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PubMed2005

Dynamics of a quantitative character subject only to stabilising selection.

The implications of stabilising selection on a quantitative trait, in the absence of other evolutionary forces, are theoretically investigated in a randomly mating population. The dynamics of various statistics that describe the alleles contributing to the trait are determined and used to infer the behaviour of the trait. Dynamical solutions of the distribution of allelic effects and the distribution of the trait are found when all initial distributions of allelic effects are Gaussian and linkage disequilibria are neglected. Some results for the behaviour of the mean and the variance of genotypic effects of the population, when subject to a moving optimum, are derived. When the initial distributions of allelic effects are not Gaussian, but possess a small asymmetry, the mean and the variance of the allelic effects differ only slightly from the Gaussian results. By contrast, the third central moments of allelic effects, are, at all loci, strictly zero in the Gaussian case but are generally non-zero for non-symmetric initial distributions. To leading order in a quantitative measure of the asymmetry of the distribution, we determine the third central moment of allelic effects.

Alleles↗

PubMed2026

Recent gene duplication and structural remodeling drive rapid lineage-specific gene family evolution in plants.

Gene duplication promotes the generation of novel gene functions and trait diversity across species. Here, we present DupHIST, a computational pipeline that reconstructs the hierarchical timing of gene duplications by integrating maximum likelihood (ML)-based phylogeny with substitution-derived timing via statistical smoothing. Applied to over 4.5 million genes from 114 plant genomes, we successfully inferred duplication histories across nearly 130,000 orthogroups. This large-scale analysis showed that 53.0% of genes arose from recent, lineage-specific duplications, with high concentrations in particular multi-copy families. Among these, NLR, C48, and P450 families exemplified how recently duplicated genes undergo rapid stepwise structural remodeling. This process was primarily driven by small-scale mutations, including insertions, deletions, and frameshifts, that rapidly accumulated shortly after duplication. By resolving the precise duplication order, we reconstructed these architectural changes, thereby enabling both the inference of putative ancestral structures and the exploration of functional diversification arising from structural remodeling. Structure-based clustering further uncovered that recently duplicated, uncharacterized genes retain core domain structures resembling known functional proteins even across phylogenetically distant species lacking sequence homology. Our findings reveal that recent gene duplications and subsequent structural remodeling represent a widespread and lineage-specific force driving rapid diversification of gene families in plants.

Gene duplication history↗

PubMed2006

How and when did Old World ratsnakes disperse into the New World?

To examine Holarctic snake dispersal, we inferred a phylogenetic tree from four mtDNA genes and one scnDNA gene for most species of the Old World (OW) and New World (NW) colubrid group known as ratsnakes. Ancestral area distributions are estimated for various clades using divergence-vicariance analysis and maximum likelihood on trees produced using Bayesian inference. Dates of divergence for the same clades are estimated using penalized likelihood with statistically crosschecked calibration references obtained from the Miocene fossil record. With ancestral areas and associated dates estimated, various hypotheses concerning the age and environment associated with the origin of ratsnakes and the dispersal of NW taxa from OW ancestors were tested. Results suggest that the ratsnakes originated in tropical Asia in the late Eocene and subsequently dispersed to the Western and Eastern Palearctic by the early Oligocene. These analyses also suggest that the monophyletic NW ratsnakes (the Lampropeltini) diverged from OW ratsnakes and dispersed through Beringia in the late Oligocene/early Miocene when this land bridge was mostly composed of deciduous and coniferous forests.

Animals↗

PubMed2006

Random data set generation to support microarray analysis.

As microarray analyses become increasingly routine, involving the simultaneous investigation of huge numbers of genes, researchers can easily search for and uncover what appear to be promising patterns in their data. In such circumstances tools are needed to help decide the extent to which these patterns are meaningful or can be explained by chance alone. The purpose of this chapter is to describe examples of the use of microarray analysis for inferential purposes and how validation of inference is addressed by Monte-Carlo techniques, which essentially amounts to investigation of statistical methods on synthetic or random data sets.

Animals↗

PubMed1997

Secondary endpoints cannot be validly analyzed if the primary endpoint does not demonstrate clear statistical significance.

There is lack of consensus surrounding the interpretation of observed treatment effects for secondary clinical endpoints when the primary endpoint for which the clinical trial was initially designed does not meet the objective of a demonstrated effect. We provide some arguments to support caution in making inferences for secondary endpoints in this situation. We examine the definitions of primary and secondary endpoints within the context of a hypothesis-testing framework for multiple endpoints, and we address the relationship of the correlation structure of these endpoints and the statistical adjustments needed to preserve experiment-wise type I error for a valid inference. We also address the hypothesis-testing framework and the estimation framework for valid inference, focusing on the interpretation of p-values associated with differentially powered hypothesis tests for each endpoint to detect an important clinical effect. We point out the limitations on the strength of evidence (and quantification of uncertainty) for a secondary endpoint effect that can be derived from only one study and introduce the likelihood of replication of the finding in another study of identical size and design as a useful concept to guide this interpretation.

