Publications by authors named "David Whiteman"

425 Publications

Examining Evidence For A Causal Association Between Telomere Length & Nevus Count.

J Invest Dermatol 2021 Oct 14. Epub 2021 Oct 14.

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.

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http://dx.doi.org/10.1016/j.jid.2021.09.021DOI Listing
October 2021

Predicting obesity and smoking using medication data: A machine-learning approach.

Pharmacoepidemiol Drug Saf 2021 Oct 5. Epub 2021 Oct 5.

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Purpose: Administrative health datasets are widely used in public health research but often lack information about common confounders. We aimed to develop and validate machine learning (ML)-based models using medication data from Australia's Pharmaceutical Benefits Scheme (PBS) database to predict obesity and smoking.

Methods: We used data from the D-Health Trial (N = 18 000) and the QSkin Study (N = 43 794). Smoking history, and height and weight were self-reported at study entry. Linkage to the PBS dataset captured 5 years of medication data after cohort entry. We used age, sex, and medication use, classified using anatomical therapeutic classification codes, as potential predictors of smoking (current or quit <10 years ago; never or quit ≥10 years ago) and obesity (obese; non-obese). We trained gradient-boosted machine learning models using data for the first 80% of participants enrolled; models were validated using the remaining 20%. We assessed model performance overall and by sex and age, and compared models generated using 3 and 5 years of PBS data.

Results: Based on the validation dataset using 3 years of PBS data, the area under the receiver operating characteristic curve was 0.70 (95% confidence interval [CI] 0.68-0.71) for predicting obesity and 0.71 (95% CI 0.70-0.72) for predicting smoking. Models performed better in women than in men. Using 5 years of PBS data resulted in marginal improvement.

Conclusions: Medication data in combination with age and sex can be used to predict obesity and smoking. These models may be of value to researchers using data collected for administrative purposes.
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http://dx.doi.org/10.1002/pds.5367DOI Listing
October 2021

Cigarette Smoking and Estrogen-Related Cancer-Letter.

Cancer Epidemiol Biomarkers Prev 2021 Oct;30(10):1977

Department of Population Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

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http://dx.doi.org/10.1158/1055-9965.EPI-21-0666DOI Listing
October 2021

Out-of-pocket medical expenses compared across five years for patients with one of five common cancers in Australia.

BMC Cancer 2021 Sep 25;21(1):1055. Epub 2021 Sep 25.

QIMR Berghofer Medical Research Institute, Population Health Department, Herston, Brisbane, Q4006, Australia.

Background: Patient medical out-of-pocket expenses are thought to be rising worldwide yet data describing trends over time is scant. We evaluated trends of out-of-pocket expenses for patients in Australia with one of five major cancers in the first-year after diagnosis.

Methods: Participants from the QSKIN Sun and Health prospective cohort Study with a histologically confirmed breast, colorectal, lung, melanoma, or prostate cancer diagnosed between 2011 and 2015 were included (n = 1965). Medicare claims data on out-of-pocket expenses were analysed using a two-part model adjusted for year of diagnosis, health insurance status, age and education level. Fisher price and quantity indexes were also calculated to assess prices and volumes separately.

Results: On average, patients with cancer diagnosed in 2015 spent 70% more out-of-pocket on direct medical expenses than those diagnosed in 2011. Out-of-pocket expenses increased significantly for patients with breast cancer (mean AU$2513 in 2011 to AU$6802 in 2015). Out-of-pocket expenses were higher overall for individuals with private health insurance. For prostate cancer, expenses increased for those without private health insurance over time (mean AU$1586 in 2011 to AU$4748 in 2014) and remained stable for those with private health insurance (AU$4397 in 2011 to AU$5623 in 2015). There were progressive increases in prices and quantities of medical services for patients with melanoma, breast and lung cancer. For all cancers, prices increased for medicines and doctor attendances but fluctuated for other medical services.

Conclusion: Out-of-pocket expenses for patients with cancer have increased substantially over time. Such increases were more pronounced for women with breast cancer and those without private health insurance. Increased out-of-pocket expenses arose from both higher prices and higher volumes of health services but differ by cancer type. Further efforts to monitor patient out-of-pocket costs and prevent health inequities are required.
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http://dx.doi.org/10.1186/s12885-021-08756-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466922PMC
September 2021

Assessing the genetic relationship between gastro-esophageal reflux disease and risk of COVID-19 infection.

Hum Mol Genet 2021 Sep 6. Epub 2021 Sep 6.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Brisbane, Australia.

Background: Symptoms related with Gastro-esophageal reflux disease (GERD) were previously shown to be linked with increased risk for the 2019 coronavirus disease (COVID-19). We aim to interrogate the possibility of a shared genetic basis between GERD and COVID-19 outcomes.

Methods: Using published GWAS data for GERD (78 707 cases; 288 734 controls) and COVID-19 susceptibility (up to 32 494 cases; 1.5 million controls), we examined the genetic relationship between GERD and three COVID-19 outcomes: risk of developing severe COVID-19, COVID-19 hospitalization and overall COVID-19 risk. We estimated the genetic correlation between GERD and COVID-19 outcomes followed by Mendelian randomization (MR) analyses to assess genetic causality. Conditional analyses were conducted to examine whether known COVID-19 risk factors (obesity, smoking, type-II diabetes, coronary artery disease) can explain the relationship between GERD and COVID-19.

Results: We found small to moderate genetic correlations between GERD and COVID-19 outcomes (rg between 0.06-0.24). MR analyses revealed a OR of 1.15 (95% CI: 0.96-1.39) for severe COVID-19; 1.16 (1.01-1.34) for risk of COVID-19 hospitalization; 1.05 (0.97-1.13) for overall risk of COVID-19 per doubling of odds in developing GERD. The genetic correlation/associations between GERD and COVID-19 showed mild attenuation towards the null when obesity and smoking was adjusted for.

