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The foodscape: classification and field validation of secondary data sources across urban/rural and socio-economic classifications in England

Sun, 01 Apr 2012 23:00:00 GMT

Title: The foodscape: classification and field validation of secondary data sources across urban/rural and socio-economic classifications in England Authors: Lake, Amelia A; Burgoine, Thomas; Stamp, Elaine; Grieve, Rachael Abstract: Abstract Background In recent years, alongside the exponential increase in the prevalence of overweight and obesity, there has been a change in the food environment (foodscape). This research focuses on methods used to measure and classify the foodscape. This paper describes the foodscape across urban/rural and socio-economic divides. It examines the validity of a database of food outlets obtained from Local Authority sources (secondary level & desk based), across urban/rural and socio-economic divides by conducting fieldwork (ground-truthing). Additionally this paper tests the efficacy of using a desk based classification system to describe food outlets, compared with ground-truthing. Methods Six geographically defined study areas were purposively selected within North East England consisting of two Lower Super Output Areas (LSOAs; a small administrative geography) each. Lists of food outlets were obtained from relevant Local Authorities (secondary level & desk based) and fieldwork (ground-truthing) was conducted. Food outlets were classified using an existing tool. Positive predictive values (PPVs) and sensitivity analysis was conducted to explore validation of secondary data sources. Agreement between 'desk' and 'field' based classifications of food outlets were assessed. Results There were 438 food outlets within all study areas; the urban low socio-economic status (SES) area had the highest number of total outlets (n = 210) and the rural high SES area had the least (n = 19). Differences in the types of outlets across areas were observed. Comparing the Local Authority list to fieldwork across the geographical areas resulted in a range of PPV values obtained; with the highest in urban low SES areas (87%) and the lowest in Rural mixed SES (79%). While sensitivity ranged from 95% in the rural mixed SES area to 60% in the rural low SES area. There were no significant associations between field/desk percentage agreements across any of the divides. Conclusion Despite the relatively small number of areas, this work furthers our understanding of the validity of using secondary data sources to identify and classify the foodscape in a variety of geographical settings. While classification of the foodscape using secondary Local Authority food outlet data with information obtained from the internet, is not without its difficulties, desk based classification would be an acceptable alternative to fieldwork, although it should be used with caution. Description: 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.

Why choice of metric matters in public health analyses: a case study of the attribution of credit for the decline in coronary heart disease mortality in the US and other populations

Sat, 28 Jan 2012 00:00:00 GMT

Title: Why choice of metric matters in public health analyses: a case study of the attribution of credit for the decline in coronary heart disease mortality in the US and other populations Authors: Gouda, Hebe N; Critchley, Julia; Powles, John W; Capewell, Simon Abstract: Abstract Background Reasons for the widespread declines in coronary heart disease (CHD) mortality in high income countries are controversial. Here we explore how the type of metric chosen for the analyses of these declines affects the answer obtained. Methods The analyses we reviewed were performed using IMPACT, a large Excel based model of the determinants of temporal change in mortality from CHD. Assessments of the decline in CHD mortality in the USA between 1980 and 2000 served as the central case study. Results Analyses based in the metric of number of deaths prevented attributed about half the decline to treatments (including preventive medications) and half to favourable shifts in risk factors. However, when mortality change was expressed in the metric of life-years-gained, the share attributed to risk factor change rose to 65%. This happened because risk factor changes were modelled as slowing disease progression, such that the hypothetical deaths averted resulted in longer average remaining lifetimes gained than the deaths averted by better treatments. This result was robust to a range of plausible assumptions on the relative effect sizes of changes in treatments and risk factors. Conclusions Time-based metrics (such as life years) are generally preferable because they direct attention to the changes in the natural history of disease that are produced by changes in key health determinants. The life-years attached to each death averted will also weight deaths in a way that better reflects social preferences. Description: 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.

Characteristics of meta-analyses and their component studies in the Cochrane Database of Systematic Reviews: a cross-sectional, descriptive analysis

