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author:("bulbar, Max")
1.  Impact of treatment planning and delivery factors on gastrointestinal toxicity: an analysis of data from the RADAR prostate radiotherapy trial 
To assess the impact of incremental modifications of treatment planning and delivery technique, as well as patient anatomical factors, on late gastrointestinal toxicity using data from the TROG 03.04 RADAR prostate radiotherapy trial.
The RADAR trial accrued 813 external beam radiotherapy participants during 2003–2008 from 23 centres. Following review and archive to a query-able database, digital treatment plans and data describing treatment technique for 754 patients were available for analysis. Treatment demographics, together with anatomical features, were assessed using uni- and multivariate regression models against late gastrointestinal toxicity at 18-, 36- and 54-month follow-up. Regression analyses were reviewed in the context of dose-volume data for the rectum and anal canal.
A multivariate analysis at 36-month follow-up shows that patients planned using a more rigorous dose calculation algorithm (DCA) was associated with a lower risk of stool frequency (OR: 0.435, CI: 0.242–0.783, corrected p = 0.04). Patients using laxative as a method of bowel preparation had higher risk of having increased stool frequency compared to patients with no dietary intervention (OR: 3.639, CI: 1.502–8.818, corrected p = 0.04). Despite higher risks of toxicities, the anorectum, anal canal and rectum dose-volume histograms (DVH) indicate patients using laxative had unremarkably different planned dose distributions. Patients planned with a more rigorous DCA had lower median DVH values between EQD23 = 15 Gy and EQD23 = 35 Gy. Planning target volume (PTV), conformity index, rectal width and prescription dose were not significant when adjusted for false discovery rate. Number of beams, beam energy, treatment beam definition, positioning orientation, rectum-PTV separation, rectal length and mean cross sectional area did not affect the risk of toxicities.
The RADAR study dataset has allowed an assessment of technical modifications on gastrointestinal toxicity. A number of interesting associations were subsequently found and some factors, previously hypothesised to influence toxicity, did not demonstrate any significant impact. We recommend trial registries be encouraged to record technical modifications introduced during the trial in order for more powerful evidence to be gathered regarding the impact of the interventions.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-014-0282-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4271488  PMID: 25498565
Gastrointestinal toxicity; Prostate cancer; Technical modifications; Dose-volume histogram
2.  The Improving Rural Cancer Outcomes (IRCO) Trial: a factorial cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural patients with cancer in Western Australia: a study protocol 
BMJ Open  2014;4(9):e006156.
While overall survival for most common cancers in Australia is improving, the rural–urban differential has been widening, with significant excess deaths due to lung, colorectal, breast and prostate cancer in regional Australia. Internationally a major focus on understanding variations in cancer outcomes has been later presentation to healthcare and later diagnosis. Approaches to reducing time to diagnosis of symptomatic cancer include public symptom awareness campaigns and interventions in primary care to improve early cancer detection. This paper reports the protocol of a factorial cluster-randomised trial of community and general practice (GP) level interventions to reduce the time to diagnosis of cancer in rural Western Australia (WA).
Methods and analysis
The community intervention is a symptom awareness campaign tailored for rural Australians delivered through a community engagement model. The GP intervention includes a resource card with symptom risk assessment charts and local referral pathways implemented through multiple academic detailing visits and case studies. Participants are eligible if recently diagnosed with breast, colorectal, lung or prostate cancer who reside in specific regions of rural WA with a planned sample size of 1350. The primary outcome is the Total Diagnostic Interval, defined as the duration from first symptom (or date of cancer screening test) to cancer diagnosis. Secondary outcomes include cancer stage, healthcare utilisation, disease-free status, survival at 2 and 5 years and cost-effectiveness.
Ethics and dissemination
Ethics approval has been granted by the University of Western Australia and from all relevant hospital recruitment sites in WA.
Results of this trial will be reported in peer-reviewed publications and in conference presentations.
Trial registration number
Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12610000872033.
PMCID: PMC4166137  PMID: 25231496
3.  Multimorbidity in a marginalised, street-health Australian population: a retrospective cohort study 
BMJ Open  2014;4(8):e005461.
Demographic and presentation profile of patients using an innovative mobile outreach clinic compared with mainstream practice.
Retrospective cohort study.
Primary care mobile street health clinic and mainstream practice in Western Australia.
2587 street health and 4583 mainstream patients.
Main outcome measures
Prevalence and patterns of chronic diseases in anatomical domains across the entire age spectrum of patients and disease severity burden using Cumulative Illness Rating Scale (CIRS).
