166 research outputs found

    Prostate-specific antigen patterns in US and European populations:Comparison of six diverse cohorts

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    Objective: To determine whether there are differences in prostate-specific antigen (PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer (PCa). Subjects and Methods: We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations. Results: The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations. Conclusion: We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies

    Epigenome-wide change and variation in DNA methylation in childhood:Trajectories from birth to late adolescence

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    DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illumina Infinium HumanMethylation450 BeadChip. Change over time was widespread, observed at over one-half (53%) of CpGs. In most cases, DNAm was decreasing (36% of CpGs). Inter-individual variation in linear trajectories was similarly widespread (27% of CpGs). Evidence for non-linear change and inter-individual variation in non-linear trajectories was somewhat less common (11 and 8% of CpGs, respectively). Very little inter-individual variation in change was explained by sex differences (0.4% of CpGs) even though sex-specific DNAm was observed at 5% of CpGs. DNAm trajectories were distributed non-randomly across the genome. For example, CpGs with decreasing DNAm were enriched in gene bodies and enhancers and were annotated to genes enriched in immune-developmental functions. In contrast, CpGs with increasing DNAm were enriched in promoter regions and annotated to genes enriched in neurodevelopmental functions. These findings depict a methylome undergoing widespread and often non-linear change throughout childhood. They support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk

    The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip

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    DNA methylation (DNAm) is commonly assayed using the Illumina Infinium MethylationEPIC BeadChip, but there is currently little published evidence to define the lower limits of the amount of DNA that can be used whilst preserving data quality. Such evidence is valuable for analyses utilizing precious or limited DNA sources. We used a single pooled sample of DNA in quadruplicate at three dilutions to define replicability and noise, and an independent population dataset of 328 individuals (from a community-based study including US-born non-Hispanic Black and white persons) to assess the impact of total DNA input on the quality of data generated using the Illumina Infinium MethylationEPIC BeadChip. We found that data are less reliable and more noisy as DNA input decreases to 40ng, with clear reductions in data quality; and that low DNA input is associated with a reduction in power to detect EWAS associations, requiring larger sample sizes. We conclude that DNA input as low as 40ng can be used with the Illumina Infinium MethylationEPIC BeadChip, provided quality checks and sensitivity analyses are undertaken

    Epigenetic gestational age acceleration:A prospective cohort study investigating associations with familial, sociodemographic and birth characteristics

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    Abstract Background Gestational age at delivery is associated with health and social outcomes. Recently, cord blood DNA methylation data has been used to predict gestational age. The discrepancy between gestational age predicted from DNA methylation and determined by ultrasound or last menstrual period is known as gestational age acceleration. This study investigated associations of sex, socioeconomic status, parental behaviours and characteristics and birth outcomes with gestational age acceleration. Results Using data from the Avon Longitudinal Study of Parents and Children (n = 863), we found that pre-pregnancy maternal overweight and obesity were associated with greater gestational age acceleration (mean difference = 1.6 days, 95% CI 0.7 to 2.6, and 2.9 days, 95% CI 1.3 to 4.4, respectively, compared with a body mass index < 25 kg/m2, p < .001). There was evidence of an association between male sex and greater gestational age acceleration. Greater gestational age acceleration was associated with higher birthweight, birth length and head circumference of the child (mean differences per week higher gestational age acceleration: birthweight 0.1 kg, 95% CI 0.1 to 0.2, p < .001; birth length 0.4 cm, 95% CI 0.2 to 0.7, p < .001; head circumference 0.2 cm, 95% CI 0.1 to − 0.4, p < .001). There was evidence of an association between gestational age acceleration and mode of delivery (assisted versus unassisted delivery, odds ratio = 0.9 per week higher gestational age acceleration, 95% CI 0.7, 1.3 (p = .05); caesarean section versus unassisted delivery, odds ratio = 0.6, 95% CI 0.4 to 0.9 per week higher gestational age acceleration (p = .05)). There was no evidence of association for other parental and perinatal characteristics. Conclusions The associations of higher maternal body mass index and larger birth size with greater gestational age acceleration may imply that maternal overweight and obesity is associated with more rapid development of the fetus in utero. The implications of gestational age acceleration for postnatal health warrant further investigation

    Piloting the objective measurement of eating weight and speed at a population scale: a nested study within the Avon Longitudinal Study of Parents and Children [version 3; peer review: 2 approved]

