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PubMed2000

General formalism for phase combination and phase refinement: a statistical thermodynamics approach in reciprocal space.

The mean-field optimization methodology has been used to recast in a single formalism the problem of phase optimization using an arbitrary energy function in the presence of an experimentally determined phase probability distribution function. It results naturally in the generalization of the notions of figure of merit and centroid phase where the weight of the energy refinement is controlled by an effective temperature in a self-consistent manner. In the limit of high temperature, the formalism reduces of course to the Blow & Crick [Acta Cryst. (1959), 12, 794-802] classical treatment. If a model is available, Sim's [Acta Cryst. (1960), 13, 511-512] weighting scheme for a combined map appears as the first step of a refinement to be conducted until self-consistency is achieved. Assuming that MIR phases exist and that they agree reasonably well with the phases of the model, a first-order expansion gives an estimate of the changes of weights and phases to be performed for the Fourier synthesis. This provides for a new way of doing phase combination that might prove useful in challenging cases of model refinement, e.g. in large macromolecular complexes. Thermodynamic considerations have been used to discuss the best determination of weights in phase refinement; they also suggest that a variational expression of maximum likelihood is best suited as a target for refinement because it is the free energy of the system. The formalism readily allows use of solvent flattening, density averaging and the atomicity criterion to refine phases, and automatically assigns a figure of merit to each reflection. Numerical tests of the method are presented in an attempt to resolve the phase-ambiguity problem of protein crystallography in the centrosymmetric P¿1¿ space group using an energy derived from the Sayre equation.

Biopolymers↗

PubMed1999

Interactions between electronic article surveillance systems and implantable cardioverter-defibrillators.

BACKGROUND: In patients with implantable cardioverter-defibrillators (ICDs). inappropriate shocks have been reported with exposure to electronic article surveillance systems. The risk to patients with ICDs of walking through or lingering near surveillance systems requires further investigation. METHODS AND RESULTS: We evaluated the response in ICD function in 170 subjects during a 10- to 15-second midgate walk-through of and during extreme (2 minutes within 6 in of the gate) exposure to 3 common article surveillance systems. Complete testing was done in 169 subjects. During a 10- to 15-second (very slow) walk-through of the 3 surveillance systems, no interactions were observed that would negatively affect ICD function. During extreme exposure (169 subjects) and during extreme exposure and pacing via the ICD (126 subjects), interactions between the ICD and the article surveillance systems were observed in 19 subjects. In 7 subjects, this interaction was clinically relevant and would have likely (3 subjects) and possibly (4 subjects) resulted in ICD shocks. In 12 subjects, the interaction was minor. CONCLUSIONS: It is safe for a patient with an ICD to walk through electronic article surveillance systems. Lingering in a surveillance system may result in an inappropriate ICD shock.

Cardiac Pacing, Artificial↗

PubMed1993

Segregation analysis of fat mass and other body composition measures derived from underwater weighing.

Segregation patterns of three body composition measures which were derived from underwater weighing were evaluated in a random sample of 176 French-Canadian families. Two of the variables can be considered as primary partitions of weight (fat mass [FM] and fat-free mass [FFM]), while the remaining variable (percent body fat [%BF]) is a derived index combining the measures of both fat and fat-free weight. This study represents the first report investigating major gene effects for these measures. Segregation analyses revealed that a major locus hypothesis could not be rejected for two of the three phenotypes. The single exception was FFM, for which nearly 60% of the variance was accounted for by a non-Mendelian major effect, which may reflect environmentally based commingling or may be in part a function of gene-environment interactions or correlations. In contrast to the results for FFM, the results for each of FM and %BF were similar and suggested a major locus which accounted for 45% of the variance, with an additional 22%-26% due to a multifactorial component. Given the similarity of the major gene characteristics for these two phenotypes, the possibility that the same gene underlies both measures warrants investigation. A reasonable hypothesis is to consider genes that may influence nutrient partitioning, as the family of candidate genes to receive the major attention.

Adipose Tissue↗

PubMed1998

Estimating the cumulative incidence of HIV infection among persons with haemophilia in the United States of America.