Multimorbidity (2+ CIRS domains) prevalence was significantly higher in the street health cohort (46.3%, 1199/2587) than age–sex-adjusted mainstream estimate (43.1%, 2000/4583), p=0.011. Multimorbidity prevalence was significantly higher in street health patients <45 years (37.7%, 615/1649) compared with age–sex-adjusted mainstream patients (33%, 977/2961), p=0.003 but significantly lower if 65+ years (62%, 114/184 vs 90.7%, 322/355, p<0.001). Controlling for age and gender, the mean CIRS Severity Index score for street health (M=1.4, SD=0.91) was significantly higher than for mainstream patients (M=1.1, SD=0.80), p<0.001. Furthermore, 44.2% (530/1199) of street health patients had at least one level 3 or 4 score across domains compared with 18.3% (420/2294) for mainstream patients, p<0.001. Street health population comprised 29.6% (766/2587) Aboriginal patients with 50.4% (386/766) having multimorbidity compared with 44.6% (813/1821) for non-Aboriginals, p=0.007. There were no comprehensive data on Indigenous status in the mainstream cohort available for comparison. Musculoskeletal, respiratory and psychiatric domains were most commonly affected with multimorbidity significantly associated with male gender, increasing age and Indigenous status.
Age–sex-adjusted multimorbidity prevalence and disease severity is higher in the street health cohort. Earlier onset (23–34 years) multimorbidity is found in the street health cohort but prevalence is lower in 65+ years than in mainstream patients. Multimorbidity prevalence is higher for Aboriginal patients of all ages.
PMCID: PMC4139644  PMID: 25138806
PRIMARY CARE; multimorbidity; chronic disease
5.  Early discontinuation of endocrine therapy for breast cancer: who is at risk in clinical practice? 
SpringerPlus  2014;3:282.
Despite evidence supporting at least five years of endocrine therapy for early breast cancer, many women discontinue therapy early. We investigated the impact of initial therapy type and specific comorbidities on discontinuation of endocrine therapy in clinical practice.
We identified women in a population-based cohort with a diagnosis of early breast cancer and an incident dispensing of anastrozole, letrozole or tamoxifen from 2003–2008 (N = 1531). Pharmacy and health service data were used to determine therapy duration, treatment for pre-existing and post-initiation comorbidities (anxiety, depression, hot flashes, musculoskeletal pain, osteoporosis, vaginal atrophy), demographic and other clinical characteristics. Time to discontinuation of initial, and any, endocrine therapy was calculated. Cox regression determined the association of different characteristics on early discontinuation.
Initial endocrine therapy continued for a median of 2.2 years and any endocrine therapy for 4.8 years. Cumulative probability of discontinuing any therapy was 17% after one year and 58% by five years. Initial tamoxifen, pre-existing musculoskeletal pain and newly-treated anxiety predicted shorter initial therapy but not discontinuation of any therapy. Early discontinuation of any therapy was associated with newly-treated hot flashes (HR = 2.1, 95% CI = 1.3–3.3), not undergoing chemotherapy (HR = 1.4, 95% CI = 1.1–1.8) and not undergoing mastectomy (HR = 1.5, 95% CI = 1.2–1.8).
Less than half of women completed five years of endocrine therapy. Women at greatest risk of stopping any therapy early were those with newly-treated hot flashes, no initial chemotherapy, or no initial mastectomy. This suboptimal use means that the reductions in recurrence demonstrated in clinical trials may not be realised in practice.
PMCID: PMC4058005  PMID: 24936397
Persistence; Adherence; Tamoxifen; Aromatase inhibitors; 45 and up study
6.  A longitudinal cohort study of the impact of first- and both-eye cataract surgery on falls and other injuries in Vietnam 
Little information exists on the impact of cataract surgery on falls and other injuries in Vietnam. The aim of this study was to determine the impact of first and both eye cataract surgery on the number of falls and other injuries among bilateral cataract patients in Ho Chi Minh City, Vietnam.
Materials and methods
A longitudinal cohort study was conducted involving 413 bilateral cataract patients aged 50+ years. Participants were assessed at three time points: 1 week before, 1–3 months after, and 1 year after first-eye cataract surgery. Visual measures (visual acuity, contrast sensitivity and stereopsis) were taken, and self-reported falls and injury data were collected. A multilevel longitudinal Poisson regression model was used to investigate change in the number of falls after surgery.
The risk of falls decreased by 78% (incidence-rate ratio [IRR] 0.22, 95% confidence interval [CI] 0.06–0.77; P=0.018) in the year after cataract surgery for participants who had first-eye surgery only and 83% (IRR 0.17, 95% CI 0.04–0.69; P=0.012) for participants who had the second eye operated on compared to before surgery. The risk of falls was three times higher for females than males (IRR 3.13, 95% CI 1.53–6.40; P=0.002). Improved binocular contrast sensitivity was also associated with a decrease in falls (IRR 0.40, 95% CI 0.17–0.97; P=0.042). The prevalence of other injuries also decreased after cataract surgery.
Cataract surgery reduced the number of falls and other injuries in Vietnam. Contrast sensitivity may be important for ophthalmologists to consider when prioritizing patients for surgery and assessing their fall risk.
PMCID: PMC4011894  PMID: 24812501
falls; injuries; cataract surgery; longitudinal; older population; Vietnam
7.  Moving in an Environment of Induced Sensorimotor Incongruence Does Not Influence Pain Sensitivity in Healthy Volunteers: A Randomised Within-Subject Experiment 
PLoS ONE  2014;9(4):e93701.