Thu, 24 Nov 2011 00:00:00 GMT

Title: Characteristics of meta-analyses and their component studies in the Cochrane Database of Systematic Reviews: a cross-sectional, descriptive analysis Authors: Davey, Jonathan; Turner, Rebecca M; Clarke, Mike J; Higgins, Julian PT Abstract: Abstract Background Cochrane systematic reviews collate and summarise studies of the effects of healthcare interventions. The characteristics of these reviews and the meta-analyses and individual studies they contain provide insights into the nature of healthcare research and important context for the development of relevant statistical and other methods. Methods We classified every meta-analysis with at least two studies in every review in the January 2008 issue of the Cochrane Database of Systematic Reviews (CDSR) according to the medical specialty, the types of interventions being compared and the type of outcome. We provide descriptive statistics for numbers of meta-analyses, numbers of component studies and sample sizes of component studies, broken down by these categories. Results We included 2321 reviews containing 22,453 meta-analyses, which themselves consist of data from 112,600 individual studies (which may appear in more than one meta-analysis). Meta-analyses in the areas of gynaecology, pregnancy and childbirth (21%), mental health (13%) and respiratory diseases (13%) are well represented in the CDSR. Most meta-analyses address drugs, either with a control or placebo group (37%) or in a comparison with another drug (25%). The median number of meta-analyses per review is six (inter-quartile range 3 to 12). The median number of studies included in the meta-analyses with at least two studies is three (inter-quartile range 2 to 6). Sample sizes of individual studies range from 2 to 1,242,071, with a median of 91 participants. Discussion It is clear that the numbers of studies eligible for meta-analyses are typically very small for all medical areas, outcomes and interventions covered by Cochrane reviews. This highlights the particular importance of suitable methods for the meta-analysis of small data sets. There was little variation in number of studies per meta-analysis across medical areas, across outcome data types or across types of interventions being compared. Description: 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.

Optimal design for multi-arm multi-stage clinical trials

Tue, 13 Dec 2011 00:00:00 GMT

Title: Optimal design for multi-arm multi-stage clinical trials Description: 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.

Assessing the impact of road traffic on cycling for leisure and cycling to work

Thu, 09 Jun 2011 23:00:00 GMT

Title: Assessing the impact of road traffic on cycling for leisure and cycling to work Authors: Foster, Charles E; Panter, Jenna R; Wareham, Nicholas J Abstract: Abstract Background To explore the relationship between leisure and commuter cycling with objectively measured levels of road traffic and whether any relationship was affected by traffic levels directly outside of home or in local neighbourhood. Findings We conducted a secondary analysis of data from the UK European Prospective Investigation of Cancer (EPIC) Norfolk cohort in 2009. We used a geographical information system (GIS) and gender specific multivariate models to relate 13 927 participants' reported levels of cycling with an index of road traffic volume (Road Traffic Volume Index Score - RTVIS). RTVIS were calculated around each participants home, using four distance based buffers, (0.5 km, 1 km, 2 km and 3.2 km). Models were adjusted for age, social status, education, car access and deprivation. Both genders had similar decreases in leisure cycling as traffic volumes increased at greater distances from home (OR 0.42, (95% CI 0.32-0.52, p < 0.001) for women and OR 0.41, (95% CI 0.33-0.50, p < 0.001) for men in the highest quartile at 3.2 km). There was no effect of traffic volumes at any distance on commuter cycling. Conclusions Traffic volumes appear to have greater impact on leisure cycling than commuter cycling. Future research should investigate the importance of traffic on different types of cycling and include psychosocial correlates. Description: 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 a Modelling and Simulation Method Comparison and Selection Framework for Health Services Management

Wed, 18 May 2011 23:00:00 GMT

Title: Development of a Modelling and Simulation Method Comparison and Selection Framework for Health Services Management Authors: Jun, Gyuchan T; Morris, Zoe; Eldabi, Tillal; Harper, Paul; Naseer, Aisha; Patel, Brijesh; Clarkson, John P Abstract: AbstractBackgroundThere is increasing recognition that modelling and simulation can assist the process of designing health care policies, strategies and operations. However, current use is limited and the questions of what methods to use and when remain underdeveloped.MethodsThis paper proposes a modelling and simulation method comparison and selection framework developed from a comprehensive literature review, the research team's extensive expertise and inputs from potential users.ResultsTwenty eight different methods were identified, characterised by their relevance to different application areas, project life cycle stages, types of output and levels of insight, and four input resources required (time, money, knowledge and data). The characterisation is presented in matrix forms to allow quick comparison and selection. This paper also highlights significant knowledge gaps in the existing literature when assessing the applicability of particular approaches to health services management, where modelling and simulation skills are scarce let alone money and time.ConclusionsA modelling and simulation method comparison and selection framework is developed to assist with the selection of methods appropriate to supporting specific decision making processes. In particular it addresses the issue of which method is most appropriate to which specific health services management problem, what the auser might expect to be obtained from the method, and what is required to use the method. In summary, we believe the framework adds value to the scarce existing literature on methods comparison and selection. Description: 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.

Assessing subgroup effects with binary data: can the use of different effect measures lead to different conclusions?

