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PubMed2004

Score tests for dose effect in the presence of non-responders.

When only a certain proportion of subjects respond to treatment ('responders') or may never experience an event of interest (thus 'cured'), mixture models often lead to increased understanding of the treatment or disease process. This paper focuses on hypothesis testing in a dose-response framework and shows that increased power is possible by using a mixture model where both the logit of the response rate and the response mean are linear functions of the dose level. Three score tests are developed for testing an overall effect and permutation methods are used to control the type I error. Extensive simulations establish the power properties of the tests and show that our proposed score test has the best performance. The approach is illustrated by a multi-country clinical trial of rapid acting Intramuscular Olanzapine.

Algorithms↗

PubMed2006

Evolutionary rate variation among vertebrate beta globin genes: implications for dating gene family duplication events.

A comprehensive dataset of 62 beta globin gene sequences from various vertebrates was compiled to test the molecular clock and to estimate dates of gene duplications. We found that evolution of the beta globin family of genes is not clock-like, a result that is at odds with the common use of this family as an example of a constant rate of evolution over time. Divergence dates were estimated either with or without assuming the molecular clock, and both analyses produced similar date estimates, which are also in general agreement with estimates reported previously. In addition we report date estimates for seven previously unexamined duplication events within the beta globin family. Despite multiple sources of rate variation, the average rate across the beta globin phylogeny yielded reasonable estimates of divergence dates in most cases. Exceptions were cases of gene conversion, where it appears to have led to underestimates of divergence dates. Our results suggest (i) the major duplications giving rise to the paralogous beta globin genes are associated with significant evolutionary rate variation among gene lineages; and (ii) genes arising from more recent gene duplications (e.g., tandem duplications within lineages) do not appear to differ greatly in rate. We believe this pattern reflects a complex interplay of evolutionary forces where natural selection for diversifying paralogous functions and lineage-specific effects contribute to rate variation on a long-term basis, while gene conversion tends to increase sequence similarity. Gene conversion effects appear to be stronger on recent gene duplicates, as their sequences are highly similar. Lastly, phylogenetic analyses do not support a previous report that avian globins are members of a relic lineage of omega globins.

Animals↗

PubMed1997

A Weibull regression model with gamma frailties for multivariate survival data.

Frequently in the analysis of survival data, survival times within the same group are correlated due to unobserved co-variates. One way these co-variates can be included in the model is as frailties. These frailty random block effects generate dependency between the survival times of the individuals which are conditionally independent given the frailty. Using a conditional proportional hazards model, in conjunction with the frailty, a whole new family of models is introduced. By considering a gamma frailty model, often the issue is to find an appropriate model for the baseline hazard function. In this paper a flexible baseline hazard model based on a correlated prior process is proposed and is compared with a standard Weibull model. Several model diagnostics methods are developed and model comparison is made using recently developed Bayesian model selection criteria. The above methodologies are applied to the McGilchrist and Aisbett (1991) kidney infection data and the analysis is performed using Markov Chain Monte Carlo methods.

Bayes Theorem↗

PubMed2004

A trio family study showing association of the lymphotoxin-alpha N26 (804A) allele with coronary artery disease.

Family-based studies to map susceptibility genes through linkage disequilibrium have been successful in early-onset diseases where parental-proband trios are readily collected, but are believed to be unworkable for late-onset diseases such as coronary artery disease (CAD). PROCARDIS is a European multicentre study that was designed to identify susceptibility genes for CAD. We have tested the transmission of a putatively functional allele, lymphotoxin-alpha N26 (804A), in more than 400 PROCARDIS trio families. The present study demonstrates association of this allele with CAD in white Europeans, a different ethnic group with a heavier CAD burden than the Japanese in which the association was initially identified, which suggests a broad relevance to CAD susceptibility. The practicalities of implementing a trio-family design for late-onset diseases are discussed.

Alleles↗

PubMed1992

Health and geographic mobility among the recently widowed.

The death of a spouse has been described as the most disruptive and difficult role transition that an individual confronts throughout the life course. Using data from the 1984 and 1986 waves of the Longitudinal Study of Aging conducted by the National Center for Health Statistics, we examined the probability of moving associated with changes in functional disability levels over a two-year period while controlling for recent widowhood. We found that the greater the increase in instrumental disability between 1984 and 1986, the greater the probability of a move. We also found that the event of becoming a widow greatly increases the probability of a move when health declines.

