Biological plausibility and other prior information could help select genome-wide association (GWA) findings for further follow-up, but there is no consensus on which types of knowledge should be considered or how to weight them. We used experts’ opinions and empirical evidence to estimate the relative importance of 15 types of information at the single nucleotide polymorphism (SNP) and gene levels. Opinions were elicited from ten experts using a two-round Delphi survey. Empirical evidence was obtained by comparing the frequency of each type of characteristic in SNPs established as being associated with seven disease traits through GWA meta-analysis and independent replication, with the corresponding frequency in a randomly selected set of SNPs. SNP and gene characteristics were retrieved using a specially developed bioinformatics tool. Both the expert and the empirical evidence rated previous association in a meta-analysis or more than one study as conferring the highest relative probability of true association, while previous association in a single study ranked much lower. High relative probabilities were also observed for location in a functional protein domain, while location in a region evolutionarily conserved in vertebrates was ranked high by the data but not by the experts. Our empirical evidence did not support the importance attributed by the experts to whether the gene encodes a protein in a pathway or shows interactions relevant to the trait. Our findings provide insight into the selection and weighting of different types of knowledge in SNP or gene prioritization, and point to areas requiring further research.
Gene prioritization; Genome-wide association studies; Bioinformatics databases
Prioritization is the process whereby a set of possible candidate genes or SNPs is ranked so that the most promising can be taken forward into further studies. In a genome-wide association study, prioritization is usually based on the p-values alone, but researchers sometimes take account of external annotation information about the SNPs such as whether the SNP lies close to a good candidate gene. Using external information in this way is inherently subjective and is often not formalized, making the analysis difficult to reproduce. Building on previous work that has identified fourteen important types of external information, we present an approximate Bayesian analysis that produces an estimate of the probability of association. The calculation combines four sources of information: the genome-wide data, SNP information derived from bioinformatics databases, empirical SNP weights, and the researchers’ subjective prior opinions. The calculation is fast enough that it can be applied to millions of SNPS and although it does rely on subjective judgments, those judgments are made explicit so that the final SNP selection can be reproduced. We show that the resulting probability of association is intuitively more appealing than the p-value because it is easier to interpret and it makes allowance for the power of the study. We illustrate the use of the probability of association for SNP prioritization by applying it to a meta-analysis of kidney function genome-wide association studies and demonstrate that SNP selection performs better using the probability of association compared with p-values alone.
replication; prior knowledge; genome-wide studies
To determine if there is a difference in serum zinc concentration between normoglycaemic, pre-diabetic and type-2 diabetic groups and if this is associated with pancreatic beta cell function and insulin sensitivity in the former 2 groups.
Cross sectional study of a random sample of older community-dwelling men and women in Newcastle, New South Wales, Australia. Beta cell function, insulin sensitivity and insulin resistance were calculated for normoglycaemic and prediabetes participants using the Homeostasis Model Assessment (HOMA-2) calculator.
A total of 452 participants were recruited for this study. Approximately 33% (N = 149) had diabetes, 33% (N = 151) had prediabetes and 34% (N = 152) were normoglycaemic. Homeostasis Model Assessment (HOMA) parameters were found to be significantly different between normoglycaemic and prediabetes groups (p<0.001). In adjusted linear regression, higher serum zinc concentration was associated with increased insulin sensitivity (p = 0.01) in the prediabetic group. There was also a significant association between smoking and worse insulin sensitivity.
Higher serum zinc concentration is associated with increased insulin sensitivity. Longitudinal studies are required to determine if low serum zinc concentration plays a role in progression from pre-diabetes to diabetes.
Despite the increasing interest towards the biological role of L-ergothioneine, little is known about the serum concentrations of this unusual aminothiol in older adults. We addressed this issue in a representative sample of community-dwelling middle-aged and older adults.
Body mass index, estimated glomerular filtration rate, serum concentrations of L-ergothioneine, taurine, homocysteine, cysteine, glutathione, cysteinylglycine, and glutamylcysteine were evaluated in 439 subjects (age 55–85 years) randomly selected from the Hunter Community Study.
