Bayesian testing of many hypotheses ×\times many genes: A study of sleep apnea

Substantial statistical research has recently been devoted to the analysis of large-scale microarray experiments which provide a measure of the simultaneous expression of thousands of genes in a particular condition. A typical goal is the comparison of gene expression between two conditions (e.g., diseased vs. nondiseased) to detect genes which show differential expression. Classical hypothesis testing procedures have been applied to this problem and more recent work has employed sophisticated models that allow for the sharing of information across genes. However, many recent gene expression studies have an experimental design with several conditions that requires an even more involved hypothesis testing approach. In this paper, we use a hierarchical Bayesian model to address the situation where there are many hypotheses that must be simultaneously tested for each gene. In addition to having many hypotheses within each gene, our analysis also addresses the more typical multiple comparison issue of testing many genes simultaneously. We illustrate our approach with an application to a study of genes involved in obstructive sleep apnea in humans.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS241 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Bayesian testing of many hypothesis x many genes: a study of sleep apnea

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldSubstantial statistical research has recently been devoted to the analysis of large-scale microarray experiments which provide a measure of the simultaneous expression of thousands of genes in a particular condition. A typical goal is the comparison of gene expression between two conditions (eg. diseased vs. non-diseased) to detect genes which show differential expression. Classical hypothesis testing procedures have been applied to this problem and more recent work has employed sophisticated models that allow for the sharing of information across genes.However,many recent gene expression studies have an experimental design with several conditions that requires an even more involved hypothesis testing approach. In this paper, we use a hierarchical Bayesian model to address the situation where there are many hypotheses that must be simultaneously tested for each gene. In addition to having many hypotheses within each gene, our analysis also addresses the more typical multiple comparison issue of testing many genes simultaneously. We illustrate our approach with an application to a study of genes involved in obstructive sleep apnea in humans

Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis

Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profiling of human RA synovial fluid revealed physiological levels of RvD1, which - once applied to human neutrophils - attenuated chemotaxis. These results prompted analyses of the antiarthritic properties of RvD1 in a model of murine inflammatory arthritis. The stable epimer 17R-RvD1 (100 ng/day) significantly attenuated arthritis severity, cachexia, hind-paw edema, and paw leukocyte infiltration and shortened the remission interval. Metabololipidomic profiling in arthritic joints revealed 17R-RvD1 significantly reduced PGE2 biosynthesis, while increasing levels of protective SPM. Molecular analyses indicated that 17R-RvD1 enhanced expression of genes associated with cartilage matrix synthesis, and direct intraarticular treatment induced chondroprotection. Joint protective actions of 17R-RvD1 were abolished in RvD1 receptor-deficient mice termed ALX/fpr2/3-/- . These investigations open new therapeutic avenues for inflammatory joint diseases, providing mechanistic substance for the benefits of omega-3 supplementation in RA

The role of obesity, different fat compartments and sleep apnea severity in circulating leptin levels: the Icelandic Sleep Apnea Cohort study.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.To assess whether sleep apnea severity has an independent relationship with leptin levels in blood after adjusting for different measures of obesity and whether the relationship between obstructive sleep apnea (OSA) severity and leptin levels differs depending on obesity level.Cross-sectional study of 452 untreated OSA patients (377 males and 75 females), in the Icelandic Sleep Apnea Cohort (ISAC), age 54.3±10.6 (mean±s.d.), body mass index (BMI) 32.7±5.3 kg m(-2) and apnea-hypopnea index 40.2±16.1 events per h. A sleep study and magnetic resonance imaging of abdominal visceral and subcutaneous fat volume were performed, as well as fasting serum morning leptin levels were measured.Leptin levels were more highly correlated with BMI, total abdominal and subcutaneous fat volume than visceral fat volume per se. No relationship was found between sleep apnea severity and leptin levels, assessed within three BMI groups (BMI or =35 kg m(-2)). In a multiple linear regression model, adjusted for gender, BMI explained 38.7% of the variance in leptin levels, gender explained 21.2% but OSA severity did not have a significant role and no interaction was found between OSA severity and BMI on leptin levels. However, hypertension had a significant effect on the interaction between OSA severity and obesity (P=0.04). In post-hoc analysis for nonhypertensive OSA subjects (n=249), the association between leptin levels and OSA severity explained a minor but significant variance (3.2%) in leptin levels. This relationship was greatest for nonobese nonhypertensive subjects (significant interaction with obesity level). No relationship of OSA severity and leptin levels was found for hypertensive subjects (n=199).Obesity and gender are the dominant determinants of leptin levels. OSA severity is not related to leptin levels except to a minor degree in nonhypertensive nonobese OSA subjects.NIH/HL72067/HL94307, Eimskip Fund of the University of Iceland, Landspitali University Hospital Research Fun

