Histopathologically Validated Diagnostic Accuracy of PSMA-PET/CT in the Primary and Secondary Staging of Prostate Cancer and the Impact of PSMA-PET/CT on Clinical Management: A Systematic Review and Meta-analysis.

Prostate-specific membrane antigen (PSMA) is a highly expressed protein in prostate cancer (PCa) and has become an increasingly popular target for molecular imaging in recent years. PSMA based positron-emission-tomography/computed tomography (PET/CT) is a well characterised hybrid imaging modality that combines the high sensitivity of PET with the high spatial resolution of CT imaging. The combination of these two imaging modalities provides an accurate tool for detecting and managing PCa. Several diagnostic accuracy and clinical management studies investigating the role of PSMA PET/CT in PCa have been published recently. This study aimed to perform an updated systematic review and meta-analysis to evaluate the diagnostic performance of PSMA PET/CT in localised, lymph node metastatic (LNM) and recurrent PCa patients and assess its impact on the clinical management of primary and recurrent PCa. Using Medline, Embase, PubMed and Cochrane Library databases, studies reporting the diagnostic accuracy and clinical management of PSMA PET/CT were analysed based on the PRISMA guidelines. Statistical analyses were conducted using random-effects models, and meta-regression explored observed heterogeneity. Results indicate that the sensitivity and specificity of PSMA PET/CT for localised PCa were 71.0% (95% confidence interval (CI): 58.0, 81.0) and 92.0% (95% CI: 86.0, 96.0), respectively (N = 10; n = 404 patients). Sensitivity and specificity in LNM were 57.0% (95% CI: 49.0, 64.0) and 96.0% (95% CI: 95.0, 97.0) (N = 36; n = 3,659 patients). For patients with biochemical recurrence (BCR), sensitivity was 84.0% (95% CI: 74.0, 90.0), and specificity was 97.0% (95% CI: 88.0, 99.0) (N = 9; n = 818 patients). The pooled proportion of management changes in primary (N = 16; n = 1,099 patients) and recurrent (N = 40; n = 5,398 patients) PCa was 28.0% (95% CI: 23.0, 34.0) and 54.0% (95% CI: 50.0, 58.0), respectively. In conclusion, PSMA PET/CT shows moderate sensitivity and high specificity in localised and LNM disease, while the accuracy in BCR patients was high. PSMA PET/CT also had a large impact on the clinical management of PCa patients. This is the most extensive and first systematic review to include three subgroups of PCa with histologically verified diagnostic accuracy and clinical management change reported separately in primary and recurrent disease settings.

Protocol for a bandit-based response adaptive trial to evaluate the effectiveness of brief self-guided digital interventions for reducing psychological distress in university students: the Vibe Up study.

INTRODUCTION: Meta-analytical evidence confirms a range of interventions, including mindfulness, physical activity and sleep hygiene, can reduce psychological distress in university students. However, it is unclear which intervention is most effective. Artificial intelligence (AI)-driven adaptive trials may be an efficient method to determine what works best and for whom. The primary purpose of the study is to rank the effectiveness of mindfulness, physical activity, sleep hygiene and an active control on reducing distress, using a multiarm contextual bandit-based AI-adaptive trial method. Furthermore, the study will explore which interventions have the largest effect for students with different levels of baseline distress severity. METHODS AND ANALYSIS: The Vibe Up study is a pragmatically oriented, decentralised AI-adaptive group sequential randomised controlled trial comparing the effectiveness of one of three brief, 2-week digital self-guided interventions (mindfulness, physical activity or sleep hygiene) or active control (ecological momentary assessment) in reducing self-reported psychological distress in Australian university students. The adaptive trial methodology involves up to 12 sequential mini-trials that allow for the optimisation of allocation ratios. The primary outcome is change in psychological distress (Depression, Anxiety and Stress Scale, 21-item version, DASS-21 total score) from preintervention to postintervention. Secondary outcomes include change in physical activity, sleep quality and mindfulness from preintervention to postintervention. Planned contrasts will compare the four groups (ie, the three intervention and control) using self-reported psychological distress at prespecified time points for interim analyses. The study aims to determine the best performing intervention, as well as ranking of other interventions. ETHICS AND DISSEMINATION: Ethical approval was sought and obtained from the UNSW Sydney Human Research Ethics Committee (HREC A, HC200466). A trial protocol adhering to the requirements of the Guideline for Good Clinical Practice was prepared for and approved by the Sponsor, UNSW Sydney (Protocol number: HC200466_CTP). TRIAL REGISTRATION NUMBER: ACTRN12621001223820.