Median L-ergothioneine concentration in the entire cohort was 1.01 IQR 0.78–1.33 µmol/L. Concentrations were not affected by gender (P = 0.41) or by presence of chronic medical conditions (P = 0.15). By considering only healthy subjects, we defined a reference interval for L-ergothioneine serum concentrations from 0.36 (90% CI 0.31–0.44) to 3.08 (90% CI 2.45–3.76) µmol/L. Using stepwise multiple linear regression analysis L-ergothioneine was negatively correlated with age (rpartial = −0.15; P = 0.0018) and with glutamylcysteine concentrations (rpartial = −0.13; P = 0.0063).
A thorough analysis of serum L-ergothioneine concentrations was performed in a large group of community-dwelling middle-aged and older adults. Reference intervals were established. Age and glutamylcysteine were independently negatively associated with L-ergothioneine serum concentration.
End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischaemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n=2,100 Stage 1) were examined in ischemic stroke (n=4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases 55,000 controls) was used for replication (Stage 3).
Stage 1 identified 524 SNPs from 23 LD blocks having significant association (p<5 ×10-8) with one or more coagulation/fibrin phenotypes. Most striking associations included SNP rs5985 with factor XIII activity (p=2.6×10-186), rs10665 with FVII (p = 2.4×10-47) and rs505922 in the ABO gene with both von Willebrand Factor (vWF p=4.7×10-57) and factor VIII (p=1.2×10-36). In Stage 2, the 23 independent SNPs were examined in stroke cases/non-cases using MORGAM and WTCCC2 collections. SNP rs505922 was nominally associated with ischaemic stroke, odds ratio = 0.94 (95% confidence intervals, 0.88-0.99), p=0.023. Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta=0.066 (0.02) p = 0.001, a finding specific to large vessel and cardioembolic stroke (p = 0.001 and p = <0.001 respectively) but not seen with small vessel stroke (p=0.811).
ABO gene variants are associated with large vessel and cardioembolic stroke but not small vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.
GWAS; thrombosis; stroke; coagulation factor; stroke subtype
Epidemiologic studies have observed association between short sleep duration and both cardiovascular disease (CVD) and type 2 diabetes, although these results may reflect confounding by pre-existing illness. This study aimed to determine whether short sleep duration predicts future CVD or type 2 diabetes after accounting for baseline health. Baseline data for 241,949 adults were collected through the 45 and Up Study, an Australian prospective cohort study, with health outcomes identified via electronic database linkage. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals. Compared to 7h sleep, <6h sleep was associated with incident CVD in participants reporting ill-health at baseline (HR=1·38 [95% CI: 1·12-1·70]), but not after excluding those with baseline illness and adjusting for baseline health status (1·03 [0·88-1·21]). In contrast, the risk of incident type 2 diabetes was significantly increased in those with <6h versus 7h sleep, even after excluding those with baseline illness and adjusting for baseline health (HR=1·29 [1·08-1·53], P=0.004). This suggests the association is valid and does not simply reflect confounding or reverse causation. Meta-analysis of ten prospective studies including 447,124 participants also confirmed an association between short sleep and incident diabetes (1·33 [1·20-1·48]). Obtaining less than 6 hours of sleep each night (compared to 7 hours) may increase type 2 diabetes risk by approximately 30%.
Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-013-1369-1) contains supplementary material, which is available to authorized users.
Epidemiologic studies often struggle to adequately represent populations and outcomes of interest. Differences in methodology, data analysis and research questions often mean that reviews and synthesis of the existing literature have significant limitations. The current paper details our experiences in combining individual participant data from two existing cohort studies to address questions about the influence of social factors on health outcomes within a representative sample of urban to remote areas of Australia. The eXtending Treatments, Education and Networks in Depression study involved pooling individual participant data from the Australian Rural Mental Health Study (T0 N = 2639) and the Hunter Community Study (T0 N = 3253) as well as conducting a common three-year follow-up phase (T1 N = 3513). Pooling these data extended the capacity of these studies by: enabling research questions of common interest to be addressed; facilitating the harmonization of baseline measures; permitting investigation of a range of psychosocial, physical and contextual factors over time; and contributing to the development and implementation of targeted interventions for persons experiencing depression and alcohol issues.
The current paper describes the rationale, challenges encountered, and solutions devised by a project aiming to maximise the benefits derived from existing cohort studies. We also highlight opportunities for such individual participant data analyses to assess common assumptions in research synthesis, such as measurement invariance, and opportunities for extending ongoing cohorts by conducting a common follow-up phase.
