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1.  Thyroid Antibodies, Autoimmunity and Cognitive Decline: Is There a Population-Based Link? 
Autoimmunity is considered an uncommon but under-recognised cause of cognitive decline.
Serum samples from 3,253 randomly selected subjects enrolled in the Hunter Community Study, aged 55-85 years, were assayed for thyrotropin stimulatory hormone, anti-thyroid peroxidase antibodies (TPO-Ab), anti-nuclear antibodies (ANA) and extractable nuclear antigens (ENA). Cognitive function was assessed using the Audio Recorded Cognitive Screen (ARCS) tool.
TPO-Ab were found in 8.4% and ANA in 27.9% of the study population, of whom 3% had positive ENA findings. No relationship was found between the ARCS score and either TPO-Ab (coefficient = 0.133; 95% CI −0.20, 0.82, p = 0.616), ANA at a low (coefficient = 1.01; 95% CI −2.58, 0.55, p = 0.203) or a high titre (coefficient = −0.65; 95% CI −2.59, 1.28, p = 0.508), or ENA antibodies (coefficient = 5.12; 95% CI −0.53, 10.77; p = 0.076).
Autoantibody findings are common in an aging population and are not associated with cognitive decline.
PMCID: PMC4067731  PMID: 24987403
Dementia; Hashimoto disease; Encephalitis; Autoantibodies; Anti-nuclear antibodies; Nuclear antigens; Autoimmune thyroiditis; Mild cognitive impairment
2.  Quantitative 99mTc DTPA renal transplant scintigraphic parameters: assessment of interobserver agreement and correlation with graft pathologies 
Various 99mTc DTPA scintigraphic quantitative parameters for renal graft function assessment have been recommended, but none is universally accepted. In this study, 439 dynamic renal transplant scintigraphies (DRTS) were retrospectively analysed. In the first set of studies, four observers analysed the 47 random DRTS and interobserver agreement of eleven derived parameters was assessed. In the other set of studies, 181 instances of DRTS, performed on 127 recipients with renal biopsies within five days of each other were selected for correlation with pathology. Hilson’s Perfusion index (HI), ΔP, P:Pl, P:U & T10 were selected for this analysis. The pathologies were categorized into renal vascular compromise (RVC; n = 20), acute tubular necrosis (ATN; n = 40), vascular rejection (VR; n = 34), interstitial rejection (IR; n = 33), normal (NOR; n = 36) and unclassified pathologies (n = 18). A majority of the parameters showed good Intraclass correlation (ICC). HI differentiated well between grafts with RVC and the remainder of the study cohort, (p < 0.0001; AUC = 0.84); at a cut-off > 278, it had 84% sensitivity and 78% specificity (Likelihood ratio = 3.8). At < 278, it had 98% ‘negative’ predictive value for RVC. HI also showed reasonable association with VR (p = 0.02; AUC = 0.62) and IR (p = 0.009; AUC = 0.65). However, significant overlap of HI values between various subgroups was noted. Other parameters had good ICC but were not effective in differentiating graft pathologies. Of the measured parameters, only HI proved to be useful for the pathological assessment, particularly in the identification of vascular compromise. This parameter, however, has lower specificity in differentiating the other pathologies.
PMCID: PMC3999401  PMID: 24795835
Acute tubular necrosis; Hilson’s index; interobserver agreement; quantitative renal transplant DTPA scintigraphy; rejection; renal artery stenosis; renal graft
3.  Thrombolysis ImPlementation in Stroke (TIPS): evaluating the effectiveness of a strategy to increase the adoption of best evidence practice – protocol for a cluster randomised controlled trial in acute stroke care 
Stroke is a leading cause of death and disability internationally. One of the three effective interventions in the acute phase of stroke care is thrombolytic therapy with tissue plasminogen activator (tPA), if given within 4.5 hours of onset to appropriate cases of ischaemic stroke.
To test the effectiveness of a multi-component multidisciplinary collaborative approach compared to usual care as a strategy for increasing thrombolysis rates for all stroke patients at intervention hospitals, while maintaining accepted benchmarks for low rates of intracranial haemorrhage and high rates of functional outcomes for both groups at three months.
