Publications by authors named "Brigid Betz-Stablein"

27 Publications

  • Page 1 of 1

Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.

Eur J Cancer 2021 Sep 8;156:202-216. Epub 2021 Sep 8.

First Department of Dermatology, School of Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece.

Background: Multiple studies have compared the performance of artificial intelligence (AI)-based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice.

Objective: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians.

Methods: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included.

Results: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images.

Conclusions: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice.
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http://dx.doi.org/10.1016/j.ejca.2021.06.049DOI Listing
September 2021

An Australian tertiary hospital analysis of outpatient dermatology clinical and demographic characteristics.

Australas J Dermatol 2021 Aug 16. Epub 2021 Aug 16.

School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.

Objectives: Literature on dermatology outpatient demographic and clinical data is limited, and the few studies on this topic are mainly conducted overseas, with medical systems and case mix different to Australia. This study presents demographic data relating to dermatology public outpatient referrals to a tertiary hospital in Brisbane, Australia, and determines what additional structured data should be collected to formulate and evaluate initiatives to address service issues such as referral quality, triage process and wait times.

Methods: A four-year retrospective audit was undertaken, summarising all referrals (n = 7140) and clinical dermatology encounters (n = 53 844) between January 2016 and December 2019 at Princess Alexandra Hospital (PAH), the largest hospital in Metro South Health (MSH), serving a population of one million. PAH has one of the two largest public dermatology clinics in Queensland and is the only dermatology service within MSH.

Results: Patient demographic data, wait time by triage category, referral rates over time and encounter durations were collected. Structured diagnostic data (e.g. ICD-10 coding) of the provisional diagnosis, comorbidities, medications and the final diagnosis are not collected in a structured format and would be a valuable addition.

Conclusions: The clinical burden of public dermatology is increasing. Both collection and analysis of structured data pertaining to the referrals and encounters are important to help formulate, implement and evaluate initiatives that aim to improve health service provision in this area.
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http://dx.doi.org/10.1111/ajd.13677DOI Listing
August 2021

The Additive Value of 3D Total Body Imaging for Sequential Monitoring of Skin Lesions: A Case Series.

Dermatology 2021 Aug 11:1-6. Epub 2021 Aug 11.

Centre of Health Services Research, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia,

Background: Timely diagnosis is the cornerstone of melanoma morbidity and mortality reduction. 2D total body photography and dermoscopy are routinely used to assist with early detection of skin malignancies. Polarized 3D total body photography is a novel technique that enables fast image acquisition of almost the entire skin surface. We aimed to determine the added value of 3D total body photography alongside dermoscopy for monitoring cutaneous lesions.

Methods: Lesion images from high-risk individuals were assessed for long-term substantial changes via dermoscopy and 3D total body photography. Three case studies are presented demonstrating how 3D total body photography may enhance lesion analysis alongside traditional dermoscopy.

Results: 3D total body photography can assist clinicians by presenting cutaneous lesions in their skin ecosystem, thereby providing additional clinical context and enabling a more holistic assessment to aid dermoscopy interpretation. For lesion cases where previous dermoscopy is unavailable, corresponding 3D images can substitute for baseline dermoscopy. Additionally, 3D total body photography is not susceptible to artificial stretch artefacts.

Conclusion: 3D total body photography is valuable alongside dermoscopy for monitoring cutaneous lesions. Furthermore, it is capable of surveilling almost the entire skin surface, including areas not traditionally monitored by sequential imaging.
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http://dx.doi.org/10.1159/000517900DOI Listing
August 2021

Breast cancer polygenic risk scores: a 12-month prospective study of patient reported outcomes and risk management behavior.

Genet Med 2021 Aug 2. Epub 2021 Aug 2.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, VIC, Australia.

Purpose: To prospectively assess patient reported outcomes and risk management behavior of women choosing to receive (receivers) or decline (decliners) their breast cancer polygenic risk score (PRS).

Methods: Women either unaffected or affected by breast cancer and from families with no identified pathogenic variant in a breast cancer risk gene were invited to receive their PRS. All participants completed a questionnaire at study enrollment. Receivers completed questionnaires at two weeks and 12 months after receiving their PRS, and decliners a second questionnaire at 12 months post study enrollment.

Results: Of the 208 participants, 165 (79%) received their PRS. Among receivers, there were no changes in anxiety or distress following testing. However, compared to women with a low PRS, those with a high PRS reported greater genetic testing-specific distress, perceived risk, decisional regret, and less genetic testing-positive response. At 12 months, breast screening and uptake of risk-reducing strategies were consistent with current Australian guidelines of breast cancer risk management. Reasons for declining PRS included being unable to attend the appointment in person and concerns over potential emotional response.

Conclusion: The outcomes of the study provide insight into women's responses to receiving PRS and highlight the issues that need to be addressed in the associated model of genetic counseling.
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http://dx.doi.org/10.1038/s41436-021-01288-6DOI Listing
August 2021

Anatomic Distribution of Cherry Angiomas in the General Population.

Dermatology 2021 Jul 22:1-9. Epub 2021 Jul 22.

The University of Queensland Diamantina Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Queensland, Australia.

