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PubMed2002

The P1 plasmid in action: time-lapse photomicroscopy reveals some unexpected aspects of plasmid partition.

The prophage of bacteriophage P1 is a low copy number plasmid in Escherichia coli and is segregated to daughter cells by an active partition system. The dynamics of the partition process have now been successfully followed by time-lapse photomicroscopy. The process appears to be fundamentally different from that previously inferred from statistical analysis of fixed cells. A focus containing several plasmid copies is captured at the cell center. Immediately before cell division, the copies eject bi-directionally along the long axis of the cell. Cell division traps one or more plasmid copies in each daughter cell. These copies are free to move, associate, and disassociate. Later, they are captured to the new cell center to re-start the cycle. Studies with mutants suggest that the ability to segregate accurately at a very late stage in the cell cycle is dependent on a novel ability of the plasmid to control cell division. Should segregation be delayed, cell division is also delayed until segregation is successfully completed.

Bacteriophage P1↗
PubMed1998

Methodological problems in the study of sexuality and the menopause.

Few studies have considered the effects of menopause on sexuality. Large studies with representative samples using postal questionnaires have included only a few sexual variables. More comprehensive studies have tended to employ non-representative samples that raise questions concerning generalization of findings. Major problems in existing research have been: failure to collect data on variables known to affect sexuality and/or failure to utilize such data in analyses, studying only one, sometimes two, menopausal phases, gathering retrospective data, asking subjects directly about the relationship of menopause to sexuality, gathering too few sexual data, not providing a complete description of sexual measures, neglecting to report methodology clearly and completely, failing to evaluate data statistically, and inferring causation from correlations. Evidence from existing research suggests a decline in sexual interest, frequency of sexual intercourse, and vaginal lubrication in association with the menopause. Findings for variables such as capacity for orgasm, satisfaction with sex partner, and vaginal pain or discomfort are few and mixed.

Female↗
PubMed2003

Lifecycle closure, lineage sorting, and hybridization revealed in a phylogenetic analysis of European oak gallwasps (Hymenoptera: Cynipidae: Cynipini) using mitochondrial sequence data.

Oak gallwasps are cyclically parthenogenetic insects that induce a wide diversity of highly complex species- and generation-specific galls on oaks and other Fagaceae. Phylogenetic relationships within oak gallwasps remain to be established, while sexual and parthenogenetic generations of many species remain unpaired. Previous work on oak gallwasps has revealed substantial intra-specific variation, particularly between regions known to represent discrete Pleistocene glacial refuges. Here we use statistical phylogenetic inference methods on sequence data for a fragment of the mitochondrial cytochrome b gene to reconstruct the relationships among 62 oak gallwasp species. For 16 of these we also include 23 additional cytochrome b haplotype sequences from different Pleistocene refuge areas to test the effect of intra-specific variation on inter-specific phylogeny reconstruction. The reconstructed phylogenies show good intra-generic resolution and identify several conserved clades, but fail to reconstruct either very recent or very ancient divergences. Nine of the 16 species represented by multiple haplotypes are not monophyletic. The apparent discordance between the recovered gene tree and the current taxonomic classification can be explained through: (a) collapsing of some species currently known only from either a sexual or a parthenogenetic generation into a single cyclically parthenogenetic entity; (b) sorting of ancestral polymorphism in diverging lineages, and (c) horizontal transfer of haplotypes, perhaps due to hybridization within glacial refuges. Our conclusions emphasise the need for careful intra-specific sampling when reconstructing phylogenies for radiations of closely related species and imply that for certain taxonomic groups full phylogenetic resolution (using molecular markers) may not be attainable.

Animals↗
PubMed2002

The P1 plasmid is segregated to daughter cells by a 'capture and ejection' mechanism coordinated with Escherichia coli cell division.