Mapping the Patient-Reported Outcomes Measurement Information System (PROMIS-29) to EQ-5D-5L.

BACKGROUND AND OBJECTIVE: The Patient-Reported Outcomes Measurement Information System (PROMIS-29) is gaining popularity as healthcare system funders increasingly seek value-based care. However, it is limited in its ability to estimate utilities and thus inform economic evaluations. This study develops the first mapping algorithm for estimating EuroQol 5-Dimension 5-Level (EQ-5D-5L) utilities from PROMIS-29 responses using a large dataset and through extensive comparisons between econometric models. METHODS: An online survey was conducted to collect responses to PROMIS-29 and EQ-5D-5L from the general Australian population (N = 3013). Direct and indirect mapping methods were explored, including linear regression, Tobit, generalised linear model, censored regression model, beta regression (Betamix), the adjusted limited dependent variable mixture model (ALDVMM) and generalised ordered logit. The most robust model was selected by assessing the performance based on average ten-fold cross-validation geometric mean absolute error and geometric mean squared error, the predicted mean, maximum and minimum utilities, as well as the fitting across the entire distribution. RESULTS: The direct approach using ALDVMM was considered the preferred model based on lowest geometric mean absolute error and geometric mean squared error in cross-validation (0.0882, 0.0299) and its superiority in predicting the actual observed mean, full health states and lower utility extremes. The robustness and precision in prediction across the entire distribution of utilities with ALDVMM suggest it is an accurate and valid mapping algorithm. Moreover, the suggested mapping algorithm outperformed previously published algorithms using Australian data, indicating the validity of this model for economic evaluations. CONCLUSIONS: This study developed a robust algorithm to estimate EQ-5D-5L utilities from PROMIS-29. Consistent with the recent literature, the ALDVMM outperformed all other econometric models considered in this study, suggesting that the mixture models have relatively better performance and are an ideal candidate model for mapping.

Microcosting Study of Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography in Prostate Cancer.

OBJECTIVES: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has emerged as a promising imaging tool in prostate cancer diagnosis. PSMA PET/CT radiotracers are produced in-house (gallium-68, eg, 68Ga-PSMA-11) or provided by commercial entities (fluorine-18, eg, 18F-DCFPyL). Nevertheless, the cost per procedure is not well established given that current estimates have several limitations. This study aimed to establish the cost of PSMA PET/CT in Australia. METHODS: Hospitals and diagnostic facilities currently conducting PSMA PET/CT in Australia in metropolitan and regional areas completed a survey of PSMA PET/CT throughput, radiotracers involved, and the cost of assets, departmental staffing, consumables, and occupancy. Total costs were estimated using a top-down microcosting approach, involving identifying all relevant cost components and valuing each component for the average patient, and a gross costing approach, involving apportioning cost components at an aggregated level. RESULTS: Data were collected from 8 facilities. The most common radiotracer used was 18F-DCFPyL (7 facilities, 87%), followed by 68Ga-PSMA-11 (4 facilities, 50%). The average cost of PSMA PET/CT was A$1554.77 and A$1306.00 based on the microcosting and gross costing approaches, respectively. CONCLUSIONS: This study provides a detailed and accurate estimation of the cost of PSMA PET/CT in Australia. These costs can be used as a benchmark to identify potential efficiencies and help policy makers set the appropriate reimbursement rate for this procedure. The use of data from facilities using different radiotracers in metropolitan and regional areas and with different throughput increases the generalizability of the results, especially in countries with similar health systems.

Cost-Effectiveness Analysis of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computed Tomography (PET/CT) for the Primary Staging of Prostate Cancer in Australia.

BACKGROUND AND OBJECTIVES: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) combined with computed tomography (CT) is a new imaging modality to detect the extra-prostatic spread of prostate cancer. PSMA PET/CT has a higher sensitivity and specificity than conventional imaging (CT ± whole body bone scan [WBBS]). This study conducted a cost-utility analysis of PSMA PET/CT compared with conventional imaging for patients with newly diagnosed, intermediate-risk or high-risk primary prostate cancer. PERSPECTIVE: Australian healthcare perspective. SETTING: Tertiary. METHODS: A decision-analytic Markov model combined data from a variety of sources. The time horizon was 35 years. The sensitivity and specificity of PSMA PET/CT and CT alone were based on meta-analyses and the test accuracy of CT+WBBS was based on a single randomised controlled trial. Health outcomes included cases detected, life-years, and quality-adjusted life-years. Costs related to other diagnostic tests, initial treatment, adverse events, and post-disease progression were included. All costs were reported in 2021 Australian Dollars (A$). RESULTS: The deterministic incremental cost-effectiveness ratio of PSMA PET/CT was estimated to be A $21,147/quality-adjusted life-year gained versus CT+WBBS, and A$36,231/quality-adjusted life-year gained versus CT alone. The results were most sensitive to the time horizon, and the initial treatments received by patients diagnosed with metastatic cancer. The probability of PSMA PET/CT being cost effective was estimated to be 91% versus CT+WBBS and 89% versus CT alone, using a threshold of AU$50,000/quality-adjusted life-year gained. CONCLUSIONS: PSMA PET/CT is likely to be more costly than CT+WBBS or CT alone in Australia; however, it is still likely to be considered cost effective compared with conventional imaging.