Background: Cherry angiomas are common benign vascular skin lesions of unknown aetiology, found largely on the trunk. However, their exact anatomic distribution besides their truncal predisposition, and how they manifest in the general population, has not been characterised.

Methods: Three-dimensional (3D) total body imaging was obtained from 163 adult participants of a general population cohort study in Brisbane, Australia. Demographic, phenotypic, and sun behaviour characteristics were collected using a standard questionnaire along with history of melanoma and keratinocyte cancers. Cherry angiomas were identified using an automated classification algorithm with a sensitivity of 87% and a specificity of 99%, developed specifically for this study population.

Results: The 3D total body images of 163 participants were analysed. Participants had a median age of 57 years and 61% were male. On average, males had more angiomas than females (median of 16 vs. 12) and the number and size of cherry angiomas increased with age. In addition to male sex and age, an increase in angiomas was associated with Caucasian ancestry other than British/Irish only, fair skin colour opposed to medium/olive, having green/hazel eyes compared to blue/grey, and personal history of melanoma. The most common site for cherry angiomas was the front trunk, followed by the back. Interestingly, although males had more angiomas overall, females had more angiomas on the legs.

Conclusion: Describing the distribution of cherry angiomas by body site is an important step towards further understanding of the aetiology of angiomas. While personal history of melanoma is associated with an increased number of cherry angiomas, whether this association is prognostic, co-occurs with development of melanoma, or is merely fortuitous requires further investigation.
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http://dx.doi.org/10.1159/000517172DOI Listing
July 2021

Reproducible Naevus Counts Using 3D Total Body Photography and Convolutional Neural Networks.

Dermatology 2021 Jul 8:1-8. Epub 2021 Jul 8.

The University of Queensland Diamantina Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Queensland, Australia.

Background: The number of naevi on a person is the strongest risk factor for melanoma; however, naevus counting is highly variable due to lack of consistent methodology and lack of inter-rater agreement. Machine learning has been shown to be a valuable tool for image classification in dermatology.

Objectives: To test whether automated, reproducible naevus counts are possible through the combination of convolutional neural networks (CNN) and three-dimensional (3D) total body imaging.

Methods: Total body images from a study of naevi in the general population were used for the training (82 subjects, 57,742 lesions) and testing (10 subjects; 4,868 lesions) datasets for the development of a CNN. Lesions were labelled as naevi, or not ("non-naevi"), by a senior dermatologist as the gold standard. Performance of the CNN was assessed using sensitivity, specificity, and Cohen's kappa, and evaluated at the lesion level and person level.

Results: Lesion-level analysis comparing the automated counts to the gold standard showed a sensitivity and specificity of 79% (76-83%) and 91% (90-92%), respectively, for lesions ≥2 mm, and 84% (75-91%) and 91% (88-94%) for lesions ≥5 mm. Cohen's kappa was 0.56 (0.53-0.59) indicating moderate agreement for naevi ≥2 mm, and substantial agreement (0.72, 0.63-0.80) for naevi ≥5 mm. For the 10 individuals in the test set, person-level agreement was assessed as categories with 70% agreement between the automated and gold standard counts. Agreement was lower in subjects with numerous seborrhoeic keratoses.

Conclusion: Automated naevus counts with reasonable agreement to those of an expert clinician are possible through the combination of 3D total body photography and CNNs. Such an algorithm may provide a faster, reproducible method over the traditional in person total body naevus counts.
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http://dx.doi.org/10.1159/000517218DOI Listing
July 2021

Keratinocyte Cancer Mortality in Kidney Transplant Recipients.

Transplantation 2021 May 25. Epub 2021 May 25.

QIMR Berghofer Medical Research Institute, Herston, Australia. Faculty of Medicine, The University of Queensland, St Lucia, Australia. The University of Queensland Diamantina Institute, Translational Research Institute (TRI), The University of Queensland, Woolloongabba, Australia. Department of Renal Medicine, Princess Alexandra Hospital Metro South, Woolloongabba, Australia. Cancer Research UK Manchester Institute and Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.

Background: Kidney transplant recipients are at increased risk of developing and dying from keratinocyte cancer. Risk factors for keratinocyte cancer death have not been previously described.

Methods: In a cohort of kidney transplant recipients transplanted in Queensland 1995-2014, we identified keratinocyte cancer deaths by searching national transplant and state death registries to March 2020. Standardized keratinocyte cancer mortality rates and mortality ratios were calculated. We used a competing risks model to identify factors associated with keratinocyte cancer death and calculated relative risks (RRs) and 95% confidence intervals (CIs).

Results: There were 562 deaths in 1866 kidney transplant recipients (62% males; 86% Caucasian) with 25 934 person-years of follow-up, of which 36 were due to squamous cell carcinoma (SCC) and 1 to basal cell carcinoma (BCC) with standardized mortality rates of 78 (95% CI 53-111) and 2 (95% CI 0.1-11) per 100,000 person-years respectively. The standardized mortality ratio for keratinocyte cancer was 23 (95% CI 23-24). Besides Caucasian ethnicity (associated with 100% of keratinocyte cancer deaths), male sex (RR 3.24 95% CI 1.26-8.33), and older age at transplantation (≥ 50 versus <50 years RR 3.09 95% CI 1.38-6.89) were associated with increased risk of keratinocyte cancer death.

