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Simulating Pedigrees Ascertained for Multiple Disease-affected Relatives

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2018-10-15
Abstract: 

Background  Studies that ascertain families containing multiple relatives affected by disease can be useful for identification of causal, rare variants from next-generation sequencing data.

Results  We present the R package SimRVPedigree, which allows researchers to simulate pedigrees ascertained on the basis of multiple, affected relatives. By incorporating the ascertainment process in the simulation, SimRVPedigree allows researchers to better understand the within-family patterns of relationship amongst affected individuals and ages of disease onset.

Conclusions  Through simulation, we show that affected members of a family segregating a rare disease variant tend to be more numerous and cluster in relationships more closely than those for sporadic disease. We also show that the family ascertainment process can lead to apparent anticipation in the age of onset. Finally, we use simulation to gain insight into the limit on the proportion of ascertained families segregating a causal variant. SimRVPedigree should be useful to investigators seeking insight into the family-based study design through simulation.

Document type: 
Article
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perfectphyloR: An R Package For Reconstructing Perfect Phylogenies

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2019-12-23
Abstract: 

Background

A perfect phylogeny is a rooted binary tree that recursively partitions sequences. The nested partitions of a perfect phylogeny provide insight into the pattern of ancestry of genetic sequence data. For example, sequences may cluster together in a partition indicating that they arise from a common ancestral haplotype.

Results

We present an R package perfectphyloR to reconstruct the local perfect phylogenies underlying a sample of binary sequences. The package enables users to associate the reconstructed partitions with a user-defined partition. We describe and demonstrate the major functionality of the package.

Conclusion

The perfectphyloR package should be of use to researchers seeking insight into the ancestral structure of their sequence data. The reconstructed partitions have many applications, including the mapping of trait-influencing variants.

Background

A perfect phylogeny is a rooted binary tree that recursively partitions sequences. The nested partitions of a perfect phylogeny provide insight into the pattern of ancestry of genetic sequence data. For example, sequences may cluster together in a partition indicating that they arise from a common ancestral haplotype.

Results

We present an R package perfectphyloR to reconstruct the local perfect phylogenies underlying a sample of binary sequences. The package enables users to associate the reconstructed partitions with a user-defined partition. We describe and demonstrate the major functionality of the package.

Conclusion

The perfectphyloR package should be of use to researchers seeking insight into the ancestral structure of their sequence data. The reconstructed partitions have many applications, including the mapping of trait-influencing variants.

 

Document type: 
Article
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Statistical Modeling of Discrete Percentage Measurements With Application to Construction of Acceptance Bounds for Wood Failure in Structural Adhesive Testing

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2016
Abstract: 

The goals of this paper are:

(1) to provide a statistical analysis approach that is appropriate for data from an interlaboratory study where responses are measured in discrete percentages and are subject to multiple sources of random variability, and (2) to apply this model to data on wood-failure percentages from block-shear tests on structural wood adhesives.

We treat percentage responses measured in 5-point intervals as having arisen from observing 20 independent binary responses on different parts of the observed wood blocks. The overdispersion that is likely to result from the practical inadequacy of this assumption is overcome empirically by the inclusion of a random effect for blocks. We propose an analysis based on a parametric bootstrap to provide sampling distributions for statistics that regulators might wish to use in setting standards for acceptance of wood adhesives. Similar computational methods are developed to assess the fit of the model. This model is shown to provide a reasonably good fit or actual data in many of the cases to which it was applied.

Document type: 
Article
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Cardiovascular Responses to Orthostasis and Their Association With Falls in Older Adults

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2015
Abstract: 

Background

Orthostatic hypotension (OH) refers to a marked decline in blood pressure when upright. OH has a high incidence and prevalence in older adults and represents a potential intrinsic risk factor for falls in these individuals. Previous studies have not included more recent definitions for blood pressure responses to orthostasis, including initial, delayed, and recovery blood pressure responses. Furthermore, there is little research examining the relationships between cerebrovascular functioning and falling risk. Therefore, we aimed to: (i) test the association between different blood pressure responses to orthostatic stress and retrospective falling history and; (ii) test the association between cerebrovascular responses to orthostatic stress and falling history.

Methods

We tested 59 elderly residents in long term care facilities who underwent a passive seated orthostatic stress test. Beat-to-beat blood pressure and cerebral blood flow velocity (CBFV) responses were assessed throughout testing. Risk factors for falls and falling history were collected from facility records. Cardiovascular responses to orthostasis were compared between retrospective fallers (≥1 fall in the previous year) and non-fallers.