Thu, 28 Apr 2005 23:00:00 GMT

Title: Assessing subgroup effects with binary data: can the use of different effect measures lead to different conclusions? Authors: White, Ian R; Elbourne, Diana Abstract: Abstract Background In order to use the results of a randomised trial, it is necessary to understand whether the overall observed benefit or harm applies to all individuals, or whether some subgroups receive more benefit or harm than others. This decision is commonly guided by a statistical test for interaction. However, with binary outcomes, different effect measures yield different interaction tests. For example, the UK Hip trial explored the impact of ultrasound of infants with suspected hip dysplasia on the occurrence of subsequent hip treatment. Risk ratios were similar between subgroups defined by level of clinical suspicion (P = 0.14), but odds ratios and risk differences differed strongly between subgroups (P < 0.001). Discussion Interaction tests on different effect measures differ because they test different null hypotheses. A graphical technique demonstrates that the difference arises when the subgroup risks differ markedly. We consider that the test of interaction acts as a check on the applicability of the trial results to all included subgroups. The test of interaction should therefore be applied to the effect measure which is least likely a priori to exhibit an interaction. We give examples of how this might be done. Summary The choice of interaction test is especially important when the risk of a binary outcome varies widely between subgroups. The interaction test should be pre-specified and should be guided by clinical knowledge. Description: 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.

Quality determination and the repair of poor quality spots in array experiments

Sun, 25 Sep 2005 23:00:00 GMT

Title: Quality determination and the repair of poor quality spots in array experiments Authors: Tom, Brian D M; Gilks, Walter R; Brooke-Powell, Elizabeth T; Ajioka, James W Abstract: Abstract Background A common feature of microarray experiments is the occurence of missing gene expression data. These missing values occur for a variety of reasons, in particular, because of the filtering of poor quality spots and the removal of undefined values when a logarithmic transformation is applied to negative background-corrected intensities. The efficiency and power of an analysis performed can be substantially reduced by having an incomplete matrix of gene intensities. Additionally, most statistical methods require a complete intensity matrix. Furthermore, biases may be introduced into analyses through missing information on some genes. Thus methods for appropriately replacing (imputing) missing data and/or weighting poor quality spots are required. Results We present a likelihood-based method for imputing missing data or weighting poor quality spots that requires a number of biological or technical replicates. This likelihood-based approach assumes that the data for a given spot arising from each channel of a two-dye (two-channel) cDNA microarray comparison experiment independently come from a three-component mixture distribution – the parameters of which are estimated through use of a constrained E-M algorithm. Posterior probabilities of belonging to each component of the mixture distributions are calculated and used to decide whether imputation is required. These posterior probabilities may also be used to construct quality weights that can down-weight poor quality spots in any analysis performed afterwards. The approach is illustrated using data obtained from an experiment to observe gene expression changes with 24 hr paclitaxel (Taxol ®) treatment on a human cervical cancer derived cell line (HeLa). Conclusion As the quality of microarray experiments affect downstream processes, it is important to have a reliable and automatic method of identifying poor quality spots and arrays. We propose a method of identifying poor quality spots, and suggest a method of repairing the arrays by either imputation or assigning quality weights to the spots. This repaired data set would be less biased and can be analysed using any of the appropriate statistical methods found in the microarray literature. Description: 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.

An investigation of factors associated with psychiatric hospital admission despite the presence of crisis resolution teams

Mon, 01 Oct 2007 23:00:00 GMT

Title: An investigation of factors associated with psychiatric hospital admission despite the presence of crisis resolution teams Authors: Cotton, Mary-Anne; Johnson, Sonia; Bindman, Jonathan; Sandor, Andrew; White, Ian R; Thornicroft, Graham; Nolan, Fiona; Pilling, Stephen; Hoult, John; McKenzie, Nigel; Bebbington, Paul Abstract: Abstract Background Crisis resolution teams (CRTs) provide a community alternative to psychiatric hospital admission for patients presenting in crisis. Little is known about the characteristics of patients admitted despite the availability of such teams. Methods Data were drawn from three investigations of the outcomes of CRTs in inner London. A literature review was used to identify candidate explanatory variables that may be associated with admission despite the availability of intensive home treatment. The main outcome variable was admission to hospital within 8 weeks of the initial crisis. Associations between this outcome and the candidate explanatory variables were tested using first univariate and then multivariate analysis. Results Patients who were uncooperative with initial assessment (OR 10.25 95% CI-4.20–24.97), at risk of self-neglect (OR 2.93 1.42–6.05), had a history of compulsory admission (OR 2.64 1.07–6.55), assessed outside usual office hours (OR 2.34 1.11–4.94) and/or were assessed in hospital casualty departments (OR 3.12 1.55–6.26), were more likely to be admitted. Other than age, no socio-demographic features or diagnostic variables were significantly associated with risk of admission. Conclusion With the introduction of CRTs, inpatient wards face a significant challenge, as patients who cooperate little with treatment, neglect themselves, or have previously been compulsorily detained are especially likely to be admitted. The increased risk of admission associated with casualty department assessment may be remediable. Description: 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.

