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1.  Polymorphisms of SP110 Are Associated with both Pulmonary and Extra-Pulmonary Tuberculosis among the Vietnamese 
PLoS ONE  2014;9(7):e99496.
Tuberculosis (TB) is an infectious disease that remains a major cause of morbidity and mortality worldwide, yet the reasons why only 10% of people infected with Mycobacterium tuberculosis go on to develop clinical disease are poorly understood. Genetically determined variation in the host immune response is one factor influencing the response to M. tuberculosis. SP110 is an interferon-responsive nuclear body protein with critical roles in cell cycling, apoptosis and immunity to infection. However association studies of the gene with clinical TB in different populations have produced conflicting results.
To examine the importance of the SP110 gene in immunity to TB in the Vietnamese we conducted a case-control genetic association study of 24 SP110 variants, in 663 patients with microbiologically proven TB and 566 unaffected control subjects from three tertiary hospitals in northern Vietnam.
Five SNPs within SP110 were associated with all forms of TB, including four SNPs at the C terminus (rs10208770, rs10498244, rs16826860, rs11678451) under a dominant model and one SNP under a recessive model, rs7601176. Two of these SNPs were associated with pulmonary TB (rs10208770 and rs16826860) and one with extra-pulmonary TB (rs10498244).
SP110 variants were associated with increased susceptibility to both pulmonary and extra-pulmonary TB in the Vietnamese. Genetic variants in SP110 may influence macrophage signaling responses and apoptosis during M. tuberculosis infection, however further research is required to establish the mechanism by which SP110 influences immunity to tuberculosis infection.
PMCID: PMC4090157  PMID: 25006821
2.  Weighted Road Density and Allergic Disease in Children at High Risk of Developing Asthma 
PLoS ONE  2014;9(6):e98978.
Evidence for an association between traffic-related air pollution and allergic disease is inconsistent, possibly because the adverse effects may be limited to susceptible subgroups and these have not been identified. This study examined children in the Childhood Asthma Prevention Study (CAPS), potentially susceptible to air pollution effects because of a family history of asthma.
We examined cross-sectional associations at age eight years between road density within 75 m and 50 m of home address weighted by road type (traffic density), as a proxy for traffic-related air pollution, on the following allergic and respiratory outcomes: skin prick tests (SPTs), total and specific serum IgE, pre- and post-bronchodilator lung function, airway hyperresponsiveness, exhaled NO, and reported asthma and rhinitis.
Weighted road density was positively associated with allergic sensitisation and allergic rhinitis. Adjusted relative risk (RR) for house dust mite (HDM) positive SPT was 1.25 (95% CI: 1.06–1.48), for detectable house dust mite-specific IgE was 1.19 (95% CI: 1.01–1.41) and for allergic rhinitis was 1.30 (95% CI: 1.03–1.63) per 100 m local road or 33.3 m motorway within 50 m of home. Associations were also seen with small decrements of peak and mid-expiratory flows and increased risk of asthma, current wheeze and rhinitis in atopic children.
Associations between road density and allergic disease were found in a potentially susceptible subgroup of children at high risk of developing atopy and asthma.
PMCID: PMC4064977  PMID: 24949625
3.  Allergen-Specific IL-5 Responses in Early Childhood Predict Asthma at Age Eight 
PLoS ONE  2014;9(5):e97995.
The pattern of development of allergen-specific T cell cytokine responses in early childhood and their relation to later disease is poorly understood. Here we describe longitudinal changes in allergen-stimulated T cell cytokine responses and their relation to asthma and allergic disease during the first 8 years of life.
Subjects with a family history of asthma, who were enrolled antenatally in the Childhood Asthma Prevention Study (public trials registration number ACTRN12605000042640), had skin prick tests, clinical evaluation for asthma and eczema, and in vitro assessment of T cell cytokine responses to HDM extract performed at ages 18 months (n = 281), 3 years (n = 349), 5 years (n = 370) and 8 years (n = 275). We measured interleukin (IL-) 13 at 3, 5 and 8 years, and IL-5, IL-10, and interferon-γ (IFN-γ), at 18 months, 3, 5 and 8 years by ELISA. A cohort analysis was undertaken. Independent effects of cytokine responses at each age on the risk of asthma and allergic outcomes at age 8 years were estimated by multivariable logistic regression.
HDM-specific IL-5 responses increased with age. HDM-specific IL-13 and IL-10 responses peaked at age 5 years. HDM-specific IL-5 responses at 3 years, 5 years and 8 years were significantly associated with the presence of asthma and atopy at 8 years. IL-13 responses at 3 years, 5 years and 8 years were significantly associated with atopy at 8 years, but this association was not independent of the effect of IL-5. Other HDM-specific cytokine responses were not independently related to asthma or eczema at 8 years.
