The admixture maximum likelihood test to test for association between rare variants and disease phenotypes.

BACKGROUND: The development of genotyping arrays containing hundreds of thousands of rare variants across the genome and advances in high-throughput sequencing technologies have made feasible empirical genetic association studies to search for rare disease susceptibility alleles. As single variant testing is underpowered to detect associations, the development of statistical methods to combine analysis across variants - so-called "burden tests" - is an area of active research interest. We previously developed a method, the admixture maximum likelihood test, to test multiple, common variants for association with a trait of interest. We have extended this method, called the rare admixture maximum likelihood test (RAML), for the analysis of rare variants. In this paper we compare the performance of RAML with six other burden tests designed to test for association of rare variants. RESULTS: We used simulation testing over a range of scenarios to test the power of RAML compared to the other rare variant association testing methods. These scenarios modelled differences in effect variability, the average direction of effect and the proportion of associated variants. We evaluated the power for all the different scenarios. RAML tended to have the greatest power for most scenarios where the proportion of associated variants was small, whereas SKAT-O performed a little better for the scenarios with a higher proportion of associated variants. CONCLUSIONS: The RAML method makes no assumptions about the proportion of variants that are associated with the phenotype of interest or the magnitude and direction of their effect. The method is flexible and can be applied to both dichotomous and quantitative traits and allows for the inclusion of covariates in the underlying regression model. The RAML method performed well compared to the other methods over a wide range of scenarios. Generally power was moderate in most of the scenarios, underlying the need for large sample sizes in any form of association testing.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Development of an instrument to assess social functioning in dementia: The Social Functioning in Dementia scale (SF-DEM)

INTRODUCTION: Social functioning is a core domain in the life of people with dementia, but there is no accepted instrument to measure it. We aimed to develop the Social Functioning in Dementia (SF-DEM) scale and test its psychometric properties for assessing social function in people with dementia. METHODS: We interviewed people with mild dementia and family caregivers to develop patient and caregiver-rated SF-DEM versions and refined them through interviews with health care professionals. We tested its psychometric properties in 30 dyads of people with dementia and family caregivers. RESULTS: Both SF-DEM versions had content validity and demonstrated concurrent validity against a single item rating overall social functioning (patient rated r = 0.42, 95% CI [0.07–0.68]; caregiver rated r = 0.59, 95% CI [0.29–0.78]). All participants found it acceptable. Analyses showed reliability (test–retest, inter-rater, internal consistency) and indications of responsiveness to change. DISCUSSION: SF-DEM shows promise as a valid, reliable, acceptable measure of social functioning in dementia

Service evaluation of a nurse-led dental anxiety management service for adult patients

Objective: Evaluate patients’ and professionals’ experiences of a Nurse-led Dental Anxiety Management Service (NDAMS). Design: Service evaluation. Setting: The NDAMS operates as part of Sheffield Salaried Primary Dental Care Service. Subjects and methods: Questionnaire survey of anxious patients and qualitative interviews with patients and professionals Interventions: Dental nurses delivered low-level psychological interventions as part of an Integrated Care Pathway (ICP) for dental anxiety. Main outcome Measures: Dental anxiety and oral health-related quality of life (OHRQoL) questionnaires were completed by patients prior to and following NDAM. Results: A total of 187 patients were assessed as suitable for NDAM (mean age= 33.7, 77% female) and 33 had completed it at the time of the service evaluation. Of those patients who had completed the intervention significant improvements in dental anxiety and OHRQoL were reported. Professionals highlighted the importance of integrated working, adequate support and training and assessing the suitability of patients for NDAM. Conclusion: ICPs that combine pharmacological and psychological management approaches can help meet the needs of dentally anxious patients, however, early identification of patients most likely to benefit from psychological intervention should be a priority

Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial

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The prevalence and incidence of mental ill-health in adults with autism and intellectual disabilities

The prevalence, and incidence, of mental ill-health in adults with intellectual disabilities and autism were compared with the whole population with intellectual disabilities, and with controls, matched individually for age, gender, ability-level, and Down syndrome. Although the adults with autism had a higher point prevalence of problem behaviours compared with the whole adult population with intellectual disabilities, compared with individually matched controls there was no difference in prevalence, or incidence of either problem behaviours or other mental ill-health. Adults with autism who had problem behaviours were less likely to recover over a two-year period than were their matched controls. Apparent differences in rates of mental ill-health are accounted for by factors other than autism, including Down syndrome and ability level

Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety

<p>Background: Melatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment.</p> <p>Methods: Adult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit.</p> <p>Results: On the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] ≤8 μg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome.</p> <p>Conclusions: The results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. The age cut-off for response warrants further investigation.</p&gt