A mixture model-based approach to the clustering of microarray expression data

Motivation: This paper introduces the software EMMIX-GENE that has been developed for the specific purpose of a model-based approach to the clustering of microarray expression data, in particular, of tissue samples on a very large number of genes. The latter is a nonstandard problem in parametric cluster analysis because the dimension of the feature space (the number of genes) is typically much greater than the number of tissues. A feasible approach is provided by first selecting a subset of the genes relevant for the clustering of the tissue samples by fitting mixtures of t distributions to rank the genes in order of increasing size of the likelihood ratio statistic for the test of one versus two components in the mixture model. The imposition of a threshold on the likelihood ratio statistic used in conjunction with a threshold on the size of a cluster allows the selection of a relevant set of genes. However, even this reduced set of genes will usually be too large for a normal mixture model to be fitted directly to the tissues, and so the use of mixtures of factor analyzers is exploited to reduce effectively the dimension of the feature space of genes. Results: The usefulness of the EMMIX-GENE approach for the clustering of tissue samples is demonstrated on two well-known data sets on colon and leukaemia tissues. For both data sets, relevant subsets of the genes are able to be selected that reveal interesting clusterings of the tissues that are either consistent with the external classification of the tissues or with background and biological knowledge of these sets.

Genetic Covariation between Serum {gamma}-Glutamyltransferase Activity and Cardiovascular Risk Factors

Background: Several studies have shown that variation in serum gamma-glutamyltransferase (GGT) in the population is associated with risk of death or development of cardiovascular disease, type 2 diabetes, stroke, or hypertension. This association is only partly explained by associations between GGT and recognized risk factors. Our aim was to estimate the relative importance of genetic and environmental sources of variation in GGT as well as genetic and environmental sources of covariation between GGT and other liver enzymes and markers of cardiovascular risk in adult twin pairs. Methods: We recruited 1134 men and 2241 women through the Australian Twin Registry. Data were collected through mailed questionnaires, telephone interviews, and by analysis of blood samples. Sources of variation in GGT, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) and of covariation between GGT and cardiovascular risk factors were assessed by maximum-likelihood model-fitting. Results: Serum GGT, ALT, and AST were affected by additive genetic and nonshared environmental factors, with heritabilities estimated at 0.52, 0.48, and 0.32, respectively. One-half of the genetic variance in GGT was shared with ALT, AST, or both. There were highly significant correlations between GGT and body mass index; serum lipids, lipoproteins, glucose, and insulin; and blood pressure. These correlations were more attributable to genes that affect both GGT and known cardiovascular risk factors than to environmental factors. Conclusions: Variation in serum enzymes that reflect liver function showed significant genetic effects, and there was evidence that both genetic and environmental factors that affect these enzymes can also affect cardiovascular risk. (C) 2002 American Association for Clinical Chemistry.

Geographical variation in the penetrance of CDKN2A mutations for melanoma

Background: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium Methods: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14APF protein, and population melanoma incidence rates. All statistical tests were two-sided. Results: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P = .003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. Conclusions: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.

Reconciling paleodistribution models and comparative phylogeography in the Wet Tropics rainforest land snail Gnarosophia bellendenkerensis (Brazier 1875)

Comparative phylogeography has proved useful for investigating biological responses to past climate change and is strongest when combined with extrinsic hypotheses derived from the fossil record or geology. However, the rarity of species with sufficient, spatially explicit fossil evidence restricts the application of this method. Here, we develop an alternative approach in which spatial models of predicted species distributions under serial paleoclimates are compared with a molecular phylogeography, in this case for a snail endemic to the rainforests of North Queensland, Australia. We also compare the phylogeography of the snail to those from several endemic vertebrates and use consilience across all of these approaches to enhance biogeographical inference for this rainforest fauna. The snail mtDNA phylogeography is consistent with predictions from paleoclimate modeling in relation to the location and size of climatic refugia through the late Pleistocene-Holocene and broad patterns of extinction and recolonization. There is general agreement between quantitative estimates of population expansion from sequence data (using likelihood and coalescent methods) vs. distributional modeling. The snail phylogeography represents a composite of both common and idiosyncratic patterns seen among vertebrates, reflecting the geographically finer scale of persistence and subdivision in the snail. In general, this multifaceted approach, combining spatially explicit paleoclimatological models and comparative phylogeography, provides a powerful approach to locating historical refugia and understanding species' responses to them.