It has been proposed that in the same way that conflict between vestibular and visual inputs leads to motion sickness, conflict between motor commands and sensory information associated with these commands may contribute to some chronic pain states. Attempts to test this hypothesis by artificially inducing a state of sensorimotor incongruence and assessing self-reported pain have yielded equivocal results. To help clarify the effect sensorimotor incongruence has on pain we investigated the effect of moving in an environment of induced incongruence on pressure pain thresholds (PPT) and the pain experienced immediately on completion of PPT testing.
Thirty-five healthy subjects performed synchronous and asynchronous upper-limb movements with and without mirror visual feedback in random order. We measured PPT over the elbow and the pain evoked by testing. Generalised linear mixed-models were performed for each outcome. Condition (four levels) and baseline values for each outcome were within-subject factors.
There was no effect of condition on PPT (p = 0.887) or pressure-evoked pain (p = 0.771). A sensitivity analysis using only the first PPT measure after each condition confirmed the result (p = 0.867).
Inducing a state of movement related sensorimotor incongruence in the upper-limb of healthy volunteers does not influence PPT, nor the pain evoked by testing. We found no evidence that sensorimotor incongruence upregulates the nociceptive system in healthy volunteers.
PMCID: PMC3977875  PMID: 24709995
8.  Intraoperative radiotherapy for early breast cancer: do health professionals choose convenience or risk? 
The randomized TARGIT trial comparing experimental intra-operative radiotherapy (IORT) to up to 7 weeks of daily conventional external beam radiotherapy (EBRT) recruited participants in Western Australia between 2003 and 2012. We aimed to understand preferences for this evolving radiotherapy treatment for early breast cancer (EBC) in health professionals, and how they changed over time and in response to emerging data. Preferences for single dose IORT or EBRT for EBC were elicited in 2004 and 2011, together with factors that may be associated with these preferences.
Western Australian health professionals working with breast cancer patients were invited to complete a validated, self-administered questionnaire. The questionnaire used hypothetical scenarios and trade-off methodology to determine the maximum increase in risk of local recurrence health professionals were willing to accept in order to have a single dose of IORT in the place of EBRT if they were faced with this decision themselves.
Health professional characteristics were similar across the two time points although 2011 included a higher number of nurse (49% vs. 36%) and allied health (10% vs. 4%) participants and a lower number of radiation therapists (17% vs. 32% ) compared to 2004.
Health professional preferences varied, with 7.5% and 3% judging IORT unacceptable at any risk, 18% and 21% judging IORT acceptable only if offering an equivalent risk, 56% and 59% judging IORT acceptable with a low maximum increase in risk (1-3%) and 19% and 17% judging a high maximum increase in risk acceptable (4-5%), in 2004 and 2011 respectively. A significantly greater number of nurses accepted IORT as a treatment option in 2011.
Most Western Australian health professionals working with breast cancer patients are willing to accept an increase in risk of local recurrence in order to replace EBRT with IORT in a hypothetical setting. This finding was consistent over two time points spanning 7 years despite the duration of clinical experience with IORT and the publication of the early clinical results of IORT in 2010. These results need to be compared with preferences elicited from patient groups, and further investigation into the impact of personal preferences on health professionals’ advice to patients is warranted.
PMCID: PMC3907143  PMID: 24461031
Physician survey; Treatment preference; Patient preferences; Breast cancer; Intraoperative radiotherapy; Partial breast irradiation; TARGIT; Preference questionnaire; IORT; PBI
9.  Women Commencing Anastrozole, Letrozole or Tamoxifen for Early Breast Cancer: The Impact of Comorbidity and Demographics on Initial Choice 
PLoS ONE  2014;9(1):e84835.
Australian clinical guidelines recommend endocrine therapy for all women with hormone-dependent early breast cancer. Guidelines specify tamoxifen as first-line therapy for pre-menopausal women, and tamoxifen or an aromatase inhibitor (AI) for post-menopausal women depending on the risk of recurrence based on tumour characteristics including size. Therapies have different side effect profiles; therefore comorbidity may also influence choice. We examined comorbidity, and the clinical and demographic characteristics of women commencing different therapies.
Patients and Methods
We identified the first dispensing of tamoxifen, anastrozole or letrozole for women diagnosed with invasive breast cancer in the 45 and Up Study from 2004–2009 (N = 1266). Unit-level pharmacy and medical service claims, hospital, Cancer Registry, and self-reported data were linked to determine menopause status at diagnosis, tumour size, age, comorbidities, and change in subsidy restrictions. Chi-square tests and generalised regression models were used to compare the characteristics of women commencing different therapies.
Most pre-menopausal women commenced therapy with tamoxifen (91%). Anastrozole was the predominant therapy for post-menopausal women (57%), followed by tamoxifen (28%). Women with osteoporosis were less likely to commence anastrozole compared with tamoxifen (anastrozole RR = 0.7, 95% CI = 0.5–0.9). Women with arthritis were 1.6-times more likely to commence letrozole than anastrozole (95% CI = 1.1–2.1). Tamoxifen was more often initiated in women with tumours >1 cm, who were also ≥75 years. Subsidy restriction changes were associated with substantial increases in the proportion of women commencing AIs (anastrozole RR = 4.3, letrozole RR = 8.3).
