Methods for detecting gene × gene interaction in multiplex extended pedigrees

Complex diseases are multifactorial in nature and can involve multiple loci with gene × gene and gene × environment interactions. Research on methods to uncover the interactions between those genes that confer susceptibility to disease has been extensive, but many of these methods have only been developed for sibling pairs or sibships. In this report, we assess the performance of two methods for finding gene × gene interactions that are applicable to arbitrarily sized pedigrees, one based on correlation in per-family nonparametric linkage scores and another that incorporates candidate loci genotypes as covariates into an affected relative pair linkage analysis. The power and type I error rate of both of these methods was addressed using the simulated Genetic Analysis Workshop 14 data. In general, we found detection of the interacting loci to be a difficult problem, and though we experienced some modest success there is a clear need to continue developing new methods and approaches to the problem

Methods for detecting gene × gene interaction in multiplex extended pedigrees

Complex diseases are multifactorial in nature and can involve multiple loci with gene × gene and gene × environment interactions. Research on methods to uncover the interactions between those genes that confer susceptibility to disease has been extensive, but many of these methods have only been developed for sibling pairs or sibships. In this report, we assess the performance of two methods for finding gene × gene interactions that are applicable to arbitrarily sized pedigrees, one based on correlation in per-family nonparametric linkage scores and another that incorporates candidate loci genotypes as covariates into an affected relative pair linkage analysis. The power and type I error rate of both of these methods was addressed using the simulated Genetic Analysis Workshop 14 data. In general, we found detection of the interacting loci to be a difficult problem, and though we experienced some modest success there is a clear need to continue developing new methods and approaches to the problem

Review of endemic Sulawesi squirrels.

