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At least 1,081 records · Page 60Linked to original sources
PubMed2005

Tests for treatment group differences in the hazards for survival, before and after the occurrence of an intermediate event.

In many settings, one would expect that the hazard for a terminal event would change with the occurrence of an intermediate event. For example, in an AIDS clinical trial, it is of interest to assess whether there is a difference between treatments in the hazards for death prior to drop in Karnofsky performance score and in the hazards subsequent to the drop in Karnofsky score. Tests for the effect of treatment on these hazard functions, separately or jointly, are useful in conjunction with tests of overall survival. We consider four Cox regression models for the hazard function, constructed by allowing for various combinations of time-dependent stratification and time-dependent covariates, both of which are based on the occurrence of the intermediate event. Assuming a Markov transition model from the intermediate to the terminal event, partial likelihoods can be used for inference, enabling the use of standard statistical software for computation. We develop analytic approximations for the power of the derived score tests for treatment differences in the hazard functions and evaluate them through simulations. We apply our results to AIDS Clinical Trials Group (ACTG) protocol 021.

AIDS-Related Opportunistic Infections↗
PubMed1989

Analysis of epidemiologic case-base studies for binary data.

Recent developments in statistical methods for epidemiology have revived the application of sampling techniques in the design and analysis of cohort studies. The 'case-base' design involves sampling of both the cases and the cohort base of the study. This paper reviews some data-analytic imperfections of the approaches to risk ratio estimation, and modifies and advances a consistent likelihood-based procedure-analogous to Miettinen and Nurminen's proposal for a full cohort design--for interval estimation (and also point estimation and significance testing) in the context of binary case-base data. First, the procedure avoids the use of Taylor-series approximations to derive variance estimators for non-linear functions of parameters. Second, the asymptotic condition effects a simple computational expression for the chi-square function of risk ratios that is universally applicable to small samples. The statistical modelling underlying the method allows inferences about risk ratios without the assumption of rare disease either for the general population or for a particular base. The paper also extends the analysis to encompass stratified data. Finally, a numerical evaluation evinced the accurate small-sample properties of the proposed method.

Binomial Distribution↗
PubMed2005

Application of case-crossover and case-time-control study designs in analyses of time-varying predictors of T-cell homeostasis failure.

PURPOSE: To evaluate the association of sexual behavior and recreational drug exposures with T-cell homeostasis failure (TCHF), which corresponds to the onset of a rapid decline in an individual's T lymphocyte count, which occurs on average approximately 1.75 years prior to an initial diagnosis of acquired immunodeficiency syndrome (AIDS). METHODS: A case-crossover design and a case-time-control design, both nested within the Multicenter AIDS Cohort Study of 4954 homosexual and bisexual men initiated in 1983. RESULTS: In the case-crossover analysis, use of both recreational drugs and hashish were found to be protective against TCHF (odds ratios < or = 0.41), based on comparisons with four earlier control periods. However, a significant decreasing trend in the prevalence of these exposures was observed over time, thus motivating the implementation of the case-time-control design. Using the latter approach, the associations of drug use (odds ratio=0.53; 95% confidence interval (CI): 0.22, 1.28) and hashish use (odds ratio=0.46; 95% CI: 0.20, 1.05) with TCHF were no longer statistically significant. CONCLUSIONS: The difference in inferences between these approaches demonstrates the importance of evaluating temporal trends in exposures when using a case-crossover design.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Comparison of equations describing band broadening in high-performance liquid chromatography.

Several models are well established that describe band broadening in gas and liquid chromatography, including those due to Van Deemter and Knox. Comparison of competing models is complicated if raw data are noisy or if the equations to be fitted to data contain many adjustable parameters. This paper describes a comparison of fitting the Van Deemter, Knox and other equations to low noise data gathered during the separation of propyl- and methylparaben by HPLC. Equations are compared using established statistical methods, including analysis of residuals, inference of parameter estimates and Akaikes Information Criterion for model identification. This work indicates that equations that account for non-linear band broadening at elevated mobile phase velocities are more successful at describing the relationship between height equivalent to a theoretical plate, H, and the velocity of the mobile phase, u.

Chromatography, High Pressure Liquid↗
PubMed2006

Comparative analysis of base correlations in 5' untranslated regions of various species.