An investigation of the population impact of variation in HbA1c levels in older people in England and Wales: from a population based multi-centre longitudinal study

Mon, 11 Feb 2008 00:00:00 GMT

Title: An investigation of the population impact of variation in HbA1c levels in older people in England and Wales: from a population based multi-centre longitudinal study Authors: Gao, Lu; Matthews, Fiona E; Sargeant, Lincoln A; Brayne, Carol; MRC-CFAS Abstract: Abstract Background Diabetes is common in the older population and is increasing. Glycated hemoglobin (HbA1c) is an indicator of average blood glucose concentration over the past three months. The HbA1c test is currently one of clinical methods used to check diabetes control. Recent studies have suggested diabetes is a risk factor for dementia, cognitive dysfunction and physical disability. In addition, there have reported the relationship between HbA1c and mortality on all cause, cardiovascular disease and cognitive function, but few studies have investigated the relationship concentrating on the older population. The aim of this study is to investigate the association between the level of HbA1c and mortality from all causes, incident cardiovascular disease, cognitive decline and physical disability in people aged 65 and over in England and Wales. Methods 1139 men and women aged 69 years and over who were participants in a ten year population based ageing multi-centre, longitudinal study who had HbA1c measurements after 5–6 years of follow up. All participants were flagged for death notification including causes at the Office of National Statistics. Information on health including vascular conditions, cognitive status, physical function and dementia were available from the study both before and after the HbA1c measurement. Survival analyses and logistic regression were conducted. Results Mortality from all causes, cardiovascular and ischaemic heart disease increased with increasing HbA1c. Participants with diagnosed diabetes or who had HbA1c≥ 7% but no self-reported diabetes had increased mortality risk from all causes and cardiovascular diseases. The respondents in the group HbA1c ≥7% who had not been diagnosed with diabetes had a significantly higher risk (odds ratio = 4.8 95% CI: 1.1 to 21.6) of developing dementia. Individuals who had self-reported diabetes but a HbA1c level <7% had mortality and dementia incidence comparable to individuals without diabetes and HbA1c <7%. Conclusion The findings support previous reports that bio-markers of glucose metabolism are associated with long term outcomes, such as mortality and dementia.

A Bayesian Change point model for differential gene expression patterns of the DosR regulon of Mycobacterium tuberculosis

Fri, 22 Feb 2008 00:00:00 GMT

Title: A Bayesian Change point model for differential gene expression patterns of the DosR regulon of Mycobacterium tuberculosis Authors: Zhang, Yi; Hatch, Kim A; Wernisch, Lorenz; Bacon, Joanna Abstract: Abstract Background Low oxygen availability has been shown previously to stimulate M. tuberculosis to establish non-replicative persistence in vitro. The two component sensor/regulator dosRS is a major mediator in the transcriptional response of M. tuberculosis to hypoxia and controls a regulon of approximately 50 genes that are induced under this condition. The aim of this study was to determine whether the induction of the entire DosR regulon is triggered as a synchronous event or if induction can unfold as a cascade of events as the differential expression of subsets of genes is stimulated by different oxygen availabilities. Results A novel aspect of our work is the use of chemostat cultures of M. tuberculosis which allowed us to control environmental conditions very tightly. We exposed M. tuberculosis to a sudden drop in oxygen availability in chemostat culture and studied the transcriptional response of the organism during the transition from a high oxygen level (10% dissolved oxygen tension or DOT) to a low oxygen level (0.2% DOT) using DNA microarrays. We developed a Bayesian change point analysis method that enabled us to detect subtle shifts in the timing of gene induction. It results in probabilities of a change in gene expression at certain time points. A computational analysis of potential binding sites upstream of the DosR-controlled genes shows how the transcriptional responses of these genes are influenced by the affinity of these binding sites to DosR. Our study also indicates that a subgroup of DosR-controlled genes is regulated indirectly. Conclusion The majority of the dosR-dependent genes were up-regulated at 0.2% DOT, which confirms previous findings that these genes are triggered by hypoxic environments. However, our change point analysis also highlights genes which were up-regulated earlier at levels of about 8% DOT indicating that they respond to small fluctuations in oxygen availability. Our analysis shows that there are pairs of divergent genes where one gene in the pair is up-regulated before the other, presumably for a flexible response to a constantly changing environment in the host. Description: 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.