Activities of Daily Living↗

PubMed2005

A Bayesian framework for SNP identification.

As evolutionary models for single-nucleotide polymorphisms (SNPs) become available, methods for using them in the context of evolutionary information and expert prior information is a necessity. We formulate a probability model for SNPs as a Bayesian inference problem. Using this framework we compare the individual and combined predictive ability of four evolutionary models of varying levels of specificity on three SNP databases (two specifically targeted at functional SNPs) by calculating posterior probabilities and generating Receiver Operating Characteristic (ROC) curves. We discover that none of the models do exceptionally well, in some cases no better than a random-guess model. However, we demonstrate that several properties of the Bayesian formulation improve the predictability of SNPs in the three databases, specifically the ability to utilize mixtures of evolutionary models and a prior based on the genetic code.

Bayes Theorem↗

PubMed2007

Introduction to macromolecular refinement.

The process of refinement is such a large problem in function minimization that even the computers of today cannot perform the calculations to properly fit X-ray diffraction data. Each of the refinement packages currently under development reduces the difficulty of this problem by utilizing a unique combination of targets, assumptions, and optimization methods. This chapter summarizes the basic methods and underlying assumptions in the commonly used refinement packages. This information can guide the selection of a refinement package that is best suited for a particular refinement project.

Bayes Theorem↗

PubMed2004

Bayesian estimation of survival functions under stochastic precedence.

When estimating the distributions of two random variables, X and Y, investigators often have prior information that Y tends to be bigger than X. To formalize this prior belief, one could potentially assume stochastic ordering between X and Y, which implies Pr(X < or = z) > or = Pr(Y < or = z) for all z in the domain of X and Y. Stochastic ordering is quite restrictive, though, and this article focuses instead on Bayesian estimation of the distribution functions of X and Y under the weaker stochastic precedence constraint, Pr(X < or = Y) > or = 0.5. We consider the case where both X and Y are categorical variables with common support and develop a Gibbs sampling algorithm for posterior computation. The method is then generalized to the case where X and Y are survival times. The proposed approach is illustrated using data on survival after tumor removal for patients with malignant melanoma.

Bayes Theorem↗

PubMed2005

Directly parameterized regression conditioning on being alive: analysis of longitudinal data truncated by deaths.

For observational longitudinal studies of geriatric populations, outcomes such as disability or cognitive functioning are often censored by death. Statistical analysis of such data may explicitly condition on either vital status or survival time when summarizing the longitudinal response. For example a pattern-mixture model characterizes the mean response at time t conditional on death at time S = s (for s > t), and thus uses future status as a predictor for the time t response. As an alternative, we define regression conditioning on being alive as a regression model that conditions on survival status, rather than a specific survival time. Such models may be referred to as partly conditional since the mean at time t is specified conditional on being alive (S > t), rather than using finer stratification (S = s for s > t). We show that naive use of standard likelihood-based longitudinal methods and generalized estimating equations with non-independence weights may lead to biased estimation of the partly conditional mean model. We develop a taxonomy for accommodation of both dropout and death, and describe estimation for binary longitudinal data that applies selection weights to estimating equations with independence working correlation. Simulation studies and an analysis of monthly disability status illustrate potential bias in regression methods that do not explicitly condition on survival.

Activities of Daily Living↗

PubMed1999

Spousal negative responses to cancer patients: the role of social restriction, spouse mood, and relationship satisfaction.

This cross-sectional study examined perceptions of spousal negative behaviors in 219 cancer patients. A mediational model was proposed to explain why a spouse might respond negatively to an ill partner because of greater restriction on activities as functional impairment increases. A moderating effect of the spouse's marital satisfaction assessed 3 months before other study measures was also proposed. Results provided support for the proposed model. The relationship between increasing patient functional impairment and spousal negative behaviors was medicated by greater restriction in spouse activities, as well as spousal negative mood. A marginally significant moderating effect for marital satisfaction was found. Although these results must be replicated with a prospective study, the findings begin to shed light on why spouses might respond in negative ways to an ill partner.

Adult↗

PubMed2001

Evaluation of gene-finding programs on mammalian sequences.