Clinical Trials as Topic↗

PubMed2001

Predicting crossover generation in DNA shuffling.

We introduce a quantitative framework for assessing the generation of crossovers in DNA shuffling experiments. The approach uses free energy calculations and complete sequence information to model the annealing process. Statistics obtained for the annealing events then are combined with a reassembly algorithm to infer crossover allocation in the reassembled sequences. The fraction of reassembled sequences containing zero, one, two, or more crossovers and the probability that a given nucleotide position in a reassembled sequence is the site of a crossover event are estimated. Comparisons of the predictions against experimental data for five example systems demonstrate good agreement despite the fact that no adjustable parameters are used. An in silico case study of a set of 12 subtilases examines the effect of fragmentation length, annealing temperature, sequence identity and number of shuffled sequences on the number, type, and distribution of crossovers. A computational verification of crossover aggregation in regions of near-perfect sequence identity and the presence of synergistic reassembly in family DNA shuffling is obtained.

Algorithms↗

PubMedDate not supplied

Symmetry in square contingency tables: tests of hypotheses and confidence interval construction.

Bowker's test, a generalization of McNemar's test, performs well under the hypothesis of symmetry, but the estimator of variance used in the test is biased when the table is asymmetric and this calls into question the test's performance in non-null situations. We seek an alternative to Bowker's test in search of methods for simultaneous inference that are valid when the hypothesis of symmetry is false. We apply multivariate normal theory to develop chi-square tests and simultaneous confidence intervals for inferences concerning symmetry in k X k contingency tables. We propose a modified Wald statistic as a competitor to Bowker's test. We also proffer quadratic estimators of confidence intervals. In large samples, the recommended test statistic rejects the null hypothesis at the stated level of significance when the null hypothesis is true and always rejects with greater power than Bowker's test. The proffered interval estimators provide good simultaneous coverage of the pairwise differences between the population proportions at the stated confidence level.

Biometry↗

PubMed2003

Gene networks inference using dynamic Bayesian networks.

This article deals with the identification of gene regulatory networks from experimental data using a statistical machine learning approach. A stochastic model of gene interactions capable of handling missing variables is proposed. It can be described as a dynamic Bayesian network particularly well suited to tackle the stochastic nature of gene regulation and gene expression measurement. Parameters of the model are learned through a penalized likelihood maximization implemented through an extended version of EM algorithm. Our approach is tested against experimental data relative to the S.O.S. DNA Repair network of the Escherichia coli bacterium. It appears to be able to extract the main regulations between the genes involved in this network. An added missing variable is found to model the main protein of the network. Good prediction abilities on unlearned data are observed. These first results are very promising: they show the power of the learning algorithm and the ability of the model to capture gene interactions.

Algorithms↗

PubMed2003

Sources of variation in ecophysiological parameters in Douglas-fir and grand fir canopies.

Forest process models predict ecosystem responses from climate variables and physiological parameters. The parameters describe key ecosystem attributes, often as lumped averages. However, the sources and magnitude of variation in these physiological parameters are unknown, which complicates sampling if models are to be parameterized with field measurements. We measured several key parameters, which had been identified by sensitivity analyses of three models, in Abies grandis (Dougl.) Lindl. and Pseudotsuga menziesii var. glauca (Beissn.) Franco trees throughout the growing season. Trees were sampled at eight sites across the interior northwest of the USA. At each site, fertilized and control plots were sampled. The design provided statistical replication for the analysis of variance within a site, allowing us to draw inferences about a regional population of stands. Specific leaf area (SLA) varied by canopy position and treatment (P = 0.0003), by date of sampling (P < 0.0001) and by species (P = 0.0188). Mass-based foliar nitrogen concentration (%N) increased during the summer in both species (P = 0.0019), but at a faster rate in P. menziesii var. glauca than in A. grandis. Sun foliage had a higher mean %N (1.00, SE = 0.02%) than shade foliage (0.92 +/- 0.01%). Apparent quantum yield (Phi) varied among treatments, between species and between canopy positions; each of these variables interacted with date of sampling (P = 0.0207, P < 0.0001 and P = 0.0344, respectively). In A. grandis, mean Phi values (+/- SE) were 0.048 +/- 0.006 mol CO2 (mol incident photon)-1 for sun foliage and 0.067 +/- 0.007 mol CO2 (mol incident photon)(-1) for shade foliage. In P. menziesii, the corresponding mean Phi values were 0.032 +/- 0.003 and 0.047 +/- 0.004 mol CO2 (mol incident photon)-1. Parameters SLA, %N and Phi were all influenced by date, fertilizer treatment, species and crown position. We discuss methods of inferring quantum yields from light response curves and their utility for parameterizing process models. Parameter mean values are presented for each site; these tables provide a documented data set for the parameterization of models describing the western interior forests of the USA.

