Reporting on covariate adjustment in randomised controlled trials before and after revision of the 2001 CONSORT statement: a literature review

<p>Abstract</p> <p>Objectives</p> <p>To evaluate the use and reporting of adjusted analysis in randomised controlled trials (RCTs) and compare the quality of reporting before and after the revision of the CONSORT Statement in 2001.</p> <p>Design</p> <p>Comparison of two cross sectional samples of published articles.</p> <p>Data Sources</p> <p>Journal articles indexed on PubMed in December 2000 and December 2006.</p> <p>Study Selection</p> <p>Parallel group RCTs with a full publication carried out in humans and published in English</p> <p>Main outcome measures</p> <p>Proportion of articles reported adjusted analysis; use of adjusted analysis; the reason for adjustment; the method of adjustment and the reporting of adjusted analysis results in the main text and abstract.</p> <p>Results</p> <p>In both cohorts, 25% of studies reported adjusted analysis (84/355 in 2000 vs 113/422 in 2006). Compared with articles reporting only unadjusted analyses, articles that reported adjusted analyses were more likely to specify primary outcomes, involve multiple centers, perform stratified randomization, be published in general medical journals, and recruit larger sample sizes. In both years a minority of articles explained why and how covariates were selected for adjustment (20% to 30%). Almost all articles specified the statistical methods used for adjustment (99% in 2000 vs 100% in 2006) but only 5% and 10%, respectively, reported both adjusted and unadjusted results as recommended in the CONSORT guidelines.</p> <p>Conclusion</p> <p>There was no evidence of change in the reporting of adjusted analysis results five years after the revision of the CONSORT Statement and only a few articles adhered fully to the CONSORT recommendations.</p

Genome Wide Assessment of Young Onset Parkinson's Disease from Finland

In the current study we undertook a series of experiments to test the hypothesis that a monogenic cause of disease may be detectable within a cohort of Finnish young onset Parkinson’s disease patients. In the first instance we performed standard genome wide association analyses, and subsequent risk profile analysis. In addition we performed a series of analyses that involved testing measures of global relatedness within the cases compared to controls, searching for excess homozygosity in the cases, and examining the cases for signs of excess local genomic relatedness using a sliding window approach. This work suggested that the previously identified common, low risk alleles, and the risk models associated with these alleles, were generalizable to the Finnish Parkinson’s disease population. However, we found no evidence that would suggest a single common high penetrance mutation exists in this cohort of young onset patients

Lingual juvenile xanthogranuloma in a woman: a case report

<p>Abstract</p> <p>Introduction</p> <p>Juvenile xanthogranuloma is a rare non-Langerhans cell histiocytosis that usually occurs during infancy and early childhood. The presence of single or multiple raised cutaneous lesions characterize this self-healing disorder. Extracutaneous sites are rare.</p> <p>Case presentation</p> <p>We present a rare case of oral juvenile xanthogranuloma in a 49-year-old Caucasian woman. The histopathologic diagnosis of the lingual neoformation was histiocitary proliferation with the presence of giant cells, Touton type, compatible with juvenile xanthogranuloma.</p> <p>Conclusion</p> <p>To establish an accurate diagnosis, microscopic evaluation and immunohistochemical staining are necessary. Dentists, dermatologists and general practitioners may be the first to recognize this rare condition during the inspection of the oral cavity.</p

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~ 25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value < 0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia

Widespread sex differences in gene expression and splicing in the adult human brain

There is strong evidence to show that men and women differ in terms of neurodevelopment, neurochemistry and susceptibility to neurodegenerative and neuropsychiatric disease. The molecular basis of these differences remains unclear. Progress in this field has been hampered by the lack of genome-wide information on sex differences in gene expression and in particular splicing in the human brain. Here we address this issue by using post-mortem adult human brain and spinal cord samples originating from 137 neuropathologically confirmed control individuals to study whole-genome gene expression and splicing in 12 CNS regions. We show that sex differences in gene expression and splicing are widespread in adult human brain, being detectable in all major brain regions and involving 2.5% of all expressed genes. We give examples of genes where sex-biased expression is both disease-relevant and likely to have functional consequences, and provide evidence suggesting that sex biases in expression may reflect sex-biased gene regulatory structures

Prior and Present Evidence: How Prior Experience Interacts with Present Information in a Perceptual Decision Making Task

Vibrotactile discrimination tasks have been used to examine decision making processes in the presence of perceptual uncertainty, induced by barely discernible frequency differences between paired stimuli or by the presence of embedded noise. One lesser known property of such tasks is that decisions made on a single trial may be biased by information from prior trials. An example is the time-order effect whereby the presentation order of paired stimuli may introduce differences in accuracy. Subjects perform better when the first stimulus lies between the second stimulus and the global mean of all stimuli on the judged dimension ("preferred" time-orders) compared to the alternative presentation order ("nonpreferred" time-orders). This has been conceptualised as a "drift" of the first stimulus representation towards the global mean of the stimulus-set (an internal standard). We describe the influence of prior information in relation to the more traditionally studied factors of interest in a classic discrimination task.Sixty subjects performed a vibrotactile discrimination task with different levels of uncertainty parametrically induced by increasing task difficulty, aperiodic stimulus noise, and changing the task instructions whilst maintaining identical stimulus properties (the "context").The time-order effect had a greater influence on task performance than two of the explicit factors-task difficulty and noise-but not context. The influence of prior information increased with the distance of the first stimulus from the global mean, suggesting that the "drift" velocity of the first stimulus towards the global mean representation was greater for these trials.Awareness of the time-order effect and prior information in general is essential when studying perceptual decision making tasks. Implicit mechanisms may have a greater influence than the explicit factors under study. It also affords valuable insights into basic mechanisms of information accumulation, storage, sensory weighting, and processing in neural circuits

Menopause accelerates biological aging

Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the “epigenetic clock”), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further

Purifying Selection in Deeply Conserved Human Enhancers Is More Consistent than in Coding Sequences

(c) 2014 De Silva et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Outcome based subgroup analysis: a neglected concern

A subgroup of clinical trial subjects identified by baseline characteristics is a proper subgroup while a subgroup determined by post randomization events or measures is an improper subgroup. Both types of subgroups are often analyzed in clinical trial papers. Yet, the extensive scrutiny of subgroup analyses has almost exclusively attended to the former. The analysis of improper subgroups thereby not only flourishes in numerous disguised ways but also does so without a corresponding awareness of its pitfalls. Comparisons of the grade of angina in a heart disease trial, for example, usually include only the survivors. This paper highlights some of the distinct ways in which outcome based subgroup analysis occurs, describes the hazards associated with it, and proposes a simple alternative approach to counter its analytic bias. Data from six published trials show that outcome based subgroup analysis, like proper subgroup analysis, may be performed in a post-hoc fashion, overdone, selectively reported, and over interpreted. Six hypothetical trial scenarios illustrate the forms of hidden bias related to it. That bias can, however, be addressed by assigning clinically appropriate scores to the usually excluded subjects and performing an analysis that includes all the randomized subjects. A greater level of awareness about the practice and pitfalls of outcome based subgroup analysis is needed. When required, such an analysis should maintain the integrity of randomization. This issue needs greater practical and methodologic attention than has been accorded to it thus far