Mapping intertidal habitats and an evaluation of their conservation status in Queensland, Australia

The goal of biodiversity conservation has been described as the conservation of diversity at three levels: ecosystem, species and genetic diversity. Developing a representative system of marine protected areas (MPAs) is considered an effective way to achieve this goal in the marine environment. In the absence of detailed information relating to biological distributions there has been increasing use of biodiversity surrogates to determine MPA priorities at regional levels. The development of biodiversity surrogates at fine scales (i.e. habitats) will have an increasingly important role in the identification of sites that will contribute to a representative system of MPAs. This is because it will increase the likelihood that the system will adequately achieve biodiversity objectives by ensuring protection of a greater range of habitats and species. This article provides an explanation of an intertidal shoreline habitat surrogate used to describe 24,216km of Queensland's coastline. The protective status of intertidal habitats was evaluated to assist with designing a representative system of intertidal MPAs. (C) 2002 Elsevier Science Ltd. All rights reserved.

Mating behavior of Trissolcus basalis (Wollaston) (Hymenoptera : Scelionidae): Potential for outbreeding in a predominantly inbreeding species

The mating behavior of the quasi-gregarious egg parasitoid Trissolcus basalis (Wollaston) was investigated under field conditions. Trissolcus basalis has female-biased sex ratios and is a protandrous species, with males emerging 1-2 days before females. Males competed aggressively for control of the egg mass, with one male assuming dominance and control of the egg mass, although changes in dominance occurred at least once on each egg mass observed. Typical mating behavior involved the dominant male mating his sisters immediately upon their emergence from the egg mass. These behaviors are characteristic of an inbreeding species that manifests local mate competition. However, several aspects of the mating behavior of T. basalis are inconsistent with that of an inbreeding species. Over 18% of emerging females were not mated by the dominant male upon emergence, 13% of females were not observed to be mated at all and may have left their natal site as virgins, 25% of females were mated multiple times and sometimes by multiple males, females remained near the natal site for up to several hours after emergence before emigrating, and males dispersed away from the natal site during female emergence. Trissolcus basalis may be a predominantly inbreeding species but its emergence and mating behavior suggest that low-frequency outbreeding is also likely to occur.

Combining the analyses of introgressive hybridisation and linkage mapping to investigate the genetic architecture of population divergence in the lake whitefish (Coregonus clupeaformis, Mitchill)

Adaptation and reproductive isolation, the engines of biological diversity, are still elusive when discussing the genetic bases of speciation. Namely, the number of genes and magnitude of selection acting positively or negatively on genomic traits implicated in speciation is contentious. Here, we describe the first steps of an ongoing research program aimed at understanding the genetic bases of population divergence and reproductive isolation in the lake whitefish (Coregonus clupeaformis). A preliminary linkage map originating from a hybrid cross between dwarf and normal ecotypes is presented, whereby some of the segregating AFLP markers were found to be conserved among natural populations. Maximum-likelihood was used to estimate hybrid indices from non-diagnostic markers at 998 AFLP loci. This allowed identification of the most likely candidate loci that have been under the influence of selection during the natural hybridisation of whitefish originating from different glacial races. As some of these loci could be identified on the linkage map, the possibility that selection of traits in natural populations may eventually be correlated to specific chromosomal regions was demonstrated. The future prospects and potential of these approaches to elucidate the genetic bases of adaptation and reproductive isolation among sympatric ecotypes of lake whitefish is discussed.

