Genome-wide association studies of quantitative traits with related individuals: Little (power) lost but much to be gained

For complex disease genetics research in human populations, remarkable progress has been made in recent times with the publication of a number of genome-wide association scans (GWAS) and subsequent statistical replications. These studies have identified new genes and pathways implicated in disease, many of which were not known before. Given these early successes, more GWAS are being conducted and planned, both for disease and quantitative phenotypes. Many researchers and clinicians have DNA samples available on collections of families, including both cases and controls. Twin registries around the world have facilitated the collection of large numbers of families, with DNA and multiple quantitative phenotypes collected on twin pairs and their relatives. In the design of a new GWAS with a fixed budget for the number of chips, the question arises whether to include or exclude related individuals. It is commonly believed to be preferable to use unrelated individuals in the first stage of a GWAS because relatives are 'over-matched' for genotypes. In this study, we quantify that for GWAS of a quantitative phenotype, relative to a sample of unrelated individuals surprisingly little power is lost when using relatives. The advantages of using relatives are manifold, including the ability to perform more quality control, the choice to perform within-family tests of association that are robust to population stratification, and the ability to perform joint linkage and association analysis. Therefore, the advantages of using relatives in GWAS for quantitative traits may well outweigh the small disadvantage in terms of statistical power.

Reactions to changes in work control: Implications for self-determined and non-self-determined individuals

We investigate the extent to which individuals’ global motivation (self-determined and non-self-determined types) influences adjustment (anxiety, positive reappraisal) and engagement (intrinsic motivation, task performance) in reaction to changes to the level of work control available during a work simulation. Participants (N = 156) completed 2 trials of an inbox activity under conditions of low or high work control—with the ordering of these levels varied to create an increase, decrease, or no change in work control. In support of the hypotheses, results revealed that for more self-determined individuals, high work control led to the increased use of positive reappraisal. Follow-up moderated mediation analyses revealed that the increases in positive reappraisal observed for self-determined individuals in the conditions in which work control was high by Trial 2 consequently increased their intrinsic motivation toward the task. For more non-self-determined individuals, high work control (as well as changes in work control) led to elevated anxiety. Follow-up moderated mediation analyses revealed that the increases in anxiety observed for non-self-determined individuals in the high-to-high work control condition consequently reduced their task performance. It is concluded that adjustment to a demanding work task depends on a fit between individuals’ global motivation and the work control available, which has consequences for engagement with demanding work.

The relationship between forward head posture and cervical muscle performance in healthy individuals

Background Forward head postures (FHP) are proposed to adversely load cervical spine structures. Neck muscles provide support for the neck, and thus an imbalance in neck muscle performance could potentially contribute to the development of FHP. Previous studies have not considered the interaction of multiple muscle groups with regard to postural orientation. Given the interdependence of muscles along the cervical spine for optimal orientation and physical support of the vertebral column, the performance of a single muscle group may not accurately reflect the coordinated ability of the muscles to maintain a neutral neck posture. Purpose The purpose of this study was to investigate the relationship between FHP and the balance between the cervical extensor and flexor muscle groups in healthy individuals. We hypothesised that the magnitude of FHP would be associated with the strength and endurance performance ratios between the cervical extensor and flexor muscle groups. Methods Twenty male and 24 female volunteers were photographed in the sagittal plane wearing surface markers. The FHP of each participant was measured via the tragus-sternum marker distance over two conditions: (1)in relaxed standing and (2)during a sustained sitting task. Maximal strength (Nm) and endurance (s) performance of the extensor and flexor muscle groups were recorded at the upper (craniocervical flexion/extension (CCF/CCE)) and lower (cervicothoracic flexion/extension (CTF/CTE)) cervical regions. Muscle performance measures were expressed as extension:flexion ratios and their relation to FHP evaluated. A stepwise multiple regression analysis using backward elimination was utilised to examine the relationship between the postural measures and the muscle performance ratio measures. Separate models were used for the two different postural conditions (standing, sustained sitting). Gender was included as a constant correction factor in all regression models. Where gender was a significant variable in the model, analyses were repeated separately for males and females. Results Greater FHP in standing was significantly associated with reduced proportional CTE to CCF strength in females (R2 = 0.21, P = 0.03) and greater proportional CTE to CTF strength in males (R2 = 0.23, P = 0.03). A greater drift into FHP during sustained sitting was associated with a relative reduction in CCE endurance proportional to CTF endurance in females only (R2 = 0.27, P = 0.017). Conclusion(s) This initial study indicates that the balance in performance between the cervical flexor and extensor muscle groups may impact FHP in healthy individuals. However, the findings were inconsistent across different muscle performance ratios and gender. Larger scale studies are therefore now needed to further clarify the relationship between FHP and muscle performance. Implications The findings suggest that relative performance of the various cervical muscle groups needs to be accounted for when considering postural correction strategies in the clinical setting, as is often recommended.