HDM-specific IL-5 responses at age 3 years or later are the best measure of T cell function for predicting asthma at age 8 years.
PMCID: PMC4038510  PMID: 24875149
4.  Breastfeeding and Snoring: A Birth Cohort Study 
PLoS ONE  2014;9(1):e84956.
To investigate the relationship between breastfeeding and snoring in childhood.
In a cohort of children with a family history of asthma who were recruited antenatally we prospectively recorded data on infant feeding practices throughout the first year of life. Snoring status and witnessed sleep apnea were measured at age 8 years by parent-completed questionnaire. Associations were estimated by logistic regression with, and without, adjustment for sets of confounders designed to exclude biasing effects.
Habitual snoring was reported in 18.8% of the sample, and witnessed apnea in 2.7%. Any breastfeeding for longer than one month was associated with a reduced risk of habitual snoring at age 8 (adjusted OR 0.48, 95% CI 0.29 to 0.81) and duration of breastfeeding was inversely associated with the prevalence of habitual snoring (adjusted OR 0.79, 95% CI 0.62 to 1.00). Any breastfeeding for longer than 1 month was associated with a lower risk of witnessed sleep apnea (adjusted OR 0.17, 95% CI 0.04 to 0.71). The protective associations were not mediated by BMI, current asthma, atopy or rhinitis at age 8 years.
Breastfeeding for longer than one month decreases the risk of habitual snoring and witnessed apneas in this cohort of children with a family history of asthma. The underlying mechanism remains unclear but the finding would be consistent with a beneficial effect of the breast in the mouth on oropharyngeal development with consequent protection against upper airway dysfunction causing sleep-disordered breathing.
PMCID: PMC3885662  PMID: 24416321
5.  Correction: Completion of Treatment for Latent Tuberculosis Infection with Monthly Drug Dispensation Directly through the Tuberculosis Clinic 
PLoS ONE  2013;8(12):10.1371/annotation/4498fd07-acae-49bb-abf2-d2e914a249d0.
PMCID: PMC3857938
6.  Household contact investigation for tuberculosis in Vietnam: study protocol for a cluster randomized controlled trial 
Trials  2013;14:342.
Tuberculosis is an infectious disease that continues to cause considerable morbidity and mortality globally. Only 65% of patients worldwide are currently diagnosed. Contact investigation is a strategy that aims to increase case detection and reduce transmission of tuberculosis, yet there is little evidence to show its effectiveness.
We will conduct a cluster randomized controlled trial of contact investigation within the national tuberculosis control program of Vietnam. Household contacts of patients with smear-positive pulmonary tuberculosis will be invited to attend district tuberculosis units for symptom screening, examination, and chest radiography on four occasions over a two-year period. The primary endpoint is clinically confirmed tuberculosis among contacts during the 24 months of follow-up, ascertained using capture-recapture analysis. Microbiologically proven tuberculosis and treatment completion rates among contacts diagnosed with tuberculosis will be secondary endpoints. The incremental cost-effectiveness ratio will be estimated. The study will have 80% power to detect a 50% increase in the primary endpoint in the active intervention arm compared with the control arm. The study will include 8,829 contacts in each of the active screening and control groups, within 70 districts in 8 provinces in Vietnam, in both rural and urban settings.
The effectiveness of contact investigation as a tool for improved tuberculosis case finding has not been established. This cluster randomized trial will provide valuable operational information for national tuberculosis programs in high-prevalence countries, in order to select the most cost-effective strategies to improve tuberculosis case detection.
Trial registration
The ACT2 study has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000600044).
PMCID: PMC4015151  PMID: 24138766
Contact tracing; Mycobacterium tuberculosis; Public health; Pulmonary tuberculosis; Screening; Tuberculosis
7.  What Patient Factors Predict Physicians’ Decision Not to Treat Latent Tuberculosis Infection in Tuberculosis Contacts? 
PLoS ONE  2013;8(9):e76552.
The study aimed to determine factors that are associated with physicians’ decision to offer treatment for latent tuberculosis infection (LTBI) in contacts of patients with tuberculosis.
We performed a nested case-control study in a cohort of contacts of patients with pulmonary tuberculosis who had a tuberculin skin test (TST) ≥ 10 mm. Cases were those who were offered treatment for LTBI. Controls were randomly selected from those who were not offered treatment for LTBI by the reviewing physician. Odds ratios were estimated by multivariate logistic regression.