Conclusions: Keratinocyte cancer mortality in kidney transplant recipients is over 20 times higher than in the general population. Most keratinocyte cancer deaths are due to cutaneous SCC, however, BCC can be fatal. Education in skin cancer prevention is essential to avoid unnecessary deaths from keratinocyte cancer amongst kidney transplant recipients.
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http://dx.doi.org/10.1097/TP.0000000000003827DOI Listing
May 2021

Development of a Checklist Tool to Assess the Quality of Skin Lesion Images Acquired by Consumers Using Sequential Mobile Teledermoscopy.

Dermatology 2021 Apr 13:1-8. Epub 2021 Apr 13.

Centre of Health Services Research, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.

Background: Mobile teledermoscopy is an emerging technology that involves imaging and digitally sending dermoscopic images of skin lesions to a clinician for assessment. High-quality, consistent images are required for accurate telediagnoses when monitoring lesions over time. To date there are no tools to assess the quality of sequential images taken by consumers using mobile teledermoscopy. The purpose of this study was to develop a tool to assess the quality of images acquired by consumers.

Methods: Participants imaged skin lesions that they felt were concerning at baseline, 1-, and 2-months. A checklist to assess the quality of consumer sequential imaging of skin lesions was developed based on the International Skin Imaging Collaboration guidelines. A scale was implemented to grade the quality of the images: 0 (low) to 18 (very high). Intra- and inter-reliability of the checklist was assessed using Bland-Altman analysis. Using this checklist, the consistency with which 85 sets of images were scored by 2 evaluators were compared using Kappa statistics. Items with a low Kappa value <0.4 were removed.

Results: After reliability testing, 5 of the items were removed due to low Kappa values (<0.4) and the final checklist included 13 items surveying: lesion selection; image orientation; lighting; field of view; focus and depth of view. Participants had a mean age of 41 years (range 19-73), and 67% were female. Most participants (84%, n = 71/85) were able to select and image the correct lesion over time for both the dermoscopic and overview images. Younger participants (<40 years old) scored significantly higher (8.1 ± 2.1) on the imaging checklist compared to older participants (7.1 ± 2.4; p = 0.037). Participants had most difficulty with consistent image orientation.

Conclusions: This checklist could be used as a triage tool to filter images acquired by consumers prior to telediagnosis evaluation, which would improve the efficiency and accuracy of teledermatology and teledermoscopy processes. It may also be used to provide feedback to the consumers to improve image acquisition over time.
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http://dx.doi.org/10.1159/000515158DOI Listing
April 2021

A patient-centric dataset of images and metadata for identifying melanomas using clinical context.

Sci Data 2021 01 28;8(1):34. Epub 2021 Jan 28.

The University of Queensland Diamantina Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Australia.

Prior skin image datasets have not addressed patient-level information obtained from multiple skin lesions from the same patient. Though artificial intelligence classification algorithms have achieved expert-level performance in controlled studies examining single images, in practice dermatologists base their judgment holistically from multiple lesions on the same patient. The 2020 SIIM-ISIC Melanoma Classification challenge dataset described herein was constructed to address this discrepancy between prior challenges and clinical practice, providing for each image in the dataset an identifier allowing lesions from the same patient to be mapped to one another. This patient-level contextual information is frequently used by clinicians to diagnose melanoma and is especially useful in ruling out false positives in patients with many atypical nevi. The dataset represents 2,056 patients (20.8% with at least one melanoma, 79.2% with zero melanomas) from three continents with an average of 16 lesions per patient, consisting of 33,126 dermoscopic images and 584 (1.8%) histopathologically confirmed melanomas compared with benign melanoma mimickers.
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http://dx.doi.org/10.1038/s41597-021-00815-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843971PMC
January 2021

Quantitative analysis of the splice variants expressed by the major hepatitis B virus genotypes.

Microb Genom 2021 01;7(1)

Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.

Hepatitis B virus (HBV) is a major human pathogen that causes liver diseases. The main HBV RNAs are unspliced transcripts that encode the key viral proteins. Recent studies have shown that some of the HBV spliced transcript isoforms are predictive of liver cancer, yet the roles of these spliced transcripts remain elusive. Furthermore, there are nine major HBV genotypes common in different regions of the world, these genotypes may express different spliced transcript isoforms. To systematically study the HBV splice variants, we transfected human hepatoma cells, Huh7, with four HBV genotypes (A2, B2, C2 and D3), followed by deep RNA-sequencing. We found that 13-28 % of HBV RNAs were splice variants, which were reproducibly detected across independent biological replicates. These comprised 6 novel and 10 previously identified splice variants. In particular, a novel, singly spliced transcript was detected in genotypes A2 and D3 at high levels. The biological relevance of these splice variants was supported by their identification in HBV-positive liver biopsy and serum samples, and in HBV-infected primary human hepatocytes. Interestingly the levels of HBV splice variants varied across the genotypes, but the spliced pregenomic RNA SP1 and SP9 were the two most abundant splice variants. Counterintuitively, these singly spliced SP1 and SP9 variants had a suboptimal 5' splice site, supporting the idea that splicing of HBV RNAs is tightly controlled by the viral post-transcriptional regulatory RNA element.
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http://dx.doi.org/10.1099/mgen.0.000492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115900PMC
January 2021

Evaluation of the efficacy of 3D total-body photography with sequential digital dermoscopy in a high-risk melanoma cohort: protocol for a randomised controlled trial.

