Phenotypic Complexity, Measurement Bias, and Poor Phenotypic Resolution Contribute to the Missing Heritability Problem in Genetic Association Studies

Background The variance explained by genetic variants as identified in (genome-wide) genetic association studies is typically small compared to family-based heritability estimates. Explanations of this ‘missing heritability’ have been mainly genetic, such as genetic heterogeneity and complex (epi-)genetic mechanisms. Methodology We used comprehensive simulation studies to show that three phenotypic measurement issues also provide viable explanations of the missing heritability: phenotypic complexity, measurement bias, and phenotypic resolution. We identify the circumstances in which the use of phenotypic sum-scores and the presence of measurement bias lower the power to detect genetic variants. In addition, we show how the differential resolution of psychometric instruments (i.e., whether the instrument includes items that resolve individual differences in the normal range or in the clinical range of a phenotype) affects the power to detect genetic variants. Conclusion We conclude that careful phenotypic data modelling can improve the genetic signal, and thus the statistical power to identify genetic variants by 20-99

Interview on Kinship and Household

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Automated peritoneal lavage: An extremely rapid and safe way to induce hypothermia in post-resuscitation patients

Introduction: Mild therapeutic hypothermia (MTH) is a worldwide used therapy to improve neurological outcome in patients successfully resuscitated after cardiac arrest (CA). Preclinical data suggest that timing and speed of induction are related to reduction of secondary brain damage and improved outcome.Methods: Aiming at a rapid induction and stable maintenance phase, MTH induced via continuous peritoneal lavage (PL) using the Velomedix® Inc. automated PL system was evaluated and compared to historical controls in which hypothermia was achieved using cooled saline intravenous infusions and cooled blankets. Results: In 16 PL patients, time to reach the core target temperature of 32.5°C was 30 minutes (interquartile range (IQR): 19 to 60), which was significantly faster compare to 150 minutes (IQR: 112 to 240) in controls. The median rate of cooling during the induction phase in the PL group of 4.1°C/h (IQR: 2.2 to 8.2) was significantly faster compared to 0.9°C/h (IQR: 0.5 to 1.3) in controls. During the 24-hour maintenance phase mean core temperature in the PL patients was 32.38 ± 0.18°C (range: 32.03 to 32.69°C) and in control patients 32.46 ± 0.48°C (range: 31.20 to 33.63°C), indicating more steady temperature control in the PL group compared to controls. Furthermore, the coefficient of variation (VC) for temperature during the maintenance phase was lower in the PL group (VC: 0.5%) compared to the control group (VC: 1.5%). In contrast to 23% of the control patients, none of the PL patients showed an overshoot of hypothermia below 31°C during the maintenance phase. Survival and neurological outcome was not different between the two groups. Neither shivering nor complications related to insertion or use of the PL method were observed.Conclusions: Using PL in post-CA patients results in a rapidly reached target temperature and a very precise maintenance, unprecedented in clinical studies evaluating MTH techniques. This opens the way to investigate the effects on neurological outcome and survival of ultra-rapid cooling compared to standard cooling in controlled trials in various patient groups.Trial Registration: ClinicalTrials.gov: NCT01016236. © 2013 de Waard et al.; licensee BioMed Central Ltd

Fatores associados à infecção pelo uso do cateter central de inserção periférica em Unidade de Terapia Intensiva Neonatal

Estudo epidemiológico, longitudinal e analítico, desenvolvido em um hospital de Minas Gerais, com o objetivo de analisar os fatores associados à infecção pelo uso do cateter central de inserção periférica em recém-nascidos internados em unidade de terapia intensiva. A coleta dos dados foi realizada por meio de uma ficha estruturada, preenchida pelos profissionais e verificada pelos pesquisadores. Foram estudados 291 cateteres inseridos em 233 recém-nascidos. Os fatores associados à retirada por suspeita de infecção foram: prematuridade, peso ao nascer até 1.500 gramas, cateter de poliuretano, localização não centralizada do cateter e tempo de uso superior a 30 dias. Após ajuste multivariado, permaneceram independentemente associados: peso inferior a 2.500 gramas na inserção, reparo e tempo de uso do cateter. Conclui-se que fatores relacionados à prática dos profissionais contribuíram para a retirada dos cateteres, sinalizando para a necessidade de intervenções que melhorem a segurança e a eficácia em seu uso

Clinical Efficacy of Blue Light Full Body Irradiation as Treatment Option for Severe Atopic Dermatitis