There were 195 cases and 279 controls. The following factors were significantly (positively or negatively) associated with being offered LTBI treatment in the multivariate analysis: female gender (OR 2.9; 95% CI 1.6–5.5), TST conversion (OR 3.9; 2.0–7.9), TST > 20 mm (OR 4.1; 1.8–9.1, for TST of 21–30 mm and OR 7.9; 2.6–23.8, for TST >30 mm), sputum smear positive index case (OR 12.7; 4.5–36.1), being overseas-born and immigration more than 2 years ago (OR 0.1; 0.06–0.3), being a health care worker (OR 0.2; 0.1–0.6), being a non-household contact of the TB index case (OR 0.3; 0.2–0.6) and age >35 years (OR 0.2; 0.1–0.5 for age 35 to 54.9 years and OR 0.04; 0.01–0.2 for age ≥55 years). Previous BCG vaccine and chest x-ray findings were not significantly associated with physicians’ decision to offer treatment for LTBI.
Most factors that influenced physicians’ decisions on treatment for LTBI were based on evidence of an association with risk of developing TB or risk of having an adverse reaction to treatment for LTBI. However, the decreased likelihood of offering treatment for LTBI to people born overseas, men and health care workers, was apparently not based on any evidence of risk. Efforts should be made to ensure that these groups are given access to treatment for LTBI.
PMCID: PMC3786986  PMID: 24098794
8.  Contact Tracing of Tuberculosis: A Systematic Review of Transmission Modelling Studies 
PLoS ONE  2013;8(9):e72470.
The WHO recommended intervention of Directly Observed Treatment, Short-course (DOTS) appears to have been less successful than expected in reducing the burden of TB in some high prevalence settings. One strategy for enhancing DOTS is incorporating active case-finding through screening contacts of TB patients as widely used in low-prevalence settings. Predictive models that incorporate population-level effects on transmission provide one means of predicting impacts of such interventions. We aim to identify all TB transmission modelling studies addressing contact tracing and to describe and critically assess their modelling assumptions, parameter choices and relevance to policy. We searched MEDLINE, SCOPUS, COMPENDEX, Google Scholar and Web of Science databases for relevant English language publications up to February 2012. Of the 1285 studies identified, only 5 studies met our inclusion criteria of models of TB transmission dynamics in human populations designed to incorporate contact tracing as an intervention. Detailed implementation of contact processes was only present in two studies, while only one study presented a model for a high prevalence, developing world setting. Some use of relevant data for parameter estimation was made in each study however validation of the predicted impact of interventions was not attempted in any of the studies. Despite a large body of literature on TB transmission modelling, few published studies incorporate contact tracing. There is considerable scope for future analyses to make better use of data and to apply individual based models to facilitate more realistic patterns of infectious contact. Combined with a focus on high burden settings this would greatly increase the potential for models to inform the use of contract tracing as a TB control policy. Our findings highlight the potential for collaborative work between clinicians, epidemiologists and modellers to gather data required to enhance model development and validation and hence better inform future public health policy.
PMCID: PMC3762785  PMID: 24023742
9.  Most Personal Exposure to House Dust Mite Aeroallergen Occurs during the Day 
PLoS ONE  2013;8(7):e69900.
The bed is commonly regarded as the main site of house dust mite exposure; however this has not been directly established by continuous measurements. The objective of this study was to determine the pattern of personal exposure to mite aeroallergen over 24 hours.
12 adults each collected 9 sequential samples (8 during the day, mean 115 mins, and one overnight, mean 514 mins) over 24 hours using a portable air-pump (2L/min) connected to an IOM filter located on the shoulder during the day and on the bed head overnight. Samples were analysed for mite allergen Der p 1 by ELISA. Location and activity were recorded. A mixed model analysis was performed to determine exposure as a function of 14 categories of activity.
Personal aeroallergen exposure differed widely over time, both within and between subjects. The highest average exposure (1117 pg/m3, 95% CI: 289-4314) occurred on public transport and the lowest overnight in bed (45 pg/m3, 95% CI: 17-17), which contributed only 9.8% (95% CI: 4.4%-15.1%) of total daily exposure. Aeroallergens were not related to bed reservoirs.
The study challenges the current paradigm that the bed is the main site of HDM exposure and instead suggests most exposure occurs in association with domestic activity and proximity to other people. Effective mite interventions, designed to improve asthma outcomes, need to first identify and then address the multiple sources of aeroallergen exposure.
PMCID: PMC3722239  PMID: 23894558
10.  Congenital Rubella Syndrome in Fiji, 1995–2010 
Journal of Tropical Medicine  2013;2013:956234.