An examination of machine learning to map non-preference based patient reported outcome measures to health state utility values.

Non-preference-based patient-reported outcome measures (PROMs) are popular in health outcomes research. These measures, however, cannot be used to estimate health state utilities, limiting their usefulness for economic evaluations. Mapping PROMs to a multi-attribute utility instrument is one solution. While mapping is commonly conducted using econometric techniques, failing to specify the complex interactions between variables may lead to inaccurate prediction of utilities, resulting in inaccurate estimates of cost-effectiveness and suboptimal funding decisions. These issues can be addressed using machine learning. This paper evaluates the use of machine learning as a mapping tool. We adopt a comprehensive approach to compare six machine learning techniques with eight econometric techniques to map the Patient-Reported Outcomes Measurement Information System Global Health 10 (PROMIS-GH10) to the EuroQol five dimensions (EQ-5D-5L). Using data collected from 2015 Australians, we find the least absolute shrinkage and selection operator (LASSO) model out-performed all machine learning techniques and the adjusted limited dependent variable mixture model (ALDVMM) out-performed all econometric techniques, with the LASSO performing better than ALDVMM. The variable selection feature of LASSO was then used to enhance the performance of the ALDVMM in a hybrid model. Our analysis identifies the potential benefits and challenges of using machine learning techniques for mapping and offers important insights for future research.

Lynch syndrome testing of colorectal cancer patients in a high-income country with universal healthcare: a retrospective study of current practice and gaps in seven australian hospitals.

BACKGROUND: To inform effective genomic medicine strategies, it is important to examine current approaches and gaps in well-established applications. Lynch syndrome (LS) causes 3-5% of colorectal cancers (CRCs). While guidelines commonly recommend LS tumour testing of all CRC patients, implementation in health systems is known to be highly variable. To provide insights on the heterogeneity in practice and current bottlenecks in a high-income country with universal healthcare, we characterise the approaches and gaps in LS testing and referral in seven Australian hospitals across three states. METHODS: We obtained surgery, pathology, and genetics services data for 1,624 patients who underwent CRC resections from 01/01/2017 to 31/12/2018 in the included hospitals. RESULTS: Tumour testing approaches differed between hospitals, with 0-19% of patients missing mismatch repair deficiency test results (total 211/1,624 patients). Tumour tests to exclude somatic MLH1 loss were incomplete at five hospitals (42/187 patients). Of 74 patients with tumour tests completed appropriately and indicating high risk of LS, 36 (49%) were missing a record of referral to genetics services for diagnostic testing, with higher missingness for older patients (0% of patients aged ≤ 40 years, 76% of patients aged > 70 years). Of 38 patients with high-risk tumour test results and genetics services referral, diagnostic testing was carried out for 25 (89%) and identified a LS pathogenic/likely pathogenic variant for 11 patients (44% of 25; 0.7% of 1,624 patients). CONCLUSIONS: Given the LS testing and referral gaps, further work is needed to identify strategies for successful integration of LS testing into clinical care, and provide a model for hereditary cancers and broader genomic medicine. Standardised reporting may help clinicians interpret tumour test results and initiate further actions.

The cost-effectiveness of unilateral cochlear implants in UK adults.