Spatial structure and habitat variation in a grasshopper hybrid zone

A hybrid zone between the grasshoppers Chorthippus brunneus and C. jacobsi (Orthoptera: Acrididae) in northern Spain has been analyzed for variation in morphology and ecology. These species are readily distinguished by the number of stridulatory pegs on the hind femur. Both sexes are fully winged and inhabit disturbed habitats throughout the study area. We develop a maximum-likelihood approach to fitting a two-dimensional cline to geographical variation in quantitative traits and for estimating associations of population mean with local habitat. This method reveals a cline in peg number approximately 30 km south of the Picos de Europa Mountains that shows substantial deviations in population mean compared with the expectations of simple tension zone models. The inclusion of variation in local vegetation in the model explains a significant proportion of the residual variation in peg number, indicating that habitat-genotype associations contribute to the observed spatial pattern. However, this association is weak, and a number of populations continue to show strong deviations in mean even after habitat is included in the final model. These outliers may be the result of long-distance colonization of sites distant from the cline center or may be due to a patchy pattern of initial contact during postglacial expansion. As well as contrasting with the smooth hybrid zones described for Chorthippus parallelus, this situation also contrasts with the mosaic hybrid zones observed in Gryllus crickets and in parts of the hybrid zone between Bombina toad species, where habitat-genotype associations account for substantial amounts of among-site variation.

Local complexity of Delone sets and crystallinity

This paper characterizes when a Delone set X in R-n is an ideal crystal in terms of restrictions on the number of its local patches of a given size or on the heterogeneity of their distribution. For a Delone set X, let N-X (T) count the number of translation-inequivalent patches of radius T in X and let M-X (T) be the minimum radius such that every closed ball of radius M-X(T) contains the center of a patch of every one of these kinds. We show that for each of these functions there is a gap in the spectrum of possible growth rates between being bounded and having linear growth, and that having sufficiently slow linear growth is equivalent to X being an ideal crystal. Explicitly, for N-X (T), if R is the covering radius of X then either N-X (T) is bounded or N-X (T) greater than or equal to T/2R for all T > 0. The constant 1/2R in this bound is best possible in all dimensions. For M-X(T), either M-X(T) is bounded or M-X(T) greater than or equal to T/3 for all T > 0. Examples show that the constant 1/3 in this bound cannot be replaced by any number exceeding 1/2. We also show that every aperiodic Delone set X has M-X(T) greater than or equal to c(n)T for all T > 0, for a certain constant c(n) which depends on the dimension n of X and is > 1/3 when n > 1.

Permian Palynofloral Assemblages of the Chaco-Paraná Basin (Argentina): Systematics and Stratigraphic Significance

Core samples from an upper Palaeozoic, partly glaciogene borehole section (Ordóñez: YPF Cd O es-1) in the southern Chaco-Paraná Basin (Córdoba Province, northeastern Argentina) have produced variable palynological results. Samples from the lower part of the section (i.e., from the diamictite-bearing upper Ordóñez Formation) proved non-palyniferous. Those from the overlying, essentially post-glacial Victoriano Rodríguez Formation yielded spore-pollen assemblages in varying concentrations and in good to excellent states of preservation, thus providing the material basis for the present account. The palynomorph taxa represented in the assemblages comprise 20 species of spores (distributed among 14 genera) and 25 species of pollen grains (14 genera). The majority of the species are described in systematic detail. One trilete spore species -Convolutispora archangelskyi- is newly proposed. Several other, possibly new species (three of trilete spores, one of monosaccate pollen) are represented insufficiently for other than informal naming. The following new combinations, also of trilete spore species, are instituted: Converrucosisporites confluens (Archangelsky & Gamerro, 1979), C. micronodosus (Balme & Hennelly, 1956), and Anapiculatisporites tereteangulatus (Balme & Hennelly, 1956). Sculptural intergradation (granulate through verrucate) among three species -Granulatisporites austroamericanus Archangelsky & Gamerro, 1979, C. confluens, and C. micronodosus- prompts their informal grouping, proposed herein, as the Converrucosisporites confluens Morphon, which is also recognizable elsewhere in the Gondwanan Permian. The possibility, if not the likelihood, that G. austroamericanus is conspecific with Microbaculispora tentula Tiwari, 1965 is canvassed. The palynologically productive borehole section of the Victoriano Rodríguez Formation studied here is assignable to the middle to upper Cristatisporites Zone and to the succeeding Striatites Zone, thus signifying an Early Permian age for this section and facilitating correlation with strata of the Paraná and Paganzo Basins. From this and prior work, the Ordóñez well sequence embracing the Ordóñez and Victoriano Rodríguez Formations includes, in addition to the latter two zones, the preceding (late Pennsylvanian) Potonieisporites-Lundbladispora Zone which is known from the lower to mid-upper part of the Ordóñez Formation. Thus, the Carboniferous-Permian boundary can be inferred to lie within the upper part of the latter formation