Setting. A nationwide study in Fiji. Objective. To describe the incidence of congenital rubella syndrome (CRS) and its relationship to the incidence of notified cases of rubella in Fiji from 1995 to 2010. Design. Descriptive, retrospective review of all recorded congenital abnormalities associated with live births in Fiji over 16 years. Results. There were 294 infants who met the criteria for CRS. Of these, 95% were classified as “suspected” cases, 5% were “clinically confirmed,” and none were “laboratory confirmed cases”. There was a significant linear increase over the study period in the incidence of CRS (odds ratio 1.045 per year, 95% CI 1.019 to 1.071, P ≤ 0.001). There was no significant association between the incidence of CRS and the reported incidence of rubella (P = 0.3). Conclusion. There is a rising trend in reports of suspected CRS cases in Fiji. This highlights the need to strengthen surveillance for CRS through improvements in clinical and laboratory diagnosis to confirm or exclude suspected cases. It is also important to ensure high coverage of rubella vaccination in Fiji.
PMCID: PMC3574747  PMID: 23431317
11.  Contact investigation for tuberculosis: a systematic review and meta-analysis 
The European Respiratory Journal  2012;41(1):140-156.
Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines.
We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB.
After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2–4.4%, I2=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9–1.8%, I2=95.9%), and latent TB infection was 51.5% (95% CI 47.1–55.8%, I2=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1–4.5%, I2=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8–12.6%, I2=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1–1.8%, I2=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2–32.4%, I2=99.5%). There was substantial heterogeneity among published studies.
Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.
PMCID: PMC3533588  PMID: 22936710
Contact tracing; early diagnosis; human; Mycobacterium tuberculosis; systematic review; tuberculosis
12.  Identification of IL6R and chromosome 11q13.5 as risk loci for asthma 
Lancet  2011;378(9795):1006-1014.
We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying asthma.
We performed a genome-wide association study (GWAS) in 2,669 physician-diagnosed asthmatics and 4,528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-SNP scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset.
Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR=1.09, combined P=2.4×10−8) in the interleukin-6 receptor gene (IL6R) and rs7130588 (OR=1.09, P=1.8×10−8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR = 1.33, P = 7×10−4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-SNP association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that may be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP and BACH2.
The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma.
A full list of funding sources appears at the end of the paper.
PMCID: PMC3517659  PMID: 21907864
13.  Respiratory Health before and after the Opening of a Road Traffic Tunnel: A Planned Evaluation 
PLoS ONE  2012;7(11):e48921.
The construction of a new road tunnel in Sydney, Australia, and concomitant reduction in traffic on a major road presented the opportunity to study the effects of this traffic intervention on respiratory health.
We made measurements in a cohort of residents in the year before the tunnel opened (2006) and in each of two years afterwards (2007–2008). Cohort members resided in one of four exposure zones, including a control zone. Each year, a respiratory questionnaire was administered (n = 2,978) and a panel sub-cohort (n = 380) performed spirometry once and recorded peak expiratory flow and symptoms twice daily for nine weeks.
There was no consistent evidence of improvement in respiratory health in residents living along the bypassed main road, despite a reduction in traffic from 90,000 to 45,000 vpd. Residents living near tunnel feeder roads reported more upper respiratory symptoms in the survey but not in the panel sub-cohort. Residents living around the tunnel ventilation stack reported more upper and lower respiratory symptoms and had lower spirometric volumes after the tunnel opened. Air pollutant levels measured near the stack did not increase over the study period.
The finding of adverse health effects among residents living around the stack is unexpected and difficult to explain, but might be due to unmeasured pollutants or risk factors or an unrecognized pollutant source nearby. The lack of improvement in respiratory health among people living along the bypassed main road probably reflects a minimal change in exposure due to distance of residence from the road.
PMCID: PMC3510202  PMID: 23209560
14.  Contact Investigation in Households of Patients with Tuberculosis in Hanoi, Vietnam: A Prospective Cohort Study 
PLoS ONE  2012;7(11):e49880.
Existing tuberculosis control strategies in Vietnam are based on symptomatic patients attending health services for investigation. This approach has not resulted in substantial reductions in the prevalence of tuberculosis disease, despite the National Tuberculosis Program achieving high treatment completion rates. Alternative approaches are being considered.
To determine the feasibility and yield of contact investigation in households of patients with smear positive pulmonary tuberculosis among household members of tuberculosis patients in Hanoi, Vietnam.
Household contacts of patients with smear positive pulmonary tuberculosis were recruited at four urban and rural District Tuberculosis Units in Hanoi. Clinical and radiological screening was conducted at baseline, six months and 12 months. Sputum microscopy and culture was performed in contacts suspected of having tuberculosis. MIRU-VNTR molecular testing was used to compare the strains of patients and their contacts with disease.