Falls in advanced old age: recalled falls and prospective follow-up of over-90-year-olds in the Cambridge City over-75s Cohort study

Mon, 17 Mar 2008 00:00:00 GMT

Title: Falls in advanced old age: recalled falls and prospective follow-up of over-90-year-olds in the Cambridge City over-75s Cohort study Authors: Fleming, Jane; Matthews, Fiona E; Brayne, Carol; (CC75C) Cambridge City over-75s Cohort Abstract: Abstract Background The "oldest old" are now the fastest growing section of most western populations, yet there are scarcely any data concerning even the common problem of falls amongst the very old. Prospective data collection is encouraged as the most reliable method for researching older people's falls, though in clinical practice guidelines advise taking a history of any recalled falls. This study set out to inform service planning by describing the epidemiology of falls in advanced old age using both retrospectively and prospectively collected falls data. Methods Design: Re-survey of over-90-year-olds in a longitudinal cohort study – cross-sectional interview and intensive 12-month follow-up. Participants and setting: 90 women and 20 men participating in a population-based cohort (aged 91–105 years, in care-homes and community-dwelling) recruited from representative general practices in Cambridge, UK Measurements: Prospective falls data were collected using fall calendars and telephone follow-up for one year after cross-sectional survey including fall history. Results 58% were reported to have fallen at least once in the previous year and 60% in the 1-year follow-up. The proportion reported to have fallen more than once was lower using retrospective recall of the past year than prospective reports gathered the following year (34% versus 45%), as were fall rates (1.6 and 2.8 falls/person-year respectively). Repeated falls in the past year were more highly predictive of falls during the following year – IRR 4.7, 95% CI 2.6–8.7 – than just one – IRR 3.6, 95% CI 2.0–6.3, using negative binomial regression. Only 1/5 reportedly did not fall during either the year before or after interview. Conclusion Fall rates in this representative sample of over-90-year-olds are even higher than previous reports from octogenarians. Recalled falls last year, particularly repeated falls, strongly predicted falls during follow-up. Similar proportions of people who fell were reported by retrospective and prospective methods covering two consecutive years. Recall methods may underestimate numbers of repeated falls and the extent of recurrent falling. Professionals caring for people of advanced age can easily ask routinely whether someone has fallen at all, or more than once, in the past year to identify those at high risk of subsequent falls.

Relationship between the EQ-5D index and measures of clinical outcomes in selected studies of cardiovascular interventions

Thu, 26 Nov 2009 00:00:00 GMT

Title: Relationship between the EQ-5D index and measures of clinical outcomes in selected studies of cardiovascular interventions Authors: Goldsmith, Kimberley A; Dyer, Matthew T; Schofield, Peter M; Buxton, Martin J; Sharples, Linda D Abstract: Abstract Background The EuroQoL 5D (EQ-5D) has been widely used in studies of cardiac disease, but its measurement properties in this group are not well established. The study aimed to quantify the relationship between measures commonly used in studies of cardiac disease and the EQ-5D index across different levels of disease severity. Methods Patient-level data from 7 studies of cardiac interventions were used, which included randomised trials and observational studies. Relationships between the EQ-5D index and commonly used cardiac measures, Canadian Cardiovascular Society (CCS) angina severity class, treadmill exercise time (ETT) and scales of the Seattle Angina Questionnaire (SAQ) were examined. Mixed effects linear regression was used to assess these relationships, with the EQ-5D index as the response. Results Study sample sizes ranged from 68 to 2419. Mean baseline EQ-5D index ranged from 0.77 in patients at diagnosis (95% CI 0.75, 0.78) to 0.43 in patients with advanced disease (95% CI 0.39, 0.48) and differed significantly across studies (p < 0.001). There was evidence of a ceiling effect in patients at diagnosis. The minimum clinically important difference of a one minute increase in ETT was associated with a 0.019 (95% CI 0.014, 0.025) increase in EQ-5D index. One class increase in CCS was associated with a 0.11 (95% CI 0.09, 0.13) decrease in EQ-5D index. A 10 unit increase in SAQ scales was associated with increases between 0.04 and 0.07 in EQ-5D index (95% CIs 0.03, 0.05 and 0.05, 0.08). Tests of heterogeneity indicated the EQ-5D-covariate relationships were consistent across levels of disease severity for ETT and the treatment satisfaction scale of the SAQ, but heterogeneous for age, gender, CCS angina class and other scales of the SAQ. Conclusion The EQ-5D index varies with coronary disease severity. The relationship between the EQ-5D index and an outcome measure used in cardiac intervention studies, ETT, was consistent across disease severity levels, but the relationship between demographic variables, CCS angina class and most of the SAQ scales and the EQ-5D index was heterogeneous for patients with different levels of coronary disease. Differences in the EQ-5D index associated with clinically important differences in cardiac measures can be quantified and vary between three important examples - angina class, ETT and SAQ. Description: 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.