Does flexibility of the cervical and thoracic spine influence forward head posture in healthy individuals?

Background: Forward head posture (FHP) is a commonly reported deviation from a neutral neck posture, usually implying a protracted head position in the sagittal plane. Habitual FHP has been associated with a higher incidence of painful neck disorders, changes in joint mobility and muscle behaviour within the cervicothoracic regions. One factor that has received attention in the literature with regards to FHP is flexibility of the neck. A number of previous studies have previously investigated the relationship between neck flexibility and neck posture under different conditions, but at present this relationship is unclear.

Individuals on the Move : Body Condition Dependent Dispersal and Quasi-Local Competition in Metapopulations

Individual movement is very versatile and inevitable in ecology. In this thesis, I investigate two kinds of movement body condition dependent dispersal and small-range foraging movements resulting in quasi-local competition and their causes and consequences on the individual, population and metapopulation level. Body condition dependent dispersal is a widely evident but barely understood phenomenon. In nature, diverse relationships between body condition and dispersal are observed. I develop the first models that study the evolution of dispersal strategies that depend on individual body condition. In a patchy environment where patches differ in environmental conditions, individuals born in rich (e.g. nutritious) patches are on average stronger than their conspecifics that are born in poorer patches. Body condition (strength) determines competitive ability such that stronger individuals win competition with higher probability than weak individuals. Individuals compete for patches such that kin competition selects for dispersal. I determine the evolutionarily stable strategy (ESS) for different ecological scenarios. My models offer explanations for both dispersal of strong individuals and dispersal of weak individuals. Moreover, I find that within-family dispersal behaviour is not always reflected on the population level. This supports the fact that no consistent pattern is detected in data on body condition dependent dispersal. It also encourages the refining of empirical investigations. Quasi-local competition defines interactions between adjacent populations where one population negatively affects the growth of the other population. I model a metapopulation in a homogeneous environment where adults of different subpopulations compete for resources by spending part of their foraging time in the neighbouring patches, while their juveniles only feed on the resource in their natal patch. I show that spatial patterns (different population densities in the patches) are stable only if one age class depletes the resource very much but mainly the other age group depends on it.

Resolution directing the hazan not to offer any mitzvot for any individuals but those customary

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Evolutionary Genetics in the WIld : from Populations to Individuals

Predicting evolutionary outcomes and reconstructing past evolutionary transitions are among the main goals of evolutionary biology. Ultimately, understanding the mechanisms of evolutionary change will also provide answers to the timely question of whether and how organisms will adapt to changing environmental conditions. In this thesis, I have investigated the relative roles of natural selection, random genetic drift and genetic correlations in the evolution of complex traits at different levels of organisation from populations to individuals. I have shown that natural selection has been the driving force behind body shape divergence of marine and freshwater threespine stickleback (Gasterosteus aculeatus) populations, while genetic drift may have played a significant role in the more fine scale divergence among isolated freshwater populations. These results are concurrent with the patterns that have emerged in the published studies comparing the relative importance of natural selection and genetic drift as explanations for population divergence in different traits and taxa. I have also shown that body shape and armour divergence among threespine stickleback populations is likely to be biased by the patterns of genetic variation and covariation. Body shape and armour variation along the most likely direction of evolution the direction of maximum genetic variance reflects the general patterns of variation observed wild populations across the distribution range of the threespine stickleback. Conversely, it appears that genetic correlations between the sexes have not imposed significant constraints on the evolution of sexual dimorphism in threespine stickleback body shape and armour. I have demonstrated that the patterns of evolution seen in the wild can be experimentally recreated to tease out the effects of different selection agents in detail. In addition, I have shown how important it is to take into account the correlative nature of traits, when making interpretations about the effects of natural selection on individual traits. Overall, this thesis provides a demonstration of how considering the relative roles of different mechanism of evolutionary change at different levels of organisation can aid in an emergence of a comprehensive picture of how adaptive divergence in wild populations occurs.