OBJECTIVE: The National Institute for Health and Care Excellence (NICE) updated its eligibility criteria for unilateral cochlear implants (UCIs) in 2019. NICE claimed this would not impact the cost-effectiveness results used within its 2009 technology appraisal guidance. This claim is uncertain given changed clinical practice and increased healthcare unit costs. Our objective was to estimate the cost-effectiveness estimates of UCIs in UK adults with severe to profound hearing loss within the contemporary NHS environment. METHODS: A cost-utility analysis employing a Markov model was undertaken to compare UCIs with hearing aids or no hearing aids for people with severe to profound hearing loss. A clinical pathway was developed to estimate resource use. Health-related quality of life, potential adverse events, device upgrades and device failure were captured. Unit costs were derived mostly from the NHS data. Probabilistic sensitivity analysis further assessed the effect of uncertain model inputs. RESULTS: A UCI is likely to be deemed cost-effective when compared to a hearing aid (£11,946/QALY) or no hearing aid (£10,499/QALY). A UCI has an 93.0% and 98.7% likelihood of being cost-effective within the UK adult population when compared to a hearing aid or no hearing aid, respectively. ICERs were mostly sensitive to the proportion of people eligible for cochlear implant, discount rate, surgery and device costs and processor upgrade cost. CONCLUSION: UCIs remain cost-effective despite changes to clinical practice and increased healthcare unit costs. Updating the NICE criteria to provide better access UCIs is projected to increase annual implants in adults and children by 70% and expenditure by £28.6 million within three years. This increased access to UCIs will further improve quality of life of recipients and overall social welfare.

An Economic Evaluation of Australia's Newborn Hearing Screening Program: A Within-Study Cost-Effectiveness Analysis.

OBJECTIVES: Hearing loss is one of the most prevalent congenital disorders among children. Many countries have implemented universal newborn hearing screening (UNHS) for the early diagnosis and treatment of hearing loss. Despite widespread implementation, the value for money of UNHS is unclear due to lack of cost and outcomes data from rigorous study designs. The objective of this research is to conduct a within-study cost-effectiveness analysis of UNHS compared with targeted screening (targeting children with risk factors of hearing loss) from the Australian healthcare system perspective. This evaluation is the first economic evaluation to assess the cost-effectiveness of UNHS compared to targeted screening using real-world data from a natural experiment. DESIGN: The evaluation assumed the Australian healthcare system perspective and considered a time horizon of 5 years. Utilities were estimated using responses to the Health Utilities Index Mark III. Screening costs were estimated based on the Victorian Infant Hearing Screening Program. Ongoing costs were estimated based on administrative data, while external data sources were used to estimate costs related to hearing services. Missing data were handled using the multiple imputation method. Outcome measures included quality-adjusted life years (QALYs) and four language and communication-related outcomes: Peabody Picture Vocabulary Test, Wechsler Nonverbal Scale of Ability, Progressive Achievement Test, and comprehensive, expressive, and total language scores based on the Preschool Language Scale. RESULTS: On average, the UNHS cost an extra Australian dollar (A$)22,000 per diagnosed child and was associated with 0.45 more QALYs per diagnosed child compared with targeted screening to 5 years, resulting in an incremental cost-effectiveness ratio (ICER) of A$48,000 per QALY gained. The ICERs for language outcomes lay between A$3,900 (for expressive language score) and A$83,500 per one-point improvement in language score (for Wechsler Nonverbal Scale of Ability). UNHS had a 69% probability of being more cost-effective compared to targeted screening at a willingness to pay threshold of A$60,000 per QALY gained. ICERs were most sensitive to the screening costs. CONCLUSIONS: The evaluation demonstrated the usefulness of a within-study economic evaluation to understand the value for money of the UNHS program in the Australian context. Findings from this evaluation suggested that screening costs were the key driver of cost-effectiveness results. Most outcomes were not significantly different between UNHS and targeted screening groups. The ICER may be overestimated due to the short follow-up period. Further research is warranted to include long-term resource use and outcome data, late diagnosis, transition and remission between severity levels, and timing of diagnosis and treatment.

Cost-Effectiveness of Screening Preschool Children for Hearing Loss in Australia.