BMJ Open 2019 11 10;9(11):e032969. Epub 2019 Nov 10.

School of Public Health, The University of Queensland, Brisbane, Queensland, Australia.

Introduction: Melanoma is Australia's fourth most common cancer. Early detection is fundamental in maximising health outcomes and minimising treatment costs. To date, population-based screening programmes have not been justified in health economic studies. However, a skin surveillance approach targeting high-risk individuals could improve the cost-benefit ratio.

Methods And Analysis: This paper describes a 2-year longitudinal randomised controlled trial (RCT) to compare routine clinical care (control) with an intensive skin surveillance programme (intervention) consisting of novel three-dimensional (3D) total-body photography (TBP), sequential digital dermoscopy and melanoma-risk stratification, in a high-risk melanoma cohort. Primary outcomes will evaluate clinical, economic and consumer impact of the intervention. Clinical outcomes will evaluate differences in the rate of lesion excisions/biopsies per person, benign to malignant ratio for excisions and thickness of melanomas diagnosed. A health economic analysis using government data repositories will capture healthcare utilisation and costs relating to skin surveillance. Consumer questionnaires will examine intervention acceptability, the psychological impact, and attitudes towards melanoma risk and sun protective behaviour. Secondary outcomes include the development of a holistic risk algorithm incorporating clinical, phenotypic and genetic factors to facilitate the identification of those most likely to benefit from this surveillance approach. Furthermore, the feasibility of integrating the intervention with teledermatology to enhance specialist care in remote locations will be evaluated. This will be the first RCT to compare a targeted surveillance programme utilising new 3D TBP technology against current routine clinical care for individuals at high risk of melanoma.

Ethics And Dissemination: This study has received Human Research Ethics Committee (HREC) approval from both Metro South Health HREC (HREC/17/QPAH/816) and The University of Queensland HREC (2018000074).

Trial Registration Number: ANZCTR12618000267257; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-032969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858160PMC
November 2019

Combined treatment and prevention strategies for hepatitis C virus elimination in the prisons in New South Wales: a modelling study.

Addiction 2020 05 12;115(5):901-913. Epub 2019 Nov 12.

Viral Immunology Systems Program, Kirby Institute, University of New South Wales, Sydney, NSW, Australia.

Background And Aims: Australia is currently on track to meet the World Health Organization (WHO) global hepatitis C virus (HCV) elimination goals by 2030, reflecting universal subsidized access to testing and direct-acting antiviral (DAA) treatment. In New South Wales, DAA treatment in prisons has scaled-up substantially, with 1000 prisoners treated in 2017. However, HCV prevalence and incidence in this setting is high, which could undermine elimination efforts. This study aimed to test the preventative effects of DAA treatment scale-up, opiate substitution treatment (OST) and needle and syringe programme (NSP) strategies for prisons.

Design: Modelling study using an individual-based mathematical model of a typical prison setting. The model was calibrated against Australian epidemiological data sets and executed in-prison events for each individual daily, including movements between prisons, changes in risk behaviour and uptake of prevention measures such as OST and NSP, as well as DAA treatment. Scenarios were projected from 2018 to 2030.

Setting: New South Wales prisons.

Participants: New South Wales prisoners.

Measurements: Variables including prison populations, prevalence and incidence rate were calculated. Prisoners were described by demographic characteristics, HCV infection history, risk behaviours and accessing treatment and prevention measures in varied security settings.

Findings: Increasing the number of prisoners treated for HCV to 2000 annually was projected to reduce the HCV incidence rate to 8.69 [95% confidence interval (CI) = 8.17, 9.20] per 100 person-years (100 p.y.). Combined treatment and prevention strategies were necessary to reduce the projected incidence rate to 5.22 (95% CI = 5.13, 5.52) per 100 p.y. Considering the expected reductions in the prevalence of chronic HCV in the Australian community, incidence rate was predicted to drop to 0.93 (95% CI = 0.92, 0.98) per 100 p.y. by 2030.

Conclusions: This model, which simulates prison scenarios to inform Australia's national hepatitis C virus elimination efforts, suggests that continued direct-acting antiviral (coverage in the community combined with a moderate increase of direct-acting antiviral treatments in prisons, and introduction of improved harm reduction via opiate substitution treatment and/or needle and syringe programmes, makes hepatitis C virus elimination feasible in Australian prisons.
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http://dx.doi.org/10.1111/add.14830DOI Listing
May 2020

Epidemic surveillance in a low resource setting: lessons from an evaluation of the Solomon Islands syndromic surveillance system, 2017.

BMC Public Health 2018 Dec 20;18(1):1395. Epub 2018 Dec 20.

University of New South Wales, Sydney, NSW, 2052, Australia.