The findings indicate interplay of comorbidity and therapy choice for women with invasive breast cancer. Most post-menopausal women commenced therapy with anastrozole; however, letrozole and tamoxifen were more often initiated for women with comorbid arthritis and osteoporosis, respectively. Tamoxifen was also more common for women with tumours >1 cm and aged ≥75 years. Subsidy restrictions appear to have strongly influenced therapy choice.
PMCID: PMC3879327  PMID: 24392158
10.  Cyclical Variation in the Incidence of Childhood Type 1 Diabetes in Western Australia (1985–2010) 
Diabetes Care  2012;35(11):2300-2302.
To examine the incidence of childhood type 1 diabetes in Western Australia from 1985–2010.
Incidence rates were calculated for children aged 0–14 years and were analyzed by calendar year, sex, and age at diagnosis.
There were 1,873 cases, and the mean incidence was 18.1/100,000 person-years (95% CI: 17.5–19.2). The incidence increased by 2.3% a year (1.6–2.9%) with a sinusoidal 5-year cyclical variation of 14% (7–22%). The lowest rate of increase in incidence was observed in 0–4-year-olds.
The cyclical pattern in incidence observed supports the role of environmental factors in childhood type 1 diabetes.
PMCID: PMC3476891  PMID: 22837374
11.  Early Loss of the Glucagon Response to Hypoglycemia in Adolescents With Type 1 Diabetes 
Diabetes Care  2012;35(8):1757-1762.
To assess the glucagon response to hypoglycemia and identify influencing factors in patients with type 1 diabetes compared with nondiabetic control subjects.
Hyperinsulinemic hypoglycemic clamp studies were performed in all participants. The glucagon response to both hypoglycemia and arginine was measured, as well as epinephrine, cortisol, and growth hormone responses to hypoglycemia. Residual β-cell function was assessed using fasting and stimulated C-peptide.
Twenty-eight nonobese adolescents with type 1 diabetes (14 female, mean age 14.9 years [range 11.2–19.8]) and 12 healthy control subjects (6 female, 15.3 years [12.8–18.7]) participated in the study. Median duration of type 1 diabetes was 0.66 years (range 0.01–9.9). The glucagon peak to arginine stimulation was similar between groups (P = 0.27). In contrast, the glucagon peak to hypoglycemia was reduced in the group with diabetes (95% CI): 68 (62–74) vs. 96 (87–115) pg/mL (P < 0.001). This response was greater than 3 SDs from baseline for only 7% of subjects with type 1 diabetes in comparison with 83% of control subjects and was lost at a median duration of diabetes of 8 months and as early as 1 month after diagnosis (R = −0.41, P < 0.01). There was no correlation in response with height, weight, BMI, and HbA1c. Epinephrine, cortisol, and growth hormone responses to hypoglycemia were present in both groups.
The glucagon response to hypoglycemia in adolescents with type 1 diabetes is influenced by the duration of diabetes and can be lost early in the course of the disease.
PMCID: PMC3402257  PMID: 22699295
12.  Authors' response 
PMCID: PMC3310014
13.  Ascertaining invasive breast cancer cases; the validity of administrative and self-reported data sources in Australia 
Statutory State-based cancer registries are considered the ‘gold standard’ for researchers identifying cancer cases in Australia, but research using self-report or administrative health datasets (e.g. hospital records) may not have linkage to a Cancer Registry and need to identify cases. This study investigated the validity of administrative and self-reported data compared with records in a State-wide Cancer Registry in identifying invasive breast cancer cases.
Cases of invasive breast cancer recorded on the New South Wales (NSW) Cancer Registry between July 2004 and December 2008 (the study period) were identified for women in the 45 and Up Study. Registry cases were separately compared with suspected cases ascertained from: i) administrative hospital separations records; ii) outpatient medical service claims; iii) prescription medicines claims; and iv) the 45 and Up Study baseline survey. Ascertainment flags included diagnosis codes, surgeries (e.g. lumpectomy), services (e.g. radiotherapy), and medicines used for breast cancer, as well as self-reported diagnosis. Positive predictive value (PPV), sensitivity and specificity were calculated for flags within individual datasets, and for combinations of flags across multiple datasets.
Of 143,010 women in the 45 and Up Study, 2039 (1.4%) had an invasive breast tumour recorded on the NSW Cancer Registry during the study period. All of the breast cancer flags examined had high specificity (>97.5%). Of the flags from individual datasets, hospital-derived ‘lumpectomy and diagnosis of invasive breast cancer’ and ‘(lumpectomy or mastectomy) and diagnosis of invasive breast cancer’ had the greatest PPV (89% and 88%, respectively); the later having greater sensitivity (59% and 82%, respectively). The flag with the highest sensitivity and PPV ≥ 85% was 'diagnosis of invasive breast cancer' (both 86%). Self-reported breast cancer diagnosis had a PPV of 50% and sensitivity of 85%, and breast radiotherapy had a PPV of 73% and a sensitivity of 58% compared with Cancer Registry records. The combination of flags with the greatest PPV and sensitivity was ‘(lumpectomy or mastectomy) and (diagnosis of invasive breast cancer or breast radiotherapy)’ (PPV and sensitivity 83%).