Conclusions: Susceptibility for GERD and risk of COVID-19 hospitalization were genetically correlated, with MR findings supporting a potential causal role between the two. The genetic association between GERD and COVID-19 was partially attenuated when obesity is accounted for, consistent with obesity being a major risk factor for both diseases.
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http://dx.doi.org/10.1093/hmg/ddab253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522419PMC
September 2021

"Repeatability of Repeatability": the stability of self-reported melanoma risk factors in two independent samples.

Aust N Z J Public Health 2021 Oct 2;45(5):469-473. Epub 2021 Sep 2.

Cancer Control Group, QIMR Berghofer Medical Research Institute, Queensland.

Objective: To determine the test-retest repeatability of a self-completed survey with items capturing skin cancer risk factors.

Methods: We invited 238 randomly selected participants of the QSkin II cohort to complete the baseline survey a second time. Responses were compared using kappa statistics and intraclass correlation coefficients to quantify agreement for categorical and continuous variables, respectively. We compared the performance of key items with that observed in an earlier repeatability study using the same survey instrument in an independent cohort.

Results: Measures of phenotypic characteristics had moderate to almost-perfect test-retest repeatability (e.g. eye colour weighted kappa (κ ) = 0.87, 95% confidence interval [CI]: 0.81, 0.92). Items measuring sun exposure showed lower agreement (κ range 0.36-0.54) compared with phenotypic characteristics (κ range 0.59-0.87). Items relating to treatment of skin cancers demonstrated almost-perfect test-retest repeatability (e.g. excisions for skin cancers κ 0.85, 95%CI: 0.80, 0.89). In aggregate, the repeatability of key items was very similar across the two independent repeatability samples.

Conclusion: Fair to almost-perfect repeatability for self-reported skin cancer risk factors was robust across independent and temporally distant cohorts. Implications for public health: These self-assessed risk factors for skin cancer are repeatable and suitable for use in clinical practice and research.
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http://dx.doi.org/10.1111/1753-6405.13147DOI Listing
October 2021

Polygenic Risk Scores Derived From Varying Definitions of Depression and Risk of Depression.

JAMA Psychiatry 2021 Oct;78(10):1152-1160

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.

Importance: Genetic studies with broad definitions of depression may not capture genetic risk specific to major depressive disorder (MDD), raising questions about how depression should be operationalized in future genetic studies.

Objective: To use a large, well-phenotyped single study of MDD to investigate how different definitions of depression used in genetic studies are associated with estimation of MDD and phenotypes of MDD, using polygenic risk scores (PRSs).

Design, Setting, And Participants: In this case-control polygenic risk score analysis, patients meeting diagnostic criteria for a diagnosis of MDD were drawn from the Australian Genetics of Depression Study, a cross-sectional, population-based study of depression, and controls and patients with self-reported depression were drawn from QSkin, a population-based cohort study. Data analyzed herein were collected before September 2018, and data analysis was conducted from September 10, 2020, to January 27, 2021.

Main Outcome And Measures: Polygenic risk scores generated from genome-wide association studies using different definitions of depression were evaluated for estimation of MDD in and within individuals with MDD for an association with age at onset, adverse childhood experiences, comorbid psychiatric and somatic disorders, and current physical and mental health.

Results: Participants included 12 106 (71% female; mean age, 42.3 years; range, 18-88 years) patients meeting criteria for MDD and 12 621 (55% female; mean age, 60.9 years; range, 43-87 years) control participants with no history of psychiatric disorders. The effect size of the PRS was proportional to the discovery sample size, with the largest study having the largest effect size with the odds ratio for MDD (1.75; 95% CI, 1.73-1.77) per SD of PRS and the PRS derived from ICD-10 codes documented in hospitalization records in a population health cohort having the lowest odds ratio (1.14; 95% CI, 1.12-1.16). When accounting for differences in sample size, the PRS from a genome-wide association study of patients meeting diagnostic criteria for MDD and control participants was the best estimator of MDD, but not in those with self-reported depression, and associations with higher odds ratios with childhood adverse experiences and measures of somatic distress.

Conclusions And Relevance: These findings suggest that increasing sample sizes, regardless of the depth of phenotyping, may be most informative for estimating risk of depression. The next generation of genome-wide association studies should, like the Australian Genetics of Depression Study, have both large sample sizes and extensive phenotyping to capture genetic risk factors for MDD not identified by other definitions of depression.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.1988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358814PMC
October 2021

Vitamin D supplementation and risk of falling: outcomes from the randomized, placebo-controlled D-Health Trial.

J Cachexia Sarcopenia Muscle 2021 Aug 1. Epub 2021 Aug 1.

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Background: Falls cause considerable morbidity and mortality in older people. It is unclear how vitamin D supplementation affects falls risk, particularly when taken at high doses. We sought to determine whether monthly high-dose vitamin D supplementation reduces risk and incidence of falls.

Methods: We used data from the randomized, double-blind, placebo-controlled D-Health Trial conducted in Australia. Between February 2014 and May 2015, 21 315 participants aged 60-84 years were randomized (1:1) to monthly doses of either 60 000 IU of colecalciferol or placebo for a maximum of 5 years. People who reported a history of osteomalacia, sarcoidosis, hyperparathyroidism, hypercalcaemia or kidney stones or who were taking >500 IU/day supplementary vitamin D were ineligible. Each year, we collected blood samples from ~450 randomly sampled participants from each trial arm and measured 25-hydroxyvitamin D [25(OH)D]. Falls, a prespecified tertiary outcome, were ascertained using annual surveys and, for a subset of participants, 3-month falls diaries. The primary outcome for this analysis was any fall in the month before completing an annual survey. As part of our process to maintain blinding, we used random samples of participants (surveys, n = 16 000; diaries, n = 2400), with equal numbers per group. Participants with no outcome data were excluded. Following an intention-to-treat approach, we analysed outcomes using logistic, ordinal and negative binomial regression. Registration: Australian New Zealand Clinical Trials Registry (ACTRN12613000743763); registered 4 July 2013.

