Chapter 11: Genome-wide association studies Bush, William S; Moore, Jason H
PLOS computational biology/PLoS computational biology,
12/2012, Letnik:
8, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Genome-wide association studies (GWAS) have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts ...underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.
Calls for primary care providers (PCPs) to offer obese patients behavioral weight-loss counseling have not been accompanied by adequate guidance on how such care could be delivered. This randomized ...trial compared weight loss during a 2-year period in response to three lifestyle interventions, all delivered by PCPs in collaboration with auxiliary health professionals (lifestyle coaches) in their practices.
We randomly assigned 390 obese adults in six primary care practices to one of three types of intervention: usual care, consisting of quarterly PCP visits that included education about weight management; brief lifestyle counseling, consisting of quarterly PCP visits combined with brief monthly sessions with lifestyle coaches who instructed participants about behavioral weight control; or enhanced brief lifestyle counseling, which provided the same care as described for the previous intervention but included meal replacements or weight-loss medication (orlistat or sibutramine), chosen by the participants in consultation with the PCPs, to potentially increase weight loss.
Of the 390 participants, 86% completed the 2-year trial, at which time, the mean (±SE) weight loss with usual care, brief lifestyle counseling, and enhanced brief lifestyle counseling was 1.7±0.7, 2.9±0.7, and 4.6±0.7 kg, respectively. Initial weight decreased at least 5% in 21.5%, 26.0%, and 34.9% of the participants in the three groups, respectively. Enhanced lifestyle counseling was superior to usual care on both these measures of success (P=0.003 and P=0.02, respectively), with no other significant differences among the groups. The benefits of enhanced lifestyle counseling remained even after participants given sibutramine were excluded from the analyses. There were no significant differences between the intervention groups in the occurrence of serious adverse events.
Enhanced weight-loss counseling helps about one third of obese patients achieve long-term, clinically meaningful weight loss. (Funded by the National Heart, Lung, and Blood Institute; POWER-UP ClinicalTrials.gov number, NCT00826774.).
Background
Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy.
Objectives
...To examine the efficacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the effect of riluzole upon functional health.
Search methods
We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 April 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1966 to April 2011), EMBASE (1980 to May 2011) and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field.
Selection criteria
Types of studies: randomized controlled trials
Types of participants: adults with a diagnosis of amyotrophic lateral sclerosis
Types of interventions: treatment with riluzole or placebo
Types of outcome measures:
Primary: pooled hazard ratio of tracheostomy‐free survival over all time points with riluzole 100 mg.
Secondary: per cent mortality with riluzole 50 mg, 100 mg and 200 mg; neurologic function, muscle strength and adverse events.
Data collection and analysis
One author performed data extraction and two other authors checked them. One author checked the data and entered them into the computer. The other authors verified the data entry. We obtained missing data from the trial authors whenever possible.
Main results
The four trials examining tracheostomy‐free survival included a total of 974 riluzole‐treated patients and 503 placebo‐treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three‐fold increase in serum alanine transferase was more frequent in riluzole‐treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31).
Authors' conclusions
Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.
Adenotonsillectomy is commonly performed in children with the obstructive sleep apnea syndrome, yet its usefulness in reducing symptoms and improving cognition, behavior, quality of life, and ...polysomnographic findings has not been rigorously evaluated. We hypothesized that, in children with the obstructive sleep apnea syndrome without prolonged oxyhemoglobin desaturation, early adenotonsillectomy, as compared with watchful waiting with supportive care, would result in improved outcomes.
We randomly assigned 464 children, 5 to 9 years of age, with the obstructive sleep apnea syndrome to early adenotonsillectomy or a strategy of watchful waiting. Polysomnographic, cognitive, behavioral, and health outcomes were assessed at baseline and at 7 months.