Single slice vs. volumetric MR assessment of visceral adipose tissue: reliability and validity among the overweight and obese.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Visceral adipose tissue (VAT) is associated with abnormal cardiovascular and metabolic profiles. Total VAT volume of the abdominal compartment by magnetic resonance imaging (MRI) is the gold-standard measurement for VAT but is costly and time consuming. Prior studies suggest VAT area on a single slice MR image may serve as a surrogate for total VAT volume but it is unknown if this relationship is maintained in overweight and obese men and women. Untreated sleep apnea subjects enrolled into the Icelandic Sleep Apnea Cohort (ISAC) underwent abdominal MRI. VAT area and subcutaneous adipose tissue (SAT) area at the L2-L3 and L4-L5 interspaces and total VAT and SAT volumes were determined by manual examination using image analysis software; 539 men and 129 women with mean ages of 54.1 and 58.8 years and mean BMI of 32.2 kg/m(2) and 33.7 kg/m(2), respectively, were studied. Mean total VAT volume was 40% smaller and mean total SAT was 25% larger among females compared with males. The correlation with VAT volume was significantly larger for L2-L3 VAT area (r = 0.96) compared to L4-L5 VAT area (r = 0.83). The difference in correlation coefficients was statistically significant (nonparametric bootstrap P < 0.001 with 95% confidence interval (CI) for the difference from 0.11 to 0.15. VAT area at L2-L3 was also significantly better correlated with VAT volume than traditional anthropometric variables. Linear regression analyses demonstrated that L2-L3 area alone was sufficient for predicting total VAT volume and that the nature of the linear association was maintained across all levels of obesity and in both genders.NIH HL070267 HL09430

Systematic literature review of determinants of sedentary behaviour in older adults:a DEDIPAC study

BACKGROUND: Older adults are the most sedentary segment of society and high sedentary time is associated with poor health and wellbeing outcomes in this population. Identifying determinants of sedentary behaviour is a necessary step to develop interventions to reduce sedentary time. METHODS: A systematic literature review was conducted to identify factors associated with sedentary behaviour in older adults. Pubmed, Embase, CINAHL, PsycINFO and Web of Science were searched for articles published between 2000 and May 2014. The search strategy was based on four key elements: (a) sedentary behaviour and its synonyms; (b) determinants and its synonyms (e.g. correlates, factors); (c) types of sedentary behaviour (e.g. TV viewing, sitting, gaming) and (d) types of determinants (e.g. environmental, behavioural). Articles were included in the review if specific information about sedentary behaviour in older adults was reported. Studies on samples identified by disease were excluded. Study quality was rated by means of QUALSYST. The full review protocol is available from PROSPERO (PROSPERO 2014: CRD42014009823). The analysis was guided by the socio-ecological model framework. RESULTS: Twenty-two original studies were identified out of 4472 returned by the systematic search. These included 19 cross-sectional, 2 longitudinal and 1 qualitative studies, all published after 2011. Half of the studies were European. The study quality was generally high with a median of 82 % (IQR 69-96 %) using Qualsyst tool. Personal factors were the most frequently investigated with consistent positive association for age, negative for retirement, obesity and health status. Only four studies considered environmental determinants suggesting possible association with mode of transport, type of housing, cultural opportunities and neighbourhood safety and availability of places to rest. Only two studies investigated mediating factors. Very limited information was available on contexts and sub-domains of sedentary behaviours. CONCLUSION: Few studies have investigated determinants of sedentary behaviour in older adults and these have to date mostly focussed on personal factors, and qualitative studies were mostly lacking. More longitudinal studies are needed as well as inclusion of a broader range of personal and contextual potential determinants towards a systems-based approach, and future studies should be more informed by qualitative work

Few-emitter lasing in single ultra-small nanocavities

Funding: We acknowledge support from EPSRC grants EP/G060649/1, EP/L027151/1, EP/G037221/1, EP/T014032/1, EPSRC NanoDTC, and from the European Research Council (ERC) under Horizon 2020 research and innovation programme PICOFORCE (Grant Agreement No. 883703), THOR (Grant Agreement No. 829067) and POSEIDON (Grant Agreement No. 861950). O.S.O acknowledges the support of a Rubicon fellowship from the Netherlands Organisation for Scientific Research.Lasers are ubiquitous for information storage, processing, communications, sensing, biological research, and medical applications. To decrease their energy and materials usage, a key quest is to miniaturize lasers down to nanocavities. Obtaining the smallest mode volumes demands plasmonic nanocavities, but for these, gain comes from only single or few emitters. Until now, lasing in such devices was unobtainable due to low gain and high cavity losses. Here, we demonstrate a form of “few emitter lasing” in a plasmonic nanocavity approaching the single-molecule emitter regime. The few-emitter lasing transition significantly broadens, and depends on the number of molecules and their individual locations. We show this non-standard few-emitter lasing can be understood by developing a theoretical approach extending previous weak-coupling theories. Our work paves the way for developing nanolaser applications as well as fundamental studies at the limit of few emitters.Publisher PDFPeer reviewe

Response to Therapeutic Sleep Deprivation: A Naturalistic Study of Clinical and Genetic Factors and Post-treatment Depressive Symptom Trajectory