Results: Mean treatment duration was 4.3 years (standard deviation [SD] = 1.4 years). Mean serum 25(OH)D concentrations during the trial were 114.8 (SD 30.3) nmol/L and 77.5 (SD 25.2) nmol/L in the vitamin D and placebo groups, respectively. Survey and diary analytic sets included 15 416 and 2200 participants, respectively; approximately half were randomized to vitamin D (surveys: 50.1%; diaries: 50.4%). Vitamin D had no effect on falling in the past month (odds ratio [OR] 1.02, 95% confidence interval [CI] 0.95-1.10). There was an interaction with body mass index (BMI) (P-interaction = 0.001); vitamin D increased risk in participants with BMI < 25 kg/m (OR 1.25, 95% CI 1.09-1.43), but there was no effect in those with BMI ≥ 25 kg/m (OR 0.95, 95% CI 0.87-1.04). Analyses of diary data were consistent with these findings. The incidence of hypercalcaemia and kidney stones did not differ between groups.

Conclusions: Monthly high-dose vitamin D supplementation did not reduce risk of falling. A possible increased risk of falling with vitamin D supplementation in people with normal BMI warrants further investigation.
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http://dx.doi.org/10.1002/jcsm.12759DOI Listing
August 2021

Polygenic Risk Scores Stratify Keratinocyte Cancer Risk among Solid Organ Transplant Recipients with Chronic Immunosuppression in a High Ultraviolet Radiation Environment.

J Invest Dermatol 2021 Jun 2. Epub 2021 Jun 2.

Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia.

Solid organ transplant recipients (SOTRs) have elevated risks for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), especially in high UVR environments. We assessed whether polygenic risk scores can improve the prediction of BCC and SCC risks and multiplicity over and above the traditional risk factors in SOTRs in a high UV setting. We built polygenic risk scores for BCC (n = 594,881) and SCC (n = 581,431) using UK Biobank and 23andMe datasets, validated them in the Australian QSkin Sun and Health Study cohort (n > 6,300), and applied them in SOTRs in the skin tumor in allograft recipients cohort from Queensland, Australia, a high UV environment. About half of the SOTRs with a high genetic risk developed BCC (absolute risk = 45.45%, 95% confidence interval = 33.14-58.19%) and SCC (absolute risk = 44.12%, 95% confidence interval = 32.08-56.68%). For both cancers, SOTRs in the top quintile were at >3-fold increased risk relative to those in the bottom quintile. The respective polygenic risk scores improved risk predictions by 2% for BCC (area under the curve = 0.77 vs. 0.75, P = 0.0691) and SCC (area under the curve = 0.84 vs. 0.82, P = 0.0260), over and above the established risk factors, and 19.03% (for BCC) and 18.10% (for SCC) of the SOTRs were reclassified in a high/medium/low risk scenario. The polygenic risk scores also added predictive accuracy for tumor multiplicity (BCC R = 0.21 vs. 0.19, P = 3.2 × 10; SCC R = 0.30 vs. 0.27, P = 4.6 × 10).
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http://dx.doi.org/10.1016/j.jid.2021.03.034DOI Listing
June 2021

Polyunsaturated Fatty Acid Levels and the Risk of Keratinocyte Cancer: A Mendelian Randomization Analysis.

Cancer Epidemiol Biomarkers Prev 2021 Aug 4;30(8):1591-1598. Epub 2021 Jun 4.

Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Background: Keratinocyte cancer is the commonest cancer, imposing a high economic burden on the health care system. Observational studies have shown mixed associations between polyunsaturated fatty acids (PUFA) and keratinocyte cancer, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We explored whether genetically predicted PUFA levels are associated with BCC and SCC risks.

Methods: We conducted a two-sample Mendelian randomization study using PUFA level genome-wide association studies (GWAS) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium ( > 8,000), and the meta-analysis GWASs from UKB, 23andMe, and Qskin for BCC ( = 651,138) and SCC ( = 635,331) risk.

Results: One SD increase in genetically predicted levels of linoleic acid [OR = 0.94, 95% confidence interval (CI) = 0.91-0.97, = 1.4 × 10] and alpha-linolenic acid (OR = 0.91, 95% CI = 0.86-0.96, = 5.1 × 10) was associated with a reduced BCC risk, while arachidonic acid (OR = 1.04, 95% CI = 1.02-1.06, = 3.2 × 10) and eicosapentaenoic acid (OR = 1.10, 95% CI = 1.04-1.16, = 1.5 × 10) were associated with an increased BCC risk.

Conclusions: Higher genetically predicted levels of linoleic acid and alpha-linolenic acid were associated with a reduced BCC risk, but arachidonic acid and eicosapentaenoic acid were associated with a higher BCC risk.

Impact: PUFA-related diet and supplementation could influence BCC etiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1765DOI Listing
August 2021

Epidemiology of cutaneous melanoma and keratinocyte cancer in white populations 1943-2036.

Eur J Cancer 2021 Jul 29;152:18-25. Epub 2021 May 29.

QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia; The University of Queensland, School of Public Health, Herston Road, Herston, QLD 4006, Australia.

Objectives: Cutaneous melanoma (CM) and keratinocyte cancer (KC) cause considerable morbidity and mortality. We analysed long-term trends of CM and KC in different white populations.

Material And Methods: Age-standardised (European Standard Population 2013) incidence and mortality rates (ASIR, ASMR) of CM were extracted from cancer registries in Denmark, New Zealand and the US SEER-Database. ASIRs of KC were sourced from registries of the German federal states Saarland and Schleswig-Holstein, and from Scotland. Age-period-cohort models were used to project melanoma incidence trends.

Results: In Denmark between 1943 and 2016, melanoma ASIR increased from 1.1 to 46.5 in males, and from 1.0 to 48.5 in females, estimated to reach 60.0 and 73.1 in males and females by 2036. Melanoma mortality in Denmark (1951-2016) increased from 1.4 to 6.7 (males) and 1.2 to 3.7 (females). In New Zealand between 1948 and 2016, ASIR increased from 2.7 to 81.0 (males) and from 3.8 to 54.7 (females), slight declines are estimated by 2036 for both genders. Melanoma mortality increased six-fold in New Zealand males between 1950 and 2016; smaller increases were observed in females. We observed three- to four-fold increases in melanoma incidence in US whites, predicted to rise to 56.1 and 36.2 in males and females until 2036. Melanoma mortality also increased among US whites between 1970 and 2017, female melanoma mortality remained stable. Similar trends are shown for KC.