Methods and design
A cluster randomised controlled trial of 20 hospitals across 3 Australian states with 2 groups: multi- component multidisciplinary collaborative intervention as the experimental group and usual care as the control group. The intervention is based on behavioural theory and analysis of the steps, roles and barriers relating to rapid assessment for thrombolysis eligibility; it involves a comprehensive range of strategies addressing individual-level and system-level change at each site. The primary outcome is the difference in tPA rates between the two groups post-intervention. The secondary outcome is the proportion of tPA treated patients in both groups with good functional outcomes (modified Rankin Score (mRS <2) and the proportion with intracranial haemorrhage (mRS ≥2), compared to international benchmarks.
TIPS will trial a comprehensive, multi-component and multidisciplinary collaborative approach to improving thrombolysis rates at multiple sites. The trial has the potential to identify methods for optimal care which can be implemented for stroke patients during the acute phase. Study findings will include barriers and solutions to effective thrombolysis implementation and trial outcomes will be published whether significant or not.
Trial registration
Australian New Zealand Clinical Trials Registry: ACTRN12613000939796
PMCID: PMC4016636  PMID: 24666591
Collaborative intervention; Thrombolysis; Acute stroke; Evidence-based practice; Quality improvement; Cluster randomised controlled trial; Multidisciplinary approach
4.  The Architecture of Risk for Type 2 Diabetes: Understanding Asia in the Context of Global Findings 
The prevalence of Type 2 diabetes is rising rapidly in both developed and developing countries. Asia is developing as the epicentre of the escalating pandemic, reflecting rapid transitions in demography, migration, diet, and lifestyle patterns. The effective management of Type 2 diabetes in Asia may be complicated by differences in prevalence, risk factor profiles, genetic risk allele frequencies, and gene-environment interactions between different Asian countries, and between Asian and other continental populations. To reduce the worldwide burden of T2D, it will be important to understand the architecture of T2D susceptibility both within and between populations. This review will provide an overview of known genetic and nongenetic risk factors for T2D, placing the results from Asian studies in the context of broader global research. Given recent evidence from large-scale genetic studies of T2D, we place special emphasis on emerging knowledge about the genetic architecture of T2D and the potential contribution of genetic effects to population differences in risk.
PMCID: PMC3976842  PMID: 24744783
5.  Importance of different types of prior knowledge in selecting genome-wide findings for follow-up 
Genetic epidemiology  2013;37(2):10.1002/gepi.21705.
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.
PMCID: PMC3725558  PMID: 23307621
Gene prioritization; Genome-wide association studies; Bioinformatics databases
6.  SNP prioritization using a Bayesian probability of association 
Genetic epidemiology  2012;37(2):10.1002/gepi.21704.
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.
PMCID: PMC3725584  PMID: 23280596
replication; prior knowledge; genome-wide studies
7.  Is Serum Zinc Associated with Pancreatic Beta Cell Function and Insulin Sensitivity in Pre-Diabetic and Normal Individuals? Findings from the Hunter Community Study 
PLoS ONE  2014;9(1):e83944.
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.
PMCID: PMC3885544  PMID: 24416185
8.  Clinical and Biochemical Correlates of Serum L-Ergothioneine Concentrations in Community-Dwelling Middle-Aged and Older Adults 
PLoS ONE  2014;9(1):e84918.
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.
PMCID: PMC3879362  PMID: 24392160
9.  Ischaemic stroke is associated with the ABO locus: the Euroclot study 
Annals of neurology  2013;73(1):16-31.
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.
PMCID: PMC3582024  PMID: 23381943
GWAS; thrombosis; stroke; coagulation factor; stroke subtype
10.  Short Sleep Duration Is Associated with Risk of Future Diabetes but Not Cardiovascular Disease: a Prospective Study and Meta-Analysis 
PLoS ONE  2013;8(11):e82305.
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%.
PMCID: PMC3840027  PMID: 24282622
11.  Genome-wide association study of endometrial cancer in E2C2 
Human Genetics  2013;133:211-224.
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.
PMCID: PMC3898362  PMID: 24096698
12.  Integrating and extending cohort studies: lessons from the eXtending Treatments, Education and Networks in Depression (xTEND) study 
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.