Background: Solomon Islands is one of the least developed countries in the world. Recognising that timely detection of outbreaks is needed to enable early and effective response to disease outbreaks, the Solomon Islands government introduced a simple syndromic surveillance system in 2011. We conducted the first evaluation of the system and the first exploration of a national experience within the broader multi-country Pacific Syndromic Surveillance System to determine if it is meeting its objectives and to identify opportunities for improvement.

Methods: We used a multi-method approach involving retrospective data collection and statistical analysis, modelling, qualitative research and observational methods.

Results: We found that the system was well accepted, highly relied upon and designed to account for contextual limitations. We found the syndromic algorithm used to identify outbreaks was moderately sensitive, detecting 11.8% (IQR: 6.3-25.0%), 21.3% (IQR: 10.3-36.8%), 27.5% (IQR: 12.8-52.3%) and 40.5% (IQR: 13.5-65.7%) of outbreaks that caused small, moderate, large and very large increases in case presentations to health facilities, respectively. The false alert rate was 10.8% (IQR: 4.8-24.5%). Rural coverage of the system was poor. Limited workforce, surveillance resourcing and other 'upstream' health system factors constrained performance.

Conclusions: The system has made a significant contribution to public health security in Solomon Islands, but remains insufficiently sensitive to detect small-moderate sized outbreaks and hence should not be relied upon as a stand-alone surveillance strategy. Rather, the system should sit within a complementary suite of early warning surveillance activities including event-based, in-patient- and laboratory-based surveillance methods. Future investments need to find a balance between actions to address the technical and systems issues that constrain performance while maintaining simplicity and hence sustainability.
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http://dx.doi.org/10.1186/s12889-018-6295-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302379PMC
December 2018

'Mind your Moles' study: protocol of a prospective cohort study of melanocytic naevi.

BMJ Open 2018 09 19;8(9):e025857. Epub 2018 Sep 19.

Cancer and Population Studies, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Introduction: Having many melanocytic naevi or 'moles' on the skin is the strongest predictor of melanoma; thus, much can be learnt from investigating naevi in the general population. We aim to improve the understanding of the epidemiology and biology of naevi by conducting a 3-year prospective study of melanocytic naevi in adults.

Methods And Analysis: This is a population-based cohort study of melanocytic naevi in 200 adults aged 20-69 years recruited via the Australian electoral roll. At baseline, participants will complete a questionnaire on their sun behaviour and health and undergo a clinical examination. Three-dimensional (3D) total-body photography will be used to record the images of skin lesions. Pigmented naevi will be analysed in terms of number, diameter, colour and border irregularity using automated analysis software (excluding scalp, beneath underwear and soles of feet). All naevi ≥5 mm will be recorded using the integrated dermoscopy photographic system. A saliva sample will be obtained at baseline for genomic DNA analysis of pigmentation, naevus and melanoma-associated genes using the Illumina HumanCoreExome platform. The sun behaviour and health follow-up questionnaire, clinical examination and 3D total-body photography will be repeated every 6 months for 3 years. The first 50 participants will also undergo manual counts of naevi ≥2 mm and ≥5 mm at baseline, 6-month and 12-month follow-ups. Microbiopsy and excision of naevi of research interest is planned to commence at the 18-month time point among those who agree to donate samples for detailed histopathological and molecular assessment.

Ethics And Dissemination: This study was approved by the Metro South Health Human Research Ethics Committee in April 2016 (approval number: HREC/16/QPAH/125). The findings will be disseminated through peer-reviewed and non-peer-reviewed publications and presentations at conferences.
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http://dx.doi.org/10.1136/bmjopen-2018-025857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150134PMC
September 2018

Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis.

Neuropsychopharmacology 2017 Aug 22;42(9):1752-1765. Epub 2017 Mar 22.

Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED of morphine alone. In addition, the ED for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.
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http://dx.doi.org/10.1038/npp.2017.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520783PMC
August 2017

Modelling retinal pulsatile blood flow from video data.

Stat Methods Med Res 2018 05 1;27(5):1575-1584. Epub 2016 Sep 1.

3 Lions Eye Institute, University of Western Australia, Australia.

Modern day datasets continue to increase in both size and diversity. One example of such 'big data' is video data. Within the medical arena, more disciplines are using video as a diagnostic tool. Given the large amount of data stored within a video image, it is one of most time consuming types of data to process and analyse. Therefore, it is desirable to have automated techniques to extract, process and analyse data from video images. While many methods have been developed for extracting and processing video data, statistical modelling to analyse the outputted data has rarely been employed. We develop a method to take a video sequence of periodic nature, extract the RGB data and model the changes occurring across the contiguous images. We employ harmonic regression to model periodicity with autoregressive terms accounting for the error process associated with the time series nature of the data. A linear spline is included to account for movement between frames. We apply this model to video sequences of retinal vessel pulsation, which is the pulsatile component of blood flow. Slope and amplitude are calculated for the curves generated from the application of the harmonic model, providing clinical insight into the location of obstruction within the retinal vessels. The method can be applied to individual vessels, or to smaller segments such as 2 × 2 pixels which can then be interpreted easily as a heat map.
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http://dx.doi.org/10.1177/0962280216665504DOI Listing
May 2018

Incident Hepatitis C Virus Genotype Distribution and Multiple Infection in Australian Prisons.