Conclusions: In white populations, incidence of CM and KC significantly increased. CM incidence continues to rise in the short term but is predicted to decline in future.
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http://dx.doi.org/10.1016/j.ejca.2021.04.029DOI Listing
July 2021

Patient and Tumour Characteristics of Keratoacanthoma in a Large, Community-based Cohort Study from Queensland, Australia.

Acta Derm Venereol 2021 Jun 2;101(6):adv00469. Epub 2021 Jun 2.

Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Keratoacanthomas are common keratinocyte skin tumours. However, there is little community-based data published on the clinical features of keratoacanthoma. The aim of this study was to describe the patient and tumour characteristics of keratoacanthomas, as well as their treatment patterns. Data were obtained from the QSkin Sun and Health study, a prospective cohort of 40,438 randomly sampled and consented participants aged 40-69 years in Queensland, Australia. In 2010, a baseline survey collected data, including demography, phenotype, ultraviolet radiation exposure, medical history and lifestyle. Histopathological reports of keratoacanthomas arising until 30 June 2014 were reviewed. In total, 584 participants developed 738 keratoacanthomas; 18% of participants developed multiple tumours. Common patient characteristics were male sex (58%), age ≥60 years (76%), fair skin (80%), and previous history of actinic keratoses/keratinocyte cancers (89%). Keratoacanthomas were commonly located on the legs/feet (48%), and rarely on the the head/neck (7%). Excision was the most frequently used surgical method (71%) Evidence of histopathological regression was reported in 67% of keratoacanthomas, suggesting a potential for spontan-eous resolution in a significant proportion of keratoacanthomas.
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http://dx.doi.org/10.2340/00015555-3824DOI Listing
June 2021

International Increases in Merkel Cell Carcinoma Incidence Rates between 1997 and 2016.

J Invest Dermatol 2021 Apr 28. Epub 2021 Apr 28.

Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Australia. Electronic address:

Relatively little is known about the epidemiology of Merkel cell carcinoma (MCC) with regard to international trends in incidence, specifically relating to differences by age, sex, and anatomic site. We examined the trends in sex-specific incidence of MCC in the United States, Australia, New Zealand, Scotland, and Norway over a 20-year period (1997-2016) as well as the site-specific incidence trends in the United States. We used Joinpoint regression models to estimate the average annual percentage change in the incidence. In the total United States population, we observed an average annual percentage change of 2.7% (95% confidence interval [CI] = 2.0-3.3) for MCC, with sex-specific incidence increasing from 0.55 to 1.03 per 100,000 in men and from 0.28 to 0.45 per 100,000 in women. MCC incidence also increased in Queensland, Australia (average annual percentage change 1.8%, 95% CI = 0.7-2.8), New Zealand (2.0%, 95% CI = 0.4-3.7), Scotland (3.7%, 95% CI = 2.0-5.5), and Norway (4.0%, 95% CI = 2.1-5.9). In all populations, MCC incidence was higher in men than in women. Between 1993 and 2016 in the United States, the incidence of MCC of the head and neck and upper and lower limbs increased in both sexes. Despite being an uncommon malignancy, our analyses show that MCC incidence is steadily increasing both in areas of low and those of high ambient UVR levels.
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http://dx.doi.org/10.1016/j.jid.2021.04.007DOI Listing
April 2021

International Trends in Esophageal Squamous Cell Carcinoma and Adenocarcinoma Incidence.

Am J Gastroenterol 2021 05;116(5):1072-1076

Section of Cancer Surveillance, International Agency for Research on Cancer, Lyon, France.

Introduction: We aimed to improve our understanding of the epidemiology of squamous cell carcinoma and adenocarcinoma of the esophagus.

Methods: We estimated average annual percent change and analyzed age-period-cohort trends on population-based cancer data.

Results: We found decreases in squamous cell carcinoma incidence in half of male populations (largest decrease in US black males [average annual percent change -7.6]) and increases in adenocarcinoma incidence in nearly a third of populations. Trends may be associated with a mix of birth cohort and period effects.

Discussion: More complete data and evidence are needed to conclude the reasons for the observed trends (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/AJG/B823).
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http://dx.doi.org/10.14309/ajg.0000000000001121DOI Listing
May 2021

Predicting deseasonalised serum 25 hydroxy vitamin D concentrations in the D-Health Trial: An analysis using boosted regression trees.

Contemp Clin Trials 2021 05 6;104:106347. Epub 2021 Mar 6.

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Public Health, The University of Queensland, Brisbane, Australia. Electronic address:

Background: The D-Health Trial aims to determine whether monthly high-dose vitamin D supplementation can reduce the mortality rate and prevent cancer. We did not have adequate statistical power for subgroup analyses, so could not justify the high cost of collecting blood samples at baseline. To enable future exploratory analyses stratified by baseline vitamin D status, we developed models to predict baseline serum 25 hydroxy vitamin D [25(OH)D] concentration.

Methods: We used data and serum 25(OH)D concentrations from participants who gave a blood sample during the trial for compliance monitoring and were randomised to placebo. Data were partitioned into training (80%) and validation (20%) datasets. Deseasonalised serum 25(OH)D concentrations were dichotomised using cut-points of 50, 60 and 75 nmol/L. We fitted boosted regression tree models, based on 13 predictors, and evaluated model performance using the validation data.

Results: The training and validation datasets had 1788 (10.5% <50 nmol/L, 23.1% <60 nmol, 48.8 <75 nmol/L) and 447 (11.9% <50 nmol/L, 25.7% <60 nmol/L, and 49.2% <75 nmol/L) samples, respectively. Ambient UV radiation and total intake of vitamin D were the strongest predictors of 'low' serum 25(OH)D concentration. The area under the receiver operating characteristic curves were 0.71, 0.70, and 0.66 for cut-points of <50, <60 and <75 nmol/L respectively.