OBJECTIVES: While all newborns in Australia are tested for congenital hearing loss through universal newborn hearing screening programs, some children will acquire hearing loss in their first five years of life. Delayed diagnosed or undiagnosed hearing loss in children can have substantial immediate- and long-term consequences. It can significantly reduce school readiness, language and communication development, social and emotional development, and mental health. It can also compromise lifetime educational achievements and employment opportunities and future economic contribution to society through lost productivity. The need for a universal hearing screening program for children entering their first year of primary school has been noted in two separate Australian Government hearing inquiries in the last decade. Sound Scouts is a hearing screening application (app) that tests for hearing loss in children using a tablet or mobile device, supervised by parents at home. It tests for sensorineural or permanent conductive hearing loss and central auditory processing disorder in children. In 2018 the Australian Government funded the roll-out of Sound Scouts to allow up to 600,000 children to test their hearing using Sound Scouts. This study estimated the cost-effectiveness of screening 5-year-old children for hearing loss using Sound Scouts at home, compared with no screening. DESIGN: A decision-analytic model was developed to estimate the incremental costs and quality-adjusted life years (QALYs) of administering Sound Scouts over a 20-year time horizon. Testing accuracy was based on comparing Sound Scouts test results to clinical test results while other parameters were based on published data. Costs were estimated from the perspective of the Australian health care system. Univariate and probabilistic sensitivity analyses were undertaken. RESULTS: Sound Scouts is estimated to result in an average incremental cost of A$61.02 and an average incremental increase in QALYs of 0.01. This resulted in an incremental cost-effectiveness ratio of A$5392 per QALY gained, which is likely to be considered cost-effective by Australian decision makers. Screening with Sound Scouts was found to have a 96.2 per cent probability of being cost-effective using a threshold of A$60,000 per QALY gained. CONCLUSIONS: Using Sound Scouts to screen five-year-old children for hearing loss (at home) is likely to be cost-effective. Screening children using Sound Scouts will result in early identification and intervention in childhood hearing loss, thereby reducing early childhood disadvantage through cumulative gains in quality of life, education, and economic outcomes over their lifetime.

Application of an economic evaluation approach to making regulatory decisions regarding access to medicines: advantages, challenges and recommendations.

Initially patients require a prescription to access most new medicines. Some medicines may later be reclassified, allowing patients to access them without a prescription. Currently, Australian Therapeutic Goods Administration guidelines regarding reclassification decisions focus on patient risk rather than on potential benefits to patient health and the healthcare system. We conducted two extensive case studies demonstrating an economic evaluation approach to medicine reclassification in Australia, which were presented at various conferences and to key stakeholders. This article discusses the advantages and challenges of using an economic evaluation approach to inform medicine reclassification decisions. Advantages identified include systematically and transparently synthesising evidence from multiple sources; predicting the overall expected impact of reclassification on health outcomes and costs before it occurs; considering a broader range of risks and benefits; aggregation of health impacts into a single measure (quality-adjusted life years); identification of drivers of uncertainty; insight into the effects of different regulatory decisions; and improved consistency of evidence. Challenges include data availability and quality, estimating behavioural changes, model complexity, the lack of an incremental cost-effectiveness ratio threshold, and funding of economic analyses. We recommend that regulatory decision makers use an economic evaluation approach to help inform reclassification decisions, although economic evaluation results should be considered as part of the broader body of evidence. Ultimately, the use of an economic evaluation approach will contribute to helping decision makers maximise population health outcomes in an efficient way. What is known about the topic? In the past, decisions regarding medicine reclassification have generally been made using a deliberative approach focusing on patient risk. However, there are also potential benefits to patient health and effects on the healthcare system. Increasing awareness of these benefits have led to the development of alternative approaches to decision making, including an economic evaluation approach. What does this paper add? This article discusses the advantages and challenges of using an economic evaluation approach to inform medicine reclassification decisions compared with alternative approaches. What are the implications for practitioners? Economic evaluation results should be considered as part of the broader body of evidence regarding the types of health impacts, the extent of the available evidence, who will be affected, and the role of medical practitioners and pharmacists in mitigating any risks. However, awareness of the advantages and challenges of this approach in advance will help mitigate some of the challenges and increase acceptance of the economic evaluation results by decision makers and stakeholders.

The cost-effectiveness of Cochlear implants in Swedish adults.

BACKGROUND: Research has shown unilateral cochlear implants (CIs) significantly improve clinical outcomes and quality of life in adults. However, only 13% of eligible Swedish adults currently use a unilateral CI. The objective was to estimate the cost-effectiveness of unilateral CIs compared to a hearing aid for Swedish adults with severe to profound hearing loss. METHODS: A Markov model with a lifetime horizon and six-month cycle length was developed to estimate the benefits and costs of unilateral CIs from the Swedish health system perspective. A treatment pathway was developed through consultation with clinical experts to estimate resource use and costs. Unit costs were derived from the Swedish National Board of Health and Welfare and the Swedish Association of Local Authorities and Regions. Health outcomes were reported in terms of Quality Adjusted Life Years (QALYs). RESULTS: Unilateral CIs for Swedish adults with severe to profound hearing loss are likely to be deemed cost-effective when compared to a hearing aid (SEK 140,474 per QALY gained). The results were most sensitive to the age when patients are implanted with a CI and the proportion of patients eligible for CIs after triage. CONCLUSIONS: An increase in the prevalence of Swedish adults with severe to profound hearing loss is expected as the population ages. Earlier implantation of unilateral CIs improves the cost-effectiveness among people eligible for CIs. Unilateral CIs are an efficacious and cost-effective option to improve hearing and quality of life in Swedish adults with severe to profound hearing loss.