We used complementary approaches to estimate the cumulative incidence of infection with the human immunodeficiency virus (HIV) among persons with haemophilia in the United States of America. One approach, ratio estimation, divided the cumulative number of haemophiliacs diagnosed with acquired immunodeficiency syndrome (AIDS) in the United States by the corresponding cumulative proportion with AIDS among HIV-positive subjects in the Multicenter Hemophilia Cohort Study (MHCS). The other approach, back-calculation, reconstructed past HIV incidence from national surveillance of AIDS using essentially non-parametric estimates of the hazard functions for AIDS and for pre-AIDS death. We derived confidence intervals that fully incorporated uncertainty about the hazard functions. Results from the two approaches were consistent. Around 9200 haemophiliacs became infected during the course of the epidemic. Of them, around 7000 were living with HIV or AIDS as of 31 December 1992 and at least 5630 as of 31 December 1995. Credible calculations for this group must account for those who die before AIDS and for the significantly longer incubation times in those infected as children or adolescents. The consistency of back-calculation and cohort data in haemophiliacs supports the use of back-calculation to estimate prevalence in other populations.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Modeling age of onset and residual familial correlations for the linkage analysis of bipolar disorder.

We applied regressive modeling to the data described by Stine et al. [1995] and further explored the possible linkage of bipolar disorder to marker D18S41 on chromosome 18. We performed analyses to determine age-dependent penetrance functions that best fit the data and that allow for residual familial correlations. Specifically, we introduce here a simple method to allow for a sibling correlations. that is not due to segregation at the linked locus, and then extend the results of Stine et al. [1995] by using the best fitting "regressive" model of this kind as input into a lod score linkage analysis. Although a formal segregation analysis was not attempted, a surprising finding was that, except for doubtful linkage to D18S41, there is little evidence for genetic transmission of bipolar disorder in these families.

Age of Onset↗

PubMed1999

Brain segmentation and the generation of cortical surfaces.

This paper describes methods for white matter segmentation in brain images and the generation of cortical surfaces from the segmentations. We have developed a system that allows a user to start with a brain volume, obtained by modalities such as MRI or cryosection, and constructs a complete digital representation of the cortical surface. The methodology consists of three basic components: local parametric modeling and Bayesian segmentation; surface generation and local quadratic coordinate fitting; and surface editing. Segmentations are computed by parametrically fitting known density functions to the histogram of the image using the expectation maximization algorithm [DLR77]. The parametric fits are obtained locally rather than globally over the whole volume to overcome local variations in gray levels. To represent the boundary of the gray and white matter we use triangulated meshes generated using isosurface generation algorithms [GH95]. A complete system of local parametric quadratic charts [JWM+95] is superimposed on the triangulated graph to facilitate smoothing and geodesic curve tracking. Algorithms for surface editing include extraction of the largest closed surface. Results for several macaque brains are presented comparing automated and hand surface generation.

Algorithms↗

PubMed1997

The prediction of child maltreatment in Greek families.

OBJECTIVE: The study had two aims: First, to identify characteristics of physically maltreating families in the Attica region of Greece; and second, to produce a checklist of high risk predictors which may be used for screening, as an assessment, to enable secondary prevention of physical abuse and neglect. METHOD: A case control design was used with individual matching. The sample comprised 197 physically abused and neglected children and their families referred to a multidisciplinary team. These were compared with 163 control children and their families attending a community health center. RESULTS: The findings suggest that abusing families differ from controls on a number of variables related to child, parental, and family characteristics. The statistical analysis produced a checklist of 15 Predictors. Their classification into High, Medium, and Low Predictors pointed out that the most prominent characteristics were those associated with parents' own adverse life experiences, mental health problems, bad quality of relationship between spouses, and parental neglect of the child's hygiene. The predictive ability of the checklist produced a sensitivity of 92% and a specificity of 96% (logistic regression) and a sensitivity of 86.8% and a specificity of 96.3% (discriminant function). The use of this checklist for screening is discussed with emphasis on methodological and ethical issues. Special emphasis is given on the cultural relevance of such an application within the Greek cultural milieu. CONCLUSION: The findings indicate that secondary prevention of child maltreatment in Greece is feasible by using a checklist of risk factors as predictors. Such screening should be accompanied by clinical assessment based on qualitative aspects of mother-infant interaction. Special emphasis should be given to the cultural relevance of this approach while ethical issues should be considered.

Adolescent↗

PubMed2005

Are fluctuating asymmetry studies adequately sampled? Implications of a new model for size distribution.

