Probabilistic Uncertainty Analysis Research Articles

OP81 Cost Effectiveness Of Human Papillomavirus Extended Genotyping For Cervical Cancer Screening In Singapore

IntroductionThe World Health Organization recommends the human papillomavirus (HPV) test for cervical cancer screening. HPV partial genotyping (PGT) identifies HPV16 and HPV18 individually and the 12 other high-risk HPV genotypes (hrHPV) collectively. In contrast, HPV extended genotyping (XGT) identifies six hrHPV individually (HPV16,18,31,45,51, and 52) and the other eight in three groups (HPV33/58, HPV56/59/66, and HPV35/39/68). XGT allows better risk stratification for patient management and monitoring of persistent same-genotype infections (PSGI), which convey a higher risk for cervical cancer. This study compared the cost, quality-adjusted life-years (QALYs), and resource use of XGT with PGT when used as the primary cervical cancer screening method in Singapore.MethodsA discretely integrated condition event simulation was developed for screening 500,122 women aged 30 to 69 years over five years from the health system perspective, using a three percent annual discount. For XGT, women with HPV35/39/51/56/59/66/68 and reflex cytology of atypical squamous cells of undetermined significance were recalled for a repeat screening in one year, instead of the immediate colposcopy referral that occurs with PGT. At repeat screening, colposcopy was only provided for women with PSGI on XGT. Published data from Singapore were used for inputs and supplemented with data from international literature. Deterministic and probabilistic uncertainty analyses were conducted. Scenario analysis was conducted to simulate various HPV burdens among women. XGT was cost effective when the incremental cost-effectiveness ratio (ICER) relative to PGT was below SGD100,000 (USD118,906) (gross domestic product per capita in 2021).ResultsXGT was cost effective relative to PGT (ICER SGD16,370 [USD19,465]), with fewer colposcopies (n=7,130; 19%), liquid-based cytology tests (n=6,027; 7%), and clinic consultations (n=9,787; 2%) but more HPV tests (n=2,446; 0.5%). The ICER was most sensitive to the relative cost of XGT and the cost of PGT. XGT remained cost effective in one-way sensitivity analysis in all 1,000 probabilistic uncertainty simulations and in scenario analysis with various HPV burdens.ConclusionsXGT can provide a cost effective, risk-based approach to primary cervical cancer screening, with lower resource utilization than PGT.

Estimating the global impact of rotavirus vaccines on child mortality

ObjectivesWe estimated the global impact of rotavirus vaccines on deaths among children under five years old by year. MethodsWe used a proportionate outcomes model with a finely disaggregated age structure to estimate rotavirus deaths prevented by vaccination over the period 2006-2019 in 186 countries. We ran deterministic and probabilistic uncertainty analyses and compared our estimates to surveillance-based estimates in 20 countries. ResultsWe estimate that rotavirus vaccines prevented 139,000 under-five rotavirus deaths (95% uncertainty interval 98,000-201,000) in the period 2006-2019. In 2019 alone, rotavirus vaccines prevented 15% (95% uncertainty interval 11-21%) of under-five rotavirus deaths (0.5% of child mortality). Assuming global use of rotavirus vaccines and coverage equivalent to other co-administered vaccines could prevent 37% of under-five rotavirus deaths (1.2% of child mortality). Our estimates were sensitive to the choice of rotavirus mortality burden data and several vaccine impact modeling assumptions. The World Health Organization's recommendation to remove age restrictions in 2012 could have prevented up to 17,000 rotavirus deaths in the period 2013-2019. Our modeled estimates of rotavirus vaccine impact were broadly consistent with estimates from post-vaccination surveillance sites. ConclusionRotavirus vaccines have made a valuable contribution to global public health. Enhanced rotavirus mortality prevention strategies are needed in countries with high mortality in under-5-year-old children.

Cost-effectiveness analysis of full versus selective root canal retreatment.

