Alicja R. Rudnicka

Genome-wide association study identifies five loci associated with lung function

Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.

Lessons for cluster randomized trials in the twenty-first century: a systematic review of trials in primary care

Background Evidence suggests that cluster randomized trials are often poorly designed and analysed. There is little recent research on the methodologic quality of cluster randomized trials and none focuses on primary health care where these trials are increasingly common. Methods We conducted a systematic review of recent cluster randomized trials in primary health care, searching the Cochrane Controlled Trials Register. We also searched for unpublished trials in conference proceedings, and the UK National Research Register. We assess methodologic quality using a checklist, articulate problems facing investigators conducting these trials, and examine the extent to which carrying out a cluster randomized trial (as opposed to an individually randomized trial) in primary care may reduce power. Results We found 367 trial reports. Many trials were reported more than once. We characterize 152 independent cluster randomized trials in primary health care published between 1997 and 2000, and brie‘y describe 47 trials unpublished at December 2000. The quality of design and analysis was variable. Of published trials reporting sample size calculations 20% accounted for clustering in these calculations, 59% of published trials accounted for clustering in analyses. Unpublished trials were more recent and of higher quality. Reporting quality was better in journals reporting more cluster randomized trials. Many trial investigators reported problems with adherence to protocol, recruitment and type of intervention. Conclusions Methodologic quality of cluster randomized trials in primary health care is variable and reporting needs improvement. The use of cluster randomization should be indicated in the title or abstract so these kinds of trials are easier to identify. Communicating appropriate methodology to health care researchers continues to be a challenge. Cluster randomized trials should always be piloted and information from pilots and unsuccessful trials shared more widely. Introduction Cluster randomized trials, in which groups or clusters of individuals rather than the individuals themselves are randomized to intervention and control groups, are increasingly popular and particularly common in primary health care. This is because much current primary health service research centres on interventions to improve practice [1], often involving changes in patient behaviour, health professional behaviour, or organization. Controlled trials randomizing individual

How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom

Aims: To predict the burden of blindness, partial sight, and visual impairment (binocular visual acuity 6/18 or less) due to late stage age related macular degeneration (AMD) in the ageing population of the United Kingdom. Methods: A systematic review, followed by a request for data, was used to establish a pooled prevalence of AMD and corresponding visual loss. Prevalence figures were applied to the UK population. Using UK population trends, the future burden of AMD over the coming decade was established. Results: Pooled data from six studies showed that the prevalence of visual loss caused by AMD increased exponentially from the age of 70–85 years of age, with 3.5% (95% CI 3.0 to 4.1) having visual impairment beyond the age of 75 years. The authors estimate that there are currently 214 000 (95% CI 151 000 to 310 000) with visual impairment caused by AMD (suitable for registration). This number is expected to increase to 239 000 (95% CI 168 000 to 346 000) by the year 2011. Currently there are 172 000 (95% CI 106 000 to 279 000) and 245 000 (95% CI 163 000 to 364 000) with geographical and neovascular AMD, respectively. Conclusions: Estimates of visual impairment agree with official statistics for the number registered partially sighted or blind, caused by AMD, and are well below other figures often cited. Although these estimates are associated with wide confidence intervals (CI) and a number of caveats, they represent the best available data, which can be used to guide health and social care provision for older people in the UK setting. Implications for low vision services are outlined.

Ethnic and gender differences in physical activity levels among 9–10-year-old children of white European, South Asian and African–Caribbean origin: the Child Heart Health Study in England (CHASE Study)

BACKGROUNDnEthnic differences in physical activity in children in the UK have not been accurately assessed. We made objective measurements of physical activity in 9-10-year-old British children of South Asian, black African-Caribbean and white European origin.nnnMETHODSnCross-sectional study of urban primary school children (2006-07). Actigraph-GT1M activity monitors were worn by 2071 children during waking hours on at least 1 full day. Ethnic differences in mean daily activity [counts, counts per minute of registered time (CPM) and steps] were adjusted for age, gender, day of week and month. Multilevel modelling allowed for repeated days within individual and clustering within school.nnnRESULTSnIn white Europeans, mean daily counts, CPM and mean daily steps were 394,785, 498 and 10,220, respectively. South Asian and black Caribbean children recorded more registered time per day than white Europeans (34 and 36 min, respectively). Compared with white Europeans, South Asians recorded 18 789 fewer counts [95% confidence interval (CI) 6390-31 187], 41 fewer CPM 95% CI 26-57) and 905 fewer steps (95% CI 624-1187). Black African-Caribbeans recorded 25 359 more counts (95% CI 14 273-36 445), and similar CPM, but fewer steps than white Europeans. Girls recorded less activity than boys in all ethnic groups, with 74 782 fewer counts (95% CI 66 665-82 899), 84 fewer CPM (95% CI 74-95) and 1484 fewer steps (95% CI 1301-1668).nnnCONCLUSIONnBritish South Asian children have lower objectively measured physical activity levels than European whites and black African-Caribbeans.