Estimating and evaluating the statistics of gapped local-alignment scores

We present a novel maximum-likelihood-based algorithm for estimating the distribution of alignment scores from the scores of unrelated sequences in a database search. Using a new method for measuring the accuracy of p-values, we show that our maximum-likelihood-based algorithm is more accurate than existing regression-based and lookup table methods. We explore a more sophisticated way of modeling and estimating the score distributions (using a two-component mixture model and expectation maximization), but conclude that this does not improve significantly over simply ignoring scores with small E-values during estimation. Finally, we measure the classification accuracy of p-values estimated in different ways and observe that inaccurate p-values can, somewhat paradoxically, lead to higher classification accuracy. We explain this paradox and argue that statistical accuracy, not classification accuracy, should be the primary criterion in comparisons of similarity search methods that return p-values that adjust for target sequence length.

Guideline-discordant care in acute myocardial infarction: predictors and outcomes

Objectives: To determine (i) factors which predict whether patients hospitalised with acute myocardial infarction (AMI) receive care discordant with recommendations of clinical practice guidelines; and (ii) whether such discordant care results in worse outcomes compared with receiving guideline-concordant care. Design: Retrospective cohort study. Setting: Two community general hospitals. Participants: 607 consecutive patients admitted with AMI between July 1997 and December 2000. Main outcome measures: Clinical predictors of discordant care; crude and risk-adjusted rates of inhospital mortality and reinfarction, and mean length of hospital stay. Results: At least one treatment recommendation for AMI was applicable for 602 of the 607 patients. Of these patients, 411(68%) received concordant care, and 191 (32%) discordant care. Positive predictors at presentation of discordant care were age > 65 years (odds ratio [OR], 2.5; 95% Cl, 1.7-3.6), silent infarction (OR, 2.7; 95% Cl, 1.6-4.6), anterior infarction (OR, 2.5; 95% Cl, 1.7-3.8), a history of heart failure (OR, 6.3; 95% Cl, 3.7-10.7), chronic atrial fibrillation (OR, 3.2; 95% Cl, 1.5-6.4); and heart rate greater than or equal to 100 beats/min (OR, 2.1; 95% Cl, 1.4-3.1). Death occurred in 12.0% (23/191) of discordant-care patients versus 4.6% (19/411) of concordant-care patients (adjusted OR, 2.42; 95% Cl, 1.22-4.82). Mortality was inversely related to the level of guideline concordance (P = 0.03). Reinfarction rates also tended to be higher in the discordant-care group (4.2% v 1.7%; adjusted OR, 2.5; 95% Cl, 0.90-7.1). Conclusions: Certain clinical features at presentation predict a higher likelihood of guideline-discordant care in patients presenting with AMI Such care appears to increase the risk of inhospital death.

Testing the relationship between morphological and molecular rates of change along phylogenies

Molecular evolution has been considered to be essentially a stochastic process, little influenced by the pace of phenotypic change. This assumption was challenged by a study that demonstrated an association between rates of morphological and molecular change estimated for total-evidence phylogenies, a finding that led some researchers to challenge molecular date estimates of major evolutionary radiations. Here we show that Omland's (1997) result is probably due to methodological bias, particularly phylogenetic nonindependence, rather than being indicative of an underlying evolutionary phenomenon. We apply three new methods specifically designed to overcome phylogenetic bias to 13 published phylogenetic datasets for vertebrate taxa, each of which includes both morphological characters and DNA sequence data. We find no evidence of an association between rates of molecular and morphological rates of change.

Nonverbal narratives: Listening to people with severe intellectual disability

This article describes an exploratory study that examined the perspectives of practitioners who spend much of their working day listening to and in some ways interpreting for people with severe intellectual disabilities. On the basis of focus group interviews with 23 professional disability-sector workers, including speech therapists, psychologists, and human service workers, the article reports on the importance of a practitioner's values and experience in successful interactions with individuals who rely on self-developed nonsymbolic communication repertoires. The article includes a discussion of the likelihood of including individuals with severe intellectual disabilities in narrative research.