Variable structure motifs for transcription factor binding sites

Thu, 14 Jan 2010 00:00:00 GMT

Title: Variable structure motifs for transcription factor binding sites Authors: Reid, John E; Evans, Kenneth J; Dyer, Nigel; Wernisch, Lorenz; Ott, Sascha Abstract: Abstract Background Classically, models of DNA-transcription factor binding sites (TFBSs) have been based on relatively few known instances and have treated them as sites of fixed length using position weight matrices (PWMs). Various extensions to this model have been proposed, most of which take account of dependencies between the bases in the binding sites. However, some transcription factors are known to exhibit some flexibility and bind to DNA in more than one possible physical configuration. In some cases this variation is known to affect the function of binding sites. With the increasing volume of ChIP-seq data available it is now possible to investigate models that incorporate this flexibility. Previous work on variable length models has been constrained by: a focus on specific zinc finger proteins in yeast using restrictive models; a reliance on hand-crafted models for just one transcription factor at a time; and a lack of evaluation on realistically sized data sets. Results We re-analysed binding sites from the TRANSFAC database and found motivating examples where our new variable length model provides a better fit. We analysed several ChIP-seq data sets with a novel motif search algorithm and compared the results to one of the best standard PWM finders and a recently developed alternative method for finding motifs of variable structure. All the methods performed comparably in held-out cross validation tests. Known motifs of variable structure were recovered for p53, Stat5a and Stat5b. In addition our method recovered a novel generalised version of an existing PWM for Sp1 that allows for variable length binding. This motif improved classification performance. Conclusions We have presented a new gapped PWM model for variable length DNA binding sites that is not too restrictive nor over-parameterised. Our comparison with existing tools shows that on average it does not have better predictive accuracy than existing methods. However, it does provide more interpretable models of motifs of variable structure that are suitable for follow-up structural studies. To our knowledge, we are the first to apply variable length motif models to eukaryotic ChIP-seq data sets and consequently the first to show their value in this domain. The results include a novel motif for the ubiquitous transcription factor Sp1. Description: 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.

Statistical model comparison applied to common network motifs

Wed, 03 Mar 2010 00:00:00 GMT

Title: Statistical model comparison applied to common network motifs Authors: Domedel-Puig, Nuria; Pournara, Iosifina; Wernisch, Lorenz Abstract: Abstract Background Network motifs are small modules that show interesting functional and dynamic properties, and are believed to be the building blocks of complex cellular processes. However, the mechanistic details of such modules are often unknown: there is uncertainty about the motif architecture as well as the functional form and parameter values when converted to ordinary differential equations (ODEs). This translates into a number of candidate models being compatible with the system under study. A variety of statistical methods exist for ranking models including maximum likelihood-based and Bayesian methods. Our objective is to show how such methods can be applied in a typical systems biology setting. Results We focus on four commonly occurring network motif structures and show that it is possible to differentiate between them using simulated data and any of the model comparison methods tested. We expand one of the motifs, the feed forward (FF) motif, for several possible parameterizations and apply model selection on simulated data. We then use experimental data on three biosynthetic pathways in Escherichia coli to formally assess how current knowledge matches the time series available. Our analysis confirms two of them as FF motifs. Only an expanded set of FF motif parameterisations using time delays is able to fit the third pathway, indicating that the true mechanism might be more complex in this case. Conclusions Maximum likelihood as well as Bayesian model comparison methods are suitable for selecting a plausible motif model among a set of candidate models. Our work shows that it is practical to apply model comparison to test ideas about underlying mechanisms of biological pathways in a formal and quantitative way. Description: 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.