Pooling individual participant data can be a worthwhile venture, particularly where adequate representation is beyond the scope of existing research, where the effects of interest are small though important, where events are of relatively low frequency or rarely observed, and where issues are of immediate regional or national interest. Benefits such as these can enhance the utility of existing projects and strengthen requests for further research funding.
Cohort studies; Remoteness; Mental health; Individual participant data analysis; Research methods
Alcohol screening and brief intervention is recommended for widespread implementation in health care systems, but it is not used routinely in most countries for a variety of reasons. Electronic screening and brief intervention (e-SBI), in which patients complete a Web-based questionnaire and are provided with personalized feedback on their drinking, is a promising alternative to practitioner delivered intervention, but its efficacy in the hospital outpatient setting has not been established.
The objective of our study was to establish the feasibility of conducting a full-scale randomized controlled trial to determine whether e-SBI reduces alcohol consumption in hospital outpatients with hazardous or harmful drinking.
The study was conducted in the outpatient department of a large public hospital in Newcastle (population 540,000), Australia. Adults with appointments at a broad range of medical and surgical outpatient clinics were invited to complete an e-SBI program on a laptop, and to report their impressions via a short questionnaire. Follow-up assessments were conducted 2-8 weeks later by email and post.
We approached 172 outpatients and 108/172 (62.8%) agreed to participate. Of the 106 patients capable of self-administering the e-SBI, 7/106 (6.6%) did not complete it (3 due to technical problems and 4 because they were called for their appointment), 15/106 (14.2%) indicated that they had not consumed any alcohol in the past 12 months, 43/106 (40.6%) screened negative for unhealthy alcohol use (scored less than 5 on the Alcohol Use Disorders Identification Test Consumption [AUDIT-C] questions), 33/106 (31.1%) screened positive for hazardous or harmful drinking (AUDIT-C score 5-9), and 8/106 (7.5%) screened positive for possible alcohol dependence (AUDIT-C score 10-12). Among the subgroup with hazardous or harmful drinking, 27/33 (82%) found the feedback on their drinking very, quite, or somewhat useful, 33/33 (100%) thought the intervention would appeal to most or some of the people who attend the service, and 22/30 (73%) completed the follow-up. We also found that some well established procedures used in trials of e-SBI in the primary care setting did not translate to the hospital outpatient setting (1) we experienced delays because the e-SBI program had to be developed and maintained by the health service’s information technology staff for security reasons, (2) recruiting patients as they left the reception desk was impractical because patients tended to arrive at the beginning of the clinics with few arrivals thereafter, and (3) use of a laptop in a fixed location resulted in some patients rushing through the e-SBI so they could return to their seat in the area they had been advised to wait in.
e-SBI is acceptable to outpatients and with some adaptation to organizational and physical conditions, it is feasible to recruit and screen patients and to deliver the intervention without disrupting normal service provision. This suggests that e-SBI could be provided routinely in this important setting if shown to be efficacious.
alcohol; drinking; screening; brief intervention; hospital; outpatients; Internet
The demographic, health and contextual factors associated with quality of life impairment are investigated in older persons from New South Wales, Australia. We examine the impact of cardiovascular and affective conditions on impairment and the potential moderating influence of comorbidity and remoteness.
Data from persons aged 55 and over were drawn from two community cohorts sampling from across urban to very remote areas. Hierarchical linear regressions were used to assess: 1) the impact of cardiovascular and affective conditions on physical and psychological quality of life impairment; and 2) any influence of remoteness on these effects (N = 4364). Remoteness was geocoded to participants at the postal code level. Secondary data sources were used to examine the social capital and health service accessibility correlates of remoteness.
Physical impairment was consistently associated with increased age, male gender, lower education, being unmarried, retirement, stroke, heart attack/angina, depression/anxiety, diabetes, hypertension, current obesity and low social support. Psychological impairment was consistently associated with lower age, being unmarried, stroke, heart attack/angina, depression/anxiety and low social support. Remoteness tended to be associated with lower psychological impairment, largely reflecting overall urban versus rural differences. The impacts of cardiovascular and affective conditions on quality of life were not influenced by remoteness. Social capital increased and health service accessibility decreased with remoteness, though no differences between outer-regional and remote/very remote areas were observed. Trends suggested that social capital was associated with lower psychological impairment and that the influence of cardiovascular conditions and social capital on psychological impairment was greater for persons with a history of affective conditions. The beneficial impact of social capital in reducing psychological impairment was more marked for those experiencing financial difficulty.