Cell Respiration↗

PubMed2006

Autoimmune diseases co-occurring within individuals and within families: a systematic review.

BACKGROUND: Autoimmune diseases have been observed to coexist both within individuals and within families. It is unclear whether clinical reports of comorbid autoimmune diseases represent chance findings or true associations. This systematic review evaluates the current level of evidence on the coexistence of selected autoimmune diseases within individuals and families. We reviewed the associations among 4 TH1-associated autoimmune diseases: insulin-dependent diabetes mellitus, autoimmune (Hashimoto) thyroiditis, rheumatoid arthritis, and multiple sclerosis. METHODS: Studies quantifying the coexistence between the selected diseases, published through March 2004, were identified from Medline and Embase searches. Study eligibility was determined on the basis of preestablished criteria, and relevant data were extracted according to a fixed protocol. We determined the prevalence of comorbid autoimmune disease according to index disease and then compiled summary statistics. Heterogeneity among studies was assessed by exact likelihood ratio tests and Monte Carlo inference. RESULTS: We found 54 studies that met the eligibility criteria. Of these, 52 studies examined the coexistence of disease within individuals and 9 studies examined within-family associations. The majority of studies were uncontrolled and did not account for confounding factors. There was substantial evidence for heterogeneity among studies. Although inconclusive, the data appear to support an increased prevalence of autoimmune thyroiditis among patients with rheumatoid arthritis and those with insulin-dependent diabetes mellitus, and an inverse association between rheumatoid arthritis and multiple sclerosis. CONCLUSION: Although the available evidence does not permit firm conclusions regarding comorbidities among the selected autoimmune diseases, results are sufficiently suggestive to warrant further study.

Arthritis, Rheumatoid↗

PubMed2025

Identifying independent causal cell types for human diseases and risk variants.

The SNP-heritability of human diseases is extremely enriched in candidate regulatory elements (cREs) from disease-relevant cell types. Critical next steps are to understand whether these enrichments are driven by multiple causal cell types and whether individual variants impact disease risk via a single or multiple of cell types. Here, we propose CT-FM and CT-FM-SNP, 2 methods accounting for cREs shared across cell types to identify independent sets of causal cell types for a trait and its candidate causal variants, respectively. We applied CT-FM to 63 GWAS summary statistics (average N = 417K) using 924 cRE annotations, primarily from ENCODE4. CT-FM inferred 79 sets of causal cell types, with corresponding SNP-annotations explaining 39.0 ± 1.8% of trait SNP-heritability. It identified 14 traits with independent causal cell types, uncovering previously unexplored cellular mechanisms in height, schizophrenia and autoimmune diseases. We applied CT-FM-SNP to 39 UK Biobank traits and predicted high-confidence causal cell types for 3,091 candidate causal non-coding SNPs-trait pairs. Our results suggest that most SNPs affect a phenotype via a single set of cell types, whereas pleiotropic SNPs might target different cell types depending on the phenotype context. Altogether, CT-FM and CT-FM-SNP shed light on how genetic variants act collectively and individually at the cellular level to affect disease risk.

Journal Article↗

PubMed2026

Association Between the Root Canal Microbiome and Apical Lesion Size: An Observational Shotgun Metagenomic Study.

