Estimates Of Benefits Research Articles

Statistical noise in PD-(L)1 inhibitor trials: Unravelling the durable-responder effect

BackgroundProgrammed-death-1/ligand-1 inhibitors (PD-1/L1i’s) have emerged as pivotal treatments for many cancers. A notable feature of this class of medicines is the dichotomous response pattern: A small (but clinically-relevant) percentage of patients (5% - 20%) benefit from deep and durable responses resembling functional cures (durable responders), while most patients experience only a modest or negligible response. Accurately predicting durable responders remains elusive due to the lack of a reliable biomarker. Another notable feature of these medicines is that different PD-1/L1’s have obtained statistically significant results, leading to marketing approval, for some cancer indications, but not for others, with no discernible pattern. These puzzling inconsistencies have generated extensive discussions among oncologists. Proposed (but not entirely convincing) explanations include true underlying differences in efficacy for some types of cancer, but not others; or subtle differences in trial design. ObjectiveTo investigate a less-explored hypothesis—the durable-responder effect: An initially unidentified group of durable responders generates more statistical noise than anticipated, leading to low-powered randomised controlled trials (RCTs) that report randomly variable results. Study designEmploying simulation, this investigation divides participants in PD-(L)1i RCTs into two groups: durable responders and patients with a more modest response. Drawing on published data for melanoma, lung and urothelial cancers, multiple pre-specified scenarios are replicated 50,000 times, systematically varying the durable-responder percentage from 5% to 20% and the modest-response hazard ratio for overall survival [HR(OS)] from 0.8 to 1.0. This allowed evaluation of the effect of durable responders on power, point estimates of the treatment effect for OS, and the probability of a misleading signal for harm. ResultsWhen the treatment effect for the modest responders is similar to the comparator arm, statistical power remains below 80%, limiting the ability to reliably detect durable responders. Conversely, there is a material probability of obtaining a statistically significant result that exaggerates the treatment effect by chance. For instance, with an average HR(OS) of 0.93 (corresponding to 5% durable responders), statistically significant trials (7.2%) show an average HR(OS) of 0.77. Additionally, when 5% are durable responders, there is a 20% probability that the HR(OS) will exceed 1.0—suggesting potential harm, when none exists. ConclusionThis paper adds to the possible explanations for the puzzlingly inconsistent results from PD-(L)1i RCTs. Initially unidentified durable responders introduce features typical of imprecise, low-powered studies: a propensity for false-negative results; estimates of benefit that might not replicate; and misleading signals for harm.

Combined Assessment of Function and Survival to Demonstrate the Effect of Treatment on Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative disorder for which there are currently no disease-modifying treatments. Recent trials of potential therapies had durations of 12 months, which may be insufficient because of nonrandom missingness due to death. Longer durations, incorporating PSP Rating Scale and survival, can reduce the potential for type II error. Selecting efficacy measures more sensitive to disease modification may facilitate identification of treatment effect. The objective of this study was to evaluate the simulated phase 3 PSP trial assessing the effect of disease-modifying intervention on a novel combined primary endpoint comprising function (PSP Rating Scale) and survival, the Combined Assessment of Function and Survival (CAFS), and to determine operating characteristics of the CAFS. To simulate PSP progression in the trial population, we developed models of PSP Rating Scale and survival using data from published clinical studies. These models were used to define operating characteristics of the CAFS for use in a phase 3 trial. The sample size determined (N = 384; 1:1 randomization) would provide >80% power to detect significant treatment effects on the CAFS compared with placebo. The CAFS provides good operating characteristics and increased power to detect moderate treatment effects on the PSP Rating Scale. We propose a trial design allowing potential detection of treatment effects at a preplanned interim analysis after participants complete 12 months of treatment, with assessment of effects of treatment (≤24 months) on survival. Use of the CAFS could provide a comprehensive and robust estimate of the clinical benefit of future therapies. © 2024 UCB. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Estimation of individual lifetime cardiovascular disease risk and treatment benefit in patients with established atherosclerotic cardiovascular disease: the updated SMART-REACH2 model