Cost-Effectiveness of Cardiovascular Magnetic Resonance in Diagnosing Coronary Artery Disease in the Australian Health Care System.

BACKGROUND: Coronary artery disease (CAD) remains a major public health problem in Australia and globally. A variety of imaging techniques allow for both anatomical and functional assessment of CAD and selection of the optimal investigation pathway is challenging. Cardiovascular magnetic resonance (CMR) is not widely used in Australia, partly due to perceived cost and lack of Federal Government reimbursement compared to the alternative techniques. The aim of this study was to estimate the cost-effectiveness of different diagnostic strategies in identifying significant CAD in patients with chest pain suggestive of angina using the evidence gathered in the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 (CE-MARC trial), analysed from the Australian health care perspective. METHODS: A decision analytic model coupled with three distinct Markov models allowed eight potential clinical investigation strategies to be considered; combinations of exercise electrocardiogram stress testing (EST), single-photon emission computed tomography (SPECT), stress CMR, and invasive coronary angiography (ICA). Costs were from the Australian health care system in Australian dollars, and outcomes were measured in terms of quality-adjusted life-years. Parameter estimates were derived from the CE-MARC and EUropean trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease (EUROPA) trials, and from reviews of the published literature. RESULTS: The most cost-effective diagnostic strategy, based on a cost-effectiveness threshold of $45,000 to $75,000 per QALY gained, was EST, followed by stress CMR if the EST was positive or inconclusive, followed by ICA if the stress CMR was positive or inconclusive; this held true in the base case and the majority of scenario analyses. CONCLUSIONS: This economic evaluation shows that an investigative strategy of stress CMR if EST is inconclusive or positive is the most cost-effective approach for diagnosing significant coronary disease in chest pain patients within the Australian health care system.

Pathways to a cancer-free future: a protocol for modelled evaluations to minimise the future burden of colorectal cancer in Australia.

INTRODUCTION: With almost 50% of cases preventable and the Australian National Bowel Cancer Screening Program in place, colorectal cancer (CRC) is a prime candidate for investment to reduce the cancer burden. The challenge is determining effective ways to reduce morbidity and mortality and their implementation through policy and practice. Pathways-Bowel is a multistage programme that aims to identify best-value investment in CRC control by integrating expert and end-user engagement; relevant evidence; modelled interventions to guide future investment; and policy-driven implementation of interventions using evidence-based methods. METHODS AND ANALYSIS: Pathways-Bowel is an iterative work programme incorporating a calibrated and validated CRC natural history model for Australia (Policy1-Bowel) and assessing the health and cost outcomes and resource use of targeted interventions. Experts help identify and prioritise modelled evaluations of changing trends and interventions and critically assess results to advise on their real-world applicability. Where appropriate the results are used to support public policy change and make the case for optimal investment in specific CRC control interventions. Fourteen high-priority evaluations have been modelled or planned, including evaluations of CRC outcomes from the changing prevalence of modifiable exposures, including smoking and body fatness; potential benefits of daily aspirin intake as chemoprevention; increasing CRC incidence in people aged <50 years; increasing screening participation in the general and Aboriginal and Torres Strait Islander populations; alternative screening technologies and modalities; and changes to follow-up surveillance protocols. Pathways-Bowel is a unique, comprehensive approach to evaluating CRC control; no prior body of work has assessed the relative benefits of a variety of interventions across CRC development and progression to produce a list of best-value investments. ETHICS AND DISSEMINATION: Ethics approval was not required as human participants were not involved. Findings are reported in a series of papers in peer-reviewed journals and presented at fora to engage the community and policymakers.

Understanding implementation success: protocol for an in-depth, mixed-methods process evaluation of a cluster randomised controlled trial testing methods to improve detection of Lynch syndrome in Australian hospitals.