Selective root-canal retreatment has been proposed as an alternative to full retreatment in multirooted, root-canal-filled teeth with evidence of apical pathology, where only the affected root(s) is retreated. Whilst this option may save costs initially, failures and retreatments may compensate for these initial savings. We assessed the cost-effectiveness of full versus selective root-canal retreatment using data from a recent clinical pilot study, employing a modelling approach. A Markov model was constructed to follow up a previously root-canal treated maxillary molar with apical pathology on a single root (mesio-buccal), receiving either selective or full root-canal retreatment. A private-payer perspective in Dutch health care was adopted. Permanent molar teeth with apical lesions on the mesial root were simulated over the lifetime of initially 50-year-old patients. Teeth could have endodontic complications and require interventions such as retreatment or tooth extraction and replacement. Costs were calculated based on the Dutch dental fee catalogues. Monte-Carlo microsimulations were performed to assess lifetime costs and effectiveness (measured as tooth retention time), and the resulting cost-effectiveness. Probabilistic joint uncertainty and sensitivity analyses were performed, and cost-effectiveness at different willingness-to-pay-thresholds was evaluated. In the base-case scenario, selective retreatment was less costly (2137; 2.5%-97.5% percentiles: 1944-2340 Euro) and more effective (19.6; 18.3-20.8 Years) than full retreatment (2495; 2305-2671 Euro; 16.5; 15.2-17.9 Years) in 100% of the simulations and regardless of the willingness-to-pay threshold. Only in a worst case scenario was selective retreatment more costly, but remained more effective. Selective retreatment, when clinically applicable, is likely to be more cost-effective than full retreatment in endodontically treated molars with persistent apical periodontitis. Our results should be interpreted with caution because the quality of the underlying data is limited.

Impact and cost-effectiveness of strategies to prevent respiratory syncytial virus (RSV) disease in Vietnam: A modelling study

BackgroundNew prevention strategies for respiratory syncytial virus (RSV) are emerging, but it is unclear if they will be cost-effective in low- and middle-income countries. We evaluated the potential impact and cost-effectiveness of two strategies to prevent RSV disease in young children in Vietnam. MethodsWe used a static cohort model with a finely disaggregated age structure (weeks of age <5 years) to calculate the RSV disease burden in Vietnam, with and without a single dose of maternal vaccine (RSVpreF, Pfizer) or of monoclonal antibody (Nirsevimab, Sanofi, Astra Zeneca). Each strategy was compared to no pharmaceutical intervention, and to each other. We assumed both strategies would be administered year round over a ten-year period. The primary outcome measure was the cost per disability-adjusted life year (DALY) averted, from a societal perspective. We ran probabilistic and deterministic uncertainty analyses. ResultsWith central input assumptions for RSVpreF vaccine ($25/dose, 69 % efficacy, 6 months protection) and Nirsevimab ($25/dose, 77 % efficacy, 5 months protection), both options had similar cost-effectiveness ($3442 versus $3367 per DALY averted) when compared separately to no pharmaceutical intervention. RSVpreF vaccine had a lower net cost than Nirsevimab (net discounted cost of $213 m versus $264 m) but prevented fewer RSV deaths (24 % versus 31 %). Our results were very sensitive to assumptions about the dose price, efficacy, and duration of protection. At $5/dose and a willingness-to-pay threshold of 0.5 times the national GDP per capita, both prevention strategies have the potential to be cost-effective. ConclusionsRSVpreF vaccine and Nirsevimab may be cost-effective in Vietnam if appropriately priced.