Cardiovascular and affective conditions are key determinants of physical and psychological impairment. Persons affected by physical-psychological comorbidity experience greater psychological impairment. Social capital is associated with community remoteness and may ameliorate the psychological impairment associated with affective disorders and financial difficulties. The use of classifications of remoteness that are sensitive to social and health service accessibility determinants of health may better inform future investigations into the impact of context on quality of life outcomes.
Cardiovascular disease; Urban–rural; Social capital; Quality of life; Physical and psychological health; Over 55 years
Objective. To conduct a systematic review and meta-analysis of hemoglobin effect on the pregnancy outcomes. Methods. We searched MEDLINE and SCOPUS from January 1, 1990 to April 10, 2011. Observational studies addressing association between hemoglobin and adverse pregnancy outcomes were selected. Two reviewers independently extracted data. A mixed logistic regression was applied to assess the effects of hemoglobin on preterm birth, low birth weight, and small for gestational age. Results. Seventeen studies were included in poolings. Hemoglobin below 11 g/dL was, respectively, 1.10 (95% CI: 1.02–1.19), 1.17 (95% CI: 1.03–1.32), and 1.14 (95% CI: 1.05–1.24) times higher risk of preterm birth, low birth weight, and small for gestational age than normal hemoglobin in the first trimester. In the third trimester, hemoglobin below 11 g/dL was 1.30 (95% CI: 1.08–1.58) times higher risk of low birth weight. Hemoglobin above 14 g/dL in third trimester decreased the risk of preterm term with ORs of 0.50 (95% CI: 0.26–0.97), but it might be affected by publication bias. Conclusions. Our review suggests that hemoglobin below 11 g/dl increases the risk of preterm birth, low birth weight, and small gestational age in the first trimester and the risk of low birth weight in the third trimester.
Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10−8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.
Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in animal models of lung disease but have not previously been examined for their association with spirometric measures of lung function in humans.
This study measured serum concentrations of asymmetric and symmetric dimethylarginine in a representative sample of older community-dwelling adults and determined their association with spirometric lung function measures.
Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and L-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults from the Hunter Community Study. The five key lung function measures included as outcomes were Forced Expiratory Volume in 1 second, Forced Vital Capacity, Forced Expiratory Volume in 1 second to Forced Vital Capacity ratio, Percent Predicted Forced Expiratory Volume in 1 second, and Percent Predicted Forced Vital Capacity.
Measurements and Main Results
In adjusted analyses there were statistically significant independent associations between a) higher asymmetric dimethylarginine, lower Forced Expiratory Volume in 1 second and lower Forced Vital Capacity; and b) lower L-arginine/asymmetric dimethylarginine ratio, lower Forced Expiratory Volume in 1 second, lower Percent Predicted Forced Expiratory Volume in 1 second and lower Percent Predicted Forced Vital Capacity. By contrast, no significant associations were observed between symmetric dimethylarginine and lung function.
After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum asymmetric dimethylarginine was independently associated with a reduction in key measures of lung function. Further research is needed to determine if methylarginines predict the decline in lung function.
To determine serum zinc level and other relevant biological markers in normal, prediabetic and diabetic individuals and their association with Homeostasis Model Assessment (HOMA) parameters.
This cross-sectional study was conducted between March and December 2009. Any patient aged ≥30 years attending the medicine outpatient department of a medical university hospital in Dhaka, Bangladesh and who had a blood glucose level ordered by a physician was eligible to participate.
A total of 280 participants were analysed. On fasting blood sugar results, 51% were normal, 13% had prediabetes and 36% had diabetes. Mean serum zinc level was lowest in prediabetic compared to normal and diabetic participants (mean differences were approximately 65 ppb/L and 33 ppb/L, respectively). In multiple linear regression, serum zinc level was found to be significantly lower in prediabetes than in those with normoglycemia. Beta cell function was significantly lower in prediabetes than normal participants. Adjusted linear regression for HOMA parameters did not show a statistically significant association between serum zinc level, beta cell function (P = 0.07) and insulin resistance (P = 0.08). Low serum zinc accentuated the increase in insulin resistance seen with increasing BMI.
Participants with prediabetes have lower zinc levels than controls and zinc is significantly associated with beta cell function and insulin resistance. Further longitudinal population based studies are warranted and controlled trials would be valuable for establishing whether zinc supplementation in prediabetes could be a useful strategy in preventing progression to Type 2 diabetes.
