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At least 811 records · Page 45Linked to original sources
PubMed2004

Statistical methods for analyzing tissue microarray data.

Tissue microarrays (TMAs) are a new high-throughput tool for the study of protein expression patterns in tissues and are increasingly used to evaluate the diagnostic and prognostic importance of biomarkers. TMA data are rather challenging to analyze. Covariates are highly skewed, non-normal, and may be highly correlated. We present statistical methods for relating TMA data to censored time-to-event data. We review methods for evaluating the predictive power of Cox regression models and show how to test whether biomarker data contain predictive information above and beyond standard pathology covariates. We use nonparametric bootstrap methods to validate model fitting indices such as the concordance index. We also present data mining methods for characterizing high risk patients with simple biomarker rules. Since researchers in the TMA community routinely dichotomize biomarker expression values, survival trees are a natural choice. We also use bump hunting (patient rule induction method), which we adapt to the use with survival data. The proposed methods are applied to a kidney cancer tissue microarray data set.

Algorithms↗
PubMed2000

Bayesian fine-scale mapping of disease loci, by hidden Markov models.

We present a new multilocus method for the fine-scale mapping of genes contributing to human diseases. The method is designed for use with multiple biallelic markers-in particular, single-nucleotide polymorphisms for which high-density genetic maps will soon be available. We model disease-marker association in a candidate region via a hidden Markov process and allow for correlation between linked marker loci. Using Markov-chain-Monte Carlo simulation methods, we obtain posterior distributions of model parameter estimates including disease-gene location and the age of the disease-predisposing mutation. In addition, we allow for heterogeneity in recombination rates, across the candidate region, to account for recombination hot and cold spots. We also obtain, for the ancestral marker haplotype, a posterior distribution that is unique to our method and that, unlike maximum-likelihood estimation, can properly account for uncertainty. We apply the method to data for cystic fibrosis and Huntington disease, for which mutations in disease genes have already been identified. The new method performs well compared with existing multi-locus mapping methods.

Alleles↗
PubMed2000

Analysis of Clines with Variable Selection and Variable Migration.

We report a likelihood-based method that estimates both dispersal and natural selection using the rate of change of the shape of a cline when selection and migration are not constant through time. We have investigated the case of local adaptation of the mosquito Culex pipiens to organophosphate insecticides in the Montpellier area in France. We have analyzed the modification of the clinal patterns at two resistance loci during the period from breeding to overwintering. We show that mosquitoes migrate extensively from breeding to overwintering sites at a rate that is markedly different from previous estimates made during the breeding season only. This migration is also strongly asymmetrical, which can be explained by different geographical distributions of breeding and overwintering sites, by variation in mosquito density along the transect, or by behavioral biases. We found that the starting time of overwintering is likely to vary between northern and southern populations and that substantial fitness costs are associated with resistance alleles at the two loci during overwintering. These results illustrate how demography and adaptive microevolution can be studied using selected markers. The method provides a framework to use population genetics and statistical models to reveal ecological and evolutionary processes.

asymmetrical gene flow↗
PubMed2002

Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria.

Molecular assays for monitoring sulfadoxine-pyrimethamine-resistant Plasmodium falciparum have not been implemented because of the genetic and statistical complexity of the parasite mutations that confer resistance and their relation to treatment outcomes. This study analyzed pretreatment dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes and treatment outcomes in a double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment for uncomplicated P. falciparum malaria. Multiple logistic regression was used to identify mutations that were predictive of treatment failure and to identify interactions and confounding factors. Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations (the "quintuple mutant") were associated with sulfadoxine-pyrimethamine treatment failure but not with chlorproguanil-dapsone treatment failure. The presence of a single DHFR mutation (Arg-59) with a single DHPS mutation (Glu-540) accurately predicted the presence of the quintuple mutant. If this model is validated in other populations, it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa.

Antimalarials↗
PubMed2003

A neutral explanation for the correlation of diversity with recombination rates in humans.

One of the most striking findings to emerge from the study of genomic patterns of variation is that regions with lower recombination rates tend to have lower levels of intraspecific diversity but not of interspecies divergence. This uncoupling of variation within and between species has been widely interpreted as evidence that natural selection shapes patterns of genetic variability genomewide. We revisited the relationship between diversity, divergence, and recombination in humans, using data from closely related species and better estimates of recombination rates than previously available. We show that regions that experience less recombination have reduced divergence to chimpanzee and to baboon, as well as lower levels of diversity. This observation suggests that mutation and recombination are associated processes in humans, so that the positive correlation between diversity and recombination may have a purely neutral explanation. Consistent with this hypothesis, diversity levels no longer increase significantly with recombination rates after correction for divergence to chimpanzee.

Animals↗
PubMed2004

The African diaspora: mitochondrial DNA and the Atlantic slave trade.