Results

Retrospective fallers had larger delayed declines in systolic arterial pressure (SAP) compared to non-fallers (p  = 0.015). Fallers also showed poorer early (2 min) and late (15 min) recovery of SAP. Fallers had a greater decline in systolic CBFV.

Conclusions

Older adults with a positive falling history have impaired orthostatic control of blood pressure and CBFV. With better identification and understanding of orthostatic blood pressure impairments earlier intervention and management can be implemented, potentially reducing the associated risk of morbidity and mortality. Future studies should utilize the updated OH definitions using beat-to-beat technology, rather than conventional methods that may offer less accurate detection.

Document type: 
Article
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Joint Identification of Location and Dispersion Effects in Unreplicated Two-Level Factorials

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2015-10
Abstract: 

Most procedures that have been proposed to identify dispersion effects in unreplicated factorial designs assume that location effects have been identified correctly. Incorrect identi- fication of location effects may impair subsequent identification of dispersion effects. We develop a model for joint identification of location and dispersion effects that can reliably identify active effects of both types. The joint model is estimated using maximum likelihood, and hence effect selection is done using a specially derived information criterion. An exhaustive search through a limited version of the space of possible models is conducted. Both a single-model output and model averaging are considered. The method is shown to be capable of identifying sensible location-dispersion models that are missed by methods that rely on sequential estimation of location and dispersion effects.

Document type: 
Article

Over the Hill at 24: Persistent Age-Related Cognitive-Motor Decline in Reaction Times in an Ecologically Valid Video Game Task Begins in Early Adulthood

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2014-04-09
Abstract: 

Typically studies of the effects of aging on cognitive-motor performance emphasize changes in elderly populations. Although some research is directly concerned with when age-related decline actually begins, studies are often based on relatively simple reaction time tasks, making it impossible to gauge the impact of experience in compensating for this decline in a real world task. The present study investigates age-related changes in cognitive motor performance through adolescence and adulthood in a complex real world task, the real-time strategy video game StarCraft 2. In this paper we analyze the influence of age on performance using a dataset of 3,305 players, aged 16-44, collected by Thompson, Blair, Chen & Henrey [1]. Using a piecewise regression analysis, we find that age-related slowing of within-game, self-initiated response times begins at 24 years of age. We find no evidence for the common belief expertise should attenuate domain-specific cognitive decline. Domain-specific response time declines appear to persist regardless of skill level. A second analysis of dual-task performance finds no evidence of a corresponding age-related decline. Finally, an exploratory analyses of other age-related differences suggests that older participants may have been compensating for a loss in response speed through the use of game mechanics that reduce cognitive load.

Document type: 
Article
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Resource Selection by the California Condor (Gymnogyps californianus) Relative to Terrestrial-Based Habitats and Meteorological Conditions

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2014-02-11
Abstract: 

Condors and vultures are distinct from most other terrestrial birds because they use extensive soaring flight for their daily movements. Therefore, assessing resource selection by these avian scavengers requires quantifying the availability of terrestrial-based habitats, as well as meteorological variables that influence atmospheric conditions necessary for soaring. In this study, we undertook the first quantitative assessment of habitat- and meteorological-based resource selection in the endangered California condor (Gymnogyps californianus) within its California range and across the annual cycle. We found that condor use of terrestrial areas did not change markedly within the annual cycle, and that condor use was greatest for habitats where food resources and potential predators could be detected and where terrain was amenable for taking off from the ground in flight (e.g., sparse habitats, coastal areas). Condors originating from different release sites differed in their use of habitat, but this was likely due in part to variation in habitats surrounding release sites. Meteorological conditions were linked to condor use of ecological subregions, with thermal height, thermal velocity, and wind speed having both positive (selection) and negative (avoidance) effects on condor use in different areas. We found little evidence of systematic effects between individual characteristics (i.e., sex, age, breeding status) or components of the species management program (i.e., release site, rearing method) relative to meteorological conditions. Our findings indicate that habitat type and meteorological conditions can interact in complex ways to influence condor resource selection across landscapes, which is noteworthy given the extent of anthropogenic stressors that may impact condor populations (e.g., lead poisoning, wind energy development). Additional studies will be valuable to assess small-scale condor movements in light of these stressors to help minimize their risk to this critically endangered species.