Background and Purpose
Ischemic stroke (IS) shares many common risk factors with coronary artery disease (CAD). We hypothesized that genetic variants associated with myocardial infarction (MI) or CAD may be similarly involved in the etiology of IS. To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS.
Meta-analyses of the associations between the 11 MI-associated SNPs and IS were performed using 6865 cases and 11 395 control subjects recruited from 9 studies. SNPs were either genotyped directly or imputed; in a few cases a surrogate SNP in high linkage disequilibrium was chosen. Logistic regression was performed within each study to obtain study-specific βs and standard errors. Meta-analysis was conducted using an inverse variance weighted approach assuming a random effect model.
Despite having power to detect odds ratio of 1.09–1.14 for overall IS and 1.20–1.32 for major stroke subtypes, none of the SNPs were significantly associated with overall IS and/or stroke subtypes after adjusting for multiple comparisons.
Our results suggest that the major common loci associated with MI risk do not have effects of similar magnitude on overall IS but do not preclude moderate associations restricted to specific IS subtypes. Disparate mechanisms may be critical in the development of acute ischemic coronary and cerebrovascular events.
cerebral infarct; genetics; ischemia
Hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (LS) is a cancer syndrome characterised by early-onset epithelial cancers, especially colorectal cancer (CRC) and endometrial cancer. The aim of the current study was to use SNP-array technology to identify genomic aberrations which could contribute to the increased risk of cancer in HNPCC/LS patients.
Individuals diagnosed with HNPCC/LS (100) and healthy controls (384) were genotyped using the Illumina Human610-Quad SNP-arrays. Copy number variation (CNV) calling and association analyses were performed using Nexus software, with significant results validated using QuantiSNP. TaqMan Copy-Number assays were used for verification of CNVs showing significant association with HNPCC/LS identified by both software programs.
We detected copy number (CN) gains associated with HNPCC/LS status on chromosome 7q11.21 (28% cases and 0% controls, Nexus; p = 3.60E-20 and QuantiSNP; p < 1.00E-16) and 16p11.2 (46% in cases, while a CN loss was observed in 23% of controls, Nexus; p = 4.93E-21 and QuantiSNP; p = 5.00E-06) via in silico analyses. TaqMan Copy-Number assay was used for validation of CNVs showing significant association with HNPCC/LS. In addition, CNV burden (total CNV length, average CNV length and number of observed CNV events) was significantly greater in cases compared to controls.
A greater CNV burden was identified in HNPCC/LS cases compared to controls supporting the notion of higher genomic instability in these patients. One intergenic locus on chromosome 7q11.21 is possibly associated with HNPCC/LS and deserves further investigation. The results from this study highlight the complexities of fluorescent based CNV analyses. The inefficiency of both CNV detection methods to reproducibly detect observed CNVs demonstrates the need for sequence data to be considered alongside intensity data to avoid false positive results.
HNPCC; Lynch syndrome; SNP arrays; CNVs; CNV burden
Participation rates in colorectal cancer screening (CRC) are low. Relatively little is known about screening uptake across varying levels of risk and across population groups. The purpose of the current study was to identify factors associated with (i) ever receiving colorectal cancer (CRC) testing; (ii) risk-appropriate CRC screening in accordance with guidelines; and (iii) recent colonoscopy screening.
1592 at-risk persons (aged 56–88 years) were randomly selected from the Hunter Community Study (HCS), Australia. Participants self-reported family history of CRC was used to quantify risk in accordance with national screening guidelines.
1117 participants returned a questionnaire; 760 respondents were eligible for screening and analysis. Ever receiving CRC testing was significantly more likely for persons: aged 65–74 years; who had discussed with a doctor their family history of CRC or had ever received screening advice. For respondents “at or slightly above average risk”, guideline-appropriate screening was significantly more likely for persons: aged 65–74 years; with higher household income; and who had ever received screening advice. For respondents at “moderately or potentially high risk”, guideline-appropriate screening was significantly more likely for persons: with private health insurance and who had discussed their family history of CRC with a doctor. Colonoscopy screening was significantly more likely for persons: who had ever smoked; discussed their family history of CRC with a doctor; or had ever received screening advice.
The level of risk-appropriate screening varied across populations groups. Interventions that target population groups less likely to engage in CRC screening are pivotal for decreasing screening inequalities.