An integrated machine learning approach for predicting DosR-regulated genes in Mycobacterium tuberculosis

Tue, 30 Mar 2010 23:00:00 GMT

Title: An integrated machine learning approach for predicting DosR-regulated genes in Mycobacterium tuberculosis Authors: Zhang, Yi; Hatch, Kim A; Bacon, Joanna; Wernisch, Lorenz Abstract: Abstract Background DosR is an important regulator of the response to stress such as limited oxygen availability in Mycobacterium tuberculosis. Time course gene expression data enable us to dissect this response on the gene regulatory level. The mRNA expression profile of a regulator, however, is not necessarily a direct reflection of its activity. Knowing the transcription factor activity (TFA) can be exploited to predict novel target genes regulated by the same transcription factor. Various approaches have been proposed to reconstruct TFAs from gene expression data. Most of them capture only a first-order approximation to the complex transcriptional processes by assuming linear gene responses and linear dynamics in TFA, or ignore the temporal information in data from such systems. Results In this paper, we approach the problem of inferring dynamic hidden TFAs using Gaussian processes (GP). We are able to model dynamic TFAs and to account for both linear and nonlinear gene responses. To test the validity of the proposed approach, we reconstruct the hidden TFA of p53, a tumour suppressor activated by DNA damage, using published time course gene expression data. Our reconstructed TFA is closer to the experimentally determined profile of p53 concentration than that from the original study. We then apply the model to time course gene expression data obtained from chemostat cultures of M. tuberculosis under reduced oxygen availability. After estimation of the TFA of DosR based on a number of known target genes using the GP model, we predict novel DosR-regulated genes: the parameters of the model are interpreted as relevance parameters indicating an existing functional relationship between TFA and gene expression. We further improve the prediction by integrating promoter sequence information in a logistic regression model. Apart from the documented DosR-regulated genes, our prediction yields ten novel genes under direct control of DosR. Conclusions Chemostat cultures are an ideal experimental system for controlling noise and variability when monitoring the response of bacterial organisms such as M. tuberculosis to finely controlled changes in culture conditions and available metabolites. Nonlinear hidden TFA dynamics of regulators can be reconstructed remarkably well with Gaussian processes from such data. Moreover, estimated parameters of the GP can be used to assess whether a gene is controlled by the reconstructed TFA or not. It is straightforward to combine these parameters with further information, such as the presence of binding motifs, to increase prediction accuracy. Description: 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.

Mapping of the EQ-5D index from clinical outcome measures and demographic variables in patients with coronary heart disease

Thu, 03 Jun 2010 23:00:00 GMT

Title: Mapping of the EQ-5D index from clinical outcome measures and demographic variables in patients with coronary heart disease Authors: Goldsmith, Kimberley A; Dyer, Matthew T; Buxton, Martin J; Sharples, Linda D Abstract: Abstract Background The EuroQoL 5D (EQ-5D) is a questionnaire that provides a measure of utility for cost-effectiveness analysis. The EQ-5D has been widely used in many patient groups, including those with coronary heart disease. Studies often require patients to complete many questionnaires and the EQ-5D may not be gathered. This study aimed to assess whether demographic and clinical outcome variables, including scores from a disease specific measure, the Seattle Angina Questionnaire (SAQ), could be used to predict, or map, the EQ-5D index value where it is not available. Methods Patient-level data from 5 studies of cardiac interventions were used. The data were split into two groups - approximately 60% of the data were used as an estimation dataset for building models, and 40% were used as a validation dataset. Forward ordinary least squares linear regression methods and measures of prediction error were used to build a model to map to the EQ-5D index. Age, sex, a proxy measure of disease stage, Canadian Cardiovascular Society (CCS) angina severity class, treadmill exercise time (ETT) and scales of the SAQ were examined. Results The exertional capacity (ECS), disease perception (DPS) and anginal frequency scales (AFS) of the SAQ were the strongest predictors of the EQ-5D index and gave the smallest root mean square errors. A final model was chosen with age, gender, disease stage and the ECS, DPS and AFS scales of the SAQ. ETT and CCS did not improve prediction in the presence of the SAQ scales. Bland-Altman agreement between predicted and observed EQ-5D index values was reasonable for values greater than 0.4, but below this level predicted values were higher than observed. The 95% limits of agreement were wide (-0.34, 0.33). Conclusions Mapping of the EQ-5D index in cardiac patients from demographics and commonly measured cardiac outcome variables is possible; however, prediction for values of the EQ-5D index below 0.4 was not accurate. The newly designed 5-level version of the EQ-5D with its increased ability to discriminate health states may improve prediction of EQ-5D index values. Description: 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.