PMCID: PMC3856520  PMID: 24093910
Cohort studies; Remoteness; Mental health; Individual participant data analysis; Research methods
13.  Is dietary zinc protective for type 2 diabetes? Results from the Australian longitudinal study on women’s health 
Animal studies have shown that zinc intake has protective effects against type 2 diabetes, but few studies have been conducted to examine this relationship in humans. The aim of this study is to investigate if dietary zinc is associated with risk of type 2 diabetes in a longitudinal study of mid-age Australian women.
Data were collected from a cohort of women aged 45-50 years at baseline, participating in the Australian Longitudinal Study on Women’s Health. A validated food frequency questionnaire was used to assess dietary intake and other nutrients. Predictors of 6-year incidence of type 2 diabetes were examined using multivariable logistic regression.
From 8921 participants, 333 incident cases of type 2 diabetes were identified over 6 years of follow-up. After adjustment for dietary and non-dietary factors, the highest quintile dietary zinc intake had almost half the odds of developing type 2 diabetes (OR = 0.50, 95% C.I. 0.32–0.77) compared with the lowest quintile. Similar findings were observed for the zinc/iron ratio; the highest quintile had half the odds of developing type 2 diabetes (OR = 0.50, 95% C.I 0.30-0.83) after multivariable adjustment of covariates.
Higher total dietary zinc intake and high zinc/iron ratio are associated with lower risk of type 2 diabetes in women. This finding is a positive step towards further research to determine if zinc supplementation may reduce the risk of developing type 2 diabetes.
PMCID: PMC4015935  PMID: 24093747
Diabetes; Australia; Women & Zinc
14.  Development of an Electronic Alcohol Screening and Brief Intervention Program for Hospital Outpatients With Unhealthy Alcohol Use 
JMIR Research Protocols  2013;2(2):e36.
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.
PMCID: PMC3786128  PMID: 24055787
alcohol; drinking; screening; brief intervention; hospital; outpatients; Internet
15.  Quality of life impact of cardiovascular and affective conditions among older residents from urban and rural communities 
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.
PMCID: PMC3751480  PMID: 23945355
Cardiovascular disease; Urban–rural; Social capital; Quality of life; Physical and psychological health; Over 55 years
16.  Hemoglobin Concentration and Pregnancy Outcomes: A Systematic Review and Meta-Analysis 
BioMed Research International  2013;2013:769057.
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.
PMCID: PMC3741929  PMID: 23984406
17.  Genetic Loci for Retinal Arteriolar Microcirculation 
PLoS ONE  2013;8(6):e65804.
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.
PMCID: PMC3680438  PMID: 23776548
19.  Serum Methylarginines and Spirometry-Measured Lung Function in Older Adults 
PLoS ONE  2013;8(5):e58390.
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.
PMCID: PMC3655195  PMID: 23690915
20.  Is Serum Zinc Level Associated with Prediabetes and Diabetes?: A Cross-Sectional Study from Bangladesh 
PLoS ONE  2013;8(4):e61776.
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.
PMCID: PMC3629219  PMID: 23613929
21.  Are Myocardial Infarction–Associated Single-Nucleotide Polymorphisms Associated With Ischemic Stroke? 
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.
PMCID: PMC3622211  PMID: 22363065
cerebral infarct; genetics; ischemia
22.  Continuing difficulties in interpreting CNV data: lessons from a genome-wide CNV association study of Australian HNPCC/lynch syndrome patients 
BMC Medical Genomics  2013;6:10.
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.
PMCID: PMC3626775  PMID: 23531357
HNPCC; Lynch syndrome; SNP arrays; CNVs; CNV burden
23.  Individual- and provider-level factors associated with colorectal cancer screening in accordance with guideline recommendation: a community-level perspective across varying levels of risk 
BMC Public Health  2013;13:248.
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.
PMCID: PMC3607924  PMID: 23514586
24.  A re-evaluation of the scratch test for locating the liver edge 
BMC Gastroenterology  2013;13:35.
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.
PMCID: PMC3598244  PMID: 23442829
Scratch test; Hepatomegaly; Auscultation; Liver edge; Liver span
25.  Genome-Wide Association Study of Retinopathy in Individuals without Diabetes 
PLoS ONE  2013;8(2):e54232.
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.
PMCID: PMC3564946  PMID: 23393555

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