In the absence of Cancer Registry data, administrative and self-reported data can be used to accurately identify cases of invasive breast cancer for sample identification, removing cases from a sample, or risk adjustment. Invasive breast cancer can be accurately identified using hospital-derived diagnosis alone or in combination with surgeries and breast radiotherapy.
PMCID: PMC3599953  PMID: 23399047
45 and up study; Sensitivity; Specificity; Positive predictive value; Lumpectomy; Mastectomy; Radiotherapy; Hospital diagnosis; Tamoxifen; Anastrazole; Self-report
14.  The Fremantle Primary Prevention Study: a multicentre randomised trial of absolute cardiovascular risk reduction 
Cardiovascular disease (CVD) is the leading cause of global mortality. Risk factor management in clinical practice often relies on relative risk modification rather than the more appropriate absolute risk assessment.
To determine whether patients receiving more-frequently designated GP visits had increased benefit in terms of their absolute CVD risk assessment, as compared with patients in receipt of their usual GP care.
Design and setting
Prospective, open, pragmatic block randomised study in a 1:1 group allocation ratio in three Western Australian general practices.
A convenience sample (n = 1200) of patients aged 40–80 years were randomised to 3-monthly GP visits (five in total for the intensive) or usual GP care (two in total for the opportunistic), with 12 months’ follow-up. The main outcome was absolute CVD risk scores based on the New Zealand Cardiovascular Risk Calculator. Others outcome measures were weight, height, waist circumference, blood pressure, and fasting blood lipids and glucose.
There were 600 patients per group at baseline. At 12 months’ analysis there were 543 in the intensive group and 569 in the opportunistic group. Mean (standard deviation [SD]) absolute CVD risk reduced significantly between baseline and 12 months in the intensive group (6.28% [5.11] to 6.10% [4.94]) but not in the opportunistic group (6.27% [5.10] to 6.24% [5.38]). There was a significant reduction between baseline and 12 months in mean (SD) total cholesterol (5.28 mmol/l [0.94] to 5.08 mmol/l [0.96]); low-density lipoprotein cholesterol (3.08 mmol/l [0.87] to 2.95 mmol/l [0.89]); triglyceride (1.45 mmol/l [0.86] to 1.36 mmol/l [0.84]); and in mean (SD) waist circumference in men (98.74 cm [10.70] to 97.13 cm [10.20]) and females (90.64 cm [14.62] to 88.96 cm [14.00]) in the intensive group.
A targeted approach using absolute risk calculators can be used in primary care to modify global CVD risk assessment.
PMCID: PMC3252536  PMID: 22520669
cardiovascular diseases; general practice; general practitioners; primary care; primary prevention; risk factors
15.  Reducing Rates of Severe Hypoglycemia in a Population-Based Cohort of Children and Adolescents With Type 1 Diabetes Over the Decade 2000–2009 
Diabetes Care  2011;34(11):2379-2380.
To examine rates of severe hypoglycemia (SH) in a large population-based cohort of children with type 1 diabetes and relationships to HbA1c.
Data from 1,683 children (mean [SD] age at diagnosis 10.5 [4.2]; range 1–18 years) from 2000 to 2009 were analyzed from the Western Australian Children's Diabetes Database. Rates of SH were related to HbA1c using negative binomial regression.
A total of 7,378 patient-years of data and 780 SH events were recorded. The rate of SH per 100 patient-years peaked at 17.3 in 2001 and then declined from 2004 to a nadir of 5.8 in 2006. HbA1c <7% was not associated with higher risk of SH (incidence rate ratio 1.2 [95% CI 0.9–1.6], P = 0.29) compared with HbA1c of 8–9%.
In a sample of youth with type 1 diabetes, there has been a decrease in rates of SH and a weaker relationship with glycemic control than previously observed.
PMCID: PMC3198282  PMID: 21926291
16.  The natural history of early-onset dementia: the Artemis Project 
BMJ Open  2012;2(5):e001764.
The natural history of early-onset Alzheimer's disease (AD) and fronto-temporal dementia (FTD) remains to be described in detail. We seek to describe the natural history of early onset AD and FTD in terms of changes in cognitive assessment and staging, medical history and survival.
Longitudinal prospective cohort analysis.
Neurodegenerative disorders research clinic.
In total, 155 consecutive patients with clinically confirmed sporadic early-onset AD or FTD at a neurodegenerative disorders research clinic in Subiaco, Western Australia (The Artemis Project).
A detailed history was recorded from the patients at baseline, including education, family history and medical history. Mini-mental state exam (MMSE), Global Deterioration Scale (GDS) and total functional capacity (TFC) were determined at each visit from 1994 until 2011. Kaplan-Meier survival analysis was performed.
