Joint modelling of confounding factors and prominent genetic regulators provides increased accuracy in genetical genomics studies.

Expression quantitative trait loci (eQTL) studies are an integral tool to investigate the genetic component of gene expression variation. A major challenge in the analysis of such studies are hidden confounding factors, such as unobserved covariates or unknown subtle environmental perturbations. These factors can induce a pronounced artifactual correlation structure in the expression profiles, which may create spurious false associations or mask real genetic association signals. Here, we report PANAMA (Probabilistic ANAlysis of genoMic dAta), a novel probabilistic model to account for confounding factors within an eQTL analysis. In contrast to previous methods, PANAMA learns hidden factors jointly with the effect of prominent genetic regulators. As a result, this new model can more accurately distinguish true genetic association signals from confounding variation. We applied our model and compared it to existing methods on different datasets and biological systems. PANAMA consistently performs better than alternative methods, and finds in particular substantially more trans regulators. Importantly, our approach not only identifies a greater number of associations, but also yields hits that are biologically more plausible and can be better reproduced between independent studies. A software implementation of PANAMA is freely available online at http://ml.sheffield.ac.uk/qtl/

Small-Bodied Humans from Palau, Micronesia

UNLABELLED: Newly discovered fossil assemblages of small bodied Homo sapiens from Palau, Micronesia possess characters thought to be taxonomically primitive for the genus Homo. BACKGROUND: Recent surface collection and test excavation in limestone caves in the rock islands of Palau, Micronesia, has produced a sizeable sample of human skeletal remains dating roughly between 940-2890 cal ybp. PRINCIPLE FINDINGS: Preliminary analysis indicates that this material is important for two reasons. First, individuals from the older time horizons are small in body size even relative to "pygmoid" populations from Southeast Asia and Indonesia, and thus may represent a marked case of human insular dwarfism. Second, while possessing a number of derived features that align them with Homo sapiens, the human remains from Palau also exhibit several skeletal traits that are considered to be primitive for the genus Homo. SIGNIFICANCE: These features may be previously unrecognized developmental correlates of small body size and, if so, they may have important implications for interpreting the taxonomic affinities of fossil specimens of Homo

The effectiveness, acceptability and cost-effectiveness of psychosocial interventions for maltreated children and adolescents: an evidence synthesis.

BACKGROUND: Child maltreatment is a substantial social problem that affects large numbers of children and young people in the UK, resulting in a range of significant short- and long-term psychosocial problems. OBJECTIVES: To synthesise evidence of the effectiveness, cost-effectiveness and acceptability of interventions addressing the adverse consequences of child maltreatment. STUDY DESIGN: For effectiveness, we included any controlled study. Other study designs were considered for economic decision modelling. For acceptability, we included any study that asked participants for their views. PARTICIPANTS: Children and young people up to 24 years 11 months, who had experienced maltreatment before the age of 17 years 11 months. INTERVENTIONS: Any psychosocial intervention provided in any setting aiming to address the consequences of maltreatment. MAIN OUTCOME MEASURES: Psychological distress [particularly post-traumatic stress disorder (PTSD), depression and anxiety, and self-harm], behaviour, social functioning, quality of life and acceptability. METHODS: Young Persons and Professional Advisory Groups guided the project, which was conducted in accordance with Cochrane Collaboration and NHS Centre for Reviews and Dissemination guidance. Departures from the published protocol were recorded and explained. Meta-analyses and cost-effectiveness analyses of available data were undertaken where possible. RESULTS: We identified 198 effectiveness studies (including 62 randomised trials); six economic evaluations (five using trial data and one decision-analytic model); and 73 studies investigating treatment acceptability. Pooled data on cognitive-behavioural therapy (CBT) for sexual abuse suggested post-treatment reductions in PTSD [standardised mean difference (SMD) -0.44 (95% CI -4.43 to -1.53)], depression [mean difference -2.83 (95% CI -4.53 to -1.13)] and anxiety [SMD -0.23 (95% CI -0.03 to -0.42)]. No differences were observed for post-treatment sexualised behaviour, externalising behaviour, behaviour management skills of parents, or parental support to the child. Findings from attachment-focused interventions suggested improvements in secure attachment [odds ratio 0.14 (95% CI 0.03 to 0.70)] and reductions in disorganised behaviour [SMD 0.23 (95% CI 0.13 to 0.42)], but no differences in avoidant attachment or externalising behaviour. Few studies addressed the role of caregivers, or the impact of the therapist-child relationship. Economic evaluations suffered methodological limitations and provided conflicting results. As a result, decision-analytic modelling was not possible, but cost-effectiveness analysis using effectiveness data from meta-analyses was undertaken for the most promising intervention: CBT for sexual abuse. Analyses of the cost-effectiveness of CBT were limited by the lack of cost data beyond the cost of CBT itself. CONCLUSIONS: It is not possible to draw firm conclusions about which interventions are effective for children with different maltreatment profiles, which are of no benefit or are harmful, and which factors encourage people to seek therapy, accept the offer of therapy and actively engage with therapy. Little is known about the cost-effectiveness of alternative interventions. LIMITATIONS: Studies were largely conducted outside the UK. The heterogeneity of outcomes and measures seriously impacted on the ability to conduct meta-analyses. FUTURE WORK: Studies are needed that assess the effectiveness of interventions within a UK context, which address the wider effects of maltreatment, as well as specific clinical outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003889. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Defining strawberry shape uniformity using 3D imaging and genetic mapping