Translational initiation signals, such as Shine-Dalgarno (SD) sequences in bacteria and Kozak consensus sequences in vertebrates, direct ribosomes to initiate protein synthesis from mRNAs. Investigating sequence characteristics of these signals is important, particularly to infer translational initiation mechanisms. Although various statistical analyses of translational initiation signals have been done, few have focused on base correlations that assess base dependencies in the signal sequences. We used relative entropy and mutual information to analyze base conservation and correlation, respectively, in the 5' UTRs of various species. In eukaryotes, we found peaks of relative entropy at -3 from the translational start site but no peak of mutual information at that position, indicating that the base at that position (known as the core base of the Kozak sequence) is well conserved but not correlated with neighboring bases and thus functions as a single base. We observed unexpected peaks of mutual information between positions -2 and -1 in most eukaryotes. Surprisingly these base correlation also occurred in some bacteria and archaea, although there were no base preferences at neither position. Various dinucleotide patterns existed at these positions, and the correlation between bases at -2 and -1 may be relevant to the context of translational initiation. Because dinucleotide patterns of correlated pairs of nucleotides at -2 and -1 were not unique within respective organisms, the correlation could not be found when analyzing single-nucleotide conservation. Therefore, mutual information allowed us to discover signals that were not found by simply analyzing base conservation.

5' Untranslated Regions↗
PubMed2001

Molecular phylogenetics: state-of-the-art methods for looking into the past.

As the amount of molecular sequence data in the public domain grows, so does the range of biological topics that it influences through evolutionary considerations. In recent years, a number of developments have enabled molecular phylogenetic methodology to keep pace. Likelihood-based inferential techniques, although controversial in the past, lie at the heart of these new methods and are producing the promised advances in the understanding of sequence evolution. They allow both a wide variety of phylogenetic inferences from sequence data and robust statistical assessment of all results. It cannot remain acceptable to use outdated data analysis techniques when superior alternatives exist. Here, we discuss the most important and exciting methods currently available to the molecular phylogeneticist.

Animals↗
PubMed2004

Evidence for substantial fine-scale variation in recombination rates across the human genome.

Characterizing fine-scale variation in human recombination rates is important, both to deepen understanding of the recombination process and to aid the design of disease association studies. Current genetic maps show that rates vary on a megabase scale, but studying finer-scale variation using pedigrees is difficult. Sperm-typing experiments have characterized regions where crossovers cluster into 1-2-kb hot spots, but technical difficulties limit the number of studies. An alternative is to use population variation to infer fine-scale characteristics of the recombination process. Several surveys reported 'block-like' patterns of diversity, which may reflect fine-scale recombination rate variation, but limitations of available methods made this impossible to assess. Here, we applied a new statistical method, which overcomes these limitations, to infer patterns of fine-scale recombination rate variation in 74 genes. We found extensive rate variation both within and among genes. In particular, recombination hot spots are a common feature of the human genome: 47% (35 of 74) of genes showed substantive evidence for a hot spot, and many more showed evidence for some rate variation. No primary sequence characteristics are consistently associated with precise hot-spot location, although G+C content and nucleotide diversity are correlated with local recombination rate.

Genome, Human↗
PubMed1999

Scanning electron microscope study on the efficacy of root canal wall debridement of hand versus Lightspeed instrumentation.

AIM: The aim of this in vitro study was to compare the efficacy of root canal wall debridement following hand versus LightSpeed instrumentation. METHODOLOGY: Twenty recently extracted single-rooted teeth were paired and randomly placed into two treatment groups of 10 teeth each. In group 1, a step-back instrumentation without initial coronal flaring with stainless steel Hedstroem files was used; group 2 was instrumented with Ni-Ti LightSpeed instruments. Both groups had the same irrigation regimen: 2.5% NaOCl and a 15% EDTA solution. The teeth were then decoronated and each root split longitudinally into two halves to be examined using the scanning electron microscope (SEM). The presence of superficial debris and smear layer was evaluated by a standardized grading system, and the resulting scores submitted to nonparametric statistics. RESULTS: Under the conditions of this study, the removal of superficial debris was generally excellent with both canal preparation techniques. Both techniques resulted in variable presence of residual smear layer, with a canal wall covered by smear layer as the predominant characteristic. Generally, the amount of smear layer was greater in the apical than in the middle third of the root, however, this difference was statistically significant (P < 0.005) only in hand-instrumented teeth. The use of LightSpeed instruments was associated with significantly more (P < 0.05) smear layer presence in the middle region of the root when compared with hand instrumentation. In addition, less smear layer was present in the apical region following LightSpeed instrumentation than stainless steel hand files, but this difference was not statistically significant. Differences in debridement between the two halves of the same root were more evident with LightSpeed than manual instrumentation, however, there was no statistical significance. CONCLUSIONS: It may be inferred that the choice between hand and LightSpeed instrumentation should be based on factors other than the amount of root canal debridement, which does not vary significantly according to the instruments used.

Aged↗
PubMed2002

Sexual selection driving diversification in jumping spiders.