We present an independent comparative analysis of seven recently developed gene-finding programs: FGENES, GeneMark.hmm, Genie, Genescan, HMMgene, Morgan, and MZEF. For evaluation purposes we developed a new, thoroughly filtered, and biologically validated dataset of mammalian genomic sequences that does not overlap with the training sets of the programs analyzed. Our analysis shows that the new generation of programs has substantially better results than the programs analyzed in previous studies. The accuracy of the programs was also examined as a function of various sequence and prediction features, such as G + C content of the sequence, length and type of exons, signal type, and score of the exon prediction. This approach pinpoints the strengths and weaknesses of each individual program as well as those of computational gene-finding in general. The dataset used in this analysis (HMR195) as well as the tables with the complete results are available at http://www.cs.ubc.ca/~rogic/evaluation/.

Animals↗

PubMed2005

Regulatory variation at glypican-3 underlies a major growth QTL in mice.

The genetic basis of variation in complex traits remains poorly understood, and few genes underlying variation have been identified. Previous work identified a quantitative trait locus (QTL) responsible for much of the response to selection on growth in mice, effecting a change in body mass of approximately 20%. By fine-mapping, we have resolved the location of this QTL to a 660-kb region containing only two genes of known function, Gpc3 and Gpc4, and two other putative genes of unknown function. There are no non-synonymous polymorphisms in any of these genes, indicating that the QTL affects gene regulation. Mice carrying the high-growth QTL allele have approximately 15% lower Gpc3 mRNA expression in kidney and liver, whereas expression differences at Gpc4 are non-significant. Expression profiles of the two other genes within the region are inconsistent with a factor responsible for a general effect on growth. Polymorphisms in the 3' untranslated region of Gpc3 are strong candidates for the causal sequence variation. Gpc3 loss-of-function mutations in humans and mice cause overgrowth and developmental abnormalities. However, no deleterious side-effects were detected in our mice, indicating that genes involved in Mendelian diseases also contribute to complex trait variation. Furthermore, these findings show that small changes in gene expression can have substantial phenotypic effects.

Aging↗

PubMed2006

Hidden process models for animal population dynamics.

Hidden process models are a conceptually useful and practical way to simultaneously account for process variation in animal population dynamics and measurement errors in observations and estimates made on the population. Process variation, which can be both demographic and environmental, is modeled by linking a series of stochastic and deterministic subprocesses that characterize processes such as birth, survival, maturation, and movement. Observations of the population can be modeled as functions of true abundance with realistic probability distributions to describe observation or estimation error. Computer-intensive procedures, such as sequential Monte Carlo methods or Markov chain Monte Carlo, condition on the observed data to yield estimates of both the underlying true population abundances and the unknown population dynamics parameters. Formulation and fitting of a hidden process model are demonstrated for Sacramento River winter-run chinook salmon (Oncorhynchus tshawytsha).

Animals↗

PubMed1998

Mood disorders following traumatic brain injury: identifying the extent of the problem and the people at risk.

The extent of mood disorders following traumatic brain injury (TBI), and the possible risk factors, are investigated. New data are presented from a prospective study of consecutive hospital admissions. Six months post-TBI, 99 adults completed a standardized assessment of emotional state, the Wimbledon Self-Report Scale. Cognitive performance and the impact of the injury on everyday functioning were also assessed. The rate of clinically significant mood disorders (caseness) was 38%. Of the demographic or injury characteristics, only pre-injury occupational status predicted post-injury caseness. Those unoccupied pre-injury were more likely to report mood disturbance post-injury. In contrast, post-injury occupational status was not related to caseness either for the whole group or the subgroup of those previously occupied, despite the adverse effects on occupational functioning for a significant proportion of subjects. Associations were found between emotional state and cognitive and everyday functioning 6 months post-injury. Psychosocial disabilities appeared more strongly associated to mood disorders than did physical disabilities. A significant level of unmet need has been highlighted, and possible risk factors identified, which may inform the purchase and provision of TBI rehabilitation services. Follow-up data on these subjects are available and will be reported separately.

Activities of Daily Living↗

PubMed2004

Feature selection in MLPs and SVMs based on maximum output information.