260 p. : ill. (some col.), maps ; 26 cm. "Issued June 11, 2010." Includes bibliographical references (p. 246-255).Analyses of fur color patterns, morphometric data derived from external, cranial, and dental dimensions, and distributions of collection sites for voucher specimens form the basis for a taxonomic revision of Sulawesi’s endemic squirrel fauna. Eight species of tree squirrels in Rubrisciurus and Prosciurillus and two species of ground squirrels in Hyosciurus are recognized. All are diurnal and inhabit primary forest formations. Diet consists of fruit, nuts, seeds, and arthropods. Rubrisciurus rubriventer, the largest in body size, forages on the ground and in the lower canopy layer, is found throughout Sulawesi where primary forest persists, and occurs through an altitudinal range embracing tropical lowland evergreen and lower montane rain forests; it is absent from upper montane rain forest. Five species of arboreal squirrels comprise the Prosciurillus leucomus group, a cluster of species occupying the upper forest canopy: P. leucomus, known only from lowland and montane habitats in the northern peninsula and one offshore island; P. alstoni, recorded from lowland tropical evergreen rain forest in the eastern section of Sulawesi’s central core, the east-central and southeastern arms, and two southeastern islands; P. weberi, represented by a few specimens from the coastal lowlands of the southern core of Sulawesi; P. topapuensis, endemic to the western mountain block in Sulawesi’s central core and occurring along an altitudinal gradient from lowland evergreen rain forest to upper montane rain forest; and P. rosenbergii, the only species of squirrel collected on islands in the Sangihe Archipelago north of the northeastern tip of the northern peninsula. The Prosciurillus murinus group contains two species of small body size: P. murinus, found throughout Sulawesi and in all forest formations, from the coastal lowlands to mountaintops, and a forager in the lower canopy layers; and P. abstrusus, known only from montane forest habitats on Pegunungan Mekongga in the southeastern peninsula. Of two species of ground squirrels, Hyosciurus heinrichi occupies montane forest habitats in the western mountain block of Sulawesi’s central core. It is altitudinally parapatric to H. ileile, which inhabits lowland evergreen and lower montane rain forests in the western mountain block and northeastern lowlands of central Sulawesi, and montane forest on the northern peninsula. A slightly revised classification of Sciuridae is provided in which a new tribe, Exilisciurini, is proposed for the Bornean and Philippine Exilisciurus. Previously published results of morphological and molecular analyses point to Rubrisciurus, Prosciurillus, and Hyosciurus as a monophyletic cluster, the Hyosciurina, nested within a larger clade, the Nannosciurini, which along with Exilisciurini n. tribe and Funambulini, comprise the Nannosciurinae, one of the three subfamilies constituting Sciuridae, and one that contains most of the Indomalayan genera. The present diversity of species endemic to Sulawesi was derived from an ancient lineage that crossed a sea barrier from the Sunda Shelf to Sulawesi during the late Miocene. Eight new species of hoplopleurid sucking lice ‪(‬Insecta, Anoplura‪)‬ are described as parasitizing 8 of the 10 species of squirrels endemic to Sulawesi: Hoplopleura rubrisciuri from Rubrisciurus rubriventer, Hoplopleura leucomus from Prosciurillus leucomus, Hoplopleura alstoni from Prosciurillus alstoni, Hoplopleura topapuensis from Prosciurillus topapuensis, Hoplopleura murinus from Prosciurillus murinus, Hoplopleura abstrusus from Prosciurillus abstrusus, Hoplopleura heinrichi from Hyosciurus heinrichi, and Hoplopleura ileile from Hyosciurus ileile. Examples of Prosciurillus weberi and P. rosenbergii were surveyed but no lice were recovered. A phylogenetic analysis based on cladistic principles for six species of Sulawesian squirrel lice for which both sexes were available is presented and the results discussed with respect to host relationships. These new data are incorporated into a discussion covering zoogeography of global sciurid-sucking louse associations, emphasizing the Indomalayan squirrel fauna. Globally, members of 11 genera of Anoplura parasitize sciurids, a figure far exceeding the number of anopluran genera associated with any other mammalian family. Nine of these ‪(‬the enderleinellids, Atopophthirus, Enderleinellus, Microphthirus, Phthirunculus, and Werneckia; the hoplopleurid, Paradoxophthirus; and the polyplacids, Johnsonpthirus, Linognathoides, and Neohaematopinus‪)‬ are primary parasites of sciurids. The remaining two ‪(‬the hoplopleurid Hoplopleura, and the polyplacid Polyplax‪)‬ include representatives that are acquired ‪(‬secondary‪)‬ parasites of sciurids--the majority of species in these two louse genera parasitize other groups of mammals but a small number of species have transferred to squirrel hosts. Sciurid hosts and geographic distributions of these 11 anopluran genera are discussed. Historically, representatives of Hoplopleura colonized different sciurid hosts on several separate occasions with one known species on a North American tree squirrel ‪(‬Sciurus‪)‬, two described species on North American flying squirrels ‪(‬Glaucomys‪)‬, two species parasitizing North American species of chipmunks ‪(‬Tamias and Eutamias‪)‬, 14 described species from Indomalayan nannosciurine squirrels ‪(‬Callosciurus, Tamiops, Rubrisciurus, Prosciurillus, Hyosciurus, and Funambulus‪)‬, and one species parasitizing a Chinese xerine ground squirrel ‪(‬Sciurotamias‪)‬. The zoogeography of the seven sciurid-infesting louse genera known from Southeast Asia is discussed using data from nine different countries or regions ‪(‬China, Taiwan, Thailand, peninsular Malaysia, Sumatra, Java, Borneo, the Philippines, and Sulawesi‪)‬. A reduction in the number of sciuirid-infesting anopluran genera and species is apparent from mainland northern/western regions to insular southern/eastern regions with members of seven genera and 23 species described from China but only one genus and eight species from Sulawesi. The absence of known species of Hoplopleura from Bornean and Javanese squirrels suggests that such a fauna may await discovery on one or both of these islands. Six of the eight species of Hoplopleura found parasitizing species of endemic Sulawesi squirrels were recovered as a monophyletic clade from a phylogenetic analysis employing anatomical structures associated with male and female lice. ‪(‬Two species of Sulawesi Hoplopleura are based on females and nymphs only and were not incorporated into the analysis.‪)‬ The monophyletic cluster formed by the Sulawesian squirrel lice joined with the monophyletic assemblage containing the three Sulawesi squirrel genera--Rubrisciurus, Prosciurillus, and Hyosciurus--suggest that the ancestral squirrel lineage that arrived in Sulawesi during the late Miocene may have been carrying its unique Hoplopleura parasite