Research has shown that therapeutic sleep deprivation (SD) has rapid antidepressant effects in the majority of depressed patients. Investigation of factors preceding and accompanying these effects may facilitate the identification of the underlying biological mechanisms. This exploratory study aimed to examine clinical and genetic factors predicting response to SD and determine the impact of SD on illness course. Mood during SD was also assessed via visual analogue scale. Depressed inpatients (n = 78) and healthy controls (n = 15) underwent ~36 h of SD. Response to SD was defined as a score of ≤ 2 on the Clinical Global Impression Scale for Global Improvement. Depressive symptom trajectories were evaluated for up to a month using self/expert ratings. Impact of genetic burden was calculated using polygenic risk scores for major depressive disorder. In total, 72% of patients responded to SD. Responders and non-responders did not differ in baseline self/expert depression symptom ratings, but mood differed. Response was associated with lower age (p = 0.007) and later age at life-time disease onset (p = 0.003). Higher genetic burden of depression was observed in non-responders than healthy controls. Up to a month post SD, depressive symptoms decreased in both patients groups, but more in responders, in whom effects were sustained. The present findings suggest that re-examining SD with a greater focus on biological mechanisms will lead to better understanding of mechanisms of depression

“Keeping Moving”: factors associated with sedentary behaviour among older people recruited to an exercise promotion trial in general practice

Background Sedentary behaviour is detrimental to health, even in those who achieve recommended levels of physical activity. Efforts to increase physical activity in older people so that they reach beneficial levels have been disappointing. Reducing sedentary behaviour may improve health and be less demanding of older people, but it is not clear how to achieve this. We explored the characteristics of sedentary older people enrolled into an exercise promotion trial to gain insights about those who were sedentary but wanted to increase activity. Method Participants in the ProAct65+ trial (2009–2013) were categorised as sedentary or not using a self-report questionnaire. Demographic data, health status, self-rated function and physical test performance were examined for each group. 1104 participants aged 65 & over were included in the secondary analysis of trial data from older people recruited via general practice. Results were analysed using logistic regression with stepwise backward elimination. Results Three hundred eighty seven (35 %) of the study sample were characterised as sedentary. The likelihood of being categorised as sedentary increased with an abnormal BMI (25 kg/m2) (Odds Ratio 1.740, CI 1.248–2.425), ever smoking (OR 1.420, CI 1.042–1.934) and with every additional medication prescribed (OR 1.069, CI 1.016–1.124). Participants reporting better self-rated physical health (SF-12) were less likely to be sedentary; (OR 0.961, 0.936–0.987). Participants’ sedentary behaviour was not associated with gender, age, income, education, falls, functional fitness, quality of life or number of co-morbidities. Conclusion Some sedentary older adults will respond positively to an invitation to join an exercise study. Those who did so in this study had poor self-rated health, abnormal BMI, a history of smoking, and multiple medication use, and are therefore likely to benefit from an exercise intervention

Verbal memory is linked to average oxygen saturation during sleep, not the apnea-hypopnea index nor novel hypoxic load variables

Introduction: The apnea-hypopnea index (AHI) is the current diagnostic parameter for diagnosing and estimating the severity of obstructive sleep apnea (OSA). It is, however, poorly associated with the main clinical symptom of OSA, excessive daytime sleepiness, and with the often-seen cognitive decline among OSA patients. To better evaluate OSA severity, novel hypoxic load parameters have been introduced that consider the duration and depth of oxygen saturation drops associated with apneas or hypopneas. The aim of this paper was to compare novel hypoxic load parameters and traditional OSA parameters to verbal memory and executive function in OSA patients. Method: A total of 207 adults completed a one-night polysomnography at sleep laboratory and two neuropsychological assessments, the Rey Auditory Verbal Learning Test and Stroop test. Results: Simple linear regression analyses were used to evaluate independent associations between each OSA parameter and cognitive performance. Associations were found between immediate recall and arousal index, hypoxia <90 %, average SpO2 during sleep, and DesSev100+RevSev100. Total recall was associated with all OSA parameters, and no associations were found with the Stroop test. Subsequently, sex, age, and education were included as covariates in multiple linear regression analyses for each OSA parameter and cognitive performance. The main findings of the study were that average SpO2 during sleep was a significant predictor of total recall (p < .007, β = −.188) with the regression model explaining 21.2 % of performance variation. Average SpO2 during sleep was also a significant predictor of immediate recall (p < .022, β = −.171) with the regression model explaining 11.4 % of performance variation. Neither traditional OSA parameters nor novel hypoxic load parameters predicted cognitive performance after adjustment for sex, age, and education. Conclusion: The findings validate that the AHI is not an effective indicator of cognitive performance in OSA and suggest that average oxygen saturation during sleep may be the strongest PSG predictor of cognitive decline seen in OSA. The results also underline the importance of considering age when choosing neurocognitive tests, the importance of including more than one test for each cognitive domain as most tests are not pure measures of a single cognitive factor, and the importance of including tests that cover all cognitive domains as OSA is likely to have diffuse cognitive effects.publishedVersio