Previous work on fluctuating asymmetry (FA) has highlighted its controversial relationship with environmental stress and genetic architecture. While size-based measures of FA have been assumed to have half-normal distributions within populations, studies of model developmental mechanisms have suggested other plausible distributions for FA. We investigated the distribution of FA in large empirical data sets of wing shape and wing size asymmetry from three species of insects (cotton aphid Aphis gossipyii Glover, honeybee Apis mellifera, and long-legged fly Chrysosoma crinitus). Regardless of measurement method, FA was best described by a double Pareto-lognormal (DPLN) distribution or one of its limiting functional forms. To investigate convergence of mean sample FA to the population mean at various sample sizes, we sampled repeatedly under a DPLN distribution using parameter values that best fitted our data. Sample variances are much larger, and hence, convergence is slowed considerably with univariate or multivariate size-based measures of FA in contrast to a multivariate shape-based measure of FA. We suggest that much of the past work on FA may be undersampled, and we recommend using multivariate shape-based approaches or collecting larger data sets in future studies. We also discuss the implications of the DPLN distribution for understanding the developmental mechanisms underlying FA.

Animals↗

PubMed1999

Model choice and influential cases for survival studies.

Deletion diagnostics are developed for identifying observations that influence the estimates of regression parameters and the mixture parameter in the families of relative risk functions for failure time data. The diagnostic for the regression parameters is a generalization of Cain and Lange's (1984, Biometrics 40, 493-499) measure of individual influence. The generalizations of martingale residuals, Schoenfeld's partial residuals (1982, Biometrika 69, 239-241), and score residuals by Therneau, Grambsch, and Fleming (1990, Biometrika 77, 147-160) are also obtained. The influence of some observations on regression parameters can be drastically modified as the mixture parameter changes, even for a very small change. In addition, adding or deleting some observations might result in choosing different models. The diagnostics are applied to a family proposed by Guerrero and Johnson (1982, Biometrika 69, 309-314). One illustrative example is presented.

Biometry↗

PubMed2004

Molecular phylogenetics of squamata: the position of snakes, amphisbaenians, and dibamids, and the root of the squamate tree.

Squamate reptiles (snakes, lizards, and amphisbaenians) serve as model systems for evolutionary studies of a variety of morphological and behavioral traits, and phylogeny is crucial to many generalizations derived from such studies. Specifically, the traditional dichotomy between Iguania (anoles, iguanas, chameleons, etc.) and Scleroglossa (skinks, geckos, snakes, etc.) has been correlated with major evolutionary shifts within Squamata. We present a molecular phylogenetic study of 69 squamate species using approximately 4600 (2876 parsimony-informative) base pairs (bp) of DNA sequence data from the nuclear genes RAG-1(approximately 2750 bp) and c-mos(approximately 360 bp) and the mitochondrial ND2 region (approximately 1500 bp), sampling all major clades and most major subclades. Under our hypothesis, species previously placed in Iguania, Anguimorpha, and almost all recognized squamate families form strongly supported monophyletic groups. However, species previously placed in Scleroglossa, Varanoidea, and several other higher taxa do not form monophyletic groups. Iguania, the traditional sister group of Scleroglossa, is actually highly nested within Scleroglossa. This unconventional rooting does not seem to be due to long-branch attraction, base composition biases among taxa, or convergence caused by similar selective forces acting on nonsister taxa. Studies of functional tongue morphology and feeding mode have contrasted the similar states found in Sphenodon(the nearest outgroup to squamates) and Iguania with those of Scleroglossa, but our findings suggest that similar states in Sphenodonand Iguania result from homoplasy. Snakes, amphisbaenians, and dibamid lizards, limbless forms whose phylogenetic positions historically have been impossible to place with confidence, are not grouped together and appear to have evolved this condition independently. Amphisbaenians are the sister group of lacertids, and dibamid lizards diverged early in squamate evolutionary history. Snakes are grouped with iguanians, lacertiforms, and anguimorphs, but are not nested within anguimorphs.

Animals↗

PubMed2001

Exploring extra-binomial variation in teratology data using continuous mixtures.

Discrete data from animal teratology experiments are known to exhibit extra-binomial variation. For example, we discuss a dominant lethal assay experiment in which male mice are exposed to various levels of radiation and are then mated to females. The response of interest is the number of resorptions out of the number of implantations. Most statistical work on analyzing such data has focused on modeling response rates as a function of dose of a suspected teratogen (radiation in this case) while accounting for the extra-binomial variability when calculating standard errors of the regression coefficients. Sometimes, however, when an unobserved genetic or exposure variable is suspected, the shape of the mixing distribution is of interest. We propose a mixture of beta-binomials (MBB) family of distributions that includes the non-parametric mixture of binomials model of Laird (1978) as a special case. The MBB family can accommodate a mixing distribution with one or more modes, and we develop a bootstrap test for multimodality. We apply the method to data from a dominant lethal teratology experiment.