The fate of the P1 plasmid of Escherichia coli was followed by time-lapse photomicroscopy. A GFP-ParB fusion marked the plasmid during partition (segregation) to daughter cells at slow growth rate. The process differs from that previously inferred from statistical analysis of fixed cells. A focus of plasmid copies is captured at the cell centre. Immediately before cell division, the copies eject bidirectionally along the long axis of the cell. Cell division traps one or more plasmid copies in each daughter. They are not directed to a prescribed position but are free to move, associate and disassociate. Later, they are captured to the new cell centre to restart the cycle. A null P1 par mutant associates to form a focus, but it is neither captured nor ejected. A dominant negative ParB protein forms a plasmid focus that attaches to the cell centre but never ejects. It remains captive at the centre and blocks host cell division. The cells elongate. Eventually the intact focus is pushed to one side and the cells divide simultaneously in several places at the same time. This suggests that the wild-type plasmid imposes a regulatory node on the host cell cycle, preventing cell division until its own segregation is completed.

Bacterial Proteins↗
PubMed1999

Neutral evolution of mutational robustness.

We introduce and analyze a general model of a population evolving over a network of selectively neutral genotypes. We show that the population's limit distribution on the neutral network is solely determined by the network topology and given by the principal eigenvector of the network's adjacency matrix. Moreover, the average number of neutral mutant neighbors per individual is given by the matrix spectral radius. These results quantify the extent to which populations evolve mutational robustness-the insensitivity of the phenotype to mutations-and thus reduce genetic load. Because the average neutrality is independent of evolutionary parameters-such as mutation rate, population size, and selective advantage-one can infer global statistics of neutral network topology by using simple population data available from in vitro or in vivo evolution. Populations evolving on neutral networks of RNA secondary structures show excellent agreement with our theoretical predictions.

Evolution, Molecular↗
PubMed2025

aPhyloGeo: a Python application for correlating genetic and climatic conditions.

MOTIVATION: Environmental variation and its influence on genetic diversity is a central topic in evolutionary biology and phylogeography. Accurate correlations between genetic and climatic datasets to understand the genetic adaptations of different species to specific environments. It requires integrated and reproducible workflows. RESULTS: We developed aPhyloGeo, an open-source and multiplatform application implemented in Python, for investigating correlations between genetic variation and environmental data within a phylogenetic framework. The workflow integrates multiple analytical steps, including sequence alignment, sliding window phylogenetic inference, and statistical approaches such as the Mantel test and the Procrustean randomization test. These analyses enable the identification of mutation hotspots that exhibit strong associations with environmental variables. In addition, aPhyloGeo supports multicore data processing and provides a fully reproducible pipeline for evaluating localized relationships between genomic variation and climatic distributions. AVAILABILITY AND IMPLEMENTATION: aPhyloGeo is freely available on GitHub at: https://github.com/tahiri-lab/aPhyloGeo, as both a PyPI package and as Python scripts for Linux, macOS, and Windows.

Software↗
PubMed2000

Comparing new participants of a mobile versus a pharmacy-based needle exchange program.

OBJECTIVE: To compare characteristics of first-time needle exchange participants who enrolled at a mobile van-based exchange site versus a fixed pharmacy-based exchange site, in an area where both types of needle exchange programs were available. METHODS: Demographic and drug use data were collected on needle exchange program participants on enrollment. Participants were included if they were first-time participants at the Baltimore needle exchange program between December 1997 and March 1999, and if their first visit was at either one van-based site or at one of two pharmacy-based sites. Descriptive statistics and inferences were based on the type of needle exchange into which participants enrolled. RESULTS: Among 286 first-time participants, 92% were African American, 28% were women, 11% were currently employed, 55% completed high school, and the median age was 40 years. In multivariate analyses, van-based enrollment was more common among frequent injectors (odds ratio [OR] = 2.0), but less common among African American participants (OR = 0.21). CONCLUSIONS: Our data suggest that different venues for needle exchange program settings attract different types of drug injecting participants. This suggests that offering different venue types to reach participants with differing drug use patterns will be important to optimize risk reduction strategies.

Adult↗
PubMed1994

Effects of ear plugging on single-unit azimuth sensitivity in cat primary auditory cortex. II. Azimuth tuning dependent upon binaural stimulation.