PTV-based VMAT vs. robust IMPT for head-and-neck cancer: A probabilistic uncertainty analysis of clinical plan evaluation with the Dutch model-based selection

Background and purposeIn the Netherlands, head-and-neck cancer (HNC) patients are referred for proton therapy (PT) through model-based selection (MBS). However, treatment errors may compromise adequate CTV dose. Our aims are: (i) to derive probabilistic plan evaluation metrics on the CTV consistent with clinical metrics; (ii) to evaluate plan consistency between photon (VMAT) and proton (IMPT) planning in terms of CTV dose iso-effectiveness and (iii) to assess the robustness of the OAR doses and of the risk toxicities involved in the MBS. Materials and methodsSixty HNC plans (30 IMPT/30 VMAT) were included. A robustness evaluation with 100,000 treatment scenarios per plan was performed using Polynomial Chaos Expansion (PCE). PCE was applied to determine scenario distributions of clinically relevant dosimetric parameters, which were compared between the 2 modalities. Finally, PCE-based probabilistic dose parameters were derived and compared to clinical PTV-based photon and voxel-wise proton evaluation metrics. ResultsProbabilistic dose to near-minimum volume v = 99.8% for the CTV correlated best with clinical PTV-D98% and VWmin-D98%,CTV doses for VMAT and IMPT respectively. IMPT showed slightly higher nominal CTV doses, with an average increase of 0.8 GyRBE in the median of the D99.8%,CTV distribution. Most patients qualified for IMPT through the dysphagia grade II model, for which an average NTCP gain of 10.5 percentages points (%-point) was found. For all complications, uncertainties resulted in moderate NTCP spreads lower than 3 p.p. on average for both modalities. ConclusionDespite the differences between photon and proton planning, the comparison between PTV-based VMAT and robust IMPT is consistent. Treatment errors had a moderate impact on NTCPs, showing that the nominal plans are a good estimator to qualify patients for PT.

Potential Clinical and Economic Outcomes of Over-the-Counter Hearing Aids in the US

Over-the-counter (OTC) hearing aids are now available in the US; however, their clinical and economic outcomes are unknown. To project the clinical and economic outcomes of traditional hearing aid provision compared with OTC hearing aid provision. This cost-effectiveness analysis used a previously validated decision model of hearing loss (HL) to simulate US adults aged 40 years and older across their lifetime in US primary care offices who experienced yearly probabilities of acquiring HL (0.1%-10.4%), worsening of their HL, and traditional hearing aid uptake (0.5%-8.1%/y at a fixed uptake cost of $3690) and utility benefits (0.11 additional utils/y). For OTC hearing aid provision, persons with perceived mild to moderate HL experienced increased OTC hearing aid uptake (1%-16%/y) based on estimates of time to first HL diagnosis. In the base case, OTC hearing aid utility benefits ranged from 0.05 to 0.11 additional utils/y (45%-100% of traditional hearing aids), and costs were $200 to $1400 (5%-38% of traditional hearing aids). Distributions were assigned to parameters to conduct probabilistic uncertainty analysis. Provision of OTC hearing aids, at increased uptake rates, across a range of effectiveness and costs. Lifetime undiscounted and discounted (3%/y) costs and quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Traditional hearing aid provision resulted in 18.162 QALYs, compared with 18.162 to 18.186 for OTC hearing aids varying with OTC hearing aid utility benefit (45%-100% that of traditional hearing aids). Provision of OTC hearing aids was associated with greater lifetime discounted costs by $70 to $200 along with OTC device cost ($200-$1000/pair; 5%-38% traditional hearing aid cost) due to increased hearing aid uptake. Provision of OTC hearing aids was considered cost-effective (ICER<$100 000/QALY) if the OTC utility benefit was 0.06 or greater (55% of the traditional hearing aid effectiveness). In probabilistic uncertainty analysis, OTC hearing aid provision was cost-effective in 53% of simulations. In this cost-effectiveness analysis, provision of OTC hearing aids was associated with greater uptake of hearing intervention and was cost-effective over a range of prices so long as OTC hearing aids were greater than 55% as beneficial to patient quality of life as traditional hearing aids.