Analysis of body composition in individuals with high bone mass reveals a marked increase in fat mass in women but not men

Context: High bone mass (HBM), detected in 0.2% of dual-energy x-ray absorptiometry (DXA) scans, is characterized by raised body mass index, the basis for which is unclear. Objective: To investigate why body mass index is elevated in individuals with HBM, we characterized body composition and examined whether differences could be explained by bone phenotypes, eg, bone mass and/or bone turnover. Design, Setting, and Participants: We conducted a case-control study of 153 cases with unexplained HBM recruited from 4 UK centers by screening 219 088 DXA scans. Atotal of 138 first-degree relatives (of whom 51 had HBM) and 39 spouses were also recruited. Unaffected individuals served as controls. Main Outcome Measures: We measured fat mass, by DXA, and bone turnover markers. Results: Amongwomen, fat mass was inversely related to age in controls (P<.01), but not in HBM cases (P<.96) in whom mean fat mass was 8.9 [95% CI 4.7, 13.0] kg higher compared with controls (fully adjusted mean difference, P<.001). Increased fat mass in male HBM cases was less marked (gender interaction P = .03). Compared with controls, lean mass was also increased in female HBM cases (by 3.3 [1.2, 5.4] kg; P<.002); however, lean mass increases wereless marked than fat mass increases, resulting in 4.5% lower percentage lean mass in HBM cases (P<.001). Osteocalcin was also lower in female HBM cases compared with controls (by 2.8 [0.1, 5.5]μg/L; P = .04). Differences in fat mass were fully attenuated after hip bone mineral density (BMD) adjustment (P = .52) but unchanged after adjustment for bone turnover (P < .001), whereas the greater hip BMD in female HBM cases was minimally attenuated by fat mass adjustment (P<.001). Conclusions: HBM is characterized by a marked increase in fat mass in females, statistically explained by their greater BMD, but not by markers of bone turnover. Copyright © 2013 by The Endocrine Society.

Elevated circulating sclerostin concentrations in individuals with high bone mass, with and without LRP5 mutations

CONTEXT: The role and importance of circulating sclerostin is poorly understood. High bone mass (HBM) caused by activating LRP5 mutations has been reported to be associated with increased plasma sclerostin concentrations; whether the same applies to HBM due to other causes is unknown. OBJECTIVE: Our objective was to determine circulating sclerostin concentrations in HBM. DESIGN AND PARTICIPANTS: In this case-control study, 406 HBM index cases were identified by screening dual-energy x-ray absorptiometry (DXA) databases from 4 United Kingdom centers (n = 219 088), excluding significant osteoarthritis/artifact. Controls comprised unaffected relatives and spouses. MAIN MEASURES: Plasma sclerostin; lumbar spine L1, total hip, and total body DXA; and radial and tibial peripheral quantitative computed tomography (subgroup only) were evaluated. RESULTS: Sclerostin concentrations were significantly higher in both LRP5 HBM and non-LRP5 HBM cases compared with controls: mean (SD) 130.1 (61.7) and 88.0 (39.3) vs 66.4 (32.3) pmol/L (both P < .001, which persisted after adjustment for a priori confounders). In combined adjusted analyses of cases and controls, sclerostin concentrations were positively related to all bone parameters found to be increased in HBM cases (ie, L1, total hip, and total body DXA bone mineral density and radial/tibial cortical area, cortical bone mineral density, and trabecular density). Although these relationships were broadly equivalent in HBM cases and controls, there was some evidence that associations between sclerostin and trabecular phenotypes were stronger in HBM cases, particularly for radial trabecular density (interaction P < .01). CONCLUSIONS: Circulating plasma sclerostin concentrations are increased in both LRP5 and non-LRP5 HBM compared with controls. In addition to the general positive relationship between sclerostin and DXA/peripheral quantitative computed tomography parameters, genetic factors predisposing to HBM may contribute to increased sclerostin levels.