Abstract Background The 2021 ESC Guidelines on Cardiovascular Disease (CVD) Prevention in Clinical Practice recommend using (lifetime) risk to guide preventive treatment intensification. Purpose Updating and systematically recalibrating the SMART-REACH lifetime prediction model for the estimation of lifetime risk of recurrent CVD in patients with established atherosclerotic CVD (ASCVD) to various European and international risk regions. Methods The updated SMART-REACH (i.e., SMART-REACH2) model was derived using data from 9,477 individuals between 40-90 years with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysms included in the UCC-SMART cohort in whom 2,090 ASCVD events were observed during a median follow-up of 8.9 years (interquartile range 4.5–14.1). Coefficients for type of CVD, estimated glomerular filtration rate, non-high density lipoprotein cholesterol, systolic blood pressure, duration of CVD, C-reactive protein, current smoking, and presence of diabetes were derived using sex-stratified cause-specific Cox models with age as the time axis, adjusted for the competing risk of non-CVD mortality. Lifetables were used to estimate 10-year and lifetime CVD-risk and CVD-free life expectancy. The SMART-REACH2 model was externally validated in 121,701 patients from the NOR-COR, Nor-COAST, HUNT3, SWEDEHEART, Bialystok PLUS/Polaspire, REACH-EU, and REACH non-EU (Asia, Japan, Latin America, North America) covering 43 countries. The model was recalibrated to specific risk regions based on the expected-observed ratios from representative cohorts. Performance was assessed by calibration of predicted and observed risk and Harrel’s C-statistic for discrimination. Results 16,689ASCVD events were observed in the external validation cohorts. The model was visually well calibrated for the various risk regions. The pooled C-statistic across risk regions was 0.665 [95% confidence interval 0.640-0.691], with adequate performance in the separate regions (Figure 1). Using SMART-REACH2 to estimate potential gain in CVD-free life expectancy upon treatment initiation showed varying projections. For example, two comparable 55-year-old males from the low-risk region and very high-risk region would gain an estimated 2.2 and 3.9 CVD-free life years as a result of smoking cessation (Figure 2). Conclusion(s) By using larger and more contemporary data sources, considering geographical differences, and extending the age range, the updated SMART-REACH2 model provides an improved algorithm for the estimation of lifetime risk and CVD-free life expectancy for individuals with established ASCVD, facilitating shared decision-making for cardiovascular prevention as recommended by the 2021 ESC Prevention of CVD guidelines.C-statistics across global risk regionsCase vignette

Role of epidemiology in the EU policy formulation of chemicals

Abstract Over the past 50 years, the European Union has built a robust legal framework for managing chemicals. This framework balances the benefits of using chemicals for societal well-being and economic prosperity with the need to protect human health and the environment from potential risks. As part of the EU’s Zero Pollution ambition in the context of the Green Deal, the European Commission adopted in 2020 the Chemicals Strategy for Sustainability, with the aim to better protect human health and the environment from harmful chemicals, while boosting innovation by promoting the use of safer and more sustainable chemicals. Assessing quantitative health impacts within the EC Better Regulation guidance typically involves indicators measuring the environmental burden of disease (EBD), providing a useful mean for legislators to evaluate the benefits of policy actions both in terms of health gains and cost. While such analyses are common in air pollution studies, challenges arise in the chemical legislation area, particularly in non-occupational settings, where the population is exposed to low concentrations of many chemicals through multiple exposure routes. In such contexts, the intrinsic complexities linked to exposure characterization and to the assessment of causality between the exposure and the health outcome may hinder the estimation of benefits of legislative actions. Debates may arise regarding the reliability of the underlying epidemiological studies, making challenging for policymakers to ascertain the robustness and generalizability of the findings of such analyses. Our work provides a summary and analysis of recent case studies in the context of chemicals. We focus on how epidemiological evidence was used in conducting EBD analyses in supporting better formulation of EU polices of chemicals. Speakers/Panelists Marleen Bekker Wageningen University & Research, Wageningen, Netherlands