Estimated Monetary Value of Future Research Clarifying Uncertainties Around the Optimal Adult Hearing Screening Schedule

Adult hearing screening is not routinely performed, and most individuals with hearing loss (HL) have never had their hearing tested as adults. To project the monetary value of future research clarifying uncertainties around the optimal adult hearing screening schedule. In this economic evaluation, a validated decision model of HL (DeciBHAL-US: Decision model of the Burden of Hearing loss Across the Lifespan) was used to simulate current detection and treatment of HL vs hearing screening schedules. Key model inputs included HL incidence (0.06%-10.42%/y), hearing aid uptake (0.54%-8.14%/y), screening effectiveness (1.62 × hearing aid uptake), utility benefits of hearing aids (+0.11), and hearing aid device costs ($3690). Distributions to model parameters for probabilistic uncertainty analysis were assigned. The expected value of perfect information (EVPI) and expected value of partial perfect information (EVPPI) using a willingness to pay of $100 000 per quality-adjusted life-year (QALY) was estimated. The EVPI and EVPPI estimate the upper bound of the dollar value of future research. This study was based on 40-year-old persons over their remaining lifetimes in a US primary care setting. Screening schedules beginning at ages 45, 55, 65, and 75 years, and frequencies of every 1 or 5 years. The main outcomes were QALYs and costs (2020 US dollars) from a health system perspective. The average incremental cost-effectiveness ratio for yearly screening beginning at ages 55 to 75 years ranged from $39 200 to $80 200/QALY. Yearly screening beginning at age 55 years was the optimal screening schedule in 38% of probabilistic uncertainty analysis simulations. The population EVPI, or value of reducing all uncertainty, was $8.2 to $12.6 billion varying with willingness to pay and the EVPPI, or value of reducing all screening effectiveness uncertainty, was $2.4 billion. In this economic evaluation of US adult hearing screening, large uncertainty around the optimal adult hearing screening schedule was identified. Future research on hearing screening has a high potential value so is likely justified.

Global and regional projections of the economic burden of Alzheimer's disease and related dementias from 2019 to 2050: A value of statistical life approach.

SummaryBackgroundThe burden of Alzheimer's disease and related dementias (ADRDs) is expected to grow rapidly with population aging, especially in low- and middle-income countries, in the next few decades. We used a willingness-to-pay approach to project the global, regional, and national economic burden of ADRDs from 2019 to 2050 under status quo.MethodsWe projected age group and country-specific disability-adjusted life years (DALYs) lost to ADRDs in future years based on historical growth in disease burden and available population projections. We used country-specific extrapolations of the value of a statistical life (VSL) year and its future projections based on historical income growth to estimate the economic burden – measured in terms of the value of lost DALYs – of ADRDs. A probabilistic uncertainty analysis was used to calculate point estimates and 95% uncertainty bounds of the economic burden.FindingsIn 2019, the global VSL-based economic burden of ADRDs was an estimated $2.8 trillion. The burden was projected to increase to $4.7 trillion (95% uncertainty bound: $4 trillion–$5.5 trillion) in 2030, $8.5 trillion ($6.8 trillion–$10.8 trillion) in 2040, and $16.9 trillion ($11.3 trillion–$27.3 trillion) in 2050. Low- and middle-income countries (LMICs) would account for 65% of the global VSL-based economic burden in 2050, as compared with only 18% in 2019. Within LMICs, upper-middle income countries would carry the largest VSL-based economic burden by 2050 (92% of LMICs burden and 60% of global burden).InterpretationADRDs have a large and inequitable projected future VSL-based economic burden.FundingThe Davos Alzheimer's Collaborative.

EE106 Evaluation of Full Factorial and Latin Hypercube Sampling As Alternatives to Traditional Random Selection for Probabilistic Uncertainty Analyses

Probabilistic uncertainty analysis (PUA) is common in economic evaluations, but generating enough random samples to achieve stability can be computationally intensive. This study evaluates the relative efficiency of alternative random number sampling methods to stably estimate uncertainty within a cost-effectiveness analysis.

