sample from the posterior distribution of the phylogenetic model parameters and conduct hypothesis testing using Bayes factors, the ratio of the posterior to prior odds of competing models. Here, the Bayes factors reflect the relative support of the sequence data for equal rates of evolutionary change between taxa versus unequal rates, averaged over all possible phylogenetic parameters, including the tree and root position. As the molecular clock model is a restriction of the more general unequal rates model, we use the Savage-Dickey ratio to estimate the Bayes factors. The Savage-Dickey ratio provides a convenient approach to calculating Bayes factors in favor of sharp hypotheses. Critical to calculating the Savage-Dickey ratio is a determination of the prior induced on the modeling restrictions. We demonstrate our method on a well-studied mtDNA sequence data set consisting of nine primates. We find strong support against a global molecular clock, but do find support for a local clock among the anthropoids. We provide mathematical derivations of the induced priors on branch length restrictions assuming equally likely trees. These derivations also have more general applicability to the examination of prior assumptions in Bayesian phylogenetics.

Animals↗

Above-ground space sequestration determines competitive success in juvenile beech and spruce trees.

A 2-yr phytotron study was conducted to investigate the intra- and inter-specific competitive behaviour of juvenile beech (Fagus sylvatica) and spruce (Picea abies). Competitiveness was analysed by quantifying the resource budgets that occur along structures and within occupied space of relevance for competitive interaction. Ambient and elevated CO(2) and ozone (O(3)) regimes were applied throughout two growing seasons as stressors for provoking changes in resource budgets, growth and allocation to facilitate the competition analysis. The hypothesis tested was that the ability to sequester space at low structural cost will determine the competitive success. Spruce was a stronger competitor than beech, as displayed by its higher above-ground biomass increments in mixed culture compared with monoculture. A crucial factor in the competitive success of spruce was its ability to enlarge crown volume at low structural costs, supporting the hypothesis. Interspecific competition with spruce resulted in a size-independent readjustment of above-ground allocation in beech (reduced leaf : shoot biomass ratio). The efficient use of resources for above-ground space sequestration proved to be a parameter that quantitatively reflects competitiveness.

Carbon↗