Among 545 household contacts of 212 patients, four were diagnosed with tuberculosis at baseline (prevalence 734 cases per 100,000 persons, 95% CI 17–1451) and one was diagnosed with tuberculosis during the subsequent 12 months after initial screening (incidence 180 cases per 100,000 person-years, 95% CI 44–131). Two of these cases were culture positive for M. tuberculosis and both had identical or near-identical MIRU-VNTR strain types.
Household contacts of patients with potentially infectious forms of tuberculosis have a high prevalence of disease. Household contact investigation is feasible in Vietnam. Further research is required to investigate its effectiveness.
PMCID: PMC3499505  PMID: 23166785
15.  Completion of Treatment for Latent Tuberculosis Infection with Monthly Drug Dispensation Directly through the Tuberculosis Clinic 
PLoS ONE  2012;7(11):e48900.
An Australian metropolitan TB clinic where treatment for latent tuberculosis infection (LTBI) comprises six months of isoniazid, self-administered but dispensed monthly by the clinic.
To determine the proportion of patients who complete treatment for LTBI and to identify factors associated with non-completion.
Clinical files of all patients receiving treatment for LTBI between 01/2000 and 12/2010 were reviewed. The study population comprised all patients who were commenced on isoniazid as treatment for LTBI. Odds ratios (OR) for completing treatment were estimated by logistic regression.
Of 216 patients who commenced isoniazid treatment for LTBI, 16 (75%) completed six months treatment. Fifty-three percent of the 53 patients who did not complete treatment dropped out after three months treatment. The mean (SD) age of the patients was 27 (16) years and 123 (57%) were female. The majority of patients (59%) were born overseas and 69% received treatment for LTBI because they were contacts of patients with TB. Patients' sex, age, country of birth, time since immigration for overseas born people, health care worker status, TST conversion status, chest x-ray findings, language, employment status and the indication for which treatment of LTBI was prescribed were not significantly related to treatment completion.
In a setting where isoniazid is dispensed monthly by the TB clinic, a relatively high proportion of patients who commence treatment for LTBI complete the six month scheduled course of treatment. The study did not identify any patient characteristics that predicted treatment completion. Interventions to improve completion rates should extend over the whole duration of treatment.
PMCID: PMC3489795  PMID: 23139824
16.  Body Mass Index (BMI) Trajectories from Birth to 11.5 Years: Relation to Early Life Food Intake 
Nutrients  2012;4(10):1382-1398.
Recent research has shown that the pattern of change over time, or trajectory, of body mass index (BMI) varies among children. However, the factors that underlie the heterogeneity in these trajectories remain largely unexplored. Our aim was to use a growth mixture model to empirically identify classes of BMI trajectories (from birth to 11.5 years) and examine the effects of breastfeeding, introduction of solids, as well as food and nutrient intake at 18 months on these BMI trajectories. We identified three BMI growth trajectories between birth and age 11.5 years, separately in boys and girls. Breastfeeding duration less than six months and the early introduction of solids did not adversely influence BMI trajectories in our sample but high intakes of meat, particularly high fat varieties, and high intakes of carbohydrate at age around 18 months were associated with a high BMI trajectory in boys. It is not clear whether these dietary factors confer a direct risk of higher BMI in childhood or are markers for other dietary patterns that are present early and/or develop through childhood and contribute to higher BMI.
PMCID: PMC3497001  PMID: 23201761
body mass index; developmental trajectory; obesity; breastfeeding; dietary intake; nutrition; diet; infant
17.  Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA 
PLoS ONE  2012;7(9):e44008.
Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies.
To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations.
The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10−8) and three variants reported as suggestive (P<5×10−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever.
Main Results
We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status.
Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
PMCID: PMC3461045  PMID: 23028483
18.  A pragmatic cluster randomized controlled trial of early intervention for chronic obstructive pulmonary disease by practice nurse-general practitioner teams: Study Protocol 
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of disability, hospitalization, and premature mortality. General practice is well placed to diagnose and manage COPD, but there is a significant gap between evidence and current practice, with a low level of awareness and implementation of clinical practice guidelines. Under-diagnosis of COPD is a world-wide problem, limiting the benefit that could potentially be achieved through early intervention strategies such as smoking cessation, dietary advice, and exercise. General practice is moving towards more structured chronic disease management, and the increasing involvement of practice nurses in delivering chronic care.
A pragmatic cluster randomised trial will test the hypothesis that intervention by a practice nurse-general practitioner (GP) team leads to improved health-related quality of life and greater adherence with clinical practice guidelines for patients with newly-diagnosed COPD, compared with usual care. Forty general practices in greater metropolitan Sydney Australia will be recruited to identify patients at risk of COPD and invite them to attend a case finding appointment. Practices will be randomised to deliver either practice nurse-GP partnership care, or usual care, to patients newly-diagnosed with COPD.