Probabilistic Assessment and Uncertainty Analysis of CO2 Storage Capacity of the Morrow B Sandstone—Farnsworth Field Unit

This paper presents probabilistic methods to estimate the quantity of carbon dioxide (CO2) that can be stored in a mature oil reservoir and analyzes the uncertainties associated with the estimation. This work uses data from the Farnsworth Field Unit (FWU), Ochiltree County, Texas, which is currently undergoing a tertiary recovery process. The input parameters are determined from seismic, core, and fluid analyses. The results of the estimation of the CO2 storage capacity of the reservoir are presented with both expectation curve and log probability plot. The expectation curve provides a range of possible outcomes such as the P90, P50, and P10. The deterministic value is calculated as the statistical mean of the storage capacity. The coefficient of variation and the uncertainty index, P10/P90, is used to analyze the overall uncertainty of the estimations. A relative impact plot is developed to analyze the sensitivity of the input parameters towards the total uncertainty and compared with Monte Carlo. In comparison to the Monte Carlo method, the results are practically the same. The probabilistic technique presented in this paper can be applied in different geological settings as well as other engineering applications.

Probabilistic uncertainty and sensitivity analysis of a vibratory-based actuation mechanism for a bio-inspired flapping-wing system

Probabilistic uncertainty and sensitivity analysis of a vibratory-based actuation mechanism for a bio-inspired flapping-wing system

Evaluating the impact of data quality on the accuracy of the predicted energy performance for a fixed building design using probabilistic energy performance simulations and uncertainty analysis

Probabilistic building performance simulations enables a method for evaluating how the data quality used to create input models affects the accuracy of the predicted energy performance. The method described in this paper explores an uncertainty analysis of a fixed building design and system by including the discrepancy between the declared property of a product, material, or behaviour quantified under specific conditions, and the actual performance in real-world use. The method was tested using a case study, a multi-family building, using two datasets based on different data quality to quantify the discrepancies. The models' outcome was validated against field measurements from 28 buildings built using the fixed building design. The main findings were that data quality significantly shifted the probability density curves and consequently impacted the predictions and accuracy of the predictive models, showing the importance of high-quality input models and a validation process based on a probability distribution. The study also indicated that higher quality data does not equal narrower distributions in the input models. In this case, the case study showed that, despite well-known building properties, narrowing the performance gap can only occur through larger variation in the input data models, resulting in a larger predicted energy performance interval.

3D Probabilistic Modelling and Uncertainty Analysis of Glacial and Post-Glacial Deposits of the City of Saguenay, Canada

Knowledge of the stratigraphic architecture and geotechnical properties of surficial soil sediments is essential for geotechnical risk assessment. In the Saguenay study area, the Quaternary deposits consist of a basal till layer and heterogeneous post-glacial deposits. Considering the stratigraphic setting and soil type heterogeneity, a multistep stochastic methodology is developed for 3D geological modelling and quantification of the associated uncertainties. This methodology is adopted for regional studies and involves geostatistical interpolation and simulation methods. Empirical Bayesian kriging (EBK) is applied to generate the bedrock topography map and determine the thickness of the till sediments and their uncertainties. The locally varying mean and variance of the EBK method enable accounting for data complexity and moderate nonstationarity. Sequential indicator simulation is then performed to determine the occurrence probability of the discontinuous post-glacial sediments (clay, sand and gravel) on top of the basal till layer. The individual thickness maps of the discontinuous soil layers and uncertainties are generated in a probabilistic manner. The proposed stochastic framework is suitable for heterogeneous soil deposits characterised with complex surface and subsurface datasets.

Probabilistic Uncertainty Analysis of Reliability of Systems with Complex Interconnections

In the present age, modern technical systems, such as vehicles, should have reliability requirements. The sensors and their networks used in modern technical systems can be modelled as a System with Complex Interconnections (SwCI). Most of the real SwCI in the automotive industry are sensory, as Bridge Structure System (BSS). The BSS is widely used as an example in the field of system reliability analysis. The aims of this paper are to apply the True Table Method (TTM) and the Linear Sensitivity Model of System Reliability (LSMoSR), to investigate uncertainties of reliability of BSS in different cases.