Conclusions: We exploited compliance monitoring data to develop models to predict serum 25(OH)D concentration for D-Health participants at baseline. This approach may prove useful in other trial settings where there is an obstacle to exhaustive data collection.
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http://dx.doi.org/10.1016/j.cct.2021.106347DOI Listing
May 2021

The effect of vitamin D supplementation on acute respiratory tract infection in older Australian adults: an analysis of data from the D-Health Trial.

Lancet Diabetes Endocrinol 2021 02 11;9(2):69-81. Epub 2021 Jan 11.

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Public Health, the University of Queensland, Brisbane, QLD, Australia. Electronic address:

Background: Observational studies have linked vitamin D deficiency with acute respiratory tract infection, but results from randomised controlled trials are heterogeneous. We analysed data from the D-Health Trial to determine whether supplementing older Australian adults, recruited from the general population, with monthly doses of vitamin D reduced the risk, duration, and severity of acute respiratory tract infections.

Methods: We used data from the D-Health Trial, a randomised, double-blind, placebo-controlled trial of monthly vitamin D supplementation, for which acute respiratory infection was a pre-specified trial outcome. Participants were supplemented and followed for up to 5 years. The trial was set within the Australian general population, using the Commonwealth Electoral Roll as the sampling frame, but also allowing some volunteers to participate. Participants were men and women aged 60 to 79 years (with volunteers up to age 84 years). Participants were randomly assigned to receive either vitamin D or placebo (1:1) using computer-generated permuted block randomisation, which was stratified by age, sex, and state. This was an automated process and the assignment list was not visible to study staff or investigators. Active and placebo gel capsules, identical in appearance to ensure masking, were labelled A and B and the code was not available to study staff or investigators. Participants were asked to report occurrence of acute respiratory symptoms over the previous month via annual surveys, and a subset of participants completed 8-week respiratory symptom diaries in winter. As part of our process to maintain blinding, a random sample of participants was selected for analysis of survey data and a separate sample selected for analysis of diary data. Blood samples were obtained from a random sample of participants (about 450 per group per year) and serum 25-hydroxy vitamin D (25[OH]D) concentrations were measured to monitor adherence. We used regression models to estimate odds ratios (OR), rate ratios, and rate differences. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763.

Findings: Between Jan 13, 2014, and May 26, 2015, 421 207 invitations were sent, 40 824 people were interested in participating, and 21 315 participants were recruited and randomised. Of the 16 000 participants selected for potential analysis of survey data, 15 373 were included in the analysis; 295 in the vitamin D group and 332 in the placebo group who were missing data for all five annual surveys were excluded from the analysis. Of the 3800 selected for potential analysis of diary data, 3070 were invited to complete the diaries because 730 had already withdrawn. 2598 people were included in the analysis; 218 people in the vitamin D group and 254 in the placebo group were missing data and were therefore excluded from the analysis. In blood samples collected from randomly sampled participants throughout the trial, the mean serum 25(OH)D concentration was 114·8 (SD 30·3) nmol/L in the vitamin D group and 77·5 (25·2) nmol/L in the placebo group. Vitamin D supplementation did not reduce the risk of acute respiratory tract infection (survey OR 0·98, 95% CI 0·93 to 1·02; diary OR 0·98, 0·83 to 1·15). Analyses of diary data showed reductions in the overall duration of symptoms and of severe symptoms, but these were small and unlikely to be clinically significant.

Interpretation: Monthly bolus doses of 60 000 IU of vitamin D did not reduce the overall risk of acute respiratory tract infection, but could slightly reduce the duration of symptoms in the general population. These findings suggest that routine vitamin D supplementation of a population that is largely vitamin D replete is unlikely to have a clinically relevant effect on acute respiratory tract infection.

Funding: National Health and Medical Research Council.
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http://dx.doi.org/10.1016/S2213-8587(20)30380-6DOI Listing
February 2021

Germline variants are associated with increased primary melanoma tumor thickness at diagnosis.

Hum Mol Genet 2021 01;29(21):3578-3587

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia.

Germline genetic variants have been identified, which predispose individuals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness. To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness. The analyses utilized 10 604 individuals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated individuals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 individuals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry. We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P < 5 × 10-8) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.
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http://dx.doi.org/10.1093/hmg/ddaa222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788289PMC
January 2021

Genetically determined risk of keratinocyte carcinoma and risk of other cancers.

Int J Epidemiol 2021 08;50(4):1316-1324

Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Background: Epidemiological studies have consistently documented an increased risk of developing primary non-cutaneous malignancies among people with a history of keratinocyte carcinoma (KC). However, the mechanisms underlying this association remain unclear. We conducted two separate analyses to test whether genetically predicted KC is related to the risk of developing cancers at other sites.

Methods: In the first approach (one-sample), we calculated the polygenic risk scores (PRS) for KC using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 16 896). The association between the KC PRS and each cancer site was assessed using logistic regression. In the secondary (two-sample) approach, we used genome-wide association study (GWAS) summary statistics identified from the most recent GWAS meta-analysis of KC and obtained GWAS data for each cancer site from the UK-Biobank participants only. We used inverse-variance-weighted methods to estimate risks across all genetic variants.

Results: Using the one-sample approach, we found that the risks of cancer at other sites increased monotonically with KC PRS quartiles, with an odds ratio (OR) of 1.16, 95% confidence interval (CI): 1.13-1.19 for those in KC PRS quartile 4 compared with those in quartile 1. In the two-sample approach, the pooled risk of developing other cancers was statistically significantly elevated, with an OR of 1.05, 95% CI: 1.03-1.07 per doubling in the odds of KC. We observed similar trends of increasing cancer risk with increasing KC PRS in the QSkin cohort.

Conclusion: Two different genetic approaches provide compelling evidence that an instrumental variable for KC constructed from genetic variants predicts the risk of cancers at other sites.
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http://dx.doi.org/10.1093/ije/dyaa265DOI Listing
August 2021

Early detection of melanoma in specialised primary care practice in Australia.