Specificity of Four Laboratory Approaches for Cross-Sectional HIV Incidence Determination: Analysis of Samples from Adults with Known Nonrecent HIV Infection from Five African Countries

Assays to determine cross-sectional HIV incidence misclassify some individuals with nonrecent HIV infection as recently infected, overestimating HIV incidence. We analyzed factors associated with false-recent misclassification in five African countries. Samples from 2197 adults from Botswana, Kenya, South Africa, Tanzania, and Uganda who were HIV infected > 12 months were tested using the (1) BED capture enzyme immunoassay (BED), (2) avidity assay, (3) BED and avidity assays with higher assay cutoffs (BED+ avidity screen), and (4) multiassay algorithm (MAA) that includes the BED+ avidity screen, CD4 cell count, and HIV viral load. Logistic regression identified factors associated with misclassification. False-recent misclassification rates and 95% confidence intervals were BED alone: 7.6% (6.6, 8.8); avidity assay alone: 3.5% (2.7, 4.3); BED+ avidity screen: 2.2% (1.7, 2.9); and MAA: 1.2% (0.8, 1.8). The misclassification rate for the MAA was significantly lower than the rates for the other three methods (each p < 0.05). Misclassification rates were lower when the analysis was limited to subtype C-endemic countries, with the lowest rate obtained for the MAA [0.8% (0.2, 1.9)]. Factors associated with misclassification were for BED alone: country of origin, antiretroviral treatment (ART), viral load, and CD4 cell count; for avidity assay alone: country of origin; for BED+ avidity screen: country of origin and ART. No factors were associated with misclassification using the MAA. In a multivariate model, these associations remained significant with one exception: the association of ART with misclassification was completely attenuated. A MAA that included CD4 cell count and viral load had lower false-recent misclassification than the BED or avidity assays (alone or in combination). Studies are underway to compare the sensitivity of these methods for detection of recent HIV infection

Evaluation of quality of life in adults with neurofibromatosis 1 (NF1) using the Impact of NF1 on Quality Of Life (INF1-QOL) questionnaire

Background Neurofibromatosis 1 (NF1) is an inherited, multi-system, tumour suppressor disorder with variable complications that cause psychological distress and social isolation. The study aim was to develop and validate a disease-specific questionnaire to measure quality of life (QOL) in NF1 that is suitable both as an assessment tool in clinical practice and in clinical trials of novel therapy. Methods The Impact of NF1 on Quality of Life (INF1-QOL) questionnaire was developed by a literature search for common terms, focus group (n=6), semi-structured interviews (n=21), initial drafts (n =50) and final 14 item questionnaire (n=50). Bivariate correlations between items, exploratory factor analysis, correlations with severity and EuroQol were employed. Results INF1-QOL showed good internal reliability (Cronbach’s alpha 0.87), mean total INF1-QOL score was 8.64 (SD 6.3), median 7.00, range 0-30 (possible range 0-42); no significant correlations with age or gender. The mean total EuroQol score was 7.38 (SD 2.87), median 6.5, mean global EuroQol score was 76.34 (SD 16.56), median 80. Total INF1-QOL score correlated with total EuroQol r=0.82, p<0.0001. The highest impact on QOL was moderate or severe problems with anxiety and depression (32%) and negative effects of NF1 on role and outlook on life (42%). The mean inter-relater reliability for grading of clinical severity scores was 0.71 (range 0.65-0.79), and intra-class correlation was 0.92. The mean clinical severity score was 1.95 (SD 0.65) correlating r=0.34 with total INF1-QOL score p<0.05 and correlated 0.37 with total EuroQol score p<0.01. The clinical severity score was mild in 17 (34%), moderate in 16 (32%) and 17 (34%) individuals had severe disease. Conclusions INF1-QOL is a validated, reliable disease specific questionnaire that is easy and quick to complete. Role and outlook on life and anxiety and depression have the highest impact on QOL indicating the variability, severity and unpredictability of NF1. INFI-QOL correlates moderately with clinical severity. The moderate relationship between INF1-QOL and physician rated severity emphasizes the difference between clinical and patient perception. INFI-QOL will be useful in individual patient assessment and as an outcome measure for clinical trials