The active intervention will involve the practice nurse and GP working in partnership with the patient in developing and implementing a care plan involving (as appropriate), smoking cessation, immunisation, pulmonary rehabilitation, medication review, assessment and correction of inhaler technique, nutritional advice, management of psycho-social issues, patient education, and management of co-morbidities.
The primary outcome measure is health-related quality of life, assessed with the St George’s Respiratory Questionnaire 12 months after diagnosis. Secondary outcome measures include validated disease-specific and general health related quality of life measures, smoking and immunisation status, medications, inhaler technique, and lung function. Outcomes will be assessed by project officers blinded to patients’ randomization groups.
This study will use proven case-finding methods to identify patients with undiagnosed COPD in general practice, where improved care has the potential for substantial benefit in health and healthcare utilization. The study provides the capacity to trial a new model of team-based assessment and management of newly diagnosed COPD in Australian primary care.
Trial registration
PMCID: PMC3457839  PMID: 22958678
19.  A randomised cross-over cohort study of exposure to emissions from a road tunnel ventilation stack 
BMJ Open  2012;2(4):e001201.
Background and objective
Road tunnels are increasingly important components of urban infrastructure. However, knowledge of their health impact on surrounding communities is limited. Our objective was to estimate the short-term respiratory health effects of exposure to emissions from a road tunnel ventilation stack.
We conducted a randomised cross-over cohort study in 36 volunteers who underwent three exposure scenarios in 2006 before the road tunnel opened, and in 2007 (n=27) and 2008 (n=20) after the tunnel opened. Exposure downwind of the stack was compared to upwind of the stack and to a distant heavily trafficked location adjacent to a main road. Spirometry, exhaled nitric oxide (eNO) and symptom scores were measured repeatedly during each 2 h exposure session.
Downwind locations were associated with increased reports of ‘dry nose’ (score difference 0.36; 95% CI 0.09 to 0.63) compared with the control location (2006 vs 2007/2008), but not with impaired lung function, increased airway inflammation or other symptoms. The heavily trafficked location was associated with significantly increased eNO (ratio=1.09; 95% CI 1.04 to 1.14), eye (score difference 0.05; 95% CI 0.01 to 0.10) and chest (score difference 0.21; 95% CI 0.09 to 0.33) symptoms compared to the stack locations.
There was no consistent evidence of adverse respiratory effects from short-term exposures downwind of the tunnel ventilation stack, except for dry nose symptoms. However, the findings of increased airway inflammation and symptoms in subjects after only 2 h exposure at the heavily trafficked location, are suggestive of detrimental effects of short-term exposures to traffic-related air pollution.
PMCID: PMC3425893  PMID: 22904331
Thoracic Medicine; Epidemiology; Public Health; Traffic; Air Pollution; Acute
20.  Risk of tuberculosis among people with diabetes mellitus: an Australian nationwide cohort study 
BMJ Open  2012;2(1):e000666.
Previous studies that have found an increased risk for tuberculosis (TB) in people with diabetes mellitus (DM) have been conducted in segments of the population and have not adjusted for important potential confounders. We sought to determine the RR for TB in the presence of DM in a national population with data on confounding factors in order to inform the decision-making process about latent tuberculosis infection (LTBI) screening in people with diabetes.
Whole population historical cohort study.
All Australian States and Territories with a mean TB incidence of 5.8/100 000.
Cases of TB in people with DM were identified by record linkage using the National Diabetes Services Scheme Database and TB notification databases for the years 2001–2006.
Primary and secondary outcome measures
Primary outcome was notified cases of TB. Secondary outcome was notified cases of culture-confirmed TB. RR of TB was estimated with adjustment for age, sex, TB incidence in country of birth and indigenous status.
There were 6276 cases of active TB among 19 855 283 people living in Australia between 2001 and 2006. There were 271 (188 culture positive) cases of TB among 802 087 members of the DM cohort and 130 cases of TB among 273 023 people using insulin. The crude RR of TB was 1.78 (95% CI 1.17 to 2.73) in all people with DM and 2.16 (95% CI 1.19 to 3.93) in people with DM using insulin. The adjusted RRs were 1.48 (95% CI 1.04 to 2.10) and 2.27 (95% CI 1.41 to 3.66), respectively.
The presence of DM alone does not justify screening for LTBI. However, when combined with other risk factors for TB, the presence of DM may be sufficient to justify screening and treatment for LTBI.
Article summary
Article focus
National, general population-based, historical cohort study to estimate the risk of tuberculosis (TB) among people with diabetes mellitus (DM).