Targeted vs opportunistic screening for viral hepatitis among UK migrant communities: a cost-effectiveness analysis

Worldwide eradication of chronic hepatitis B and C viruses by 2030 is a stated goal of the World Health Organization, UK government and the European Union. This study investigated the cost-effectiveness of targeted screening vs opportunistic screening for hepatitis B and C among migrant populations in the UK. Results of a previous clinical trial (HepFREE) carried out in London and Bradford were used to develop a combined decision tree and Markov simulation model. Despite a low response to invitations for vaccination, and a heterogeneous level of response between communities of different ethnic composition, this analysis shows that incentivised targeted screening is cost-effective at willingness-to-pay thresholds over £8540 per incremental quality-adjusted life year over a lifetime. Furthermore, probabilistic analysis of input parameter uncertainty suggests that the intervention has a greater than 95% probability of being cost-effective at willingness-to-pay thresholds under £30 000 per incremental quality-adjusted life year. These results strongly suggest that targeted screening should play a key part in the eradication of the hepatitis B and C viruses.

Uncertainty Representation of Natural Frequency for Laminated Composite Cylindrical Shells Considering Probabilistic and Interval Variables

Due to manufacturing errors, inaccurate measurement and working conditions changes, there are many uncertainties in laminated composite cylindrical shells, which causes the variation of vibration characteristics, and has an important influence on the overall performance. Therefore, an uncertainty representation methodology of natural frequency for laminated composite cylindrical shells is proposed, which considers probabilistic and interval variables simultaneously. The input interval variables are converted into a probabilistic density function or cumulative distribution function based on a four statistical moments method, and a unified probabilistic uncertainty analysis method is proposed to calculate the uncertainty of natural frequency. An adaptive Kriging surrogate model considering probabilistic uncertainty variables is established to accurately represent the natural frequency of laminated composite cylindrical shells. Finally, the dimensionless natural frequency of three-layer, five-layer and seven-layer laminated composite cylindrical shells with uncertainty input parameters is accurately represented. Compared with the Monte Carlo Simulation results, the mean error and standard deviation error are reduced to less than 0.07% and 4.7%, respectively, and the execution number of calculation function is significantly decreased, which fully proves the effectiveness of the proposed method.

Economic evaluation in health: Cost-utility of the incorporation of total knee replacement to the Chilean Explicit Health-Guarantees regime

Osteoarthritis is an important health condition due to its prevalence and functional deterioration, being the most common cause of disability in people over 65 years of age. The Chilean Explicit Health-Guarantees regime provides coverage for medical treatment in mild and moderate presentations, excluding surgical treatment in end-stage knee osteoarthritis. To evaluate the cost-utility of incorporating total knee replacement to the Explicit Health-Guarantees regime for over-65-years beneficiaries of the public insurance system, versus maintenance with medical treatment. A Scoping review was coducted to identify model parameters and economic evaluation based in a 6 health states Markov Model, from the perspective of the public payer and lifetime horizon. The Incremental Cost-Utility Ratio (ICUR) was calculated, and deterministic and probabilistic uncertainty analysis were performed. Twenty-two articles were selected as reference sources. If the regime were to adopt the procedure, the implication would be a benefit of 9.8 Years of Life Adjusted by Quality (QALY) versus 2.4 QALY in the scenario without access to total knee replacement. The ICUR was $ -445 689 CLP/QALY (U$D -633.8/QALY), wherein the inclusion of total knee replacement to the regime becomes a dominant alternative versus the current scenario. Each quality-adjusted life-year gained by the surgery will save CLP 445 689. At a willingness to pay of CLP 502,596/QALY (U$D 714.7/QALY), access to surgery is cost-useful with a 99.9% certainty. Total knee replacement in patients older than 65 years is a dominant alternative. Access to this procedure in the Chilean Explicit Health-Guarantees regime in the public system is cost-useful at a threshold of 1 GDP per capita.