J Clin Microbiol 2016 07 11;54(7):1855-1861. Epub 2016 May 11.

Inflammation and Infection Research Centre, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia

Hepatitis C virus (HCV) is a highly diverse pathogen that is classified into seven distinct genotypes. Simultaneous or sequential reinfection with multiple HCV genotypes is recognized in high-risk populations, such as injecting drug users (IDUs). Multiple infection is of clinical concern as different genotypes have various sensitivities to current antiviral therapies. Therefore, a better understanding of the frequency of multiple infection and of the genotypes currently being transmitted is clinically relevant. An Australian cohort of IDUs (n = 123), identified with primary incident infection, was followed for multiple infection by regular HCV RNA testing between 2005 and 2013. A total of 354 samples were tested. Sequencing of primary incident infections revealed that genotype 3a was the most common circulating genotype, followed by genotype 1a. Examination of longitudinally collected samples identified complex patterns of multiple infection, including reinfection and superinfection. In those with multiple infection, there was no apparent evidence of homotypic immunity conferring protection against reinfection of the same subtype. This study revealed frequent multiple infection in a high-risk prisoner cohort, illustrating the complex nature of HCV infection and reinfection and highlighting the need for pan-genotypic antiviral therapies.
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http://dx.doi.org/10.1128/JCM.00287-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922113PMC
July 2016

A method for near full-length amplification and sequencing for six hepatitis C virus genotypes.

BMC Genomics 2016 Mar 17;17:247. Epub 2016 Mar 17.

School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, 2052, Australia.

Background: Hepatitis C virus (HCV) is a rapidly evolving RNA virus that has been classified into seven genotypes. All HCV genotypes cause chronic hepatitis, which ultimately leads to liver diseases such as cirrhosis. The genotypes are unevenly distributed across the globe, with genotypes 1 and 3 being the most prevalent. Until recently, molecular epidemiological studies of HCV evolution within the host and at the population level have been limited to the analyses of partial viral genome segments, as it has been technically challenging to amplify and sequence the full-length of the 9.6 kb HCV genome. Although recent improvements have been made in full genome sequencing methodologies, these protocols are still either limited to a specific genotype or cost-inefficient.

Results: In this study we describe a genotype-specific protocol for the amplification and sequencing of the near-full length genome of all six major HCV genotypes. We applied this protocol to 122 HCV positive clinical samples, and had a successful genome amplification rate of 90%, when the viral load was greater than 15,000 IU/ml. The assay was shown to have a detection limit of 1-3 cDNA copies per reaction. The method was tested with both Illumina and PacBio single molecule, real-time (SMRT) sequencing technologies. Illumina sequencing resulted in deep coverage and allowed detection of rare variants as well as HCV co-infection with multiple genotypes. The application of the method with PacBio RS resulted in sequence reads greater than 9 kb that covered the near full-length HCV amplicon in a single read and enabled analysis of the near full-length quasispecies.

Conclusions: The protocol described herein can be utilised for rapid amplification and sequencing of the near-full length HCV genome in a cost efficient manner suitable for a wide range of applications.
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http://dx.doi.org/10.1186/s12864-016-2575-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4797172PMC
March 2016

Structural characteristics of the optic nerve head influencing human retinal venous pulsations.

Exp Eye Res 2016 04 15;145:341-346. Epub 2016 Feb 15.

Lions Eye Institute, The University of Western Australia, Perth, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Australia. Electronic address:

The relationship between structural characteristics of the optic nerve head and venous pulsations in the human eye remain unknown. Using photoplethysmographic techniques we investigated whether properties of the human retinal veins and their surrounding structures influence venous pulsation. 448 locations of venous pulsation were analysed from 26 normal human eyes. Green channel densitometry derived from video recordings of venous pulsations were used to generate a map of venous pulsation amplitudes along retinal veins. Optical coherence tomography was used to perform quantitative measurements of tissue characteristics at sites of high and low amplitude points as well as in a second analysis, at maximal amplitude pulsation sites from superior and inferior halves of the eyes. Structural characteristics measured included venous diameter, distance from pulsation point to cup margin, vessel length from pulsation point to vein exit, tissue thickness overlying vein, optic disc diameter and presence of a proximal arteriovenous crossing. Increasing venous pulsation amplitudes were associated with larger applied ophthalmodynamometry force, increasing venous diameter, and decreasing absolute cup margin distance (all p < 0.001). Increasing distance of maximal amplitude pulsation point to cup margin was associated with the presence of a proximal arteriovenous crossing, increasing venous diameter, and decreasing tissue depth (all p ≤ 0.001). Venous diameter and tissue depth alter venous compliance, which is likely to be a major factor determining sites of venous pulsation.
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http://dx.doi.org/10.1016/j.exer.2016.02.003DOI Listing
April 2016

Linking the T cell receptor to the single cell transcriptome in antigen-specific human T cells.

Immunol Cell Biol 2016 07 10;94(6):604-11. Epub 2016 Feb 10.

Systems Medicine in Infectious Diseases, Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia.