AIM: The aim was to characterize the taxonomic and functional composition of the microbiome involved in primary endodontic infections and to evaluate their association with the periapical lesion size using shotgun metagenomic sequencing. METHODOLOGY: Samples from primary root canal infections diagnosed with apical periodontitis were analysed with shotgun sequencing. Samples were classified according to the lesion size as small (< 3 mm) or large (> 7 mm). The bacterial DNA copies in each group were quantified by qPCR. Taxonomic and functional annotations were made using Bracken/Kraken2 and HUMAnN3 software. Species richness, Shannon, Simpson and Pielou indices were used to measure alpha diversity. The similarity of the bacterial communities between study groups was evaluated by Principal Coordinate Analysis based on Bray-Curtis distances. The ALDEx2 package was used to infer the differences between species, and the edgeR package for KEGG pathways. For all statistical analyses, p < 0.05 was considered as significant. RESULTS: A total of 49 samples were analysed, 27 with small lesions and 22 with large lesions. Species richness and Shannon indices showed differences between both groups, whereas no differences were seen according to Simpson and Pielou indices. A different community composition (PERMANOVA, p = 0.0019) was observed between the two groups. Three species were significantly enriched in the large lesion samples, Filifactor alocis, Lachnospiraceae bacterium oral taxon 500 and Olsenella uli, while three others were enriched in small lesion samples, Acinetobacter baumannii, Acinetobacter pittii and Cutibacterium acnes. Functionally, benzoate, flavonoid and steroid degradation, the sphingolipid signalling pathway and proteasome function were enriched in samples with large lesions. Monoterpenoid biosynthesis, phospholipase D signalling, the sulphur relay system and staurosporine biosynthesis were enriched in small lesions. CONCLUSIONS: Teeth with large periapical lesions harbour greater bacterial loads and exhibit a more diverse microbial community than those with small lesions. Differences in species-level taxonomic composition were observed between both groups. Functionally, large lesions are enriched in pathways associated with immune evasion and pro-inflammatory activity, whereas small lesions are characterized by pathways related to apoptosis, metabolic adaptation and anti-inflammatory processes. These findings suggest that lesion severity is also shaped by the functional potential of the microbiome to modulate host inflammation.

Humans↗

PubMed2001

Fine-scale genetically based differentiation of life-history traits in the perennial shrub Lupinus arboreus.

Across large spatial scales, plants often exhibit genetically based differentiation in traits that allow adaptation to local sites. At smaller spatial scales, sharp boundaries between edaphic conditions also can create strong gradients in selection that counteract gene flow and result in local adaptation. Few studies, however, have examined the degree to which continuous populations of perennial plants exhibit genetically based differentiation in life-history traits over small spatial scales. We quantified the degree of genetically based differentiation in adaptive traits among bush lupine (Lupinus arboreus) from nearby dune and grassland sites (sites separated by < 0.75 km) that formed part of a larger continuous population of L. arboreus. We also investigated the spatial genetic structure of bush lupine by examining how genetic structure differed between seeds and juvenile plants that were less than two years old. We calculated F-statistics from gel electrophoresis of 10 polymorphic loci. We then used these values to infer levels of gene flow. To examine differentiation in adaptive traits, we created full-sibling/half-sibling families of lupine within each area and established reciprocal common gardens at each site. Across two years, we measured canopy volume, flowering time, seed set, and mortality of progeny planted in each garden. Spatial genetic structure among seeds was virtually nonexistent (F(ST) = 0.002), suggesting that gene flow between the three areas could be quite high. However, genetic structure increased 20-fold among juvenile plants (F(ST) = 0.041). We found strong evidence for fine-scale genetically based differentiation and local adaptation in adaptive traits such as plant size, flowering phenology, fecundity, and mortality. Thus, it is likely that strong but differing selection regimes within each area drive spatial differentiation in lupine life-history traits.

Adaptation, Physiological↗

PubMed2004

Genetic polymorphisms of killer cell immunoglobulin-like receptors are associated with susceptibility to psoriasis vulgaris.

To elucidate the association between killer cell immunoglobulin-like receptors (KIRs) and psoriasis vulgaris (PV), we typed 14 KIR genes in 96 Japanese cases and 50 healthy controls using PCR with sequence-specific primers (PCR-SSP). Here we report an interesting association between certain KIRs and Japanese cases with PV. The frequencies of KIR2DS1 and KIR2DL5 were significantly increased in PV cases compared with controls (KIR2DS1, 43 of 96 (45%) in cases vs 14 of 50 (28%) in controls; KIR2DL5, 46 of 96 (48%) in cases vs 15 of 50 (30%) in controls, p<0.05 for both), and the frequency of carriage of at least one presumed "B" haplotype, inferred from patterns including KIR2DL2, KIR2DL5, and/or various combinations of activating KIRs, was also statistically increased in the PV cases (53 of 96 (55%) in cases vs 18 of 50 (36%) in controls, p<0.04). The increase in KIR2DS1 has also been observed in psoriatic arthritis, another HLA-Cw6-associated disease (Martin et al, 2002). Accordingly, KIR2DS1 may be a common denominator of both diseases.

Genetic Predisposition to Disease↗

PubMedDate not supplied

A critical analysis of the cumulative rainfall departure concept.