SURUSS in perspective.

Backgroundu2003 Until the publication of the Serum Urine and Ultrasound Screening Study (SURUSS) report, it was difficult to compare the different antenatal screening tests for Downs Syndrome because of variations in study designs. We here present the main results from SURUSS, updated to take account of recent information on nuchal translucency in Downs Syndrome pregnancies, and discuss their implications.

Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

Background— Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search. Methods and Results— A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10−52) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10−14) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10−18) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus. Conclusions— Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

Low-intensity warfarin reduces thrombin generation and fibrin turnover, but not low-grade inflammation, in men at risk of myocardial infarction

In the Thrombosis Prevention Trial (TPT), low‐intensity warfarin reduced the risk of first coronary events only when the achieved international normalized ratio (INR) was ≥1·4. To validate the likely mechanism of action of low‐intensity warfarin we measured its effects on plasma markers of thrombin generation, fibrin turnover and low‐grade inflammation in TPT participants. d‐dimer and prothrombin fragment F1·2 levels were lower at INRs ≥1·4 (Pu2003=u20030·02 and 0·03 respectively); levels fell as INR increased (P for trend 0·04 and 0·002 respectively). C‐reactive protein did not vary with INR. The efficacy of warfarin is related to reductions in thrombin generation and fibrin turnover.

Circulating markers of arterial thrombosis and late-stage age-related macular degeneration: a case-control study.

PurposeThe aim of this study was to examine the relation of late-stage age-related macular degeneration (AMD) with markers of systemic atherothrombosis.MethodsA hospital-based case–control study of AMD was undertaken in London, UK. Cases of AMD (n=81) and controls (n=77) were group matched for age and sex. Standard protocols were used for colour fundus photography and to classify AMD; physical examination included height, weight, history of or treatment for vascular-related diseases and smoking status. Blood samples were taken for measurement of fibrinogen, factor VIIc (FVIIc), factor VIIIc, prothrombin fragment F1.2 (F1.2), tissue plasminogen activator, and von Willebrand factor. Odds ratios from logistic regression analyses of each atherothrombotic marker with AMD were adjusted for age, sex, and established cardiovascular disease risk factors, including smoking, blood pressure, body mass index, and total cholesterol.ResultsAfter adjustment FVIIc and possibly F1.2 were inversely associated with the risk of AMD; per 1 standard deviation increase in these markers the odds ratio were, respectively, 0.62 (95% confidence interval 0.40, 0.95) and 0.71 (0.46, 1.09). None of the other atherothrombotic risk factors appeared to be related to AMD status. There was weak evidence that aspirin is associated with a lower risk of AMD.ConclusionsThis study does not provide strong evidence of associations between AMD and systematic markers of arterial thrombosis, but the potential effects of FVIIc, and F1.2 are worthy of further investigation.

Choice between using delta-NT or NT MoM

Spencer asks a question in the title to his paper, namely ‘Delta-NT or NT MoM: which is the most appropriate method for calculating accurate patient-specific risks for trisomy 21 in the first trimester?’1. We have read the paper, and to understand it better we would be grateful if the authors would clarify the calculation of likelihood ratios and present their observed centiles of nuchal translucency (NT) (in millimeters) in affected and unaffected pregnancies.

A Model Based Approach for Vessel Caliber Measurement in Retinal Images

The diagnostic signature of many microvasculature diseases like diabetes mellitus, hypertension and arteriosclerosis includes the changes incurred in the diameter of retinal blood vessels. Therefore estimation of precise vascular widths is a critical and demanding process in automated retinal image analysis. This paper proposes an automated system to measure the vessel caliber in the retinal images of multi-ethnic school children. The diameter measurement is based on the detection of the centerline pixels from a vessel probability map image, determining the vessel orientation at these pixels, extracting the vessel segments and later using a two dimensional model, which is optimized to fit various types of intensity profiles of vessel segments. The width is then estimated from parameters of the optimized model. The method is also used to explore the relationship between the average vessel width and the background pigmentation of the retinal image by analyzing monochromatic representations of different color spaces.