This paper presents feature selection algorithms for multilayer perceptrons (MLPs) and multiclass support vector machines (SVMs), using mutual information between class labels and classifier outputs, as an objective function. This objective function involves inexpensive computation of information measures only on discrete variables; provides immunity to prior class probabilities; and brackets the probability of error of the classifier. The maximum output information (MOI) algorithms employ this function for feature subset selection by greedy elimination and directed search. The output of the MOI algorithms is a feature subset of user-defined size and an associated trained classifier (MLP/SVM). These algorithms compare favorably with a number of other methods in terms of performance on various artificial and real-world data sets.

Algorithms↗

PubMed2002

Telephone intervention with family caregivers of stroke survivors after rehabilitation.

BACKGROUND AND PURPOSE: Social problem-solving therapy shows promise as an intervention to improve the well-being of family caregivers. There is some evidence that training in problem solving may be effectively delivered by telephone. The purpose of this study was to quantify the impact of social problem-solving telephone partnerships on primary family caregiver outcomes after stroke survivors are discharged home from a rehabilitation facility. METHODS: Using a randomized 3-group repeated-measures experimental design, 74 stroke survivors with an admitting diagnosis of ischemic stroke and their primary family caregivers were entered into the study. The intervention consisted of an initial 3-hour home visit between a trained nurse and the family caregiver within 1 week after discharge to begin problem-solving skill training. This initial session was followed by weekly (the first month) and biweekly (the second and third month) telephone contacts. RESULTS: Compared with the sham intervention and control groups, family caregivers who participated in the social problem-solving telephone partnership intervention group had better problem-solving skills; greater caregiver preparedness; less depression; and significant improvement in measures of vitality, social functioning, mental health, and role limitations related to emotional problems. There were no significant differences among the groups in caregiver burden. Satisfaction with healthcare services decreased over time in the control group while remaining comparable in the intervention and sham intervention groups. CONCLUSION: These results indicate that problem-solving training may be useful for family caregivers of stroke survivors after discharge from rehabilitative facilities.

Adaptation, Psychological↗

PubMed2006

Sex ratio, life-history invariants, and patterns of sex change in a family of protandrous gastropods.

Application of optimality theory to the evolution of life histories has been broadly successful in predicting the conditions favoring sex change, the type of change, and the timing of such changes. The size advantage hypothesis predicts that the optimal size at which an individual should change sex is a function of its size and the size and sex of its potential mates. I collected data on the size, sex, and grouping of individuals of 27 populations of 19 species of the calyptraeids, a family of protandrous marine gastropods that includes Crepidula. These data are used to test the following predictions about variation in size at sex change: (1) sex ratio is biased toward the first sex; (2) the ratio of the size at sex change to the maximum size is a life-history invariant; and (3) species that form variable-sized groups or stacks have more variation in size at sex change than species that show less variation in stack formation. Across all 19 species, sex ratio was not significantly more often biased toward the first sex than it was toward the second sex, although sex ratios were significantly male biased more often than they were significantly female biased. Sex ratios ranged from 0.05 to 0.91, and this variation was related to mode of development, skew in size distribution, and frequency of stacking, but not with maximum body size. There was little evidence that the ratio of size at sex change and maximum size is invariant. There is evidence that one of the main underlying assumptions of this life-history invariant, that male fertility increases with the same function of size in all species, is invalid for calyptraeids and probably for other animals. Finally, species that form larger stacks or mating groups had more variation in size at sex change within a population than species that were generally solitary. These results suggest that information about individual groupings should be included in predictions of life-history theory and that more information about the relationship between male fitness and size is also needed.

Animals↗

PubMed1999

Relationships between family dynamics of Finnish child-rearing families, factors causing strain and received support.

The aim of this study was to determine the relationships between family dynamics, the factors causing strain on child-rearing parents and the support available to families from public health nurses. Family dynamics was defined as the family's unique way of functioning and was conceptualized by means of six different dimensions. Questionnaires were sent to 118 families, and of these 85 mothers and 79 fathers participated in the study. According to the findings the majority of parents involved in bringing up children aged 3-4 years assessed their families to be well-functioning. There was a correlation between a low level of factors causing strain on the family and a positive evaluation of family dynamics based on the various dimensions. According to the mothers the support, i.e. emotional, appraisal and instrumental support, received from public health nurses, along with a small number of strain-causing factors on the partner relationship, correlated well with their positive assessments of the mutuality and flexibility of their families.

Adult↗