Strawberry shape uniformity is a complex trait, influenced by multiple genetic and environmental components. To complicate matters further, the phenotypic assessment of strawberry uniformity is confounded by the difficulty of quantifying geometric parameters ‘by eye’ and variation between assessors. An in-depth genetic analysis of strawberry uniformity has not been undertaken to date, due to the lack of accurate and objective data. Nonetheless, uniformity remains one of the most important fruit quality selection criteria for the development of a new variety. In this study, a 3D-imaging approach was developed to characterise berry shape uniformity. We show that circularity of the maximum circumference had the closest predictive relationship with the manual uniformity score. Combining five or six automated metrics provided the best predictive model, indicating that human assessment of uniformity is highly complex. Furthermore, visual assessment of strawberry fruit quality in a multi-parental QTL mapping population has allowed the identification of genetic components controlling uniformity. A “regular shape” QTL was identified and found to be associated with three uniformity metrics. The QTL was present across a wide array of germplasm, indicating a potential candidate for marker-assisted breeding, while the potential to implement genomic selection is explored. A greater understanding of berry uniformity has been achieved through the study of the relative impact of automated metrics on human perceived uniformity. Furthermore, the comprehensive definition of strawberry shape uniformity using 3D imaging tools has allowed precision phenotyping, which has improved the accuracy of trait quantification and unlocked the ability to accurately select for uniform berries

Validation of the Comprehensive Feeding Practices Questionnaire with parents of 10-to-12-year-olds

Abstract Background: There is a lack of validated instruments for quantifying feeding behavior among parents of older children and adolescents. The Comprehensive Feeding Practices Questionnaire (CFPQ) is a self-report measure to assess multiple parental feeding practices. The CFPQ is originally designed for use with parents of children ranging in age from about 2 to 8 years. It is previously validated with American and French parents of children within this age range. The aim of the present study was to adapt and test the validity of this measure with parents of older children (10-to-12-year-olds) in a Norwegian setting. Methods: A sample of 963 parents of 10-to-12-year-olds completed a Norwegian, slightly adapted version of the CFPQ. Scale analyses were performed to test the validity of the instrument in our sample. Results: Although a few problematic items and scales were revealed, scale analyses showed that the psychometric properties of the slightly adapted, Norwegian version of the CFPQ were surprisingly similar to those of the original CFPQ. Conclusions: Our results indicated that the CFPQ, with some small modifications, is a valid tool for measuring multiple parental feeding practices with parents of 10-to12-year-olds