Cancer Epidemiol 2021 02 24;70:101872. Epub 2020 Dec 24.

Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, 4006, Australia. Electronic address:

Background: Primary care skin cancer clinics facilitate early treatment of melanoma in Australia. We investigated the clinical and histopathological features of melanomas diagnosed and treated in an established clinic in Brisbane.

Methods: Retrospective audit of medical records of patients diagnosed with in situ or invasive primary cutaneous melanoma in a primary care clinic specializing in skin cancer, 2000-2017. Demographic and clinical data were standardly extracted by a medically-trained investigator. We used descriptive analyses to assess characteristics of patients and melanomas, and examine surgical management according to tumour thickness.

Results: Of 380 patients (median age 57 years; 57 % male) newly diagnosed with 497 histologically-confirmed primary cutaneous melanomas, 369 were in situ and 128 invasive. Of the 369 in situ melanomas, 143 (39 %) were on the trunk and 87 (24 %) on the head and neck; 247 (67 %) were diagnosed by shave biopsy; and 141 (38 %) referred for wide local excision (WLE). Of the 128 invasive melanomas, only 21 (16 %) had thickness ≥ 0.8 mm and these occurred more often on head and neck than thin invasive melanomas (p = 0.02). The majority of invasive melanomas were diagnosed by excision biopsy, and WLE was carried out in a median of 3 days (melanomas ≥ 0.8 mm) and 2 days (<0.8 mm). The doctor detected the majority of in situ (83 %) and thin invasive (73 %) melanomas during surveillance, compared with 48 % of thicker invasive melanomas ≥ 0.8 mm (p < 0.001).

Conclusion: In Australia, specialised primary care practice plays a major role in detection and treatment of early primary melanoma.
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http://dx.doi.org/10.1016/j.canep.2020.101872DOI Listing
February 2021

Accuracy of mobile digital teledermoscopy for skin self-examinations in adults at high risk of skin cancer: an open-label, randomised controlled trial.

Lancet Digit Health 2020 03 20;2(3):e129-e137. Epub 2020 Feb 20.

The Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia; Dermatology Department, Princess Alexandra Hospital, Brisbane, QLD, Australia.

Background: Skin self-examinations supplemented with mobile teledermoscopy might improve early detection of skin cancers compared with naked-eye skin self-examinations. We aimed to assess whether mobile teledermoscopy-enhanced skin self-examination can improve sensitivity and specificity of self-detection of skin cancers when compared with naked-eye skin self-examination.

Methods: This randomised, controlled trial was done in Brisbane (QLD, Australia). Eligible participants (aged ≥18 years) had at least two skin cancer risk factors as self-reported in the eligibility survey and had to own or have access to an iPhone compatible with a dermatoscope attachment (iPhone versions 5-8). Participants were randomly assigned (1:1), via a computer-generated randomisation procedure, to the intervention group (mobile dermoscopy-enhanced self-skin examination) or the control group (naked-eye skin self-examination). Control group and intervention group participants received web-based instructions on how to complete a whole body skin self-examination. All participants completed skin examinations at baseline, 1 month, and 2 months; intervention group participants submitted photographs of suspicious lesions to a dermatologist for telediagnosis after each skin examination and control group participants noted lesions on a body chart that was sent to the research team after each skin examination. All participants had an in-person whole-body clinical skin examination within 3 months of their last skin self-examination. Primary outcomes were sensitivity and specificity of skin self-examination, patient selection of clinically atypical lesions suspicious for melanoma or keratinocyte skin cancers (body sites examined, number of lesions photographed, types of lesions, and lesions missed), and diagnostic concordance of telediagnosis versus in-person whole-body clinical skin examination diagnosis. All primary outcomes were analysed in the modified intention-to-treat population, which included all patients who had a clinical skin examination within 3 months of their last skin self-examination. This trial was registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12616000989448.

Findings: Between March 6, 2017, and June 7, 2018, 234 participants consented to enrol in the study, of whom 116 (50%) were assigned to the intervention group and 118 (50%) were assigned to the control group. 199 participants (98 participants in the intervention group and 101 participants in the control group) attended the clinical skin examination and thus were eligible for analyses. Participants in the intervention group submitted 615 lesions (median 6·0 per person; range 1-24) for telediagnosis and participants in the control group identified and recorded 673 lesions (median 6·0 per person; range 1-16). At the lesion level, sensitivity for lesions clinically suspicious for skin cancer was 75% (95% CI 63-84) in the intervention group and 88% (95% CI 80-91) in the control group (p=0·04). Specificity was 87% (95% CI 85-90) in the intervention group and 89% (95% CI 87-91) in the control group (p=0·42). At the individual level, the intervention group had a sensitivity of 87% (95% CI 76-99) compared with 97% (95% CI 91-100) in the control group (p=0·26), and a specificity of 95% (95% CI 90-100) compared with 96% (95% CI 91-100) in the control group. The overall diagnostic concordance between the telediagnosis and in-person clinical skin examination was 88%.

Interpretation: The use of mobile teledermoscopy did not increase sensitivity for the detection of skin cancers compared with naked-eye skin self-examination; thus, further evidence is necessary for inclusion of skin self-examination technology for public health benefit.

Funding: National Health and Medical Research Council (Australia).
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http://dx.doi.org/10.1016/S2589-7500(20)30001-7DOI Listing
March 2020

Natural history of oral HPV infection: Longitudinal analyses in prospective cohorts from Australia.

Int J Cancer 2021 04 27;148(8):1964-1972. Epub 2020 Dec 27.

Department of Population Health, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, Queensland, Australia.