Animals↗

PubMed2001

Lessons from the past: evolutionary impacts of mass extinctions.

Mass extinctions have played many evolutionary roles, involving differential survivorship or selectivity of taxa and traits, the disruption or preservation of evolutionary trends and ecosystem organization, and the promotion of taxonomic and morphological diversifications-often along unexpected trajectories-after the destruction or marginalization of once-dominant clades. The fossil record suggests that survivorship during mass extinctions is not strictly random, but it often fails to coincide with factors promoting survival during times of low extinction intensity. Although of very serious concern, present-day extinctions have not yet achieved the intensities seen in the Big Five mass extinctions of the geologic past, which each removed > or =50% of the subset of relatively abundant marine invertebrate genera. The best comparisons for predictive purposes therefore will involve factors such as differential extinction intensities among regions, clades, and functional groups, rules governing postextinction biotic interchanges and evolutionary dynamics, and analyses of the factors that cause taxa and evolutionary trends to continue unabated, to suffer setbacks but resume along the same trajectory, to survive only to fall into a marginal role or disappear ("dead clade walking"), or to undergo a burst of diversification. These issues need to be addressed in a spatially explicit framework, because the fossil record suggests regional differences in postextinction diversification dynamics and biotic interchanges. Postextinction diversifications lag far behind the initial taxonomic and morphological impoverishment and homogenization; they do not simply reoccupy vacated adaptive peaks, but explore opportunities as opened and constrained by intrinsic biotic factors and the ecological and evolutionary context of the radiation.

Animals↗

PubMed2004

VH gene segments in the mouse and human genomes.

We have examined the mouse genome sequence to determine its VH gene segment repertoire. In all, 141 segments are mapped to a 3 Mb region of chromosome 12. There is evidence that 92 of these are functional in the mouse strain used for the genome sequence, C57BL/6J; 12 are functional in other mouse strains, and 37 are pseudogenes. The mouse VH gene segment repertoire is therefore twice the size of that in humans. The mouse and human loci bear no large-scale similarity to each other. The 104 functional segments belong to one of the 15 known sequence subgroups, which have been further clustered into eight sets here. Seven of these sets, comprising 101 sequences, are related to five of the human VH families and have the same canonical structures in their hypervariable regions. Duplication of members of one set in the distal half of the locus is mainly responsible for the larger size of the mouse repertoire. Phylogenetic analysis of the VH segments indicates that most of the sequences in the human and mouse VH loci have arisen subsequent to the divergence of the two organisms from their common ancestor.

Amino Acid Sequence↗

PubMed2001

The adaptive evolution database (TAED).

BACKGROUND: The Master Catalog is a collection of evolutionary families, including multiple sequence alignments, phylogenetic trees and reconstructed ancestral sequences, for all protein-sequence modules encoded by genes in GenBank. It can therefore support large-scale genomic surveys, of which we present here The Adaptive Evolution Database (TAED). In TAED, potential examples of positive adaptation are identified by high values for the normalized ratio of nonsynonymous to synonymous nucleotide substitution rates (KA/KS values) on branches of an evolutionary tree between nodes representing reconstructed ancestral sequences. RESULTS: Evolutionary trees and reconstructed ancestral sequences were extracted from the Master Catalog for every subtree containing proteins from the Chordata only or the Embryophyta only. Branches with high KA/KS values were identified. These represent candidate episodes in the history of the protein family when the protein may have undergone positive selection, where the mutant form conferred more fitness than the ancestral form. Such episodes are frequently associated with change in function. An unexpectedly large number of families (between 10% and 20% of those families examined) were found to have at least one branch with high KA/KS values above arbitrarily chosen cut-offs (1 and 0.6). Most of these survived a robustness test and were collected into TAED. CONCLUSIONS: TAED is a raw resource for bioinformaticists interested in data mining and for experimental evolutionists seeking candidate examples of adaptive evolution for further experimental study. It can be expanded to include other evolutionary information (for example changes in gene regulation or splicing) placed in a phylogenetic perspective.

Adaptation, Physiological↗

PubMed1995

Transient effects in the Cox proportional hazards regression model.