1. Single-unit recordings were carried out in primary auditory cortex (AI) of barbiturate-anesthetized cats. Observations were based on a sample of 131 high-best-frequency (> 5 kHz), azimuth-sensitive neurons. These were identified by their responses to a set of noise bursts, presented in the free field, that varied in azimuth and sound-pressure level (SPL). Each azimuth-sensitive neuron responded well to some levels at certain azimuths, but did not respond well to any level at other azimuths. 2. Unilateral ear plugging was used to infer each neuron's response to monaural stimulation. Ear plugs, produced by injecting a plastic ear mold compound into the external ear, attenuated sound reaching the tympanic membrane by 25-70 dB. The azimuth tuning of a large proportion of the sample (62/131), referred to as binaural directional (BD), was completely dependent upon binaural stimulation because with one ear plugged, these cells were insensitive to azimuth (either responded well at all azimuths or failed to respond at any azimuth) or in a few cases exhibited striking changes in location of azimuth function peaks. This report describes patterns of monaural responses and binaural interactions exhibited by BD neurons and relates them to each cell's azimuth and level tuning. The response of BD cells to ear plugging is consistent with the hypothesis that they derive azimuth tuning from interaural level differences present in noise bursts. Another component of the sample consisted of monaural directional (27/131) cells that derived azimuth tuning in part or entirely from monaural spectral cues. Cells in the remaining portion of the sample (42/131) responded too unreliably to permit specific conclusions. 3. Binaural interactions were inferred by statistical comparison of a cell's responses to monaural (unilateral plug) and binaural (no plug) stimulation. A larger binaural response than either monaural response was taken as evidence for binaural facilitation. A smaller binaural than monaural response was taken as evidence for binaural inhibition. Binaural facilitation was exhibited by 65% (40/62) of the BD sample (facilitatory cells). Many of these exhibited mixed interactions, i.e., binaural facilitation occurred in response to some azimuth-level combinations, and binaural inhibition to others. Binaural inhibition in the absence of binaural facilitation occurred in 35% (22/62) of the BD sample, a majority of which were EI cells, so called because they received excitatory (E) input from one ear (excitatory ear) and inhibitory (I) input from the other (inhibitory ear). One cell that exhibited binaural inhibition received excitatory input from each ear.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Trichloroethylene cancer epidemiology: a consideration of select issues.

A large body of epidemiologic evidence exists for exploring causal associations between cancer and trichloroethylene (TCE) exposure. The U.S. Environmental Protection Agency 2001 draft TCE health risk assessment concluded that epidemiologic studies, on the whole, support associations between TCE exposure and excess risk of kidney cancer, liver cancer, and lymphomas, and, to a lesser extent, cervical cancer and prostate cancer. As part of a mini-monograph on key issues in the health risk assessment of TCE, this article reviews recently published scientific literature examining cancer and TCE exposure and identifies four issues that are key to interpreting the larger body of epidemiologic evidence: a) relative sensitivity of cancer incidence and mortality data ; b) different classifications of lymphomas, including non-Hodgkin lymphoma ; c) differences in data and methods for assigning TCE exposure status ; and d) different methods employed for causal inferences, including statistical or meta-analysis approaches. The recent epidemiologic studies substantially expand the epidemiologic database, with seven new studies available on kidney cancer and somewhat fewer studies available that examine possible associations at other sites. Overall, recently published studies appear to provide further support for the kidney, liver, and lymphatic systems as targets of TCE toxicity, suggesting, as do previous studies, modestly elevated (typically 1.5-2.0) site-specific relative risks, given exposure conditions in these studies. However, a number of challenging issues need to be considered before drawing causal conclusions about TCE exposure and cancer from these data.

Animals↗
PubMed2005

Empirical bayes estimation of a sparse vector of gene expression changes.