INTRODUCTION: In multisite intervention trials, implementation success often varies widely across settings. Process evaluations are crucial to interpreting trial outcomes and understanding contextual factors and causal chains necessary for successful implementation. Lynch syndrome is a hereditary cancer predisposition conferring an increased risk of colorectal, endometrial and other cancer types. Despite systematic screening protocols to identify Lynch syndrome, the condition remains largely underdiagnosed. The Hide and Seek Project ('HaSP') is a cluster randomised controlled trial determining the effectiveness of two approaches to improving Lynch syndrome detection at eight Australian hospital networks. To enhance widespread implementation of optimal Lynch syndrome identification, there is a need to understand not only what works, but also why, in what contexts, and at what costs. Here we describe an in-depth investigation of factors influencing successful implementation of procedures evaluated in the HaSP trial. METHODS AND ANALYSIS: A mixed-methods, theory-driven process evaluation will be undertaken in parallel to the HaSP trial. Data will include: interviews of Implementation Leads and Lynch syndrome stakeholders, pre-post implementation questionnaires, audio analysis of meetings and focus groups, observation of multidisciplinary team meetings, fidelity checklists and project log analysis. Results will be triangulated and coded, drawing on the Theoretical Domains Framework, Consolidated Framework for Implementation Research and Proctor's implementation outcomes. ETHICS AND DISSEMINATION: Use of a theory-based process evaluation will enhance interpretation and generalisability of HaSP trial findings, and contribute to the implementation research field by furthering understanding of the conditions necessary for implementation success. Ethical approval has been granted and results will be disseminated via publications in peer-reviewed journals and conference presentations. At trial completion, key findings will be fed back to sites to enable refinement of intervention strategies, both in the context of Lynch syndrome and for the possible generalisability of intervention components in other genetic and broader clinical specialties. HASP TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (Identifier: ACTRN12618001072202). Registered 27 June 2018. http://www.ANZCTR.org.au/ACTRN12618001072202.aspx.

Comparing theory and non-theory based implementation approaches to improving referral practices in cancer genetics: a cluster randomised trial protocol.

BACKGROUND: Lynch syndrome (LS) is an inherited, cancer predisposition syndrome associated with an increased risk of colorectal, endometrial and other cancer types. Identifying individuals with LS allows access to cancer risk management strategies proven to reduce cancer incidence and improve survival. However, LS is underdiagnosed and genetic referral rates are poor. Improving LS referral is complex, and requires multisystem behaviour change. Although barriers have been identified, evidence-based strategies to facilitate behaviour change are lacking. The aim of this study is to compare the effectiveness of a theory-based implementation approach against a non-theory based approach for improving detection of LS amongst Australian patients with colorectal cancer (CRC). METHODS: A two-arm parallel cluster randomised trial design will be used to compare two identical, structured implementation approaches, distinguished only by the use of theory to identify barriers and design targeted intervention strategies, to improve LS referral practices in eight large Australian hospital networks. Each hospital network will be randomly allocated to a trial arm, with stratification by state. A trained healthcare professional will lead the following phases at each site: (1) undertake baseline clinical practice audits, (2) form multidisciplinary Implementation Teams, (3) identify target behaviours for practice change, (4) identify barriers to change, (5) generate intervention strategies, (6) support staff to implement interventions and (7) evaluate the effectiveness of the intervention using post-implementation clinical data. The theoretical and non-theoretical components of each trial arm will be distinguished in phases 4-5. Study outcomes include a LS referral process map for each hospital network, with evaluation of the proportion of patients with risk-appropriate completion of the LS referral pathway within 2 months of CRC resection pre and post implementation. DISCUSSION: This trial will determine the more effective approach for improving the detection of LS amongst patients with CRC, whilst also advancing understanding of the impact of theory-based implementation approaches in complex health systems and the feasibility of training healthcare professionals to use them. Insights gained will guide the development of future interventions to improve LS identification on a larger scale and across different contexts, as well as efforts to address the gap between evidence and practice in the rapidly evolving field of genomic research. TRIAL REGISTRATION: ANZCTR, ACTRN12618001072202 . Registered on 27 June 2018.

Mapping the Strengths and Difficulties Questionnaire onto the Child Health Utility 9D in a large study of children.

PURPOSE: Non-preference-based measures cannot be used to directly obtain utilities but can be converted to preference-based measures through mapping. The only mapping algorithm for estimating Child Health Utility-9D (CHU9D) utilities from Strengths and Difficulties Questionnaire (SDQ) responses has limitations. This study aimed to develop a more accurate algorithm. METHODS: We used a large sample of children (n = 6898), with negligible missing data, from the Longitudinal Study of Australian Children. Exploratory factor analysis (EFA) and Spearman's rank correlation coefficients were used to assess conceptual overlap between SDQ and CHU9D. Direct mapping (involving seven regression methods) and response mapping (involving one regression method) approaches were considered. The final model was selected by ranking the performance of each method by averaging the following across tenfold cross-validation iterations: mean absolute error (MAE), mean squared error (MSE), and MAE and MSE for two subsamples where predicted utility values were < 0.50 (poor health) or > 0.90 (healthy). External validation was conducted using data from the Child and Adolescent Mental Health Services study. RESULTS: SDQ and CHU9D were moderately correlated (ρ = - 0.52, p < 0.001). EFA demonstrated that all CHU9D domains were associated with four SDQ subscales. The best-performing model was the Generalized Linear Model with SDQ items and gender as predictors (full sample MAE: 0.1149; MSE: 0.0227). The new algorithm performed well in the external validation. CONCLUSIONS: The proposed mapping algorithm can produce robust estimates of CHU9D utilities from SDQ data for economic evaluations. Further research is warranted to assess the applicability of the algorithm among children with severe health problems.