Heterogeneity of T cells is a hallmark of a successful adaptive immune response, harnessing the vast diversity of antigen-specific T cells into a coordinated evolution of effector and memory outcomes. The T cell receptor (TCR) repertoire is highly diverse to account for the highly heterogeneous antigenic world. During the response to a virus multiple individual clones of antigen specific CD8+ (Ag-specific) T cells can be identified against a single epitope and multiple epitopes are recognised. Advances in single-cell technologies have provided the potential to study Ag-specific T cell heterogeneity at both surface phenotype and transcriptome levels, thereby allowing investigation of the diversity within the same apparent sub-population. We propose a new method (VDJPuzzle) to reconstruct the native TCRαβ from single cell RNA-seq data of Ag-specific T cells and then to link these with the gene expression profile of individual cells. We applied this method using rare Ag-specific T cells isolated from peripheral blood of a subject who cleared hepatitis C virus infection. We successfully reconstructed productive TCRαβ in 56 of a total of 63 cells (89%), with double α and double β in 18, and 7% respectively, and double TCRαβ in 2 cells. The method was validated via standard single cell PCR sequencing of the TCR. We demonstrate that single-cell transcriptome analysis can successfully distinguish Ag-specific T cell populations sorted directly from resting memory cells in peripheral blood and sorted after ex vivo stimulation. This approach allows a detailed analysis of the TCR diversity and its relationship with the transcriptional profile of different clones.
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http://dx.doi.org/10.1038/icb.2016.16DOI Listing
July 2016

Intraocular Pressure Reduction Is Associated with Reduced Venous Pulsation Pressure.

PLoS One 2016 29;11(1):e0147915. Epub 2016 Jan 29.

Lions Eye Institute, University of Western Australia, Nedlands, Australia.

Purpose: To explore whether alterations in intraocular pressure (IOP) affect vein pulsation properties using ophthalmodynamometric measures of vein pulsation pressure.

Patients And Methods: Glaucoma patients had two retinal vein pulsation pressure (VPP) measurements from upper and lower hemiveins performed by ophthalmodynamometry at least 3 months apart. All subjects had VPP and IOP recorded at two visits, with standard automated perimetry, central corneal thickness (CCT) recorded at the initial visit. Where venous pulsation was spontaneous ophthalmodynamometry could not be performed and VPP was considered equal to IOP. Change in VPP was calculated and binarized with reduction in pressure scored 1 and no change or increase scored as 0. Data analysis used a mixed logistic regression model with change in VPP as response variable and change in IOP, visual field loss (mean deviation), CCT and time interval as explanatory variables.

Results: 31 subjects (20 females) with mean age 60 years (sd 11) were examined with change in VPP being significantly associated with change in IOP (odds ratio 1.6/mmHg, 95% CI 1.2 to 2.1 in the glaucoma patients but not suspect patients (p = 0.0005).

Conclusion: Change in VPP is strongly associated with change in IOP such that a reduced intraocular pressure is associated with a subsequent reduction in VPP. This indicates that reduced IOP alters some retinal vein properties however the nature and time course of these changes is not known.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147915PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732770PMC
July 2016

Objective detection of retinal vessel pulsation.

PLoS One 2015 2;10(2):e0116475. Epub 2015 Feb 2.

Neurofinity, School of Surgery, University of Western Australia, Nedlands, Australia.

Purpose: Retinal venous pulsation detection is a subjective sign, which varies in elevated intracranial pressure, venous obstruction and glaucoma. To date no method can objectively measure and identify pulsating regions.

Method: Using high resolution video-recordings of the optic disk and retina we measured fluctuating light absorption by haemoglobin during pulsation. Pulsation amplitude was calculated from all regions of the retinal image video-frames in a raster pattern. Segmented retinal images were formed by objectively selecting regions with amplitudes above a range of threshold values. These were compared to two observers manually drawing an outline of the pulsating areas while viewing video-clips in order to generate receiver operator characteristics.

Results: 216,515 image segments were analysed from 26 eyes in 18 research participants. Using data from each eye, the median area under the receiver operator curve (AU-ROC) was 0.95. With all data analysed together the AU-ROC was 0.89. We defined the ideal threshold amplitude for detection of any pulsating segment being that with maximal sensitivity and specificity. This was 5 units (95% confidence interval 4.3 to 6.0) compared to 12 units before any regions were missed. A multivariate model demonstrated that ideal threshold amplitude increased with increased variation in video-sequence illumination (p = 0.0119), but between the two observers (p = 0.0919) or other variables.

Conclusion: This technique demonstrates accurate identification of retinal vessel pulsating regions with no areas identified manually being missed with the objective technique. The amplitude values are derived objectively and may be a significant advance upon subjective ophthalmodynamometric threshold techniques.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116475PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314073PMC
October 2015

Photoplethysmographic measurement of various retinal vascular pulsation parameters and measurement of the venous phase delay.

Invest Ophthalmol Vis Sci 2014 Sep 2;55(9):5998-6006. Epub 2014 Sep 2.

Lions Eye Institute, University of Western Australia, Nedlands, Western Australia, Australia.