Improving ecosystem services through applied agroecology on German farms: costs and benefits

Under the EU’s new “Farm to Fork” strategy, crop production systems should rapidly become more environmentally friendly. In particular, by adopting agroecological measures that support functional biodiversity and improve ecosystem services for crop production, this paper contributes to the ongoing efforts in characterizing the socio-economic effects that the upscaling of these measures entails, by looking into two key measures: flower strips and mulching. One important socio-economic aspect of their adoption is their potential impact on agricultural income; however, knowledge on costs and benefits of measures enhancing functional biodiversity at the farm level is still limited. In order to improve these shortcomings our approach makes use of data from field experiments completed with interviews to provide cost–benefit results for flower strips and organic mulching. The estimations show that for “flower strips,” on average costs could be covered by compensation payments. Regarding the in-crop measure “organic mulching,” the benefits potentially outweigh the costs under the frame conditions of organic agriculture. The analysis also highlights some obstacles and knowledge gaps in the estimation of benefits, especially for off-crop measures like flower strips.

How much protection does clopidogrel provide to cats with hypertrophic cardiomyopathy?

Cats with hypertrophic cardiomyopathy (HCM) have a risk of developing aortic thromboembolism (ATE). Clopidogrel reduces the risk of redeveloping ATE and delays recurrence of ATE in cats that have experienced an ATE episode. Consequently, cardiologists have recommended administering clopidogrel to cats as a primary preventative, suggesting that all cats with severe HCM be administered clopidogrel. However, clopidogrel is unpalatable in its manufactured format, making such administration problematic for many clients. Therefore, estimating the potential benefit of administration might help clinicians determine on a case-by-case basis the need to treat cats with clopidogrel. Relatively simple statistical analyses of currently available data, along with certain assumptions and extrapolations, allow such an estimation of benefit in terms of relative and absolute risk reduction conferred by clopidogrel. Using this approach, and provided certain assumptions are true, clopidogrel likely confers a reduction in risk of ATE in cats with moderate to severe HCM of approximately 3% to 4%. Given the difficulty of administering clopidogrel to cats, clinicians should weigh these relatively small potential benefits against the potential harms (difficulty of administration) and not necessarily insist that clients administer clopidogrel.

Estimation of Tax Benefit of US Nonprofit Hospitals

Nonprofit hospitals are under increasing scrutiny to justify the generous tax benefit they receive due to their tax-exempt status. Quantifying the value of the tax benefit they receive at the federal, state, and local levels is critical for designing informed public health policies and ensuring nonprofit hospitals' taxpayer accountability. To estimate the financial benefit that nonprofit hospitals derive from their tax-exempt status and assess how the benefit is distributed across state and local communities. Using methodologies and measures consistent with current tax law and practice and data from 2021 Medicare Cost Reports, this study calculated the total financial benefit from nonprofit hospitals' tax-exempt status for all US nonprofit hospitals with the required Cost Reports data. Nonprofit hospitals' total tax benefit, which equals the sum of federal and state income tax, sales tax, property tax, the fair market value of charitable contributions from donors, savings from tax exemptions on issued bonds, and federal unemployment tax. A total of 2927 US nonprofit hospitals received a $37.4 billion total tax benefit in 2021 from federal income tax ($11.5 billion; 31%), sales tax ($9.1 billion; 24%), property tax ($7.8 billion; 21%), state income tax ($3.7 billion; 10%), charitable contributions ($3.2 billion; 8%), bond financing ($2.1 billion; 6%), and federal unemployment tax ($200 million; <1%). Tax benefit varied substantially across states, from $25 098 (Delaware) to $159 464 (Massachusetts) per hospital bed and from $19 (Alabama) to $275 (Massachusetts) per capita. Tax benefit was highly concentrated, with 7% (n = 212) of hospitals accounting for half of the total amount. This study highlights the wide variation of nonprofit hospitals' tax benefit across states, its high concentration among a small number of hospitals, and the primary role played by state and local taxes. Policy efforts to strengthen nonprofit hospitals' taxpayer accountability are likely to be more effective when pursued at the local level. The detailed standardized estimation road map can be used by various stakeholders to estimate tax benefit for external valuation and reporting purposes, updated as laws change, and improved upon as better data sources become available.