Theory predicts that speciation rates should be accelerated in organisms undergoing sexual selection. In systems involving female choice, sexual selection acts directly on traits that may be important in prezygotic reproductive isolation, potentially fostering rapid divergence of such traits among allopatric populations. Despite the appeal of this concept, it has proven difficult to document. We provide genetic, behavioral, and simulation data illustrating that the striking and possibly recent divergence in traits of male behavior and morphology among populations of the jumping spider Habronattus pugillis can be attributed to sexual selection. We have found evidence for varying degrees of lower female response and offspring viability among some between-population crosses, consistent with the early stages of speciation. We have developed a gene-tree-based method for comparing phenotypic and genetic data sets to infer selection, and have found robust statistical evidence that directional selection has acted on male traits, by confirming that their rate of fixation exceeds that of neutral mitochondrial genes. Because these traits are apparent targets of female choice, the results indicate that sexual selection is driving divergence of phenotypes potentially crucial to the speciation process.

Animals↗
PubMedDate not supplied

Structure-based methods for the prediction of the dominant P450 enzyme in human drug biotransformation: consideration of CYP3A4, CYP2C9, CYP2D6.

Metabolic drug-drug interactions are receiving more and more attention from the in silico community. Early prediction of such interactions would not only improve drug safety but also contribute to make drug design more predictable and rational. The aim of this study was to build a simple and interpretable model for the determination of the P450 enzyme predominantly responsible for a drug's metabolism. The P450 enzymes taken into consideration were CYP3A4, CYP2D6 and CYP2C9. Physico-chemical descriptors and structural descriptors for 96 currently marketed drugs were submitted to statistical analysis using the formal inference-based recursive modelling (FIRM) method, a form of recursive partitioning. Generally accepted knowledge on metabolism by these enzymes was also used to construct a hierarchical decision tree. Robust methods of variable selection using recursive partitioning were utilised. The descriptive ability of the resulting hierarchical model is very satisfactory, with 94% of the compounds correctly classified.

Aryl Hydrocarbon Hydroxylases↗
PubMed2005

TNF-alpha promoter polymorphisms and susceptibility to human papillomavirus 16-associated cervical cancer.

BACKGROUND: Polymorphisms in the TNF-alpha promoter region have recently been shown to be associated with susceptibility to cervical cancer. Some polymorphisms have been reported to influence transcription for this cytokine. Altered local levels in the cervix may influence an individual's immune response, thereby affecting persistence of human papillomavirus (HPV) 16 infection, a primary etiological factor for cervical cancer. METHODS AND RESULTS: The association of 11 TNF-alpha single-nucleotide polymorphisms (SNPs) with susceptibility to HPV16-associated cervical cancer was investigated. Sequencing of the TNF-alpha promoter region confirmed 10 SNPs, and 1 previously unreported SNP (161 bp upstream of the transcriptional start site) was discovered. Microsphere-array flow cytometry-based genotyping was performed on 787 samples from Hispanic and non-Hispanic white women (241 from randomly selected control subjects, 205 from HPV16-positive control subjects, and 341 from HPV16-positive subjects with cervical cancer). The genotype distribution of 3 SNPs (-572, -857, and -863) was significantly different between case subjects and control subjects. Analysis of haplotypes, which were computationally inferred from genotype data, also revealed statistically significant differences in haplotype distribution between case subjects and control subjects. CONCLUSIONS: We report new associations between several TNF-alpha SNPs and susceptibility to cervical cancer that support the involvement of the TNF- alpha promoter region in development of cervical cancer.

Adolescent↗
PubMed2005

Regression-based association analysis with clustered haplotypes through use of genotypes.

Haplotype-based association analysis has been recognized as a tool with high resolution and potentially great power for identifying modest etiological effects of genes. However, in practice, its efficacy has not been as successfully reproduced as expected in theory. One primary cause is that such analysis tends to require a large number of parameters to capture the abundant haplotype varieties, and many of those are expended on rare haplotypes for which studies would have insufficient power to detect association even if it existed. To concentrate statistical power on more-relevant inferences, in this study, we developed a regression-based approach using clustered haplotypes to assess haplotype-phenotype association. Specifically, we generalized the probabilistic clustering methods of Tzeng to the generalized linear model (GLM) framework established by Schaid et al. The proposed method uses unphased genotypes and incorporates both phase uncertainty and clustering uncertainty. Its GLM framework allows adjustment of covariates and can model qualitative and quantitative traits. It can also evaluate the overall haplotype association or the individual haplotype effects. We applied the proposed approach to study the association between hypertriglyceridemia and the apolipoprotein A5 gene. Through simulation studies, we assessed the performance of the proposed approach and demonstrate its validity and power in testing for haplotype-trait association.

Apolipoprotein A-V↗
PubMed2000

EDIBLE: experimental design and information calculations in phylogenetics.