Gene microarray technology is often used to compare the expression of thousand of genes in two different cell lines. Typically, one does not expect measurable changes in transcription amounts for a large number of genes; furthermore, the noise level of array experiments is rather high in relation to the available number of replicates. For the purpose of statistical analysis, inference on the "population'' difference in expression for genes across the two cell lines is often cast in the framework of hypothesis testing, with the null hypothesis being no change in expression. Given that thousands of genes are investigated at the same time, this requires some multiple comparison correction procedure to be in place. We argue that hypothesis testing, with its emphasis on type I error and family analogues, may not address the exploratory nature of most microarray experiments. We instead propose viewing the problem as one of estimation of a vector known to have a large number of zero components. In a Bayesian framework, we describe the prior knowledge on expression changes using mixture priors that incorporate a mass at zero, and we choose a loss function that favors the selection of sparse solutions. We consider two different models applicable to the microarray problem, depending on the nature of replicates available, and show how to explore the posterior distributions of the parameters using MCMC. Simulations show an interesting connection between this Bayesian estimation framework and false discovery rate (FDR) control. Finally, two empirical examples illustrate the practical advantages of this Bayesian estimation paradigm.

Journal Article↗
PubMed1981

Breast screening by breast self-examination: an evaluation of teaching methods and materials.

A base-line survey of women's opinions on breast cancer and breast self-examination (BSE) suggested a link between high awareness of BSE and a view of breast cancer as the most worrying illness they could suffer. Data from pre-teaching questionnaires compares awareness of and performance of BSE with six opinions related to the vulnerability of women to breast cancer and to possible outcomes. Inferences from statistically significant associations, which also replicated survey findings, led to the development of three alternative models of teaching methods. The findings also suggest that "concern" is a more accurate term than "anxiety" in describing perceptions of vulnerability and of BSE.

Anxiety↗
PubMed1991

Two metamodels of causal effects.

Two metamodels, termed Model S and Model V, are proposed for definition, measurement, and generalization of quantitative causal effects. The effect is defined as a part change in score in Model S and as a part change in variance in Model V. Two additional changes, total and remainder change, are defined. The latter is due to all other factors or variables than the cause, while total change is the sum of remainder and effect change. Furthermore, it is shown how contrafactual concepts, which imply that some parts of the study situation are supposed to be otherwise, enter into the metamodels. Casual effects are defined and measured in terms of non-contrafactual concepts, except that statistical induction includes contrafactual as well as non-contrafactual inferences. Non-statistical generalization involves both kinds of inferences. Contrafactual definitions are considered inadequate, and a contrafactual interpretation of statistical adjustment is unnecessary and should be replaced by a non-contrafactual one.

Adult↗
PubMed2003

Exact inference in the proportional hazard model: possibilities and limitations.

It is suggested that inference under the proportional hazard model can be carried out by programs for exact inference under the logistic regression model. Advantages of such inference is that software is available and that multivariate models can be addressed. The method has been evaluated by means of coverage and power calculations in certain situations. In all situations coverage was above the nominal level, but on the other hand rather conservative. A different type of exact inference is developed under Type II censoring. Inference was then less conservative, however there are limitations with respect to censoring mechanism, multivariate generalizations and software is not available. This method also requires extensive computational power. Performance of large sample Wald, score and likelihood inference was also considered. Large sample methods works remarkably well with small data sets, but inference by score statistics seems to be the best choice. There seems to be some problems with likelihood ratio inference that may originate from how this method works with infinite estimates of the regression parameter. Inference by Wald statistics can be quite conservative with very small data sets.

Adolescent↗
PubMed1993

Phylogenetic inference: linear invariants and maximum likelihood.

We develop a new statistical method for inferring phylogenies, based on a likelihood ratio test. This method does not require parameter constraints but does require identical evolutionary processes in the sites considered. Another method of phylogenetic inference is the method of linear invariants, described by Cavender (1989, Molecular Biology and Evolution 6, 301-316), based on a notion of Lake (1987, Molecular Biology and Evolution 4, 167-191). We describe a sound mathematical basis for the use of linear invariants. We show that the validity of the method requires parameter constraints, but does not require that the evolutionary processes in differing sites be identical. We show that the method of linear invariants is asymptotically equivalent to a less powerful version of our likelihood ratio test, and is thus essentially a maximum likelihood technique.

Animals↗
PubMed2003

Bootstrap approach to inference and power analysis based on three test statistics for covariance structure models.