Mapping fine-scale carbon sequestration benefits and landscape spatial drivers of urban parks using high-resolution UAV data

Urban parks offer dual ecological benefits by increasing carbon sinks and reducing carbon emissions and are considered an important natural strategy for cities to achieve “double carbon” goals. However, rapid, efficient, and accurate quantification of the carbon sequestration benefits of urban parks poses a significant challenge. To address this, we utilized unmanned aerial vehicle (UAV) multispectral data to construct large-area, high-resolution models of urban park carbon sequestration benefits, replacing traditional, time-consuming, and laborious large-scale field surveys. Additionally, we explored the relationship between urban park landscape patterns and the benefits of carbon sequestration. First, we used data from 12 tree species to calculate the carbon storage based on tree species and compared these results with those calculated based on forest type. Second, three prediction models were constructed using multispectral vegetation index only, texture features only, and a combination of both, in conjunction with gradient boosting decision Trees (GBDT), random forest (RF), and backpropagation (BP) neural network to generate carbon sequestration benefit maps for the entire park. These maps allowed us to determine how variations in urban park landscape structures affect carbon stocks. The results show that UAV multispectral imagery provides a fast and accurate method for measuring the carbon sequestration benefits of urban parks and offers an alternative method for generating carbon sequestration benefit maps. This research reveals the benefits of urban park carbon sequestration and explores the spatial patterns within landscapes. The findings are of great significance for guiding the estimation of urban carbon sequestration benefits and achieving carbon neutrality.

Modeling and significance assessment of road construction participant and user benefits using expert evaluation methods

Human activities are related to obtain economic, technical, social and environmental benefits. The road construction process participants and road users have direct or indirect benefits from elaboration of new infrastructure. The number of the benefits received by individual entities is publicly discussed by politicians, lobbyists, experts and other decision-makers without having quantitative estimates of benefits, i.e., often relying on intuition or considering theoretical reasoning. The paper suggests a system of 19 benefit entities (criteria) assigned the ranks given by experts. The study involved three categories of experts, including 35 road engineers, 36 transport engineers and 61 road users. The values of the concordance coefficients obtained as a result of the conducted research were found significantly higher than critical values and showed that the opinions of the experts in each category were consistent (not contradictory). This made it possible to consider the average of the opinions of the expert group as a reliable result of solving the problem. Rank averages were replaced by the normalized weights of criteria using Average Rank Transformation into Weight-Linear (ARTIW-L) and – Nonlinear (ARTIW-N) methods. The global averages of criterion weights were used employing the Inverse Hierarchy for Assessment Main Criteria Importance (IHAMCI) method thus calculating the normalized weights of the road-related classified entities (three main criteria). The findings prove that road users benefit the most (weight 0.3485), the road construction contractor (weight 0.3325) is in the next position and the road owner (investor) takes the weight equal to 0.3190. The generated research data can be used for justifying the rationality of road investment.

Comparative Analysis of the Recovery of Cu2+ and Au from Washing Solution of Pyrite Concentrate Slag by Two Processes