Oral infection with human papillomavirus (HPV) is likely to underpin the rapidly rising incidence of oropharyngeal squamous cell carcinoma; however, there are few data describing the natural history of oral HPV infection. We recruited 704 participants aged 20 to 70 years from worksites, universities and primary care practices in Brisbane, Australia. Participants completed questionnaires at baseline, 12 and 24 months and donate four saliva samples at baseline, 6, 12 and 24 months for HPV polymerase chain reaction testing and typing. We estimated the prevalence of oral HPV infection at baseline, incidence of new infections among those HPV-negative at baseline, clearance rate and persistent infections. At baseline, 10.7% of participants had oral HPV infections from 26 different HPV types. Sexual behaviours were associated with oral HPV infection, including more partners for passionate kissing (29 or more; odds ratio [OR] 3.4, 95% confidence interval [CI] 1.5-8.0), and giving and receiving oral sex (16 or more; OR 5.4, 95% CI 1.6-17.7 and OR 5.6, 95% CI 1.6-18.7, respectively). Of 343 participants, HPV-free at baseline and with subsequent saliva samples, 87 (25%) acquired new infections over the 24 months. Sixty-eight of 87 people included in the clearance analysis (78%) cleared their oral HPV infections. Clearance was associated with being a nonsmoker (OR 12.7, 95% CI 1.3-122.8), and no previous diagnosis of a sexually transmitted infection (OR 6.2, 95% CI 2.0-19.9). New oral infections with HPV in this sample were not rare. Although most infections were cleared, clearance was not universal suggesting a reservoir of infection exists that might predispose to oropharyngeal carcinogenesis.
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http://dx.doi.org/10.1002/ijc.33442DOI Listing
April 2021

Clinical pathways and outcomes of patients with Barrett's esophagus in tertiary care settings: a prospective longitudinal cohort study in Australia, 2008-2016.

Dis Esophagus 2021 Aug;34(8)

Population Health Department, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.

Background: Clinical services for Barrett's esophagus have been rising worldwide including Australia, but little is known of the long-term outcomes of such patients. Retrospective studies using data at baseline are prone to both selection and misclassification bias. We investigated the clinical characteristics and outcomes of Barrett's esophagus patients in a prospective cohort.

Methods: We recruited patients diagnosed with Barrett's esophagus in tertiary settings across Australia between 2008 and 2016. We compared baseline and follow-up epidemiological and clinical data between Barrett's patients with and without dysplasia. We calculated age-adjusted incidence rates and estimated minimally and fully adjusted hazard ratios (HR) to identify those clinical factors related to disease progression.

Results: The cohort comprised 268 patients with Barrett's esophagus (median follow-up 5 years). At recruitment, 224 (84%) had no dysplasia, 44 (16%) had low-grade or indefinite dysplasia (LGD/IND). The age-adjusted incidence of esophageal adenocarcinoma (EAC) was 0.5% per year in LGD/IND compared with 0.1% per year in those with no dysplasia. Risk of progression to high-grade dysplasia/EAC was associated with prior LGD/IND (fully adjusted HR 6.55, 95% confidence interval [CI] 1.96-21.8) but not long-segment disease (HR 1.03, 95%CI 0.29-3.58).

Conclusions: These prospective data suggest presence of dysplasia is a stronger predictor of progression to cancer than segment length in patients with Barrett's esophagus.
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http://dx.doi.org/10.1093/dote/doaa119DOI Listing
August 2021

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.

Carcinogenesis 2021 04;42(3):369-377

Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK.

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.
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http://dx.doi.org/10.1093/carcin/bgaa132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052954PMC
April 2021

On the turbulence structure of deep katabatic flows on a gentle mesoscale slope.

Q J R Meteorol Soc 2020 Apr 23;146(728):1206-1231. Epub 2020 Jan 23.

Department of Atmospheric Sciences, University of Utah Salt Lake City Utah.

A comprehensive analysis of the turbulence structure of relatively deep midlatitude katabatic flows (with jet maxima between 20 and 50 m) developing over a gentle (1°) mesoscale slope with a long fetch upstream of the Meteor Crater in Arizona is presented. The turbulence structure of flow below the katabatic jet maximum shows many similarities with the turbulence structure of shallower katabatic flows, with decreasing turbulence fluxes with height and almost constant turbulent Prandtl number. Still stark differences occur above the jet maximum where turbulence is suppressed by strong stability, is anisotropic and there is a large sub-mesoscale contribution to the flux. Detecting the stable boundary-layer top depends on the method used (flux- vs. anisotropy-profiles) but both methods are highly correlated. The top of the stable boundary layer, however, mostly deviates from the jet maximum height or the top of the near-surface inversion. The flat-terrain formulations for the boundary-layer height correlate well with the detected top of the stable boundary layer if the near-surface and not the background stratification is used in their formulations; however, they mostly largely overestimate this boundary-layer height. The difference from flat-terrain boundary layers is also shown through the dependence of size of the dominant eddy with height. In katabatic flows the eddy size is semi-constant with height throughout the stable boundary-layer depth, whereas in flat terrain, eddy size varies significantly with height. Flux-gradient and flux-variance relationships show that turbulence data from different stable boundary-layer scaling regimes collapse on top of each other showing that the dominant dependence is not on the scaling regime but on the local stability.
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http://dx.doi.org/10.1002/qj.3734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654318PMC
April 2020

Prospective validation of a risk stratification tool for keratinocyte cancer.

Australas J Dermatol 2021 May 18;62(2):223-225. Epub 2020 Oct 18.

Department of Population Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

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http://dx.doi.org/10.1111/ajd.13485DOI Listing
May 2021

Assessment of Incidence Rate and Risk Factors for Keratoacanthoma Among Residents of Queensland, Australia.

JAMA Dermatol 2020 12;156(12):1324-1332

Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Importance: Keratoacanthoma (KA) is a common and generally benign keratinocyte skin tumor. Reports of the incidence rates of KA are scant. In addition, the risk factors for KA are not well understood, although associations with UV radiation exposure and older age have been described.

Objective: To investigate the incidence rate of KA and the risk factors for developing KA.

Design, Setting, And Participants: The study included data from 40 438 of 193 344 randomly selected residents of Queensland, Australia, who participated in the QSkin Sun and Health (QSkin) prospective population-based cohort study. All participants completed a baseline survey between 2010 and 2011 and were ages 40 to 69 years at baseline. Histopathologic reports of KA were prospectively collected until June 30, 2014, through data linkage with pathologic records. Cox proportional hazards models were used to identify risk factors associated with KA while controlling for potential confounding variables. Data were analyzed from January 2 to April 8, 2020.

