Using e-mail recruitment and an online questionnaire to establish effect size: A worked example

Background\ud Sample size calculations require effect size estimations. Sometimes, effect size estimations and standard deviation may not be readily available, particularly if efficacy is unknown because the intervention is new or developing, or the trial targets a new population. In such cases, one way to estimate the effect size is to gather expert opinion. This paper reports the use of a simple strategy to gather expert opinion to estimate a suitable effect size to use in a sample size calculation.\ud \ud Methods\ud Researchers involved in the design and analysis of clinical trials were identified at the University of Birmingham and via the MRC Hubs for Trials Methodology Research. An email invited them to participate.\ud \ud An online questionnaire was developed using the free online tool 'Survey Monkey©'. The questionnaire described an intervention, an electronic participant information sheet (e-PIS), which may increase recruitment rates to a trial. Respondents were asked how much they would need to see recruitment rates increased by, based on 90%. 70%, 50% and 30% baseline rates, (in a hypothetical study) before they would consider using an e-PIS in their research.\ud \ud Analyses comprised simple descriptive statistics.\ud \ud Results\ud The invitation to participate was sent to 122 people; 7 responded to say they were not involved in trial design and could not complete the questionnaire, 64 attempted it, 26 failed to complete it. Thirty-eight people completed the questionnaire and were included in the analysis (response rate 33%; 38/115). Of those who completed the questionnaire 44.7% (17/38) were at the academic grade of research fellow 26.3% (10/38) senior research fellow, and 28.9% (11/38) professor. Dependent upon the baseline recruitment rates presented in the questionnaire, participants wanted recruitment rate to increase from 6.9% to 28.9% before they would consider using the intervention.\ud \ud Conclusions\ud This paper has shown that in situations where effect size estimations cannot be collected from previous research, opinions from researchers and trialists can be quickly and easily collected by conducting a simple study using email recruitment and an online questionnaire. The results collected from the survey were successfully used in sample size calculations for a PhD research study protocol.\ud \u

Incorporating scale dependence in disease burden estimates:the case of human African trypanosomiasis in Uganda

The WHO has established the disability-adjusted life year (DALY) as a metric for measuring the burden of human disease and injury globally. However, most DALY estimates have been calculated as national totals. We mapped spatial variation in the burden of human African trypanosomiasis (HAT) in Uganda for the years 2000-2009. This represents the first geographically delimited estimation of HAT disease burden at the sub-country scale.Disability-adjusted life-year (DALY) totals for HAT were estimated based on modelled age and mortality distributions, mapped using Geographic Information Systems (GIS) software, and summarised by parish and district. While the national total burden of HAT is low relative to other conditions, high-impact districts in Uganda had DALY rates comparable to the national burden rates for major infectious diseases. The calculated average national DALY rate for 2000-2009 was 486.3 DALYs/100 000 persons/year, whereas three districts afflicted by rhodesiense HAT in southeastern Uganda had burden rates above 5000 DALYs/100 000 persons/year, comparable to national GBD 2004 average burden rates for malaria and HIV/AIDS.These results provide updated and improved estimates of HAT burden across Uganda, taking into account sensitivity to under-reporting. Our results highlight the critical importance of spatial scale in disease burden analyses. National aggregations of disease burden have resulted in an implied bias against highly focal diseases for which geographically targeted interventions may be feasible and cost-effective. This has significant implications for the use of DALY estimates to prioritize disease interventions and inform cost-benefit analyses

The Global Burden of Alveolar Echinococcosis

Human alveolar echinococcosis (AE), caused by the larval stage of the fox tapeworm Echinococcus multilocularis, is amongst the world's most dangerous zoonoses. Transmission to humans is by consumption of parasite eggs which are excreted in the faeces of the definitive hosts: foxes and, increasingly, dogs. Transmission can be through contact with the definitive host or indirectly through contamination of food or possibly water with parasite eggs. We made an intensive search of English, Russian, Chinese and other language databases. We targeted data which could give country specific incidence or prevalence of disease and searched for data from every country we believed to be endemic for AE. We also used data from other sources (often unpublished). From this information we were able to make an estimate of the annual global incidence of disease and disease burden using standard techniques for calculation of DALYs. Our studies suggest that AE results in a median of 18,235 cases globally with a burden of 666,433 DALYs per annum. This is the first estimate of the global burden of AE both in terms of global incidence and DALYs and demonstrates the burden of AE is comparable to several diseases in the neglected tropical disease cluster

Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's Disease: a cross-sectional study

BACKGROUND: The presence of the apolipoprotein E (APOE) ε4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the ε4 allele on hippocampal activation has not been firmly established. METHODS: The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe (MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged (mean = 54 years) individuals who had at least one parent with AD. RESULTS: We found that ε3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to ε3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in ε3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the ε3/3 homozygotes, but not in the ε3/4 heterozygotes. CONCLUSION: Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE ε4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline

Evolutionary Processes Acting on Candidate cis-Regulatory Regions in Humans Inferred from Patterns of Polymorphism and Divergence

Analysis of polymorphism and divergence in the non-coding portion of the human genome yields crucial information about factors driving the evolution of gene regulation. Candidate cis-regulatory regions spanning more than 15,000 genes in 15 African Americans and 20 European Americans were re-sequenced and aligned to the chimpanzee genome in order to identify potentially functional polymorphism and to characterize and quantify departures from neutral evolution. Distortions of the site frequency spectra suggest a general pattern of selective constraint on conserved non-coding sites in the flanking regions of genes (CNCs). Moreover, there is an excess of fixed differences that cannot be explained by a Gamma model of deleterious fitness effects, suggesting the presence of positive selection on CNCs. Extensions of the McDonald-Kreitman test identified candidate cis-regulatory regions with high probabilities of positive and negative selection near many known human genes, the biological characteristics of which exhibit genome-wide trends that differ from patterns observed in protein-coding regions. Notably, there is a higher probability of positive selection in candidate cis-regulatory regions near genes expressed in the fetal brain, suggesting that a larger portion of adaptive regulatory changes has occurred in genes expressed during brain development. Overall we find that natural selection has played an important role in the evolution of candidate cis-regulatory regions throughout hominid evolution

A functional polymorphism under positive evolutionary selection in ADRB2 is associated with human intelligence with opposite effects in the young and the elderly

Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior. © 2008 Springer Science+Business Media, LLC

Patterns of Cis Regulatory Variation in Diverse Human Populations

The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs) after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations

Sexual Selection Halts the Relaxation of Protamine 2 among Rodents

Sexual selection has been proposed as the driving force promoting the rapid evolutionary changes observed in some reproductive genes including protamines. We test this hypothesis in a group of rodents which show marked differences in the intensity of sexual selection. Levels of sperm competition were not associated with the evolutionary rates of protamine 1 but, contrary to expectations, were negatively related to the evolutionary rate of cleaved- and mature-protamine 2. Since both domains were found to be under relaxation, our findings reveal an unforeseen role of sexual selection: to halt the degree of degeneration that proteins within families may experience due to functional redundancy. The degree of relaxation of protamine 2 in this group of rodents is such that in some species it has become dysfunctional and it is not expressed in mature spermatozoa. In contrast, protamine 1 is functionally conserved but shows directed positive selection on specific sites which are functionally relevant such as DNA-anchoring domains and phosphorylation sites. We conclude that in rodents protamine 2 is under relaxation and that sexual selection removes deleterious mutations among species with high levels of sperm competition to maintain the protein functional and the spermatozoa competitive

Scaphoid Waist Internal Fixation for Fractures Trial (SWIFFT) protocol : a pragmatic multi-centre randomised controlled trial of cast treatment versus surgical fixation for the treatment of bi-cortical, minimally displaced fractures of the scaphoid waist in adults