Between the 15th and 19th centuries ad, the Atlantic slave trade resulted in the forced movement of approximately 13 million people from Africa, mainly to the Americas. Only approximately 11 million survived the passage, and many more died in the early years of captivity. We have studied 481 mitochondrial DNAs (mtDNAs) of recent African ancestry in the Americas and in Eurasia, in an attempt to trace them back to particular regions of Africa. Our results show that mtDNAs in America and Eurasia can, in many cases, be traced to broad geographical regions within Africa, largely in accordance with historical evidence, and raise the possibility that a greater resolution may be possible in the future. However, they also indicate that, at least for the moment, considerable caution is warranted when assessing claims to be able to trace the ancestry of particular lineages to a particular locality within modern-day Africa.

Black People↗
PubMed2004

Incorporating genotyping uncertainty in haplotype inference for single-nucleotide polymorphisms.

The accuracy of the vast amount of genotypic information generated by high-throughput genotyping technologies is crucial in haplotype analyses and linkage-disequilibrium mapping for complex diseases. To date, most automated programs lack quality measures for the allele calls; therefore, human interventions, which are both labor intensive and error prone, have to be performed. Here, we propose a novel genotype clustering algorithm, GeneScore, based on a bivariate t-mixture model, which assigns a set of probabilities for each data point belonging to the candidate genotype clusters. Furthermore, we describe an expectation-maximization (EM) algorithm for haplotype phasing, GenoSpectrum (GS)-EM, which can use probabilistic multilocus genotype matrices (called "GenoSpectrum") as inputs. Combining these two model-based algorithms, we can perform haplotype inference directly on raw readouts from a genotyping machine, such as the TaqMan assay. By using both simulated and real data sets, we demonstrate the advantages of our probabilistic approach over the current genotype scoring methods, in terms of both the accuracy of haplotype inference and the statistical power of haplotype-based association analyses.

Algorithms↗
PubMed2005

Rapid simulation of P values for product methods and multiple-testing adjustment in association studies.

A major aim of association studies is the identification of polymorphisms (usually SNPs) associated with a trait. Tests of association may be based on individual SNPs or on sets of neighboring SNPs, by use of (for example) a product P value method or Hotelling's T test. Linkage disequilibrium, the nonindependence of SNPs in physical proximity, causes problems for all these tests. First, multiple-testing correction for individual-SNP tests or for multilocus tests either leads to conservative P values (if Bonferroni correction is used) or is computationally expensive (if permutation is used). Second, calculation of product P values usually requires permutation. Here, we present the direct simulation approach (DSA), a method that accurately approximates P values obtained by permutation but is much faster. It may be used whenever tests are based on score statistics--for example, with Armitage's trend test or its multivariate analogue. The DSA can be used with binary, continuous, or count traits and allows adjustment for covariates. We demonstrate the accuracy of the DSA on real and simulated data and illustrate how it might be used in the analysis of a whole-genome association study.

Antidepressive Agents↗
PubMed2005

Genetic analysis of meningococci carried by children and young adults.

BACKGROUND: Neisseria meningitidis is a diverse commensal bacterium that occasionally causes severe invasive disease. The relationship between meningococcal genotype and capsular polysaccharide, the principal virulence factor and vaccine component, was investigated in carried meningococci isolated from 8000 children and young adults in Bavaria, Germany. METHODS: Of the 830 meningococci isolated (carriage rate, 10.4%) by microbiological techniques, 822 were characterized by serogrouping, multilocus sequence typing, and genetic analysis of the capsule region. Statistical and population genetic analyses were applied to these data. RESULTS: The rapid increase in carriage rates with age of carrier, the low prevalence of hyperinvasive meningococci, and the relative prevalence of the 4 disease-associated serogroups were consistent with earlier observations. There was no genetic structuring of the meningococcal population by age of carrier or sampling location; however, there was significant geographic structuring of the meningococci isolated in civil, but not military, institutions. The rate of capsule gene expression did not vary with age of carrier or meningococcal genotype, except for serogroup C, for which increased expression was associated with ST-11 (formerly ET-37) complex meningococci. CONCLUSIONS: Serogroup C capsule expression during carriage may contribute to the invasive character of ST-11 complex meningococci and to the high efficacy of meningococcal serogroup C conjugate polysaccharide vaccine.

Adolescent↗
PubMed2005

A note on exact tests of Hardy-Weinberg equilibrium.