Exposures: Demographic characteristics, phenotypes, UV radiation exposure, medical history, and lifestyle.

Results: Among 40 438 participants (mean [SD] age, 56 [8] years; 18 240 men [45.1%]), 596 individuals (mean [SD] age, 62 [6] years; 349 men [58.6%]) developed 776 KA tumors during a median follow-up period of 3.0 years (interquartile range, 2.8-3.3 years). The person-based age-standardized incidence rate for KA in the age-restricted cohort was 409 individuals per 100 000 person-years (based on the 2001 Australian population). Risk factors after adjustment for potential confounders were older age (age ≥60 years vs age <50 years; hazard ratio [HR], 6.38; 95% CI, 4.65-8.75), male sex (HR, 1.56; 95% CI, 1.33-1.84), fair skin (vs olive, dark, or black skin; HR, 3.42; 95% CI, 1.66-7.04), inability to tan (vs ability to tan deeply; HR, 1.69; 95% CI, 1.19-2.40), previous excisions of keratinocyte cancers (ever had an excision vs never had an excision; HR, 6.28; 95% CI, 5.03-7.83), current smoking (vs never smoking, HR, 2.02; 95% CI, 1.59-2.57), and high alcohol use (≥14 alcoholic drinks per week vs no alcoholic drinks per week; HR, 1.42; 95% CI, 1.09-1.86).

Conclusions And Relevance: This is, to date, the first large prospective population-based study to report the incidence rate and risk factors for KA. The high person-based incidence rate (409 individuals per 100 000 person-years) highlights the substantial burden of KA in Queensland, Australia. Furthermore, the study's findings suggest that older age (≥60 years), male sex, UV radiation-sensitive phenotypes, indications of high sun exposure (eg, previous keratinocyte cancer excisions), smoking, and high alcohol use are independent risk factors for the development of KA.
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http://dx.doi.org/10.1001/jamadermatol.2020.4097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542522PMC
December 2020

Can People Correctly Assess their Future Risk of Melanoma?

J Invest Dermatol 2021 03 12;141(3):695-698. Epub 2020 Sep 12.

Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.07.018DOI Listing
March 2021

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

Gastroenterology 2020 12 9;159(6):2065-2076.e1. Epub 2020 Sep 9.

Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Germany.

Background & Aims: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored.

Methods: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits.

Results: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals.

Conclusions: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.
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http://dx.doi.org/10.1053/j.gastro.2020.08.052DOI Listing
December 2020

Omega-3 fatty acid intake and decreased risk of skin cancer in organ transplant recipients.

Eur J Nutr 2021 Jun 9;60(4):1897-1905. Epub 2020 Sep 9.

Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, Australia.

Purpose: Organ transplant recipients have over 100-fold higher risk of developing skin cancer than the general population and are in need of further preventive strategies. We assessed the possible preventive effects of omega-3 polyunsaturated fatty acid (PUFA) intake from food on the two main skin cancers, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in kidney and liver transplant recipients.

Methods: Adult kidney or liver transplant recipients transplanted for at least 1 year and at high risk of skin cancer were recruited from the main transplant hospital in Queensland, 2012-2014 and followed until mid-2016. We estimated their dietary total long-chain omega-3 PUFAs and α-linolenic acid intakes at baseline using a food frequency questionnaire and ranked PUFA intakes as low, medium, or high. Relative risks (RRs) of skin cancer adjusted for confounding factors with 95% confidence intervals (CIs) were calculated.

Results: There were 449 transplant recipients (mean age, 55 years; 286 (64%) male). During follow-up, 149 (33%) patients developed SCC (median 2/person; range 1-40) and 134 (30%), BCC. Transplant recipients with high total long-chain omega-3 PUFA compared with low intakes showed substantially reduced SCC tumour risk (RR 0.33, 95% CI 0.18-0.60), and those with high α-linolenic acid intakes experienced significantly fewer BCCs (RR 0.40, 95% CI 0.22-0.74). No other significant associations were seen.

Conclusion: Among organ transplant recipients, relatively high intakes of long-chain omega-3 PUFAs and of α-linolenic acid may reduce risks of SCC and BCC, respectively.
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http://dx.doi.org/10.1007/s00394-020-02378-yDOI Listing
June 2021

Destructive and topical treatments of skin lesions in organ transplant recipients and relation to skin cancer.

Arch Dermatol Res 2020 Sep 5. Epub 2020 Sep 5.

Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Various treatments of keratotic skin lesions and early skin cancers are performed in organ transplant recipients (OTRs) at high risk of skin malignancies but the frequency of their use is unknown. We prospectively assessed the frequency of use of cryotherapy, diathermy, and topical therapies and also investigated their associations with background incidence of histologically-confirmed squamous-cell carcinoma (SCC) and basal cell carcinoma (BCC) in a cohort of OTRs in Queensland, Australia. Median follow-up ranged from 1.7 to 3.2 years across organ transplant groups. Among 285 kidney, 125 lung and 203 liver transplant recipients [382 (62%) male, 380 (62%) immunosuppressed > 5 years, 394 (64%) previously diagnosed with skin cancer], 306 (50%) reported treatment of skin lesions with major types of non-excision therapies during follow-up: 278 (45%) cryotherapy or diathermy; 121 (20%) topical treatments. Of these 306, 150 (49%) developed SCC at double the incidence of those who did not receive these treatments, as assessed by incidence rate ratio (IRR) adjusted for age, sex, type of organ transplant, skin color and history of skin cancer at baseline, calculated by multivariable Poisson regression (IRR = 2.1, 95% confidence interval (CI) 1.4-3.1). BCC incidence was not associated with these therapies. Skin lesions in OTRs that are treated with cryotherapy, diathermy, or topical treatment warrant judicious selection and careful follow-up.
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http://dx.doi.org/10.1007/s00403-020-02136-4DOI Listing
September 2020
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