Estimating Frequencies of Minority Nevirapine-Resistant Strains in Chronically HIV-1-Infected Individuals Naive to Nevirapine by Using Stochastic Simulations and a Mathematical Model

Nevirapine forms the mainstay of our efforts to curtail the pediatric AIDS epidemic through prevention of mother-to-child transmission of HIV-1. A key limitation, however, is the rapid selection of HIV-1 strains resistant to nevirapine following the administration of a single dose. This rapid selection of resistance suggests that nevirapine-resistant strains preexist in HIV-1 patients and may adversely affect outcomes of treatment. The frequencies of nevirapine-resistant strains in vivo, however, remain poorly estimated, possibly because they exist as a minority below current assay detection limits. Here, we employ stochastic simulations and a mathematical model to estimate the frequencies of strains carrying different combinations of the common nevirapine resistance mutations K103N, V106A, Y181C, Y188C, and G190A in chronically infected HIV-1 patients naive to nevirapine. We estimate the relative fitness of mutant strains from an independent analysis of previous competitive growth assays. We predict that single mutants are likely to preexist in patients at frequencies (similar to 0.01% to 0.001%) near or below current assay detection limits (>0.01%), emphasizing the need for more-sensitive assays. The existence of double mutants is subject to large stochastic variations. Triple and higher mutants are predicted not to exist. Our estimates are robust to variations in the recombination rate, cellular superinfection frequency, and the effective population size. Thus, with 10(7) to 10(8) infected cells in HIV-1 patients, even when undetected, nevirapine-resistant genomes may exist in substantial numbers and compromise efforts to prevent mother-to-child transmission of HIV-1, accelerate the failure of subsequent antiretroviral treatments, and facilitate the transmission of drug resistance.

Individuals' Responsibility in Corporations

I discuss role responsibly, individual responsibility and collective responsibility in corporate multinational setting. My case study is about minerals used in electronics that come from the Democratic Republic of Congo. What I try to show throughout the thesis is how many things need to be taken into consideration when we discuss the responsibility of individuals in corporations. No easy and simple answers are available. Instead, we must keep in mind the complexity of the situation at all times, judging cases on individual basis, emphasizing the importance of individual judgement and virtue, as well as the responsibility we all share as members of groups and the wider society. I begin by discussing the demands that are placed on us as employees. There is always a potential for a conflict between our different roles and also the wider demands placed on us. Role demands are usually much more specific than the wider question of how we should act as human beings. The terminology of roles can also be misleading as it can create illusions about our work selves being somehow radically separated from our everyday, true selves. The nature of collective decision-making and its implications for responsibility is important too. When discussing the moral responsibility of an employee in a corporate setting, one must take into account arguments from individual and collective responsibility, as well as role ethics. Individual responsibility is not a separate or competing notion from that of collective responsibility. Rather, the two are interlinked. Individuals' responsibilities in collective settings combine both individual responsibility and collective responsibility (which is different from aggregate individual responsibility). In the majority of cases, both will apply in various degrees. Some members might have individual responsibility in addition to the collective responsibility, while others just the collective responsibility. There are also times when no-one bears individual moral responsibility but the members are still responsible for the collective part. My intuition is that collective moral responsibility is strongly linked to the way the collective setting affects individual judgements and moulds the decisions, and how the individuals use the collective setting to further their own ends. Individuals remain the moral agents but responsibility is collective if the actions in question are collective in character. I also explore the impacts of bureaucratic ethic and its influence on the individual. Bureaucracies can compartmentalize work to such a degree that individual human action is reduced to mere behaviour. Responsibility is diffused and the people working in the bureaucracy can come to view their actions to be outside the normal human realm where they would be responsible for what they do. Language games and rules, anonymity, internal power struggles, and the fragmentation of information are just some of the reasons responsibility and morality can get blurry in big institutional settings. Throughout the thesis I defend the following theses: ● People act differently depending on their roles. This is necessary for our society to function, but the more specific role demands should always be kept in check by the wider requirements of being a good human being. ● Acts in corporations (and other large collectives) are not reducible to individual actions, and cannot be explained fully by the behaviour of individual employees. ● Individuals are responsible for the actions that they undertake in the collective as role occupiers and are very rarely off the hook. Hiding behind role demands is usually only an excuse and shows a lack of virtue. ● Individuals in roles can be responsible even when the collective is not. This depends on if the act they performed was corporate in nature or not. ● Bureaucratic structure affects individual thinking and is not always a healthy environment to work in. ● Individual members can share responsibility with the collective and our share of the collective responsibility is strongly linked to our relations. ● Corporations and other collectives can be responsible for harm even when no individual is at fault. The structure and the policies of the collective are crucial. ● Socialization plays an important role in our morality at both work and outside it. We are all responsible for the kind of moral context we create. ● When accepting a role or a position in a collective, we are attaching ourselves with the values of that collective. ● Ethical theories should put more emphasis on good judgement and decision-making instead of vague generalisations. My conclusion is that the individual person is always in the centre when it comes to responsibility, and not so easily off the hook as we sometimes think. What we do, and especially who we choose to associate ourselves with, does matter and we should be more careful when we choose who we work for. Individuals within corporations are responsible for choosing that the corporation they associate with is one that they can ascribe to morally, if not fully, then at least for the most part. Individuals are also inclusively responsible to a varying degree for the collective activities they contribute to, even in overdetermined contexts. We all are responsible for the kind of corporations we choose to support through our actions as consumers, investors and citizens.