Adjustment for important potentially confounding risk factors including age, sex, indigenous status and TB incidence in country of birth.
Key messages
Overall, people with DM have a 1.5-fold increased risk of developing TB.
The risk for TB is higher among people who are using insulin for DM.
DM accounts for a small proportion of cases of TB in a low TB incidence setting.
Strengths and limitations of this study
The strengths of this study are the cohort design, the large population size, the general population base for the study cohort and the adjustment for important potential confounders, especially TB incidence in the country of birth.
The study limitations are the unavailability of laboratory results to indicate if blood glucose levels were well or poorly controlled in people with DM and the inability to reliably distinguish between type 1 and type 2 DM in this data source.
PMCID: PMC3282295  PMID: 22331390
21.  Risk of Tuberculosis in Dialysis Patients: A Nationwide Cohort Study 
PLoS ONE  2011;6(12):e29563.
The ability to identify individuals at increased risk of developing tuberculosis (TB) has important implications for public health policy and patient care. We conducted a general population historical cohort study in all Australian States and Territories to establish the risk of TB arising in people on chronic hemo- or peritoneal dialysis.
Methodology/Principal Findings
Cases of TB disease in patients receiving chronic dialysis were identified by record linkage using the Australia & New Zealand Dialysis and Transplant Registry (ANZDATA) and State and Territory TB notification databases 2001 to 2006. Main outcome measure was the relative risk of TB in people on dialysis, adjusted for TB incidence in country of birth, sex, age and indigenous status. A total of 6,276 cases of active TB were reported among 19,855,283 people living in Australia between 2001 and 2006. Among 14,506 patients on dialysis, 37 had a notification for TB disease after commencing dialysis, of whom 28 were culture positive. The incidence of TB was 66.8/100,000/year (95% CI 47.7 to 93.2) among people on dialysis and 5.7/100,000/year (95% CI 5.5 to 5.8) in the general population. The adjusted relative risk (aRR) of TB in people on dialysis was 7.8 (95% CI 3.3 to 18.7), and the aRR of culture positive TB was 8.6 (95% CI 3.9 to 19.3).
Patients on dialysis are at increased risk of TB. The final decision to screen for, and to treat, LTBI in individual dialysis patients will be influenced by a cumulative assessment of the risk of reactivation of TB and by assessment of risk factors for adverse effects of treatment.
PMCID: PMC3246480  PMID: 22216316
22.  Lung Function Is Associated with Arterial Stiffness in Children 
PLoS ONE  2011;6(10):e26303.
In older adults, an independent association exists between impaired lung function and cardiovascular disease. This interaction might be related to the effects of aging and/or smoking. In order to explore possible childhood antecedents to this association, we hypothesized that decreased lung function and vascular stiffness might be related, in early life.
To determine the relationship between lung function and carotid augmentation index (AIx), a measure of vascular stiffness, in 8-year old children.
Data on brachial blood pressure, lung function (FEV1, FVC, FEV1/FVC, obtained by spirometry) and carotid AIx75 (AIx standardised to an arbitrary heart rate of 75 beats per minute, obtained by applanation tonometry) was available in 249 community-based 8-year old children. These healthy children had been subjects in a randomised controlled trial of two interventions (omega-3 fatty acid supplementation and house-dust mite avoidance) to prevent asthma. Smoking in pregnancy and childhood environmental tobacco smoke (ETS) exposure was prospectively collected by questionnaire. The association between lung function and carotid AIx75 was assessed in multivariate models that included sex, height, smoking status during pregnancy, ETS exposure and randomisation groups (house dust mite avoidance and dietary intervention) as covariates.
In the fully adjusted models, Carotid AIx75 was independently associated with FEV1 (standardised β = −0.17,b = −6.72, partial R2 = .02, p = 0.03), FVC (standardised β = −0.29, b = −9.31, partial R2 = 0.04, p<0.001) and FEV1/FVC (standardised β = .13, b = 18.4, partial R2 = 0.02, p = 0.04).
Lower lung volumes are associated with increased vascular stiffness at an early age. The interaction between lung function and vascular stiffness may thus represent more than just age-related alterations in both the pulmonary and vascular systems.
PMCID: PMC3201952  PMID: 22046271
23.  Respiratory Health Effects of Exposure to Low-NOx Unflued Gas Heaters in the Classroom: A Double-Blind, Cluster-Randomized, Crossover Study 
Environmental Health Perspectives  2010;118(10):1476-1482.
There are long-standing concerns about adverse effects of gas appliances on respiratory health. However, the potential adverse effect of low-NOx (nitrogen oxide) unflued gas heaters on children’s health has not been assessed.
