A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain \u3e99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

Novel flaviviruses from mosquitoes : Mosquito-specific evolutionary lineages within the phylogenetic group of mosquito-borne flaviviruses

Peer reviewe

Determining significance of pairwise co-occurrences of events in bursty sequences

<p>Abstract</p> <p>Background</p> <p>Event sequences where different types of events often occur close together arise, e.g., when studying potential transcription factor binding sites (TFBS, events) of certain transcription factors (TF, types) in a DNA sequence. These events tend to occur in bursts: in some genomic regions there are more genes and therefore potentially more binding sites, while in some, possibly very long regions, hardly any events occur. Also some types of events may occur in the sequence more often than others.</p> <p>Tendencies of co-occurrence of binding sites of two or more TFs are interesting, as they may imply a co-operative role between the TFs in regulatory processes. Determining a numerical value to summarize the tendency for co-occurrence between two TFs can be done in a number of ways. However, testing for the significance of such values should be done with respect to a relevant null model that takes into account the global sequence structure.</p> <p>Results</p> <p>We extend the existing techniques that have been considered for determining the significance of co-occurrence patterns between a pair of event types under different null models. These models range from very simple ones to more complex models that take the burstiness of sequences into account. We evaluate the models and techniques on synthetic event sequences, and on real data consisting of potential transcription factor binding sites.</p> <p>Conclusion</p> <p>We show that simple null models are poorly suited for bursty data, and they yield many false positives. More sophisticated models give better results in our experiments. We also demonstrate the effect of the window size, i.e., maximum co-occurrence distance, on the significance results.</p

Clinicians' caseload management behaviours as explanatory factors in patients' length of time on caseloads : a predictive multilevel study in paediatric community occupational therapy

Peer reviewedPublisher PD

Validation of the Burden Index of Caregivers (BIC), a multidimensional short care burden scale from Japan

BACKGROUND: We constructed a concise multidimensional care burden scale that reflects circumstances unique to Japan, with a focus on intractable neurological diseases. We surveyed 646 family caregivers of patients with intractable neurological diseases or stroke using 28 preliminary care burden scale items obtained from qualitative research. The results were used to finalize the feeling of care burden scale (BIC: burden index of caregivers), and verify its reliability and validity. METHODS: The survey was conducted among caregivers providing home health care to patients with intractable neurological diseases (PD [Parkinson's disease], SCD [spinocerebellar degeneration], MSA [multiple system atrophy], and ALS [amyotrophic lateral sclerosis]) or CVA (cerebrovascular accident) using a mailed, self-administered questionnaire between November, 2003 and May, 2004. RESULTS: Response rates for neurological and CVA caregivers were 50% and 67%, respectively, or 646 in total (PD, 279; SCD, 78; MSA, 39; ALS, 30; and CVA, 220). Item and exploratory factor analyses led to a reduction to 11 items, comprising 10 items from the 5 domains of time-dependent burden, emotional burden, existential burden, physical burden, and service-related burden; and 1 item on total burden. Examination of validity showed a moderate correlation between each domain of the BIC and the SF-8 (Health related quality of life scale, Short Form-8), while the correlation coefficient of the overall BIC and CES-D was 0.62. Correlation between the BIC and ZBI, a preexisting care burden scale, was high (r = 0.84), while that with the time spent on providing care was 0.47. The ICC (Intraclass correlation coefficient) by test-retest reliability was 0.83, and 0.68 to 0.80 by individual domain. CONCLUSION: These results show that the BIC, a new care burden scale comprising 11 items, is highly reliable and valid

Assessing pooled BAC and whole genome shotgun strategies for assembly of complex genomes