BACKGROUND: Therapy of atopic dermatitis (AD) relies on immunosuppression and/or UV irradiation. Here, we assessed clinical efficacy and histopathological alterations induced by blue light-treatment of AD within an observational, non-interventional study. METHODOLOGY/PRINCIPAL FINDINGS: 36 patients with severe, chronic AD resisting long term disease control with local corticosteroids were included. Treatment consisted of one cycle of 5 consecutive blue light-irradiations (28.9 J/cm(2)). Patients were instructed to ask for treatment upon disease exacerbation despite interval therapy with topical corticosteroids. The majority of patients noted first improvements after 2-3 cycles. The EASI score was improved by 41% and 54% after 3 and 6 months, respectively (p≤0.005, and p≤0.002). Significant improvement of pruritus, sleep and life quality was noted especially after 6 months. Also, frequency and intensity of disease exacerbations and the usage of topical corticosteroids was reduced. Finally, immunohistochemistry of skin biopsies obtained at baseline and after 5 and 15 days revealed that, unlike UV light, blue light-treatment did not induce Langerhans cell or T cell depletion from skin. CONCLUSIONS/SIGNIFICANCE: Blue light-irradiation may represent a suitable treatment option for AD providing long term control of disease. Future studies with larger patient cohorts within a randomized, placebo-controlled clinical trial are required to confirm this observation

Thought Problems from Adolescence to Adulthood: Measurement Invariance and Longitudinal Heritability

This study investigates the longitudinal heritability in Thought Problems (TP) as measured with ten items from the Adult Self Report (ASR). There were ~9,000 twins, ~2,000 siblings and ~3,000 additional family members who participated in the study and who are registered at the Netherlands Twin Register. First an exploratory factor analysis was conducted to examine the underlying factor structure of the TP-scale. Then the TP-scale was tested for measurement invariance (MI) across age and sex. Next, genetic and environmental influences were modeled on the longitudinal development of TP across three age groups (12–18, 19–27 and 28–59 year olds) based on the twin and sibling relationships in the data. An exploratory factor analysis yielded a one-factor solution, and MI analyses indicated that the same TP-construct is assessed across age and sex. Two additive genetic components influenced TP across age: the first influencing TP throughout all age groups, while the second arises during young adulthood and stays significant throughout adulthood. The additive genetic components explained 37% of the variation across all age groups. The remaining variance (63%) was explained by unique environmental influences. The longitudinal phenotypic correlation between these age groups was entirely explained by the additive genetic components. We conclude that the TP-scale measures a single underlying construct across sex and different ages. These symptoms are significantly influenced by additive genetic factors from adolescence to late adulthood

Individual Differences in Processing Speed and Working Memory Speed as Assessed with the Sternberg Memory Scanning Task

The Sternberg Memory Scanning (SMS) task provides a measure of processing speed (PS) and working memory retrieval speed (WMS). In this task, participants are presented with sets of stimuli that vary in size. After a delay, one item is presented, and participants indicate whether or not the item was part of the set. Performance is assessed by speed and accuracy for both the positive (item is part of the set) and the negative trials (items is not part of the set). To examine the causes of variation in PS and WMS, 623 adult twins and their siblings completed the SMS task. A non-linear growth curve (nLGC) model best described the increase in reaction time with increasing set size. Genetic analyses showed that WMS (modeled as the Slope in the nLGC model) has a relatively small variance which is not due to genetic variation while PS (modeled as the Intercept in the nLGC model) showed large individual differences, part of which could be attributed to additive genetic factors. Heritability was 38% for positive and 32% for negative trials. Additional multivariate analyses showed that the genetic effects on PS for positive and negative trials were completely shared. We conclude that genetic influences on working memory performance are more likely to act upon basic processing speed and (pre)motoric processes than on the speed with which an item is retrieved from short term memory

Genetic Epidemiology of Attention Deficit Hyperactivity Disorder (ADHD Index) in Adults

Context: In contrast to the large number of studies in children, there is little information on the contribution of genetic factors to Attention Deficit Hyperactivity Disorder (ADHD) in adults. Objective: To estimate the heritability of ADHD in adults as assessed by the ADHD index scored from the CAARS (Conners’ Adult ADHD Rating Scales). Design: Phenotype data from over 12,000 adults (twins, siblings and parents) registered with the Netherlands Twin Register were analyzed using genetic structural equation modeling. Main outcome measures: Heritability estimates for ADHD from the twin-family study. Results: Heritability of ADHD in adults is estimated around 30 % in men and women. There is some evidence for assortative mating. All familial transmission is explained by genetic inheritance, there is no support for the hypothesis that cultural transmission from parents to offspring is important. Conclusion: Heritability for ADHD features in adults is present, but is substantially lower than it is in children

A Twin Study of the Genetics of High Cognitive Ability Selected from 11,000 Twin Pairs in Six Studies from Four Countries

Although much genetic research has addressed normal variation in intelligence, little is known about the etiology of high cognitive abilities. Using data from 11,000 twin pairs (age range = 6-71 years) from the genetics of high cognitive abilities consortium, we investigated the genetic and environmental etiologies of high general cognitive ability (g). Age-appropriate psychometric cognitive tests were administered to the twins and used to create g scores standardized within each study. Liability-threshold model fitting was used to estimate genetic and environmental parameters for the top 15% of the distribution of g. Genetic influence for high g was substantial (0.50, with a 95% confidence interval of 0.41-0.60). Shared environmental influences were moderate (0.28, 0.19-0.37). We conclude that genetic variation contributes substantially to high g in Australia, the Netherlands, the United Kingdom and the United States. © 2009 Springer Science+Business Media, LLC