Is Reclassification of the Oral Contraceptive Pill from Prescription to Pharmacist-Only Cost Effective? Application of an Economic Evaluation Approach to Regulatory Decisions.

BACKGROUND AND OBJECTIVE: Unplanned pregnancies can lead to poorer maternal and child health outcomes. The Australian Therapeutic Goods Administration committee rejected reclassifying a range of oral contraceptive pills (OCPs) from prescription to pharmacist-only medicines in 2015, mainly based on safety concerns. Improving access to OCPs may encourage some women to use contraceptives or switch from other contraceptive methods. However, some adverse events may increase and some women may stop using condoms, increasing their risk of sexually transmitted infections. This study aimed to estimate the cost effectiveness of reclassifying OCPs from prescription to pharmacist-only. PERSPECTIVE: Healthcare system. SETTING: Australian primary care. METHODS: A Markov model was used to synthesise data from a variety of sources. The model included all Australian women aged 15-49 years (N = 5,644,701). The time horizon was 35 years. Contraceptive use before reclassification was estimated using data from the Household, Income and Labour Dynamics in Australia (HILDA) survey, while survey data informed use after reclassification. Health outcomes included pregnancies, pregnancy outcomes (live birth, miscarriage, stillbirth, ectopic pregnancy and abortion), sexually transmitted infections, adverse events (venous thromboembolism, depression, myocardial infarction and stroke), ovarian cancer cases and quality-adjusted life-years. Costs included those related to general practitioner and specialist consultations, contraceptives and other medicines, pharmacist time, hospitalisations and adverse events. All costs were reported in 2016 Australian Dollars. A 5% discount rate was applied to health outcomes and costs. RESULTS: Reclassifying OCPs resulted in 85.70 million quality-adjusted life-years experienced and costs of $46,910.14 million over 35 years, vs. 85.68 million quality-adjusted life-years experienced and costs of $50,274.95 million with OCPs remaining prescription-only. Thus, reclassifying OCPs was more effective and cost saving. However, a sensitivity analysis found that more research on the probability of pregnancy in women not using contraception and not trying to conceive is needed. CONCLUSION: Reclassifying OCPs is likely to be considered cost effective by Australian decision makers.

Cost-Effectiveness of Reclassifying Triptans in Australia: Application of an Economic Evaluation Approach to Regulatory Decisions.

BACKGROUND: Migraine is a common, chronic, disabling headache disorder. Triptans, used as an acute treatment for migraine, are available via prescription in Australia. An Australian Therapeutic Goods Administration (TGA) committee rejected reclassifying sumatriptan and zolmitriptan from prescription medicine to pharmacist-only between 2005 and 2009, largely on the basis of concerns about patient risk. Nevertheless, pharmacist-only triptans may reduce migraine duration and free up healthcare resources. OBJECTIVES: To estimate the cost-effectiveness of reclassifying triptans from prescription-only to pharmacist-only in Australia. METHODS: The study design included decision-analytic modeling combining data from various sources. Behavior before and after reclassification was estimated using medical practitioner and patient surveys and also administrative data. Health outcomes included migraine frequency and duration as well as adverse events (AEs) discussed by the TGA committee. Efficacy and AEs were estimated using randomized controlled trials and observational studies. RESULTS: Reclassifying triptans will reduce migraine duration but increase AEs. This will result in 337 quality-adjusted life-years gained at an increased cost of A$5.9 million over 10 years for all Australian adults older than 15 years (19.6 million). The incremental cost-effectiveness ratio was estimated to be A$17 412/quality-adjusted life-year gained. CONCLUSIONS: The incremental cost-effectiveness ratio is likely to be considered cost-effective by Australian decision makers. Serotonin syndrome, a key concern of the TGA committee, had little impact on the results. Further research is needed regarding pharmacist-only triptan use by migraineurs currently using over-the-counter medicines and by nonmigraineurs, the efficacy of triptans, and the risk of cardiovascular and cerebrovascular AEs and chronic headaches with triptans.