We study several aspects of bootstrap inference for covariance structure models based on three test statistics, including Type I error, power and sample-size determination. Specifically, we discuss conditions for a test statistic to achieve a more accurate level of Type I error, both in theory and in practice. Details on power analysis and sample-size determination are given. For data sets with heavy tails, we propose applying a bootstrap methodology to a transformed sample by a downweighting procedure. One of the key conditions for safe bootstrap inference is generally satisfied by the transformed sample but may not be satisfied by the original sample with heavy tails. Several data sets illustrate that, by combining downweighting and bootstrapping, a researcher may find a nearly optimal procedure for evaluating various aspects of covariance structure models. A rule for handling non-convergence problems in bootstrap replications is proposed.

Humans↗
PubMed2001

Random assignment of available cases: bootstrap standard errors and confidence intervals.

A frequently used experimental design in psychological research randomly divides a set of available cases, a local population, between 2 treatments and then applies an independent-samples t test to either test a hypothesis about or estimate a confidence interval (CI) for the population mean difference in treatment response. C. S. Reichardt and H. F. Gollob (1999) established that the t test can be conservative for this design-yielding hypothesis test P values that are too large or CIs that are too wide for the relevant local population. This article develops a less conservative approach to local population inference, one based on the logic of B. Efron's (1979) nonparametric bootstrap. The resulting randomization bootstrap is then compared with an established approach to local population inference, that based on randomization or permutation tests. Finally, the importance of local population inference is established by reference to the distinction between statistical and scientific inference.

Confidence Intervals↗
PubMedDate not supplied

Comparison of visual inspection and statistical analysis of single-subject data in rehabilitation research.

Single-subject designs are being advocated to conduct outcome research in rehabilitation environments. The methods provide an alternative to traditional designs based on statistical comparisons across groups. Data analysis in single subject research does not rely on statistical hypothesis testing of responses collected from a sample of subjects. Instead, visual inspection of patient responses graphed over time is the usual method of data analysis in single-subject research. This study examined the agreement between visual analysis and statistical tests of single-subject data for 42 hypothetical single-subject graphs. Specially constructed graphs allowed the systematic manipulation of different treatment effect sizes across a commonly used single-subject design. Thirty-two rehabilitation and health care providers rated each of the 42 graphs to determine whether a clinically significant treatment effect existed across the phases of the designs. Data analysis focused on two questions: (1) How much agreement was there between visual judgments and the results of statistical tests? and (2) What level of treatment effect was required to produce a finding of visual versus statistical significance? The agreement between visual analysis and statistical significance was high (86%). The sensitivity of visual inferences compared with statistical test results was 0.84, specificity was 0.88, and positive predictive value was 0.91. Both visual and statistical procedures were sensitive to medium and large treatment effects in the 42 single-subject graphs examined in this study.

Audiovisual Aids↗
PubMed1998

Statistical confidence for likelihood-based paternity inference in natural populations.

Paternity inference using highly polymorphic codominant markers is becoming common in the study of natural populations. However, multiple males are often found to be genetically compatible with each offspring tested, even when the probability of excluding an unrelated male is high. While various methods exist for evaluating the likelihood of paternity of each nonexcluded male, interpreting these likelihoods has hitherto been difficult, and no method takes account of the incomplete sampling and error-prone genetic data typical of large-scale studies of natural systems. We derive likelihood ratios for paternity inference with codominant markers taking account of typing error, and define a statistic delta for resolving paternity. Using allele frequencies from the study population in question, a simulation program generates criteria for delta that permit assignment of paternity to the most likely male with a known level of statistical confidence. The simulation takes account of the number of candidate males, the proportion of males that are sampled and gaps and errors in genetic data. We explore the potentially confounding effect of relatives and show that the method is robust to their presence under commonly encountered conditions. The method is demonstrated using genetic data from the intensively studied red deer (Cervus elaphus) population on the island of Rum, Scotland. The Windows-based computer program, CERVUS, described in this study is available from the authors. CERVUS can be used to calculate allele frequencies, run simulations and perform parentage analysis using data from all types of codominant markers.

Animals↗