Pattern recognition and cellular immune responses to novel Mycobacterium tuberculosis-antigens in individuals from Belarus

Background: Tuberculosis (TB) is an enduring health problem worldwide and the emerging threat of multidrug resistant (MDR) TB and extensively drug resistant (XDR) TB is of particular concern. A better understanding of biomarkers associated with TB will aid to guide the development of better targets for TB diagnosis and for the development of improved TB vaccines. Methods: Recombinant proteins (n = 7) and peptide pools (n = 14) from M. tuberculosis (M.tb) antigens associated with M.tb pathogenicity, modification of cell lipids or cellular metabolism, were used to compare T cell immune responses defined by IFN-gamma production using a whole blood assay (WBA) from i) patients with TB, ii) individuals recovered from TB and iii) individuals exposed to TB without evidence of clinical TB infection from Minsk, Belarus. Results: We identified differences in M.tb target peptide recognition between the test groups, i.e. a frequent recognition of antigens associated with lipid metabolism, e.g. cyclopropane fatty acyl phospholipid synthase. The pattern of peptide recognition was broader in blood from healthy individuals and those recovered from TB as compared to individuals suffering from pulmonary TB. Detection of biologically relevant M.tb targets was confirmed by staining for intracellular cytokines (IL-2, TNF-alpha and IFN-gamma) in T cells from non-human primates (NHPs) after BCG vaccination. Conclusions: PBMCs from healthy individuals and those recovered from TB recognized a broader spectrum of M.tb antigens as compared to patients with TB. The nature of the pattern recognition of a broad panel of M.tb antigens will devise better strategies to identify improved diagnostics gauging previous exposure to M.tb; it may also guide the development of improved TB-vaccines.

On finding a set of healthy individuals from a large population

In this paper, we explore fundamental limits on the number of tests required to identify a given number of ``healthy'' items from a large population containing a small number of ``defective'' items, in a nonadaptive group testing framework. Specifically, we derive mutual information-based upper bounds on the number of tests required to identify the required number of healthy items. Our results show that an impressive reduction in the number of tests is achievable compared to the conventional approach of using classical group testing to first identify the defective items and then pick the required number of healthy items from the complement set. For example, to identify L healthy items out of a population of N items containing K defective items, when the tests are reliable, our results show that O(K(L - 1)/(N - K)) measurements are sufficient. In contrast, the conventional approach requires O(K log(N/K)) measurements. We derive our results in a general sparse signal setup, and hence, they are applicable to other sparse signal-based applications such as compressive sensing also.

Post-absorptive glucose lowering in normal healthy individuals: An epidemiological observation

Post-absorptive glucose lowering (PALG) is observed in individuals with glucose intolerance and in healthy individuals. We report a prevalence of about 23% among healthy Asian Indians. Individuals with PALG are characterized by leaner phenotype, low body fat percentage, increased insulin sensitivity and higher fasting glucose levels. (C) 2014 Elsevier Ireland Ltd. All rights reserved.