Deviations from Hardy-Weinberg equilibrium (HWE) can indicate inbreeding, population stratification, and even problems in genotyping. In samples of affected individuals, these deviations can also provide evidence for association. Tests of HWE are commonly performed using a simple chi2 goodness-of-fit test. We show that this chi2 test can have inflated type I error rates, even in relatively large samples (e.g., samples of 1,000 individuals that include approximately 100 copies of the minor allele). On the basis of previous work, we describe exact tests of HWE together with efficient computational methods for their implementation. Our methods adequately control type I error in large and small samples and are computationally efficient. They have been implemented in freely available code that will be useful for quality assessment of genotype data and for the detection of genetic association or population stratification in very large data sets.

Genetics, Population↗
PubMed2005

Japanese quail selected for high plasma corticosterone response deposit high levels of corticosterone in their eggs.

Poor habitat quality or body condition often correlates with high responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis rather than with elevated baseline levels of glucocorticoids. We hypothesized that, for egg-laying vertebrates, high responsiveness of the HPA axis would correspond to high concentrations of corticosterone in yolk. We tested the prediction that Japanese quail (Coturnix coturnix japonica) selected for high plasma corticosterone response to brief immobilization (HS quail) would lay eggs with higher yolk corticosterone concentrations than birds selected for low response (LS quail). Quail from both lines were left undisturbed, outside of the stressors associated with daily management, before a first round of egg collection. In a second experiment, quail of both lines were experimentally stressed during the week before egg collection. In both cases we found quail from the HS line to lay eggs with significantly higher yolk corticosterone concentrations than quail of the LS line. After exposure to added experimental stressors, the line difference was more pronounced (increasing from 62% to 96%). There was no line difference in concentrations of yolk testosterone. Our results suggest that (1) genetic differences underly differences in the transfer of maternal corticosterone to yolk and (2) females may be able to control deposition of corticosterone into yolk through a mechanism independent of baseline corticosterone titers.

Animals↗
PubMed2005

Recent developments in genomewide association scans: a workshop summary and review.

With the imminent availability of ultra-high-volume genotyping platforms (on the order of 100,000-1,000,000 genotypes per sample) at a manageable cost, there is growing interest in the possibility of conducting genomewide association studies for a variety of diseases but, so far, little consensus on methods to design and analyze them. In April 2005, an international group of >100 investigators convened at the University of Southern California over the course of 2 days to compare notes on planned or ongoing studies and to debate alternative technologies, study designs, and statistical methods. This report summarizes these discussions in the context of the relevant literature. A broad consensus emerged that the time was now ripe for launching such studies, and several common themes were identified--most notably the considerable efficiency gains of multistage sampling design, specifically those made by testing only a portion of the subjects with a high-density genomewide technology, followed by testing additional subjects and/or additional SNPs at regions identified by this initial scan.

Data Interpretation, Statistical↗
PubMed1997

How to select and interpret molecular strain typing methods for epidemiological studies of bacterial infections: a review for healthcare epidemiologists. Molecular Typing Working Group of the Society for Healthcare Epidemiology of America.

Strain typing is an integral part of epidemiological investigations of nosocomial infections. Methods for distinguishing among bacterial strains have improved dramatically over the last 5 years, due mainly to the introduction of molecular technology. Although not all molecular techniques are equally effective for typing all organisms, pulsed-field gel electrophoresis is the technique currently favored for most nosocomial pathogens. Criteria to aid epidemiologists in interpreting results have been published. Nucleic acid amplification-based typing methods also are applicable to many organisms and can be completed within a single day, but interpretive criteria still are under debate. Strain typing cannot be used to replace a sound epidemiological investigation, but serves as a useful adjunct to such investigations.

Bacterial Typing Techniques↗
PubMed2006

A discrete-event approach to transcription control with dynamic event-controllability.

This paper presents a discrete-event approach to the synthesis of transcription control for a class of (computational) gene networks. Given a set of genes and protein-gene and/or protein-protein interaction patterns, this approach can be used to synthesize a transcription control induced by these interaction patterns, and as a consequence, determine the behavior of the gene network. This proposed approach is demonstrated in the synthesis of a transcription control that produces the observed (logical) behavior in the induction of a phage lambda lysogen.

Bacteriophage lambda↗
PubMed2006

A linear-time algorithm for the perfect phylogeny haplotyping (PPH) problem.

Since the introduction of the Perfect Phylogeny Haplotyping (PPH) Problem in RECOMB 2002 (Gusfield, 2002), the problem of finding a linear-time (deterministic, worst-case) solution for it has remained open, despite broad interest in the PPH problem and a series of papers on various aspects of it. In this paper, we solve the open problem, giving a practical, deterministic linear-time algorithm based on a simple data structure and simple operations on it. The method is straightforward to program and has been fully implemented. Simulations show that it is much faster in practice than prior nonlinear methods. The value of a linear-time solution to the PPH problem is partly conceptual and partly for use in the inner loop of algorithms for more complex problems, where the PPH problem must be solved repeatedly.

Algorithms↗
PubMed2006

Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.

Asian People↗