Economic evaluation of the introduction of rotavirus vaccine in Hong Kong

BackgroundRotavirus is a common cause of severe gastroenteritis in young children in Hong Kong (HK) with a high economic burden. This study aimed to evaluate the cost-effectiveness of introducing rotavirus vaccination into the HK Government’s Childhood Immunisation Programme (CIP) and to include the potential protective effect of the vaccine against seizures. MethodsA decision-support model was customised to estimate the potential impact, cost-effectiveness and benefit-risk of rotavirus vaccination in children below 5 years over the period 2020–2029 in HK. Two doses of Rotarix® and three doses of RotaTeq® were each compared to no vaccination. Rotavirus treatment costs were calculated from a governmental health sector perspective (i.e., costs of public sector treatment) and an overall health sector perspective (both governmental and patient, i.e., costs of public sector treatment, private sector treatment, transport and diapers). We ran probabilistic and deterministic uncertainty analyses. ResultsIntroduction of rotavirus vaccination in HK could prevent 49,000 (95% uncertainty interval: ~44,000–54,000) hospitalisations of rotavirus gastroenteritis and seizures and result in ~50 (95% uncertainty interval: ~25–85) intussusception hospitalisations, over the period 2020–2029 (a benefit-risk ratio of ~1000:1), compared to a scenario with no public or private sector vaccine use. The discounted vaccination cost would be US$51–57 million over the period 2020–2029 based on per-course prices of US$72 (Rotarix®) or US$78 (RotaTeq®), but this would be offset by discounted treatment cost savings of US$70 million (government) and US$127 million (governmental and patient health sector). There was a greater than 94% probability that the vaccine could be cost-saving irrespective of the vaccine product or perspective considered. All deterministic ‘what-if’ scenarios were cost-saving from an overall health sector perspective (governmental and patient). ConclusionsRotavirus vaccination is likely to be cost-saving and have a favourable benefit-risk profile in HK. Based on the assumptions made, our analysis supports its introduction into CIP.

Probabilistic Groundwater Flow, Particle Tracking and Uncertainty Analysis for Environmental Receptor Vulnerability Assessment of a Coal Seam Gas Project

The production of coalbed methane, or coal seam gas (CSG) in Australia increased 250-fold since the 1990s to around 1502 petajoules in 2019 and continues to expand. Groundwater flow in the aquifers intersected by gas wells could potentially facilitate a transport pathway for migration of contaminants or poorer quality water from deeper formations. While regulatory and mitigation mechanisms are put in place to minimize the risks, quantitative environmental impact assessments are also undertaken. When many gas wells are drilled in a wide area where many potential receptors are also spatially distributed, potential source-receptor combinations are too numerous to undertake detailed contamination risk assessment using contaminant transport modelling. However, valuable information can be gleaned from the analysis of groundwater flow directions and velocities to inform and prioritise contamination risk assessment and can precede computationally challenging stochastic contaminant transport modelling. A probabilistic particle tracking approach was developed as a computationally efficient screening analysis of contamination pathways for a planned CSG development near Narrabri in northern New South Wales, Australia. Particle tracking was run iteratively with a numerical groundwater flow model across a range of plausible parameter sets to generate an ensemble of estimated flow paths through the main Great Artesian Basin aquifer in the area. Spatial patterns of path lines and spatial relationships with potential receptors including neighbouring groundwater extraction wells and hydrologically connected ecological systems were analysed. Particle velocities ranged from 0.5 to 11 m/year and trajectories indicated dedicated contaminant transport modeling would be ideally focused at the local scale where wells are near potential receptors. The results of this type of analysis can inform the design of monitoring strategies and direct new data collection to reduce uncertainty and improve the effectiveness of adaptive management strategies and early detection of impacts.