We consider a model for mortality rates that includes both the long and short term effects of switching from an initial to a second state, for example, when patients receive an initial treatment and then switch to a second treatment. We include transient effects associated with the switch in the model through the use of time-dependent covariates. One can choose the form of the time-dependent covariate to correspond with a variety of possible transition patterns. We use an exponential decay model to compare the survival experience of transplant versus dialysis treatment of end stage renal disease (ESRD) patients from the Michigan Kidney Registry (MKR). This model involves a hazard function that has an initial effect in mortality at the time of transplant, expected to be higher, followed by a smooth exponential decay to a long term effect, expected to be lower than the risk for those remaining on dialysis. Cox and Oakes used this model to analyse the Stanford Heart Transplant data. The model implicitly suggests there is a time at which the hazard curves (and survival curves) for the treatment groups cross. Those crossing times are useful in advising patients who have the option of receiving a transplant. We describe methods for obtaining estimates of the crossing times and their associated variances, and then apply them in analysing the MKR data.

Cadaver↗

PubMed2004

Elevated salinity selects for a less diverse ammonia-oxidizing population in aquarium biofilters.

The activity and changes in the structure of the community of the ammonia-oxidizing bacteria belonging to the Betaproteobacteria were monitored in freshwater and artificial seawater biofilters for two months after inoculation with a commercial nitrifying consortium. Both in freshwater and artificial seawater, ammonium oxidation proceeded immediately after addition of the inoculum, although initial activity in artificial seawater was lower than in freshwater. Denaturing gradient gel electrophoresis of the ammonia-oxidizing bacterial community of the inoculum and the freshwater and the artificial seawater aquaria as a function of time showed that initially only one dominant ammonia-oxidizer, closely related to Nitrosomonas marina, was detectable in all the systems. The fingerprint of the ammonia-oxidizing bacterial community in the artificial seawater biofilters continued to be dominated by this single band. In the freshwater aquaria, in contrast, the composition of the ammonia-oxidizer community became more diverse after one month, with 4-7 new bands appearing in the denaturing gradient gel fingerprint. Since the inoculum is cultivated at an average salinity of 11 gl(-1), it is argued that the elevated salinity selects for a less diverse ammonia-oxidizer community in the inoculum and the artificial seawater aquaria.

Ammonia↗

PubMed2004

The structure, expression and function prediction of DAZAP2, a down-regulated gene in multiple myeloma.

In our previous studies, DAZAP2 gene expression was down-regulated in untreated patients of multiple myeloma (MM). For better studying the structure and function of DAZAP2, a full-length cDNA was isolated from mononuclear cells of a normal human bone marrow, sequenced and deposited to Genbank (AY430097). This sequence has an identical ORF (open reading frame) as the NM_014764 from human testis and the D31767 from human cell line KG-1. Phylogenetic analysis and structure prediction reveal that DAZAP2 homologues are highly conserved throughout evolution and share a polyproline region and several potential SH2/SH3 binding sites. DAZAP2 occurs as a single-copy gene with a four-exon organization. We further noticed that the functional DAZAP2 gene is located on Chromosome 12 and its pseudogene gene is on Chromosome 2 with electronic location of human chromosome in Genbank, though no genetic abnormalities of MM have been reported on Chromosome 12. The ORF of human DAZAP2 encodes a 17-kDa protein, which is highly similar to mouse Prtb. The DAZAP2 protein is mainly localized in cytoplasm with a discrete pattern of punctuated distribution. DAZAP2 may associate with carcinogenesis of MM and participate in yet-to-be identified signaling pathways to regulate proliferation and differentiation of plasma cells.

Amino Acid Sequence↗

PubMed2004

Costs of resistance: genetic correlations and potential trade-offs in an insect immune system.

Theory predicts that natural selection will erode additive genetic variation in fitness-related traits. However, numerous studies have found considerable heritable variation in traits related to immune function, which should be closely linked to fitness. This could be due to trade-offs maintaining variation in these traits. We used the Egyptian cotton leafworm, Spodoptera littoralis, as a model system to examine the quantitative genetics of insect immune function. We estimated the heritabilities of several different measures of innate immunity and the genetic correlations between these immune traits and a number of life history traits. Our results provide the first evidence for a potential genetic trade-off within the insect immune system, with antibacterial activity (lysozyme-like) exhibiting a significant negative genetic correlation with haemocyte density, which itself is positively genetically correlated with both haemolymph phenoloxidase activity and cuticular melanization. We speculate on a potential trade-off between defence against parasites and predators, mediated by larval colour, and its role in maintaining genetic variation in traits under natural selection.

Analysis of Variance↗