<p>Abstract</p> <p>Background</p> <p>We investigate if pooling BAC clones and sequencing the pools can provide for more accurate assembly of genome sequences than the "whole genome shotgun" (WGS) approach. Furthermore, we quantify this accuracy increase. We compare the pooled BAC and WGS approaches using <it>in silico </it>simulations. Standard measures of assembly quality focus on assembly size and fragmentation, which are desirable for large whole genome assemblies. We propose additional measures enabling easy and visual comparison of assembly quality, such as rearrangements and redundant sequence content, relative to the known target sequence.</p> <p>Results</p> <p>The best assembly quality scores were obtained using 454 coverage of 15× linear and 5× paired (3kb insert size) reads (15L-5P) on <it>Arabidopsis</it>. This regime gave similarly good results on four additional plant genomes of very different GC and repeat contents. BAC pooling improved assembly scores over WGS assembly, coverage and redundancy scores improving the most.</p> <p>Conclusions</p> <p>BAC pooling works better than WGS, however, both require a physical map to order the scaffolds. Pool sizes up to 12Mbp work well, suggesting this pooling density to be effective in medium-scale re-sequencing applications such as targeted sequencing of QTL intervals for candidate gene discovery. Assuming the current Roche/454 Titanium sequencing limitations, a 12 Mbp region could be re-sequenced with a full plate of linear reads and a half plate of paired-end reads, yielding 15L-5P coverage after read pre-processing. Our simulation suggests that massively over-sequencing may not improve accuracy. Our scoring measures can be used generally to evaluate and compare results of simulated genome assemblies.</p

Breastfeeding and childhood asthma: a six-year population-based cohort study

<p>Abstract</p> <p>Background</p> <p>The question of the protective effect of breastfeeding on development of asthma has raised substantial interest, but the scientific evidence of the optimal duration of breastfeeding is controversial.</p> <p>Methods</p> <p>The authors elaborated the optimal duration of breastfeeding with respect to the risk of asthma primarily, and secondarily to the risk of persistent wheezing, cough and phlegm in school age in a population-based cohort study with the baseline in 1991 and follow-up in 1997. The study population comprised 1984 children aged 7 to 14 years at the end of the follow-up (follow-up rate 77). Information on breastfeeding was based on the baseline survey and information on the health outcomes at the follow-up.</p> <p>Results</p> <p>There was a U-shaped relation between breastfeeding and the outcomes with the lowest risk with breastfeeding from four to nine months for asthma and seven to nine months for persistent wheezing, cough and phlegm.</p> <p>Conclusion</p> <p>Our results suggest a U shape relation between duration of breastfeeding and risk of asthma with an optimal duration of 4 to 6 months. A true concave relation would explain the inconsistent results from the previous studies.</p

Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells

Tumorigenesis is a multistep process involving co-operation between several deregulated oncoproteins. In this study, we unravel previously unrecognized interactions and crosstalk between Pim kinases and the Notch signaling pathway, with implications for both breast and prostate cancer. We identify Notch1 and Notch3, but not Notch2, as novel Pim substrates and demonstrate that for Notch1, the serine residue 2152 is phosphorylated by all three Pim family kinases. This target site is located in the second nuclear localization sequence (NLS) of the Notch1 intracellular domain (N1ICD), and is shown to be important for both nuclear localization and transcriptional activity of N1ICD. Phosphorylation-dependent stimulation of Notch1 signaling promotes migration of prostate cancer cells, balances glucose metabolism in breast cancer cells, and supports in vivo growth of both types of cancer cells on chick embryo chorioallantoic membranes. Furthermore, Pim-induced growth of orthotopic prostate xenografts in mice is associated with enhanced nuclear Notch1 activity. Finally, simultaneous inhibition of Pim and Notch abrogates the cellular responses more efficiently than individual treatments, opening up new vistas for combinatorial cancer therapy.</p

The Role of Inflammatory Cytokines as Intermediates in the Pathway from Increased Adiposity to Disease

Objective This study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease.Methods BMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI-driven cytokines on risk of obesity-related diseases. Results Observationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08-1.19), 1.08 (95% CI: 1.04-1.14), and 1.13 (95% CI: 1.04-1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00-1.06). There was inconsistent evidence for a protective role of MCP-1 against inflammatory bowel diseases.Conclusions Observational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI-driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.</p