Making Informed Choices about Microarray Data Analysis

This article describes the typical stages in the analysis of microarray data for non-specialist researchers in systems biology and medicine. Particular attention is paid to significant data analysis issues that are commonly encountered among practitioners, some of which need wider airing. The issues addressed include experimental design, quality assessment, normalization, and summarization of multiple-probe data. This article is based on the ISMB 2008 tutorial on microarray data analysis. An expanded version of the material in this article and the slides from the tutorial can be found at http://www.people.vcu.edu/~mreimers/OGMDA/index.html

Genetic randomization reveals functional relationships among morphologic and tissue-quality traits that contribute to bone strength and fragility

We examined femora from adult AXB/BXA recombinant inbred (RI) mouse strains to identify skeletal traits that are functionally related and to determine how functional interactions among these traits contribute to genetic variability in whole-bone stiffness, strength, and toughness. Randomization of A/J and C57BL/6J genomic regions resulted in each adult male and female RI strain building mechanically functional femora by assembling unique sets of morphologic and tissue-quality traits. A correlation analysis was conducted using the mean trait values for each RI strain. A third of the 66 correlations examined were significant, indicating that many bone traits covaried or were functionally related. Path analysis revealed important functional interactions among bone slenderness, cortical thickness, and tissue mineral density. The path coefficients describing these functional relations were similar for both sexes. The causal relationship among these three traits suggested that cellular processes during growth simultaneously regulate bone slenderness, cortical thickness, and tissue mineral density so that the combination of traits is sufficiently stiff and strong to satisfy daily loading demands. A disadvantage of these functional interactions was that increases in tissue mineral density also deleteriously affected tissue ductility. Consequently, slender bones with high mineral density may be stiff and strong but they are also brittle. Thus, genetically randomized mouse strains revealed a basic biological paradigm that allows for flexibility in building bones that are functional for daily activities but that creates preferred sets of traits under extreme loading conditions. Genetic or environmental perturbations that alter these functional interactions during growth would be expected to lead to loss of function and suboptimal adult bone quality

Multi-Trait and Multi-Environment QTL Analyses for Resistance to Wheat Diseases

BACKGROUND: Stripe rust, leaf rust, tan spot, and Karnal bunt are economically significant diseases impacting wheat production. The objectives of this study were to identify quantitative trait loci for resistance to these diseases in a recombinant inbred line (RIL) from a cross HD29/WH542, and to evaluate the evidence for the presence loci on chromosome region conferring multiple disease resistance. METHODOLOGY/PRINCIPAL FINDINGS: The RIL population was evaluated for four diseases and genotyped with DNA markers. Multi-trait (MT) analysis revealed thirteen QTLs on nine chromosomes, significantly associated with resistance. Phenotypic variation explained by all significant QTLs for KB, TS, Yr, Lr diseases were 57%, 55%, 38% and 22%, respectively. Marginal trait analysis identified the most significant QTLs for resistance to KB on chromosomes 1BS, 2DS, 3BS, 4BL, 5BL, and 5DL. Chromosomes 3AS and 4BL showed significant association with TS resistance. Significant QTLs for Yr resistance were identified on chromosomes 2AS, 4BL and 5BL, while Lr was significant on 6DS. MT analysis revealed that all the QTLs except 3BL significantly reduce KB and was contributed from parent HD29 while all resistant QTLs for TS except on chromosomes 2DS.1, 2DS.2 and 3BL came from WH542. Five resistant QTLs for Yr and six for Lr were contributed from parents WH542 and HD29 respectively. Chromosome region on 4BL showed significant association to KB, TS, and Yr in the population. The multi environment analysis for KB identified three putative QTLs of which two new QTLs, mapped on chromosomes 3BS and 5DL explained 10 and 20% of the phenotypic variation, respectively. CONCLUSIONS/SIGNIFICANCE: This study revealed that MT analysis is an effective tool for detection of multi-trait QTLs for disease resistance. This approach is a more effective and practical than individual QTL mapping analyses. MT analysis identified RILs that combine resistance to multiple diseases from parents WH542 and/or HD29