A large amount of pyrite concentrate slag washing solution is produced in China every year, and this contains valuable components such as Cu2+ and Au. The traditional treatment method not only pollutes the environment but also wastes metal resources. For the washing solution containing Cu2+ 437 mg/L and Au 0.13 mg/L, two new processes comprehensive recovery schemes were developed and compared in this paper, namely iron powder replacement pore filtration and neutralization precipitation pore filtration. When the iron powder replacement pore filtration process was adopted, Cu2+ and Au were mainly comprehensively recovered in the form of a mixture of sponge copper and particulate gold. The test results showed that the replacement optimal conditions involved a pH of 3.0, iron powder dosage of 6 g/L, and replacement time of 3.0 h. After replacement, the filter cloth with below 1 μm pore size was used for filtration. The recovery rate of Cu2+ in the washing solution was 98.13 and the total recovery rate of Au was 95.83%. Otherwise, when the neutralization precipitation pore filtration process was adopted, Cu2+ and Au were mainly comprehensively recovered in the form of a mixture of copper hydroxide and particulate gold. The test results showed that sodium hydroxide was used as the precipitant and the optimum neutralization pH value was 6.5. After precipitation, the filter cloth with a below 1 μm pore size was used for filtration. The recovery rate of Cu2+ in the washing solution was 97.35% and the total recovery rate of Au was 93.54%. The economic benefit estimation of the two processes showed that the neutralization precipitation pore filtration process had the advantages of low material consumption, low cost and high economic benefit.

Integrating the Energy Performance Gap into Life Cycle Assessments of Building Renovations

The environmental impact of building energy renovation is commonly evaluated through life cycle assessment (LCA). However, existing LCA studies often overlook the energy performance gap—a substantial disparity between calculated and actual energy use—when estimating operational energy use before and after renovation. This paper examines the influence of the energy performance gap on the comparative LCA between unrenovated and renovated buildings. First, a statistical correction model, based on a recent large-scale Flemish study, is developed to correct regulatory calculated energy use for space heating and domestic hot water in a pragmatic way. Subsequently, the model is applied to four single-family dwellings with different energy characteristics that underwent renovation in accordance with Flemish energy regulations. The results show that the anticipated environmental savings over a 60-year study period decrease significantly when the correction model is applied, reducing the estimated savings of 49–80% to 21–49%. Moreover, environmental payback times increase from 2.9–9.1 years to 10.4–22.5 years. Notably, neglecting the energy performance gap in LCAs leads to systematic underestimations of the material use significance. This research underscores the importance of integrating the energy performance gap into LCAs to obtain more accurate estimations of the environmental benefits of energy renovations.

High-dimensional private and social optimal policy valuation model for non-renewable natural resource extraction projects for multivariate public policy decisions

We present a model to find the value and sensitivity function associated with the exploitation of a non-renewable natural resource both for the mining company (private optimum) and for the government (social optimum). Improvements over previous studies are achieved by achieving a multivariate model of optimal policy valuation under a Markov decision process with stopping times based on multiple real options, proposing an iterative algorithm of stochastic approximation with supervised dynamic programming decision under Monte Carlo scenarios until obtaining convergence. Applied to a mining project (Tía María) and extended to the total reserves of a country (Peru), it provides additional decision criteria for fiscal public policy, negotiations, concessions, tax levels, community reparations, as well as benefit estimation, discounted from the potential environmental cost in countries abundant in natural resources that wish to achieve sustainability.

Water quality analysis, treatment, and economic feasibility of water services of the Neora River in the fringe area of Neora-Valley National Park, India

ABSTRACT Surface water assessment is essential for an accurate water management plan. The present investigation was focused on quality analysis, treatment, and economic feasibility of the River Neora, a raw water source in the fringe area of the Neora-Valley National Park, India. Pearson's correlations showed a positive correlation (0.629) between temperature and total solids (TS), whereas a negative correlation (−0.23) for dissolved oxygen with other parameters. In ANOVA, F-value (&amp;gt;1) was obtained for all parameters except BOD5. The water quality index (WQI) was determined to find out whether the river water meets the drinking water requirements for local inhabitants in the lower fringe. A high coliform count (approximately 4.5/100 mL) downstream further warranted the design of an advanced treatment, the electrochemical oxidation batch reactor. To maintain the water quality grade, the estimation of water benefits was mandatory. The water consumption for domestic and non-domestic purposes was calculated at 5,314,400 and 1,470,000,000 L/yr, respectively. Obtainability and no tax coverage might have led to the overexploitation of water, which paved the way for monetary evaluation (US$695.29). This study provided an overview of the potential of River Neora, which can be restored in the long run by adopting the water development policies by the government.