A random effects variance shift model for detecting and accommodating outliers in meta-analysis

Wed, 16 Feb 2011 00:00:00 GMT

Title: A random effects variance shift model for detecting and accommodating outliers in meta-analysis Authors: Gumedze, Freedom N; Jackson, Dan Abstract: Abstract Background Meta-analysis typically involves combining the estimates from independent studies in order to estimate a parameter of interest across a population of studies. However, outliers often occur even under the random effects model. The presence of such outliers could substantially alter the conclusions in a meta-analysis. This paper proposes a methodology for identifying and, if desired, downweighting studies that do not appear representative of the population they are thought to represent under the random effects model. Methods An outlier is taken as an observation (study result) with an inflated random effect variance. We used the likelihood ratio test statistic as an objective measure for determining whether observations have inflated variance and are therefore considered outliers. A parametric bootstrap procedure was used to obtain the sampling distribution of the likelihood ratio test statistics and to account for multiple testing. Our methods were applied to three illustrative and contrasting meta-analytic data sets. Results For the three meta-analytic data sets our methods gave robust inferences when the identified outliers were downweighted. Conclusions The proposed methodology provides a means to identify and, if desired, downweight outliers in meta-analysis. It does not eliminate them from the analysis however and we consider the proposed approach preferable to simply removing any or all apparently outlying results. We do not however propose that our methods in any way replace or diminish the standard random effects methodology that has proved so useful, rather they are helpful when used in conjunction with the random effects model. Description: 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.

The association of education with body mass index and waist circumference in the EPIC-PANACEA study

Thu, 17 Mar 2011 00:00:00 GMT

Title: The association of education with body mass index and waist circumference in the EPIC-PANACEA study Authors: Hermann, Silke; Rohrmann, Sabine; Linseisen, Jakob; May, Anne M; Kunst, Anton; Besson, Herve; Romaguera, Dora; Travier, Noemie; Tormo, Maria-Jose; Molina, Esther; Dorronsoro, Miren; Barricarte, Aurelio; Rodriguez, Laudina; Crowe, Francesca L; Khaw, Kay-Tee; Wareham, Nicholas J; van Boeckel, Petra G A; Bueno-de-Mesquita, H Bas; Overvad, Kim; Uhre Jakobsen, Marianne; Tjonneland, Anne; Halkjaer, Jytte; Agnoli, Claudia; Mattiello, Amalia; Tumino, Rosario; Masala, Giovanna; Vineis, Paolo; Naska, Androniki; Orfanos, Philippos; Trichopoulou, Antonia; Kaaks, Rudolf; Bergmann, Manuela M; Steffen, Annika; Van Guelpen, Bethany; Johansson, Ingegerd; Borgquist, Signe; Manjer, Jonas; Braaten, Tonje; Fagherazzi, Guy; Clavel-Chapelon, Francoise; Mouw, Traci; Norat, Teresa; Riboli, Elio; Rinaldi, Sabina; Slimani, Nadia; Peeters, Petra H M Abstract: Abstract Background To examine the association of education with body mass index (BMI) and waist circumference (WC) in the European Prospective Investigation into Cancer and Nutrition (EPIC). Method This study included 141,230 male and 336,637 female EPIC-participants, who were recruited between 1992 and 2000. Education, which was assessed by questionnaire, was classified into four categories; BMI and WC, measured by trained personnel in most participating centers, were modeled as continuous dependent variables. Associations were estimated using multilevel mixed effects linear regression models. Results Compared with the lowest education level, BMI and WC were significantly lower for all three higher education categories, which was consistent for all countries. Women with university degree had a 2.1 kg/m2 lower BMI compared with women with lowest education level. For men, a statistically significant, but less pronounced difference was observed (1.3 kg/m2). The association between WC and education level was also of greater magnitude for women: compared with the lowest education level, average WC of women was lower by 5.2 cm for women in the highest category. For men the difference was 2.9 cm. Conclusion In this European cohort, there is an inverse association between higher BMI as well as higher WC and lower education level. Public Health Programs that aim to reduce overweight and obesity should primarily focus on the lower educated population. Description: 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.

Creating web applications for spatial epidemiological analysis and mapping in R using Rwui

Thu, 31 Mar 2011 23:00:00 GMT

Title: Creating web applications for spatial epidemiological analysis and mapping in R using Rwui Authors: Newton, Richard; Deonarine, Andrew; Wernisch, Lorenz Abstract: Abstract Background Creating a user friendly web based application which executes an R script allows physicians, epidemiologists, and others unfamiliar with the statistical language to perform powerful statistical analyses easily. The geographic mapping of data is an important tool in spatial epidemiological analysis, and the R project includes many tools for such analyses, but few for visualization. Hence, web applications that run R for epidemiological analysis need to be able to present the results in a geographic format. Results Rwui is a web application for creating web based applications for running R scripts. We describe updates to Rwui that enable it to create web applications for R scripts which return the results of the analysis to the web page as geographic maps. Conclusions Rwui enables statisticians to create web applications for R scripts without the need to learn web programming. Creating a web application provides users access to an R based analysis without the need to learn R. Recent updates to Rwui have increased its applicability in the field of spatial epidemiological analysis. Description: 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.