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    Background: Effective measurement and adaption of eating behaviours (e.g., eating speed) may improve weight loss and weight over time. We assessed whether the Mandometer, a portable weighing scale connected to a computer that generates a graph of food removal rate from the plate to which it is connected, together with photo-imaging of food, might prove a less intensive and more economical approach to measuring eating behaviours at large scale. Methods: We deployed the Mandometer in the home environment to measure main meals over three days of 95 21-year-old participants of the Avon Longitudinal Study of Parents and Children. We used multi-level models to describe food weight and eating speed and, as exemplar analyses, examined the relationship of eating behaviours with body mass index (BMI), dietary composition (fat content) and genotypic variation (the FTO rs9939609 variant). Using this pilot data, we calculated the sample size required to detect differences in food weight and eating speed between groups of an exposure variable. Results: All participants were able to use the Mandometer effectively after brief training. In exemplar analyses, evidence suggested that obese participants consumed more food than those of "normal" weight (i.e., BMI 19 to <25 kg/m 2) and that A/A FTO homozygotes (an indicator of higher weight) ate at a faster rate compared to T/T homozygotes. There was also some evidence that those with a high-fat diet consumed less food than those with a low-fat diet, but little evidence that individuals with medium- or high-fat diets ate faster. Conclusions: We demonstrated the potential for assessing eating weight and speed in a short-term home setting and combining this with information in a research setting. This study may offer the opportunity to design interventions tailored for at-risk eating behaviours, offering advantages over the “one size fits all” approach of current failing obesity interventions

    Maternal pre-pregnancy BMI and gestational weight gain, offspring DNA methylation and later offspring adiposity: Findings from the Avon Longitudinal Study of Parents and Children

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    Evidence suggests that in utero exposure to undernutrition and overnutrition might affect adiposity in later life. Epigenetic modification is suggested as a plausible mediating mechanism.We used multivariable linear regression and a negative control design to examine offspring epigenome-wide DNA methylation in relation to maternal and offspring adiposity in 1018 participants.Compared with neonatal offspring of normal weight mothers, 28 and 1621 CpG sites were differentially methylated in offspring of obese and underweight mothers, respectively [false discovert rate (FDR)-corrected P-value < 0.05), with no overlap in the sites that maternal obesity and underweight relate to. A positive association, where higher methylation is associated with a body mass index (BMI) outside the normal range, was seen at 78.6% of the sites associated with obesity and 87.9% of the sites associated with underweight. Associations of maternal obesity with offspring methylation were stronger than associations of paternal obesity, supporting an intrauterine mechanism. There were no consistent associations of gestational weight gain with offspring DNA methylation. In general, sites that were hypermethylated in association with maternal obesity or hypomethylated in association with maternal underweight tended to be positively associated with offspring adiposity, and sites hypomethylated in association with maternal obesity or hypermethylated in association with maternal underweight tended to be inversely associated with offspring adiposity.Our data suggest that both maternal obesity and, to a larger degree, underweight affect the neonatal epigenome via an intrauterine mechanism, but weight gain during pregnancy has little effect. We found some evidence that associations of maternal underweight with lower offspring adiposity and maternal obesity with greater offspring adiposity may be mediated via increased DNA methylation.Gemma C Sharp, Debbie A Lawlor, Rebecca C Richmond, Abigail Fraser, Andrew Simpkin, Matthew Suderman, Hashem A Shihab, Oliver Lyttleton, Wendy McArdle, Susan M Ring, Tom R Gaunt, George Davey Smith and Caroline L Relto

    CCP4 Cloud for structure determination and project management in macromolecular crystallography

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    Nowadays, progress in the determination of three-dimensional macromolecular structures from diffraction images is achieved partly at the cost of increasing data volumes. This is due to the deployment of modern high-speed, high-resolution detectors, the increased complexity and variety of crystallographic software, the use of extensive databases and high-performance computing. This limits what can be accomplished with personal, offline, computing equipment in terms of both productivity and maintainability. There is also an issue of long-term data maintenance and availability of structure-solution projects as the links between experimental observations and the final results deposited in the PDB. In this article, CCP4 Cloud, a new front-end of the CCP4 software suite, is presented which mitigates these effects by providing an online, cloud-based environment for crystallographic computation. CCP4 Cloud was developed for the efficient delivery of computing power, database services and seamless integration with web resources. It provides a rich graphical user interface that allows project sharing and long-term storage for structure-solution projects, and can be linked to data-producing facilities. The system is distributed with the CCP4 software suite version 7.1 and higher, and an online publicly available instance of CCP4 Cloud is provided by CCP4.The following funding is acknowledged: Biotechnology and Biological Sciences Research Council (grant No. BB/L007037/1; grant No. BB/S007040/1; grant No. BB/S007083/1; grant No. BB/S005099/1; grant No. BB/S007105/1; award No. BBF020384/1); Medical Research Council (grant No.MC_UP_A025_1012; grant No. MC_U105184325); Ro¨ntgenA˚ ngstro¨m Cluster (grant No. 349-2013-597); Nederlandse Wetenschappelijke Organisatie (grant No. TKI 16219)
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