UNLABELLED: Although evolutionary inference from molecular sequences is a statistical problem, little attention has been paid to questions of experimental design. A computer program, EDIBLE, has been developed to perform likelihood calculations based on Markov process models of nucleotide substitution allied with phylogenetic trees, and from these to compute Fisher information measures under different experimental designs. These calculations can be used to answer questions of optimal experimental design in molecular phylogenetics. AVAILABILITY: Source code (ANSI C), executables and documentation for EDIBLE are available from http://ng-dec1.gen.cam. ac.uk/info/index.htmland 'downstream' Web pages. CONTACT: N.Goldman@gen.cam.ac.uk

Likelihood Functions↗
PubMed2025

Absolute copy number aware CNV calling of sub-megabase segments in ultra-low coverage single-cell DNA sequencing data.

Recent advances in ultra-low coverage whole-genome sequencing (WGS) of single cells have enabled detailed analysis of copy number variation at a throughput approaching that of single-cell RNA sequencing. However, downstream computational methods have not seen comparable advances and are largely adaptations of deep sequencing methodology with reduced precision. Here, we present ASCENT, a computational method built to take full advantage of modern direct tagmentation-based WGS at ultra-low depth. Using joint segmentation with high-resolution bins, we accurately detect small segments, achieving accurate copy number profiles even at 100 000 reads per cell. ASCENT implements true absolute copy state inference for single cells, based on statistical modeling of coverage rather than comparison to a reference, while taking variable segment copy state into account. Further, ASCENT implements per-segment copy-neutral loss of heterozygosity (LOH) calling without the need for non-tumor or bulk WGS reference. When applied to a pediatric B-ALL sample, ASCENT finds copy-neutral LOH in a small segment and a minor subclone defined by breakpoints missed in bulk WGS. Thus, by applying appropriate computational methods, single-cell WGS provides clear advantages over bulk, even at a relatively low cell number and sequencing depth.

DNA Copy Number Variations↗
PubMed1999

Seeking causal explanations in social epidemiology.

Social factors are associated with a wide variety of health outcomes. Social epidemiology has successfully used the traditional methods of surveillance and description to establish consistent relations between social factors and health status. Epidemiology as an etiologic science, however, has been largely ineffective in moving toward causal explanations for these observed patterns. Using the counterfactual approach to causal inference, the authors describe several fundamental problems that often arise when researchers seek to infer explanatory mechanisms from data on social factors. Contrasts that form standard causal effect estimates require implicit unobserved (counterfactual) quantities, because observational data provide only one exposure state for each individual. Although application of counterfactual arguments has successfully advanced etiologic understanding in other observational settings, the particular nature of social factors often leads to logical contradictions or misleading inferences when investigators fail to clearly articulate the counterfactual contrasts that are implied. For example, because social factors are often attributes of individuals and are components of structured social relations, random assignment is not plausible even as a hypothetical experiment, making typical epidemiologic contrasts inappropriate and the inference equivocal at best. Accordingly, more deliberate and creative approaches to causal inference in social epidemiology are required. Infectious disease epidemiology and systems analysis provide examples of approaches to causal inference that can be used when statistical mimicry of simple experimental designs is not tenable. In an era of increasing social inequality, valid approaches for the study of social factors and health are needed more urgently than ever.

Black or African American↗
PubMed1978

Coronary-prone behavior: one pattern or several?

A cohort of 2750 healthy men who responded to a 61-item questionnaire was studied prospectively for 4 years, by which time 67 sustained acute myocardial infarctions (AMI), 30 were discovered by ECG to have had myocardial infarctions, which had gone clinically unrecognized ("silent") (SMI), and 23 had developed classical angina pectoris without ECG changes indicative of infarction. Item analysis of the questionnaire using multi-group optimal scaling and discriminant function revealed the patterns of responses to be characteristically different among the three clinical presentations of coronary disease and those men who remained healthy. The psychological properties of the three significant dimensions of discrimination are discussed. A second study, involving largely healthy men from the same population, supported the inference that the dimensions isolated were statistically and psychologically genuine. The implication is that different facets of the coronary-prone Type A behavior pattern may be specifically associated with different clinical manifestation of coronary disease. Refinement of these dimensions may lead to more specific prediction of coronary disease risk in the future.

Angina Pectoris↗
PubMed1998

Phylogenetic information and experimental design in molecular systematics.

Despite the widespread perception that evolutionary inference from molecular sequences is a statistical problem, there has been very little attention paid to questions of experimental design. Previous consideration of this topic has led to little more than an empirical folklore regarding the choice of suitable genes for analysis, and to dispute over the best choice of taxa for inclusion in data sets. I introduce what I believe are new methods that permit the quantification of phylogenetic information in a sequence alignment. The methods use likelihood calculations based on Markov-process models of nucleotide substitution allied with phylogenetic trees, and allow a general approach to optimal experimental design. Two examples are given, illustrating realistic problems in experimental design in molecular phylogenetics and suggesting more general conclusions about the choice of genomic regions, sequence lengths and taxa for evolutionary studies.

Animals↗