Purpose: Retinal vein pulsation properties are altered by glaucoma, intracranial pressure (ICP) changes, and retinal venous occlusion, but measurements are limited to threshold measures or manual observation from video frames. We developed an objective retinal vessel pulsation measurement technique, assessed its repeatability, and used it to determine the phase relations between retinal arteries and veins.

Methods: Twenty-three eyes of 20 glaucoma patients had video photograph recordings from their optic nerve and peripapillary retina. A modified photoplethysmographic system using video recordings taken through an ophthalmodynamometer and timed to the cardiac cycle was used. Aligned video frames of vessel segments were analyzed for blood column light absorbance, and waveform analysis was applied. Coefficient of variation (COV) was calculated from data series using recordings taken within ±1 unit ophthalmodynamometric force of each other. The time in cardiac cycles and seconds of the peak (dilation) and trough (constriction) points of the retinal arterial and vein pulse waveforms were measured.

Results: Mean vein peak time COV was 3.4%, and arterial peak time COV was 4.4%. Lower vein peak occurred at 0.044 cardiac cycles (0.040 seconds) after the arterial peak (P = 0.0001), with upper vein peak an insignificant 0.019 cardiac cycles later. No difference in COV for any parameter was found between upper or lower hemiveins. Mean vein amplitude COV was 12.6%, and mean downslope COV was 17.7%.

Conclusions: This technique demonstrates a small retinal venous phase lag behind arterial pulse. It is objective and applicable to any eye with clear ocular media and has moderate to high reproducibility. ( http://www.anzctr.org.au number, ACTRN12608000274370.).
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http://dx.doi.org/10.1167/iovs.14-15104DOI Listing
September 2014

Optimizing donor selection for public cord blood banking: influence of maternal, infant, and collection characteristics on cord blood unit quality.

Transfusion 2014 Feb 27;54(2):340-52. Epub 2013 May 27.

Robertson Cell and Translational Therapy Program, Carolinas Cord Blood Bank, Duke University Medical Center, Durham, North Carolina; The EMMES Corporation, Rockville, Maryland.

Background: Banked unrelated donor umbilical cord blood (CB) has improved access to hematopoietic stem cell transplantation for patients without a suitably matched donor. In a resource-limited environment, ensuring that the public inventory is enriched with high-quality cord blood units (CBUs) addressing the needs of a diverse group of patients is a priority. Identification of donor characteristics correlating with higher CBU quality could guide operational strategies to increase the yield of banked high-quality CBUs.

Study Design And Methods: Characteristics of 5267 CBUs donated to the Carolinas Cord Blood Bank, a public bank participating in the National Cord Blood Inventory, were retrospectively analyzed. Eligible CBUs, collected by trained personnel, were processed using standard procedures. Routine quality and potency metrics (postprocessing total nucleated cell count [post-TNCC], CD34+, colony-forming units [CFUs]) were correlated with maternal, infant, and collection characteristics.

Results: High-quality CBUs were defined as those with higher post-TNCC (>1.25 × 10(9)) with CD34+ and CFUs in the upper quartile. Factors associated with higher CD34+ or CFU content included a shorter interval from collection to processing (<10 hr), younger gestational age (34-37 weeks; CD34+ and CFUs), Caucasian race, higher birthweight (>3500 g), and larger collection volumes (>80 mL).

Conclusions: We describe characteristics identifying high-quality CBUs, which can be used to inform strategies for CBU collection for public banks. Efforts should be made to prioritize collections from larger babies born before 38 weeks of gestation. CBUs should be rapidly transported to the processing laboratory. The lower quality of CBUs from non-Caucasian donors highlights the challenges of building a racially diverse public CB inventory.
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http://dx.doi.org/10.1111/trf.12257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766489PMC
February 2014

Spatial modeling of visual field data for assessing glaucoma progression.

Invest Ophthalmol Vis Sci 2013 Feb 28;54(2):1544-53. Epub 2013 Feb 28.

Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand.

Purpose: In order to reduce noise and account for spatial correlation, we applied disease mapping techniques to visual field (VF) data. We compared our calculated rates of progression to other established techniques.

Methods: Conditional autoregressive (CAR) priors, weighted to account for physiologic correlations, were employed to describe spatial and spatiotemporal correlation over the VF. Our model is extended to account for several physiologic features, such as the nerve fibers serving adjacent loci on the VF not mapping to the adjacent optic disc regions, the presence of the blind spot, and large measurement fluctuation. The models were applied to VFs from 194 eyes and fitted within a Bayesian framework using Metropolis-Hastings algorithms.

Results: Our method (SPROG for Spatial PROGgression) showed progression in 42% of eyes. Using a clinical reference, our method had the best receiver operating characteristics compared with the point-wise linear regression methods. Because our model intrinsically accounts for the large variation of VF data, by adjusting for spatial correlation, the effects of outliers are minimized, and spurious trends are avoided.

Conclusions: by using CAR priors, we have modeled the spatial correlation in the eye. combining this with physiologic information, we are able to provide a novel method for VF analysis. model diagnostics, sensitivity, and specificity show our model to be apparently superior to CURRENT POINT-wise linear regression methods. (http://www.anzctr.org.au number, ACTRN12608000274370.).
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http://dx.doi.org/10.1167/iovs.12-11226DOI Listing
February 2013
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