Estimation of (Consumer) Sustainability Benefits from Horizontal Agreements: A Quasi Ex Post Analysis

Abstract The European Commission’s new horizontal guidelines create scope for sustainability agreements and, to calculate efficiencies, suggest the estimation of consumers’ willingness to pay (WTP) for so-called “nonuse value.” We contrast estimates obtained from a hypothetical choice experiment conducted for the Netherlands’ competition authority (the “Chicken of Tomorrow” case) with estimates based on homescan data documenting consumers’ real choices between more or less animal-friendly meat, ensuring that the respective alternatives are made highly comparable. Still, the estimated WTP for the animal-friendly alternative is several times higher in the choice experiment. Given observed prices and the WTP estimated in the choice experiment, the animal-friendly alternative should have already crowded out the conventional variant. We use our findings to inform about several pitfalls both when using experimental data and when using data from true purchases.

A systematic literature review on characteristics of the front-end phase of agile software development projects and their connections to project success

ContextSoftware development of new products and services often involves a front-end phase where user needs are analysed, costs and benefits are estimated, and initial plans are created. GoalThis study aims to learn more about how the introduction of agile software development has affected practices and outcomes related to cost and benefit estimation in this front-end phase and to understand better what would improve this phase. MethodWe identified, reviewed and aggregated the results from 42 relevant research articles by searching literature databases and snowballing relevant articles. ResultsThe front-end phase of agile was found to be, on average, similar and just as comprehensive as that of non-agile software development. This may be unfortunate, given the finding that more successful agile software development is connected with less detail in cost estimation and planning-related activities. A less comprehensive front-end phase may be especially beneficial for low-risk agile software development. ConclusionThe results of this review suggest that agile principles, so far, have had a limited influence on the front-end phase. We recommend more flexibility and context-dependency in how the front-end phase of agile software development is conducted, including less comprehensive estimation and planning activities for low-risk software development contexts.

Clinical trial designs to assess treatment effects on glomerular filtration rate decline

Glomerular filtration rate (GFR) decline is used as surrogate endpoint for kidney failure. Interventions that reduce chronic kidney disease (CKD) progression often exert acute GFR reductions which differ from their long-term benefits and complicate the estimation of long-term benefit. Here, we assessed the utility of two alternative trial designs (wash-out design and active run-in randomized withdrawal design) that attempt to exclude the impact of acute effects. Post-hoc analyses of two clinical trials that characterized the effect of an intervention with acute reductions in GFR were conducted. The two trials included a wash-out period (EMPAREG-Outcome testing empagliflozin vs placebo) or an active run-in period with a randomized withdrawal (SONAR testing atrasentan vs placebo). We compared the drug effect on GFR decline calculated from the first on-treatment visit to the end-of-treatment (chronic effect in a standard randomized trial design) with GFR change calculated from randomization to end-of-wash-out, or GFR change from treatment specific baseline GFR values (GFR at start-of-run-in for placebo and end-of-run-in for atrasentan) until end-of-treatment. The effect of empagliflozin versus placebo on chronic GFR slope was 1.72 (95% confidence interval 1.49-1.94) mL/min/1.73m2 /year, similar to total GFR decline from baseline to the end of wash-out period using a linear mixed model 1.64 (1.44-1.85) mL/min/1.73m2 /year). The effect of atrasentan versus placebo on chronic GFR slope was 0.72 (0.32-1.11) mL/min/1.73m2 /year, similar to total slope from a single slope model when estimated from treatment specific baseline GFR values 0.77 (0.39-1.14) mL/min/1.73m2 /year). Statistical power of the two designs outperformed the standard randomized design. Thus, wash-out and active-run-in randomized-withdrawal trial designs are appropriate models to compute treatment effects on GFR decline.