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Article
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Randomized Controlled Ferret Study to Assess the Direct Impact of 2008–09 Trivalent Inactivated Influenza Vaccine on A(H1N1)pdm09 Disease Risk

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2014-01-27
Abstract: 

During spring-summer 2009, several observational studies from Canada showed increased risk of medically-attended, laboratory-confirmed A(H1N1)pdm09 illness among prior recipients of 2008–09 trivalent inactivated influenza vaccine (TIV). Explanatory hypotheses included direct and indirect vaccine effects. In a randomized placebo-controlled ferret study, we tested whether prior receipt of 2008–09 TIV may have directly influenced A(H1N1)pdm09 illness. Thirty-two ferrets (16/group) received 0.5 mL intra-muscular injections of the Canadian-manufactured, commercially-available, non-adjuvanted, split 2008–09 Fluviral or PBS placebo on days 0 and 28. On day 49 all animals were challenged (Ch0) with A(H1N1)pdm09. Four ferrets per group were randomly selected for sacrifice at day 5 post-challenge (Ch+5) and the rest followed until Ch+14. Sera were tested for antibody to vaccine antigens and A(H1N1)pdm09 by hemagglutination inhibition (HI), microneutralization (MN), nucleoprotein-based ELISA and HA1-based microarray assays. Clinical characteristics and nasal virus titers were recorded pre-challenge then post-challenge until sacrifice when lung virus titers, cytokines and inflammatory scores were determined. Baseline characteristics were similar between the two groups of influenza-naïve animals. Antibody rise to vaccine antigens was evident by ELISA and HA1-based microarray but not by HI or MN assays; virus challenge raised antibody to A(H1N1)pdm09 by all assays in both groups. Beginning at Ch+2, vaccinated animals experienced greater loss of appetite and weight than placebo animals, reaching the greatest between-group difference in weight loss relative to baseline at Ch+5 (7.4% vs. 5.2%; p = 0.01). At Ch+5 vaccinated animals had higher lung virus titers (log-mean 4.96 vs. 4.23pfu/mL, respectively; p = 0.01), lung inflammatory scores (5.8 vs. 2.1, respectively; p = 0.051) and cytokine levels (p>0.05). At Ch+14, both groups had recovered. Findings in influenza-naïve, systematically-infected ferrets may not replicate the human experience. While they cannot be considered conclusive to explain human observations, these ferret findings are consistent with direct, adverse effect of prior 2008–09 TIV receipt on A(H1N1)pdm09 illness. As such, they warrant further in-depth investigation and search for possible mechanistic explanations.

Document type: 
Article
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Predicting Grizzly Bear Density in Western North America

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

Conservation of grizzly bears (Ursus arctos) is often controversial and the disagreement often is focused on the estimates of density used to calculate allowable kill. Many recent estimates of grizzly bear density are now available but field-based estimates will never be available for more than a small portion of hunted populations. Current methods of predicting density in areas of management interest are subjective and untested. Objective methods have been proposed, but these statistical models are so dependent on results from individual study areas that the models do not generalize well. We built regression models to relate grizzly bear density to ultimate measures of ecosystem productivity and mortality for interior and coastal ecosystems in North America. We used 90 measures of grizzly bear density in interior ecosystems, of which 14 were currently known to be unoccupied by grizzly bears. In coastal areas, we used 17 measures of density including 2 unoccupied areas. Our best model for coastal areas included a negative relationship with tree cover and positive relationships with the proportion of salmon in the diet and topographic ruggedness, which was correlated with precipitation. Our best interior model included 3 variables that indexed terrestrial productivity, 1 describing vegetation cover, 2 indices of human use of the landscape and, an index of topographic ruggedness. We used our models to predict current population sizes across Canada and present these as alternatives to current population estimates. Our models predict fewer grizzly bears in British Columbia but more bears in Canada than in the latest status review. These predictions can be used to assess population status, set limits for total human-caused mortality, and for conservation planning, but because our predictions are static, they cannot be used to assess population trend.

Document type: 
Article
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CrypticIBDcheck: An R Package For Checking Cryptic Relatedness In Nominally Unrelated Individuals

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013
Abstract: 

Background

In population association studies, standard methods of statistical inference assume that study subjects are independent samples. In genetic association studies, it is therefore of interest to diagnose undocumented close relationships in nominally unrelated study samples.

Results

We describe the R package CrypticIBDcheck to identify pairs of closely-related subjects based on genetic marker data from single-nucleotide polymorphisms (SNPs). The package is able to accommodate SNPs in linkage disequibrium (LD), without the need to thin the markers so that they are approximately independent in the population. Sample pairs are identified by superposing their estimated identity-by-descent (IBD) coefficients on plots of IBD coefficients for pairs of simulated subjects from one of several common close relationships.

Conclusions

The methods implemented in CrypticIBDcheck are particularly relevant to candidate-gene association studies, in which dependent SNPs cluster in a relatively small number of genes spread throughout the genome. The accommodation of LD allows the use of all available genetic data, a desirable property when working with a modest number of dependent SNPs within candidate genes. CrypticIBDcheck is available from the Comprehensive R Archive Network (CRAN).

Document type: 
Article
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