Cost-Effectiveness of a 12-Month Fixed Duration of Venetoclax in Combination with Obinutuzumab Versus Chemoimmunotherapy and Other Novel Combinations in First-Line Chronic Lymphocytic Leukemia in Canada

OBJECTIVES: To estimate the cost-effectiveness of venetoclax + obinutuzumab (GAZYVA®, G), (VEN+G) in the treatment of first-line (1L) chronic lymphocytic leukemia (CLL) from a Canadian health care system cost perspective. METHODS: A three-state partitioned-survival model was used to extrapolate progression-free survival (PFS) and overall survival (OS) over a 10-year time horizon. Cost-effectiveness was estimated comparing 12-month fixed duration of VEN+G versus (vs) G + Chlorambucil (GClb) based on the CLL14 clinical trial (NCT02242942). Other comparators included Bendamustine + rituximab (BR), Chlorambucil + rituximab (Clb+R), Ibrutinib (Ibr), Acalabrutinib (Acala) and Acalabrutinib + GAZYVA (Acala+G). VEN+G was also compared to the combination of fludarabine, cyclophosphamide and rituximab (FCR) in the overall 1L CLL population which included unfit and fit patients. Relative efficacy of VEN+G vs other comparators was estimated using a network meta-analysis. Health state utilities and adverse event disutilities were derived from a systematic literature review and other published sources. Costs included CLL treatment, routine care and monitoring, adverse events, disease progression costs, subsequent treatment costs, and end of life care. Uncertainty was assessed using an underlying probabilistic model (probabilistic analysis of uncertainty generated from 5,000 iterations), through deterministic sensitivity analyses (i.e., one-way sensitivity analyses (OWSA)), and through a series of alternative scenario analyses. RESULTS: For the overall unfit 1L CLL patient population, the probabilistic total discounted costs incurred over a 10-year time horizon were as follows: $217,727 for VEN+G vs $312,287 for GClb, $399,219 for BR, $380,713 for Clb+R, $736,017 for Ibr, $868,797 for Acala and $916,139 for Acala+G. The probabilistic total discounted quality adjusted life years (QALYs) were 4.964 for VEN+G vs 4.750, 4.550, 4.422, 4.709, 5.269, and 5.359, respectively for the comparators. For the overall 1L CLL patient population, the probabilistic total discounted costs were $219,651 for VEN+G vs $312,570 for GClb, $342,195 for FCR, $397,262 for BR, $380,551 for Clb+R, $757,129 for Ibr, $868,388 for Acala, and $916,798 for Acala+G. The probabilistic total discounted QALYs were 5.888 for VEN+G vs 5.519, 5.067, 5.198, 5.073, 5.597, 6.259 and 6.380, respectively for the comparators. VEN+G was found to be less costly and more efficacious (i.e., dominant) compared to GClb, BR, Clb+R, Ibr and FCR. As a result, incremental cost utility ratios (ICERs) were not calculated for these comparators. Acala and Acala+G resulted in ICERs ranging from $1.4-$2.1 million per QALY gained relative to VEN+G, which is not cost-effective. Based on the probabilistic model and 5,000 simulations, VEN+G was found to be at least 97% cost-effective across all decision maker willingness-to-pay thresholds. The results from the deterministic model were found to be similar to the probabilistic model. Using the deterministic model, and in comparison to the most commonly prescribed treatment for 1L CLL in Canada (i.e., Ibr), the OWSA comparing VEN+G to Ibr found that the most influential variables in the model were the PFS and OS hazard ratios for Ibr and the utility values for PFS and post-progression survival. CONCLUSION: VEN+G is an effective novel fixed duration treatment option which leads to deep and durable responses for the treatment of patients with unfit 1L CLL and provides excellent value-for-money compared with existing chemoimmunotherapy and treat to progression novel combinations. Disclosures Chatterjee: Pharmerit: Current Employment. Van de Wetering:Pharmerit: Current Employment. Goeree:AbbVie Inc.: Consultancy. Desbois:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Manzi:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Manzoor:AbbVie: Current equity holder in publicly-traded company. Owen:AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. Sail:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company.