BACKGROUND: A scaphoid fracture is the most common type of carpal fracture affecting young active people. The optimal management of this fracture is uncertain. When treated with a cast, 88 to 90 % of these fractures unite; however, for the remaining 10-12 % the non-union almost invariably leads to arthritis. The alternative is surgery to fix the scaphoid with a screw at the outset. METHODS/DESIGN: We will conduct a randomised controlled trial (RCT) of 438 adult patients with a "clear" and "bicortical" scaphoid waist fracture on plain radiographs to evaluate the clinical effectiveness and cost-effectiveness of plaster cast treatment (with fixation of those that fail to unite) versus early surgical fixation. The plaster cast treatment will be immobilisation in a below elbow cast for 6 to 10 weeks followed by mobilisation. If non-union is confirmed on plain radiographs and/or Computerised Tomogram at 6 to 12 weeks, then urgent surgical fixation will be performed. This is being compared with immediate surgical fixation with surgeons using their preferred technique and implant. These treatments will be undertaken in trauma units across the United Kingdom. The primary outcome and end-point will be the Patient Rated Wrist Evaluation (a patient self-reported assessment of wrist pain and function) at 52 weeks and also measured at 6, 12, 26 weeks and 5 years. Secondary outcomes include an assessment of radiological union of the fracture; quality of life; recovery of wrist range and strength; and complications. We will also qualitatively investigate patient experiences of their treatment. DISCUSSION: Scaphoid fractures are an important public health problem as they predominantly affect young active individuals in the more productive working years of their lives. Non-union, if untreated, can lead to arthritis which can disable patients at a very young age. There is a rapidly increasing trend for immediate surgical fixation of these fractures but there is insufficient evidence from existing RCTs to support this. The SWIFFT Trial is a rigorously designed and adequately powered study which aims to contribute to the evidence-base to inform clinical decisions for the treatment of this common fracture in adults. TRIAL REGISTRATION: The trial is registered with the International Standard Randomised Controlled Trial Register ( ISRCTN67901257 ). Date registration assigned was 13/02/2013

Weight outcomes audit in 1.3 million adults during their first 3 months' attendance in a commercial weight management programme

Background: Over sixty percent of adults in the UK are now overweight/obese. Weight management on a national scale requires behavioural and lifestyle solutions that are accessible to large numbers of people. Evidence suggests commercial weight management programmes help people manage their weight but there is little research examining those that pay to attend such programmes rather than being referred by primary care. The objective of this analysis was to evaluate the effectiveness of a UK commercial weight management programme in self-referred, fee-paying participants. Methods: Electronic weekly weight records were collated for self-referred, fee-paying participants of Slimming World groups joining between January 2010 and April 2012. This analysis reports weight outcomes in 1,356,105 adult, non-pregnant participants during their first 3 months’ attendance. Data were analysed by regression, ANOVA and for binomial outcomes, chi-squared tests using the R statistical program. Results: Mean (SD) age was 42.3 (13.6) years, height 1.65 m (0.08) and start weight was 88.4 kg (18.8). Mean start BMI was 32.6 kg/m² (6.3 kg/m²) and 5 % of participants were men. Mean weight change of all participants was −3.9 kg (3.6), percent weight change −4.4 (3.8), and BMI change was −1.4 kg/m² (1.3). Mean attendance was 7.8 (4.3) sessions in their first 3 months. For participants attending at least 75 % of possible weekly sessions (n = 478,772), mean BMI change was −2.5 kg/m² (1.3), weight change −6.8 kg (3.7) and percent weight change −7.5 % (3.5). Weight loss was greater in men than women absolutely (−6.5 (5.3) kg vs −3.8 (3.4) kg) and as a percentage (5.7 % (4.4) vs 4.3 % (3.7)), respectively. All comparisons were significant (p < 0.001). Level of attendance and percent weight loss in the first week of attendance together accounted for 55 % of the variability in weight lost during the study period. Conclusions: A large-scale commercial lifestyle-based weight management programme had a significant impact on weight loss outcomes over 3 months. Higher levels of attendance led to levels of weight loss known to be associated with significant clinical benefits, which on this scale may have an impact on public health