Our goal was to compare the respiratory health effects and air quality consequences of exposure to low-NOx unflued gas heaters with exposure to non–indoor-air-emitting flued gas heaters in school classrooms.
We conducted a double-blind, cluster-randomized, crossover study in 400 primary school students attending 22 schools in New South Wales, Australia. Children measured their lung function and recorded symptoms and medication use twice daily. Nitrogen dioxide (NO2) and formaldehyde concentrations were measured in classrooms using passive diffusion badges.
NO2 concentrations were, on average, 1.8 times higher [95% confidence interval (CI), 1.6–2.1] and formaldehyde concentrations were, on average, 9.4 ppb higher (95% CI, 5.7–13.1) during exposure to unflued gas versus flued gas heaters. Exposure to the unflued gas heaters was associated with increased cough reported in the evening [odds ratio (OR) = 1.16; 95% CI, 1.01–1.34] and wheeze reported in the morning (OR = 1.38; 95% CI, 1.04–1.83). The association with wheeze was greater in atopic subjects. There was no evidence of an adverse effect on lung function.
We conclude that classroom exposure to low-NOx unflued gas heaters causes increased respiratory symptoms, particularly in atopic children, but is not associated with significant decrements in lung function. It is important to seek alternative sources of heating that do not have adverse effects on health.
PMCID: PMC2957932  PMID: 20663737
children; nitrogen dioxide; randomized controlled trial; respiratory health effects; schools
24.  Low Rates of Pseudomonas aeruginosa Misidentification in Isolates from Cystic Fibrosis Patients▿  
Journal of Clinical Microbiology  2009;47(5):1503-1509.
Pseudomonas aeruginosa is an important cause of pulmonary infection in cystic fibrosis (CF). Its correct identification ensures effective patient management and infection control strategies. However, little is known about how often CF sputum isolates are falsely identified as P. aeruginosa. We used P. aeruginosa-specific duplex real-time PCR assays to determine if 2,267 P. aeruginosa sputum isolates from 561 CF patients were correctly identified by 17 Australian clinical microbiology laboratories. Misidentified isolates underwent further phenotypic tests, amplified rRNA gene restriction analysis, and partial 16S rRNA gene sequence analysis. Participating laboratories were surveyed on how they identified P. aeruginosa from CF sputum. Overall, 2,214 (97.7%) isolates from 531 (94.7%) CF patients were correctly identified as P. aeruginosa. Further testing with the API 20NE kit correctly identified only 34 (59%) of the misidentified isolates. Twelve (40%) patients had previously grown the misidentified species in their sputum. Achromobacter xylosoxidans (n = 21), Stenotrophomonas maltophilia (n = 15), and Inquilinus limosus (n = 4) were the species most commonly misidentified as P. aeruginosa. Overall, there were very low rates of P. aeruginosa misidentification among isolates from a broad cross section of Australian CF patients. Additional improvements are possible by undertaking a culture history review, noting colonial morphology, and performing stringent oxidase, DNase, and colistin susceptibility testing for all presumptive P. aeruginosa isolates. Isolates exhibiting atypical phenotypic features should be evaluated further by additional phenotypic or genotypic identification techniques.
PMCID: PMC2681828  PMID: 19261796
25.  Associations between statins and COPD: a systematic review 
Statins have anti-inflammatory and immunomodulating properties which could possibly influence inflammatory airways disease. We assessed evidence for disease modifying effects of statin treatment in patients with chronic obstructive pulmonary disease (COPD).
A systematic review was conducted of studies which reported effects of statin treatment in COPD. Data sources searched included MEDLINE, EMBASE and reference lists.
Eight papers reporting nine original studies met the selection criteria. One was a randomized controlled trial (RCT), one a retrospective nested case-control study, five were retrospective cohort studies of which one was linked with a case-control study, and one was a retrospective population-based analysis. Outcomes associated with treatment with statins included decreased all-cause mortality in three out of four studies (OR/HR 0.48–0.67 in three studies, OR 0.99 in one study), decreased COPD-related mortality (OR 0.19–0.29), reduction in incidence of respiratory-related urgent care (OR 0.74), fewer COPD exacerbations (OR 0.43), fewer intubations for COPD exacerbations (OR 0.1) and attenuated decline in pulmonary function. The RCT reported improvement in exercise capacity and dyspnea after exercise associated with decreased levels of C-reactive protein and Interleukin-6 in statin users, but no improvement of lung function.
There is evidence from observational studies and one RCT that statins may reduce morbidity and/or mortality in COPD patients. Further interventional studies are required to confirm these findings.
PMCID: PMC2716302  PMID: 19594891

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