Patients with FTD were more likely to have a family history of dementia (p=0.026), to develop at least one cerebrovascular risk factor (p=0.003), manifest depression (Fisher's exact p=0.007) and to die during the follow-up period (Pearson χ2 8.97, p=0.003). Kaplan-Meier survival estimates revealed a highly significant difference in the proportion of patients surviving the follow-up period (log rank 7.25, p=0.007) with FTD patients experiencing poorer survival than those with AD. The mean MMSE and TFC were consistently lower in those with FTD compared with those with AD over a decade of follow-up; mean GDS was consistently higher in those with FTD over the follow-up period.
We believe that the difference in survival in patients with AD and FTD in our cohort might relate to the development of one or more cerebrovascular risk factors in FTD patients and the severity of the underlying pathology.
PMCID: PMC3488731  PMID: 23059847
17.  On your bike! a cross-sectional study of the individual, social and environmental correlates of cycling to school 
Active school transport (AST) has declined rapidly in recent decades. While many studies have examined walking, cycling to school has received very little attention. Correlates of cycling are likely to differ to those from walking and cycling enables AST from further distances. This study examined individual, social and environmental factors associated with cycling to school among elementary school-aged children, stratified by gender.
Children (n = 1197) attending 25 Australian primary schools located in high or low walkable neighborhoods, completed a one-week travel diary and a parent/child questionnaire on travel habits and attitudes.
Overall, 31.2% of boys and 14.6% of girls cycled ≥ 1 trip/week, however 59.4% of boys and 36.7% of girls reported cycling as their preferred school transport mode. In boys (but not girls), school neighborhood design was significantly associated with cycling: i.e., boys attending schools in neighborhoods with high connectivity and low traffic were 5.58 times more likely to cycle (95% CI 1.11-27.96) and for each kilometer boys lived from school the odds of cycling reduced by 0.70 (95% CI 0.63-0.99). Irrespective of gender, cycling to school was associated with parental confidence in their child's cycling ability (boys: OR 10.39; 95% CI 3.79-28.48; girls: OR 4.03; 95% CI 2.02-8.05), parental perceived convenience of driving (boys: OR 0.42; 95% CI 0.23-0.74; girls: OR 0.40; 95% CI 0.20-0.82); and child's preference to cycle (boys: OR 5.68; 95% CI 3.23-9.98; girls: OR 3.73; 95% CI 2.26-6.17).
School proximity, street network connectivity and traffic exposure in school neighborhoods was associated with boys (but not girls) cycling to school. Irrespective of gender, parents need to be confident in their child's cycling ability and must prioritize cycling over driving.
PMCID: PMC3224764  PMID: 22074261
Cycling; children; active school transport; physical activity
18.  Maternal Age at Birth and Childhood Type 1 Diabetes: A Pooled Analysis of 30 Observational Studies 
Diabetes  2009;59(2):486-494.
The aim if the study was to investigate whether children born to older mothers have an increased risk of type 1 diabetes by performing a pooled analysis of previous studies using individual patient data to adjust for recognized confounders.
Relevant studies published before June 2009 were identified from MEDLINE, Web of Science, and EMBASE. Authors of studies were contacted and asked to provide individual patient data or conduct prespecified analyses. Risk estimates of type 1 diabetes by maternal age were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were used to derive combined odds ratios and to investigate heterogeneity among studies.
Data were available for 5 cohort and 25 case-control studies, including 14,724 cases of type 1 diabetes. Overall, there was, on average, a 5% (95% CI 2–9) increase in childhood type 1 diabetes odds per 5-year increase in maternal age (P = 0.006), but there was heterogeneity among studies (heterogeneity I2 = 70%). In studies with a low risk of bias, there was a more marked increase in diabetes odds of 10% per 5-year increase in maternal age. Adjustments for potential confounders little altered these estimates.
There was evidence of a weak but significant linear increase in the risk of childhood type 1 diabetes across the range of maternal ages, but the magnitude of association varied between studies. A very small percentage of the increase in the incidence of childhood type 1 diabetes in recent years could be explained by increases in maternal age.
PMCID: PMC2809958  PMID: 19875616
19.  Decreased IP-10 and Elevated TGFβ1 Levels are Associated with Viral Clearance Following Therapy in Patients with Hepatitis C Virus 
Disease markers  2010;28(5):273-280.
The role of pro-fibrogenic cytokines in the outcome of infections with hepatitis C virus (HCV) and the response to treatment with pegylated interferon-alpha (pegIFNα) and ribavirin remains unclear. To address this issue, we assessed hepatic fibrosis and plasma markers pertinent to T-cell mediated fibrogenesis and inflammation at the start of treatment. Levels of soluble (s)CD30, interleukin-13 receptor alpha 2 (IL-13Rα2), total and active transforming growth factor-beta 1 (TGFβ1), interleukin-18 (IL-18) and interferon-gamma inducible protein-10 (IP-10, CXCL10) were correlated with the severity of fibrosis and with treatment outcome using multiple logistic regression modelling. The Hepascore algorithm was confirmed as a marker of fibrosis, but was a poor predictor of treatment outcome. Inclusion of all immunological markers improved prediction based on Hepascore alone (p = 0.045), but optimal prediction was achieved with an algorithm (“TIPscore”) based on TGFβ1 (total), IP-10, age, sex and HCV genotype (p = 0.003 relative to Hepascore). Whilst this was only marginally more effective than predictions based on HCV genotype age and sex (p = 0.07), it associates high TGFβ1 and low IP-10 levels with a failure of therapy.