Canadian 24-hour movement guidelines for adults aged 18-64 years and adults aged 65 years or older: an integration of physical activity, sedentary behaviour, and sleep

The Canadian Society for Exercise Physiology assembled a Consensus Panel representing national organizations, content experts, methodologists, stakeholders, and end-users and followed an established guideline development procedure to create the Canadian 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older: An Integration of Physical Activity, Sedentary Behaviour, and Sleep. These guidelines underscore the importance of movement behaviours across the whole 24-h day. The development process followed the strategy outlined in the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. A large body of evidence was used to inform the guidelines including 2 de novo systematic reviews and 4 overviews of reviews examining the relationships among movement behaviours (physical activity, sedentary behaviour, sleep, and all behaviours together) and several health outcomes. Draft guideline recommendations were discussed at a 4-day in-person Consensus Panel meeting. Feedback from stakeholders was obtained by survey (n = 877) and the draft guidelines were revised accordingly. The final guidelines provide evidence-based recommendations for a healthy day (24-h), comprising a combination of sleep, sedentary behaviours, and light-intensity and moderate-to-vigorous-intensity physical activity. Dissemination and implementation efforts with corresponding evaluation plans are in place to help ensure that guideline awareness and use are optimized. Novelty First ever 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older with consideration of a balanced approach to physical activity, sedentary behaviour, and sleep Finalizes the suite of 24-Hour Movement Guidelines for Canadians across the lifespa

Development of a ParticipACTION App–Based Intervention for Improving Postsecondary Students’ 24-Hour Movement Guideline Behaviors: Protocol for the Application of Intervention Mapping

Background:The Canadian 24-Hour Movement Guidelines for adults provide specific recommendations for levels of physical activity, sedentary behavior, and sleep (ie, the movement behaviors) required for optimal health. Performance of the movement behaviors is associated with improved mental well-being. However, most postsecondary students do not meet the movement behavior recommendations within the Canadian 24-Hour Movement Guidelines and experience increased stress and declining well-being, suggesting the need for an intervention targeting students’ movement behaviors.Objective:We aimed to develop and implement a theory-informed intervention intended to improve the movement behaviors and mental well-being of first-year postsecondary students.Methods:The Intervention Mapping protocol was applied in the development and implementation of the intervention. Intervention Mapping entailed performing a needs assessment, determining the intervention outcomes, selecting theory- and evidence-based change methods and applications, preparing and producing intervention plans and materials, developing the implementation plan, and finally developing an evaluation plan. The Theoretical Domains Framework and the Behavior Change Wheel were also used in conjunction with the Intervention Mapping protocol to ensure a solid theoretical basis for the intervention. This protocol led to the development and implementation of a 6-week, theory-informed ParticipACTION app–based intervention aimed at helping first-year postsecondary students improve their movement behaviors and mental well-being. The developed app content provided students with information on each of the movement behaviors and behavioral strategies (ie, goal setting, action planning, monitoring, and coping planning). The use of Intervention Mapping allowed for the continuous involvement of various multidisciplinary partners and end users, ensuring that the intervention design and implementation was appropriate for the target audience. The feasibility, acceptability, and potential impact of the intervention will be examined in a subsequent proof-of-concept study at 2 Canadian university campuses.Results:Participant recruitment occurred during September 2021, and the intervention was conducted from October to December 2021. The deadline for completion of the postintervention questionnaire by participants was mid-December 2021. The analysis of data examining the feasibility, acceptability, and potential impact of the intervention began in January 2022, with the publication of the proof-of-concept evaluation expected in 2023.Conclusions:Intervention Mapping with the Theoretical Domains Framework and Behavior Change Wheel was a useful approach to combine evidence and theoretical concepts to guide the design and implementation of a ParticipACTION app–based intervention targeting postsecondary students’ movement behaviors and mental well-being. This process may serve as an example for other researchers developing multiple behavior change app–based interventions. Should the forthcoming evaluation demonstrate the intervention’s acceptability, feasibility, and potential impact, the intervention may provide a scalable method of improving postsecondary students’ movement behaviors and mental well-being