A reliable and accurate estimation of liver size by physical examination is an important aspect of the clinical assessment of a patient. The scratch test uses auscultation to detect the lower liver edge by using the difference in sound transmission through the abdominal cavity over solid and hollow organs. The test is thought to be particularly useful if the abdomen is tense, distended, obese, or very tender. Although the sign is often taught to medical students and residents, the value of the technique for detecting the liver edge has become controversial.
The study was performed in two parts. In the first part, 18 patients undergoing upper abdominal ultrasound as outpatients were randomly selected and the scratch test was performed by two raters independently, followed by ultrasound (USG) as the reference standard. In the second part of the study, the two raters independently performed the scratch test on separate randomly selected patients (15 patients by rater 1, and 16 patients by rater 2), followed by USG.
Agreement between raters on the scratch test was very high, with an intra-class correlation coefficient of 0.97. The agreement between the raters and the USG was 0.37 using Spearman’s rho. A Bland –Altman plot indicated that, on average, raters underestimated the distance from the right costal margin to the liver edge by only about 2.4 centimeters compared to USG. This translates into 37% and 54% of raters’ estimates falling within 2 and 3 cm of USG estimates. Each unit increase in BMI increased the discrepancy between raters and USG by 0.26 cm (p = 0.012).
The scratch test has very high reproducibility and overall agreement between the scratch test and USG was moderate, with a spearman’s rho of 0.37. The accuracy may potentially be improved by using the point of initial sound transmission rather than the point of maximal transmission. We conclude that the scratch test deserves further investigation.
Scratch test; Hepatomegaly; Auscultation; Liver edge; Liver span
Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.
No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, −1.3±0.23 (beta ± standard error), p = 6.6×10−9. Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r2 ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.
This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
The role of small solute clearance on mortalities in patients with CAPD has been controversial. We therefore conducted a study with 3 years' follow up in adult patients who participated in the CAPD-first policy.
There were 11,523 patients with end-stage renal disease who participated in the CAPD-first policy between 2008 and 2011. Among them, 1,177 patients were included in the retrospective cohort study. A receiver operating characteristic curve was applied to calibrate the cutoffs of tKt/V, rKt/V and tCrcl. Kaplan-Meier and Cox-regression models with time varying covariates were applied to estimate overall death rate, probability of death and prognosis, respectively.
The cutoffs of rKt/V and tKt/V were 0.25 and 1.75, respectively. The Cox regression suggested that the higher these clearance parameters, the lower the risks of death after adjusting for covariables. The risks of death for those above these cutoffs were 57% (HR = 0.43, 95% CI: 0.31, 0.60) and 29% (HR = 0.71, 95% CI: 0.52, 0.98) lower for rKt/V and tKt/V, respectively. Age, serum albumin, hemoglobin, systolic blood pressure, and ultra-filtration volume significantly affected the mortality outcome.
Our study suggested that the cutoffs of 0.25 and 1.75 for rKt/V and tKt/V might be associated with mortality in CAPD patients. A minimum tKt/V of 1.75 should be targeted, but increased dialysis dosage to achieve tKt/V > 2.19 adds no further benefit. Serum albumin, hemoglobin, SBP, and UF volume are also associated with mortality. However, our study may face with selection and other unobserved confounders, so further randomized controlled trials are required to confirm these cutoffs.
Adequacy indices; CAPD; Continuous ambulatory peritoneal dialysis; Mortality; Peritoneal small solute clearance; Prognostic factors
Serum homocysteine, when studied singly, has been reported to be positively associated both with the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine [ADMA, via inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity] and with symmetric dimethylarginine (SDMA). We investigated combined associations between transsulfuration pathway thiols, including homocysteine, and serum ADMA and SDMA concentrations at population level.
Data on clinical and demographic characteristics, medication exposure, C-reactive protein, serum ADMA and SDMA (LC-MS/MS), and thiols (homocysteine, cysteine, taurine, glutamylcysteine, total glutathione, and cysteinylglycine; capillary electrophoresis) were collected from a sample of the Hunter Community Study on human ageing [n = 498, median age (IQR) = 64 (60–70) years].