PMCID: PMC3833614  PMID: 20592450
Hepatitis C virus; interferon-based therapy; chemokines; fibrosis
20.  Does smoking status affect the likelihood of consulting a doctor about respiratory symptoms? A pilot survey in Western Australia 
BMC Family Practice  2009;10:16.
Smokers attribute respiratory symptoms, even when severe, to everyday causes and not as indicative of ill-health warranting medical attention. The aim of this pilot study was to conduct a structured vignette survey of people attending general practice to determine when they would advise a person with respiratory symptoms to consult a medical practitioner. Particular reference was made to smoking status and lung cancer.
Participants were recruited from two general practices in Western Australia. Respondents were invited to complete self-administered questionnaires containing nine vignettes chosen at random from a pool of sixty four vignettes, based on six clinical variables. Twenty eight vignettes described cases with at least 5% risk of cancer. For analysis these were dubbed 'cancer vignettes'. Respondents were asked if they would advise a significant other to consult a doctor with their respiratory symptoms. Logistic regression and non-parametric tests were used to analyse the data.
Three hundred questionnaires were distributed and one hundred and forty completed responses were collected over six weeks. The majority (70.3%) of respondents were female aged forty and older. A history of six weeks' of symptoms, weight loss, cough and breathlessness independently increased the odds of recommending a consultation with a medical practitioner by a factor of 11.8, 2.11, 1.40 and 4.77 respectively. A history of smoking independently increased the odds of the person being thought 'likely' or 'very likely' to have cancer by a factor of 2.46. However only 32% of cancer vignettes with a history of cigarette smoking were recognised as presentations of possible cancer.
Even though a history of cigarette smoking was more likely to lead to the suggestion that a symptomatic person may have cancer we did not confirm that smokers would be more likely to be advised to consult a doctor, even when presenting with common symptoms of lung cancer.
PMCID: PMC2652431  PMID: 19220917
21.  Comorbidity and repeat admission to hospital for adverse drug reactions in older adults: retrospective cohort study 
Objectives To identify factors that predict repeat admission to hospital for adverse drug reactions (ADRs) in older adults.
Design Population based retrospective cohort study.
Setting All public and private hospitals in Western Australia.
Participants 28 548 patients aged ≥60 years with an admission for an ADR during 1980-2000 followed for three years using the Western Australian data linkage system.
Results 5056 (17.7%) patients had a repeat admission for an ADR. Repeat ADRs were associated with sex (hazard ratio 1.08, 95% confidence interval 1.02 to 1.15, for men), first admission in 1995-9 (2.34, 2.00 to 2.73), length of hospital stay (1.11, 1.05 to 1.18, for stays ≥14 days), and Charlson comorbidity index (1.71, 1.46 to 1.99, for score ≥7); 60% of comorbidities were recorded and taken into account in analysis. In contrast, advancing age had no effect on repeat ADRs. Comorbid congestive cardiac failure (1.56, 1.43 to 1.71), peripheral vascular disease (1.27, 1.09 to 1.48), chronic pulmonary disease (1.61, 1.45 to 1.79), rheumatological disease (1.65, 1.41 to 1.92), mild liver disease (1.48, 1.05 to 2.07), moderate to severe liver disease (1.85, 1.18 to 2.92), moderate diabetes (1.18, 1.07 to 1.30), diabetes with chronic complications (1.91, 1.65 to 2.22), renal disease (1.93, 1.71 to 2.17), any malignancy including lymphoma and leukaemia (1.87, 1.68 to 2.09), and metastatic solid tumours (2.25, 1.92 to 2.64) were strong predictive factors. Comorbidities requiring continuing care predicted a reduced likelihood of repeat hospital admissions for ADRs (cerebrovascular disease 0.85, 0.73 to 0.98; dementia 0.62, 0.49 to 0.78; paraplegia 0.73, 0.59 to 0.89).
Conclusions Comorbidity, but not advancing age, predicts repeat admission for ADRs in older adults, especially those with comorbidities often managed in the community. Awareness of these predictors can help clinicians to identify which older adults are at greater risk of admission for ADRs and, therefore, who might benefit from closer monitoring.
PMCID: PMC2615549  PMID: 19129307
22.  Referring patients to specialists: A structured vignette survey of Australian and British GPs 
In Australia and in the United Kingdom (UK) access to specialists is sanctioned by General Practitioners (GPs). It is important to understand how practitioners determine which patients warrant referral.