Evaluation of trends in time-series, such as precipitation or ground water levels, is an essential element in many hydrologic evaluations, including water resource studies and planning efforts. The cumulative rainfall departure (CRD) from normal rainfall is a concept sometimes utilized to evaluate the temporal correlation of rainfall with surface water or ground water levels. Permutations of the concept have been used to estimate recharge or aquifer storativity, and in attempts to explain declining ground water levels. The cumulative departure concept has hydrologic meaning in the short term, as a generalized evaluation of either meager or abundant rainfall, and when utilized in connection with a detailed water budget analysis can be used in a predictive fashion. However, the concept can be misapplied if extended over lengthy periods. Misapplication occurs because of several factors including the separation of the mean and median in nonnormal distributions, how the choice of beginning and end points of the data can affect the results, the lack of consideration that above-average rainfall can reset the hydrologic system without mathematically eliminating the accumulated deficit, and the lack of support for the necessary inference that rainfall events and hydrologic levels widely separated in time are linked. Standard statistical techniques are available to reliably determine trends and can provide rigorous statistical measures of the significance of conclusions. Misuse of the CRD concept can lead to erroneous and unsupported conclusions regarding hydrologic relationships and can potentially result in misguided water resource decision-making.

Decision Making↗

PubMed1994

Quantal mechanism of long-term potentiation in hippocampal mossy-fiber synapses.

1. The quantal mechanism underlying the expression of long-term potentiation (LTP) was studied in the mossy-fiber (mf) synapses of the rat hippocampus. Whole-cell recordings were used to measure the excitatory postsynaptic currents (EPSCs) before and after LTP induction in brain slices maintained at 31 +/- 1 degrees C. 2. Evoked EPSCs were recorded from 473 CA3 pyramidal neurons. The mf synapses were stimulated using paired pulses (40-ms interpulse interval) repeated every 2-10 s. At least 400 pairs of mf responses were obtained before and during the expression of LTP, which was produced by high-frequency (100 Hz) mf stimulation. Sufficiently stationary data were obtained from five neurons that exhibited LTP and that also satisfied strict criteria and procedures that are necessary for eliciting and identifying unitary mf responses. 3. Three independent lines of evidence implicated a presynaptic component to the mechanism underlying mf LTP. The first was based on a graphical version of the classical method of variance. The graphical variance (GV) method was evaluated by clamping the cell at two different holding potentials during paired-pulse facilitation (PPF). The results indicated that the GV method can distinguish changes in mean quantal content m and mean quantal size q in rat mf synapses. The same analysis, when applied to PPF before and after LTP induction, indicated that both result from an increase in m. 4. The second line of evidence was based on the classical method of failures. Consistent with the inference that mf LTP is due to an increase in m, there was a statistically significant reduction in the number of quantal release failures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2005

Genestrace: phenomic knowledge discovery via structured terminology.

The era of applied genomic medicine is quickly approaching accompanied by the increasing availability of detailed genetic information. Understanding the genetic etiology behind complex, multi-gene diseases remains an important challenge. In order to uncover the putative genetic etiology of complex diseases, we designed a method that explores the relationships between two major terminological and ontological resources: the Unified Medical Language System (UMLS) and the Gene Ontology (GO). The UMLS has a mainly clinical emphasis; Gene Ontology has become the standard for biological annotations of genes and gene products. Using statistical and semantic relationships within and between the two resources, we are able to infer relationships between disease concepts in the UMLS and gene products annotated using GO and its associated databases. We validated our inferences by comparing them to the known gene-disease relationships, as defined in the Online Mendelian Inheritance in Man's morbidmap (OMIM). The proof-of-concept methods presented here are unique in that they bypass the ambiguity of the direct extraction of gene or disease term from MEDLINE. Additionally, our methods provide direct links to clinically significant diseases through established terminologies or ontologies. The preliminary results presented here indicate the potential utility of exploiting the existing, manually curated relationships in biomedical resources as a tool for the discovery of potentially valuable new gene-disease relationships.

Computational Biology↗

PubMed1991

Occupational physician staffing in large US corporations.

Increased provision of occupational health services outside the workplace has been accompanied by signs of change in the quantity and structure of in-house corporate services. The occupational physician:employee ratios of the 25 largest US corporations were compared with each other, with the probable level of hazard as suggested by Bureau of Labor Statistics reports, and with both gross and per-capita measures of profitability. We infer that large corporations still employ a disproportionate share of available occupational health expertise. Oil and chemical companies employ the largest number of occupational physicians per capita; computer, electronics, and scientific equipment manufacturers employ the largest number of occupational physicians per capita relative to occupational illness/injury/lost workdays per capita. Tobacco companies employ the fewest occupational physicians by either measure. Corporate profitability explained more than half the variability for the one large within-sector comparison and appeared most related to employment practices for the most-successful and least-successful companies.

Industry↗