Regression analysis showed that: a) age (P = 0.001), gender (P = 0.03), lower estimated glomerular filtration rate (eGFR, P = 0.08), body mass index (P = 0.008), treatment with beta-blockers (P = 0.03), homocysteine (P = 0.02), and glutamylcysteine (P = 0.003) were independently associated with higher ADMA concentrations; and b) age (P = 0.001), absence of diabetes (P = 0.001), lower body mass index (P = 0.01), lower eGFR (P<0.001), cysteine (P = 0.007), and glutamylcysteine (P<0.001) were independently associated with higher SDMA concentrations. No significant associations were observed between methylated arginines and either glutathione or taurine concentrations.
After adjusting for clinical, demographic, biochemical, and pharmacological confounders the combined assessment of transsulfuration pathway thiols shows that glutamylcysteine has the strongest and positive independent associations with ADMA and SDMA. Whether this reflects a direct effect of glutamylcysteine on DDAH activity (for ADMA) and/or cationic amino acid transport requires further investigations.
Electronic screening and brief intervention (e-SBI) is a promising alternative to screening and brief intervention by health-care providers, but its efficacy in the hospital outpatient setting, which serves a large proportion of the population, has not been established. The aim of this study is to estimate the effect of e-SBI in hospital outpatients with hazardous or harmful drinking.
This randomized controlled trial will be conducted in the outpatient department of a large tertiary referral hospital in Newcastle (population 540,000), Australia. Some 772 adults with appointments at a broad range of medical and surgical outpatient clinics who score 5–9 inclusive on the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) subscale will be randomly assigned in a 1:1 ratio to electronic alcohol screening alone (control) or to e-SBI. As randomization will be effected by computer, researchers and participants (who will be invited to participate in a study of alcohol use over time) will be blinded to group assignment. The primary analysis will be based on the intention-to-treat principle and compare weekly volume (grams of alcohol) and the full AUDIT score with a six-month reference period between the groups six months post randomization. Secondary outcomes, assessed six and 12 months after randomization, will include drinking frequency, typical occasion quantity, proportion who report binge drinking, proportion who report heavy drinking, and health-care utilization.
If e-SBI is efficacious in outpatient settings, it offers the prospect of systematically and sustainably reaching a large number of hazardous and harmful drinkers, many of whom do not otherwise seek or receive help.
Australian New Zealand Clinical Trials Registry ACTRN12612000905864.
Alcohol; Screening; Brief intervention; Internet; Intervention; Clinical trials; Hospital outpatients
We conducted a genome-wide association (GWA) meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese1 and European2 ancestry. We show that rs12700667 on chromosome 7p15.2, previously found in Europeans, replicates in Japanese (P = 3.6 × 10−3), and confirm association of rs7521902 on 1p36.12 near WNT4. In addition, we establish association of rs13394619 in GREB1 on 2p25.1 and identify a novel locus on 12q22 near VEZT (rs10859871). Excluding European cases with minimal or unknown severity, we identified additional novel loci on 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and produced P < 5 × 10−8 in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the European and Japanese GWA cohorts (P = 8.8 × 10−11), indicating that many weakly associated SNPs represent true endometriosis risk loci and risk prediction and future targeted disease therapy may be transferred across these populations.
Chronic arsenic exposure and its association with hypertension in adults are inconclusive and this cross-sectional study investigated the association. The study was conducted between January and July 2009 among 1,004 participants from 1,682 eligible women and men aged ≥30 years living in rural Bangladesh who had continuously consumed arsenic-contaminated drinking water for at least 6 months. Hypertension was defined as systolic blood pressure ≥140 mmHg (systolic hypertension) and diastolic blood pressure ≥90 mmHg (diastolic hypertension). Pulse pressure was calculated by deducting diastolic from systolic pressure and considered to be increased when the difference was ≥55 mmHg. The prevalence of hypertension was 6.6% (95% CI: 5.1–8.3%). After adjustment for other factors, no excess risk of hypertension was observed for arsenic exposure >50μg/L or to that of arsenic exposure as quartiles or as duration. Arsenic concentration as quartiles and >50 μg/L did show a strong relationship with increased pulse pressure (adjusted OR: 3.54, 95% CI: 1.46–8.57), as did arsenic exposure for ≥10 years (adjusted OR: 5.25, 95% CI: 1.41–19.51). Arsenic as quartiles showed a dose response relationship with increased pulse pressure. Our study suggests an association between higher drinking water arsenic or duration and pulse pressure, but not hypertension.
arsenic; drinking-water; hypertension; pulse-pressure; Bangladesh