A self-administered structured vignette postal survey of General Practitioners in Western Australia and the United Kingdom. Sixty-four vignettes describing patients with colorectal symptoms were constructed encompassing six clinical details. Nine vignettes, chosen at random, were presented to each individual. Respondents were asked if they would refer the patient to a specialist and how urgently. Logistic regression and parametric tests were used to analyse the data
We received 260 completed questionnaires. 58% of 'cancer vignettes' were selected for 'urgent' referral. 1632/2367 or 69% of all vignettes were selected for referral. After adjusting for clustering the model suggests that 38.4% of the variability is explained by all the clinical variables as well as the age and experience of the respondents. 1012 or 42.8 % of vignettes were referred 'urgently'. After adjusting for clustering the data suggests that 31.3 % of the variability is explained by the model. The age of the respondents, the location of the practice and all the clinical variables were significant in the decision to refer urgently.
GPs' referral decisions for patients with lower bowel symptoms are similar in the two countries. We question the wisdom of streaming referrals from primary care without a strong evidence base and an effective intervention for implementing guidelines. We conclude that implementation must take into account the profile of patients but also the characteristics of GPs and referral policies.
PMCID: PMC2262087  PMID: 18194578
23.  Assessing Liver Fibrosis with Serum Marker Models 
Clinical Biochemist Reviews  2007;28(1):3-10.
Chronic liver disease is characterised by liver fibrosis, which may lead to cirrhosis. Conventional serum-based liver function tests do not give information on either the presence or the rate of progress of liver fibrosis. The reference diagnostic test to detect fibrosis is liver biopsy, a procedure subject to various limitations, including risk of patient injury and sampling error.
Serum markers have been evaluated for the determination of fibrosis either singly or combined as a panel of markers, however diagnostic accuracy is greatest in studies using a panel together with an algorithm, which generates a predictive score. Serum marker models, especially those targeted at hepatitis C, have multiplied in spectacular fashion over the last five years, with most models regularly achieving a median area under the receiver operating characteristic curve (ROCC) of 0.80 versus liver biopsy. Five years after publication of the first major serum marker model, the first study to document clinical outcomes reported that applying the model to hepatitis C patients improved prediction of decompensated cirrhosis and survival compared to liver biopsy.
An obstacle to widespread adoption of serum marker models has been the lack of uniform performance indicators, such as diagnostic odds ratios and likelihood ratios. At present, serum marker models are not considered sufficiently reliable to replace liver biopsy in patients with chronic liver disease. However with continued evaluation in parallel with liver biopsy rapid advances are being made.
PMCID: PMC1904421  PMID: 17603636
24.  Pregnancy after breast cancer: population based study 
BMJ : British Medical Journal  2006;334(7586):194.
Objectives To identify women who survived breast cancer and subsequently conceived and to determine the rate of pregnancy (proportion), management, outcome of the cancer, and outcome of the first subsequent pregnancy.
Design Population based descriptive study with cases identified from the Western Australian data linkage system and validated by review of medical charts. Supplementary data obtained from hospital and clinician records.
Setting Western Australia, 1982-2003.
Participants Women aged <45 with a diagnosis of breast cancer who subsequently conceived.
Main outcome measures Pregnancy outcome and rate, survival, time from diagnosis to pregnancy.
Results Sixty two (54%) women with a diagnosis of breast cancer who subsequently conceived did so less than two years after their diagnosis: 29 of them had an abortion, 27 had a live birth, and six miscarried. Within a proportional hazards regression model subsequent pregnancy was associated with improved overall survival (hazard ratio 0.59, 95% confidence interval 0.37 to 0.95). When the model was stratified by time from diagnosis subsequent pregnancy was associated with improved overall survival in women who waited at least 24 months to conceive (0.48, 0.27 to 0.83) and a non-significant protective effect was seen for women who waited at least six months to become pregnant.
Conclusions Our study does not support the current medical advice given to premenopausal women with a diagnosis of with breast cancer to wait two years before attempting to conceive. This recommendation may be valid for women who are receiving treatment or have systemic disease at diagnosis, but for women with localised disease early conception, six months after completing their treatment, is unlikely to reduce survival.
PMCID: PMC1781958  PMID: 17158581
25.  Constructing indices representing supportiveness of the physical environment for walking using the Rasch measurement model 
The objectives of this study were to use the Rasch model to 1) assess the psychometric properties of a physical environmental audit instrument and 2) to develop indices of interrelated environmental attributes that summarize environmental supportiveness for walking.
A set of items were derived representing two conceptual physical environmental constructs: 1) functional/safety, and; 2) aesthetics. Ad hoc criteria based on point-biserial and Rasch-based fit statistics were used to examine the construct validity and internal reliability of the two constructs.
The Rasch-based fit statistics assisted in identifying 12 items that belonged to the functional/safety construct and 4 items that belonged to the aesthetic construct. The reliability of the two constructs were low to moderate (functional/safety rβ = 0.19 and aesthetics rβ = 0.35).
Given the vast number of built environmental attributes, a means of developing summary indices is essential. Future studies should assess the reliability and validity of indices that summarize physical environmental characteristics conducive to walking before testing them in predictive models of physical activity. More research examining procedures for measuring the built environment and techniques for analyzing environmental data are needed to guide future research in this area.
PMCID: PMC1764897  PMID: 17173695

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