The average baseline value for the primary outcome, the attention and executive-function score on the Developmental Neuropsychological Assessment (with scores ranging from 50 to 150 and higher scores indicating better functioning), was close to the population mean of 100, and the change from baseline to follow-up did not differ significantly according to study group (mean ±SD improvement, 7.1±13.9 in the early-adenotonsillectomy group and 5.1±13.4 in the watchful-waiting group; P=0.16). In contrast, there were significantly greater improvements in behavioral, quality-of-life, and polysomnographic findings and significantly greater reduction in symptoms in the early-adenotonsillectomy group than in the watchful-waiting group. Normalization of polysomnographic findings was observed in a larger proportion of children in the early-adenotonsillectomy group than in the watchful-waiting group (79% vs. 46%).
As compared with a strategy of watchful waiting, surgical treatment for the obstructive sleep apnea syndrome in school-age children did not significantly improve attention or executive function as measured by neuropsychological testing but did reduce symptoms and improve secondary outcomes of behavior, quality of life, and polysomnographic findings, thus providing evidence of beneficial effects of early adenotonsillectomy. (Funded by the National Institutes of Health; CHAT ClinicalTrials.gov number, NCT00560859.).
Accurate prediction of disease risk based on the genetic make-up of an individual is essential for effective prevention and personalized treatment. Nevertheless, to date, individual genetic variants ...from genome-wide association studies have achieved only moderate prediction of disease risk. The aggregation of genetic variants under a polygenic model shows promising improvements in prediction accuracies. Increasingly, electronic health records (EHRs) are being linked to patient genetic data in biobanks, which provides new opportunities for developing and applying polygenic risk scores in the clinic, to systematically examine and evaluate patient susceptibilities to disease. However, the heterogeneous nature of EHR data brings forth many practical challenges along every step of designing and implementing risk prediction strategies. In this Review, we present the unique considerations for using genotype and phenotype data from biobank-linked EHRs for polygenic risk prediction.
Background: Body mass index (BMI) and percentage body fat (%BF) are widely used to assess adiposity. These indexes fail to account for independent contributions of fat mass (FM) and lean body mass ...(LBM) to body weight, which vary according to age, sex, pubertal status, and population ancestry in the pediatric population.Objective: The objective was to develop pediatric reference curves for fat mass index (FMI) and lean body mass index (LBMI) and evaluate the effects of population ancestry and LBM on measures of excess adiposity (BMI, %BF, and FMI).Design: Sex-specific FMI and LBMI reference curves relative to age for children and adolescents aged 8–20 y were generated from cross-sectional body-composition data measured by dual-energy X-ray absorptiometry from NHANES.Results: The mean LBMI z score was higher in blacks (males: 0.26; females: 0.45) than in whites (males: −0.07; females: −0.09) and Mexican Americans (males: 0.05; females: −0.09). The positive predictive value of overweight by BMI to identify excess adiposity defined by FMI was lower in blacks (males: 35.9%; females: 30.3%) than in whites (males: 65.4%; females: 52.2%) and Mexican Americans (males: 73.3%; females: 68.3%). Participants classified as having excess adiposity by FMI but normal adiposity by %BF had significantly higher BMI, LBMI, and height z scores than did those classified as having excess adiposity by %BF but normal adiposity by FMI.Conclusions: Relative to FMI, the prevalence of excess adiposity is overestimated by BMI in blacks and underestimated by %BF in individuals with high LBM. The use of FMI and LBMI improves on the use of %BF and BMI by allowing for the independent assessment of FM and LBM.
Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research ...has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia-from the premorbid through the prodromal stages to syndromal psychosis-and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and other investigators supporting this pathophysiological hypothesis, as well as its implications for early detection and therapeutic intervention.
Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based ...immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.
Over the last decade, researchers have used virtual- and mixed-reality (VR-MR) techniques for various safety-related applications such as training, hazard monitoring, and preconstruction planning. ...This paper reviews the recent trends in virtual- and mixed-reality applications in construction safety, explicitly focusing on virtual-reality and mixed-reality techniques as the two major types of computer-generated simulated experiences. Following a systematic literature assessment methodology, this study summarizes the results of articles that have been published over the last decade and illustrates the research trends of virtual- and mixed-reality applications in construction safety while focusing on the technological components of individual studies.
PDF