Cost-Effectiveness of Predictive Maintenance for Offshore Wind Farms: A Case Study

The successful implementation of predictive maintenance for offshore wind farms suffers from a poor understanding of the consequential short-term impacts and a lack of research on how to evaluate the cost-efficiency of such efforts. This paper aims to develop a methodology to explore the short-term marginal impacts of predictive maintenance applied to an already existing preventive maintenance strategy. This method will be based on an analysis of the performance of the underlying predictive model and the costs considered under specific maintenance services. To support this analysis, we develop a maintenance efficiency measure able to estimate the efficiency of both the underlying prediction model used for predictive maintenance and the resulting maintenance efficiency. This distinction between the efficiency of the model and the service results will help point out insufficiencies in the predictive maintenance strategy, as well as facilitate calculations on the cost–benefits of the predictive maintenance implementation. This methodology is validated on a realistic case study of an annual service mission for an offshore wind farm and finds that the efficiency metrics described in this paper successfully support cost–benefit estimates.

Island restoration to rebuild seabird populations and amplify coral reef functioning.

Mobile organisms like seabirds can provide important nutrient flows between ecosystems, but this connectivity has been interrupted by the degradation of island ecosystems. Island restoration (via invasive species eradications and the restoration of native vegetation) can reestablish seabird populations and their nutrient transfers between their foraging areas, breeding colonies, and adjacent nearshore habitats. Its diverse benefits are making island restoration increasingly common and scalable to larger islands and whole archipelagos. We identified the factors that influence breeding seabird abundances throughout the Chagos Archipelago in the Indian Ocean and conducted predictive modeling to estimate the abundances of seabirds that the archipelago could support under invasive predator eradication and native vegetation restoration scenarios. We explored whether the prey base exists to support restored seabird populations across the archipelago, calculated the nitrogen that restored populations of seabirds might produce via their guano, and modeled the cascading conservation gains that island restoration could provide. Restoration was predicted to increase breeding pairs of seabirds to over 280,000, and prey was predicted to be ample to support the revived seabird populations. Restored nutrient fluxes were predicted to result in increases in coral growth rates, reef fish biomasses, and parrotfish grazing and bioerosion rates. Given these potential cross-ecosystem benefits, our results support island restoration as a conservation priority that could enhance resilience to climatic change effects, such as sea-level rise and coral bleaching. We encourage the incorporation of our estimates of cross-ecosystem benefits in prioritization exercises for island restoration.

Adjustment for imbalances in baseline characteristics in the MAGNITUDE phase 3 study confirms the clinical benefit of niraparib in combination with abiraterone acetate plus prednisone in patients with metastatic prostate cancer

BackgroundMAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and cost‑effectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes. MethodsIPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2-altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model. ResultsImprovements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints. ConclusionsIPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2-altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies. Trial registrationNCT03748641 (MAGNITUDE)

Development and validation of RSClin N+ tool for hormone receptor-positive (HR+), HER2-negative (HER2-), node-positive breast cancer.

508 Background: The RSClin tool was developed to provide estimates of recurrence risk and absolute chemotherapy benefit for patients with HR+/HER2- node-negative breast cancer using the 21-gene recurrence score (RS) and clinicopathologic factors. For patients with node-positive disease, we developed a new tool (RSClin N+) to increase the prognostic and predictive utility of risk estimates by combining RS with clinicopathologic factors and menopausal status. Methods: We used Cox regression to estimate 5-year risk of invasive disease or death (iDFS) and likelihood ratio (LR) tests to compare fit of RSClin N+ with RS alone and clinicopathologic factors (tumor grade, tumor size, positive lymph nodes [N1/N2], age) alone in 5283 node-positive patients treated with chemoendocrine therapy (CET) vs endocrine therapy alone (ET) in the S8814 (n=367: N1=227, N2=140, all postmenopausal) and RxPONDER (n/N1=4916) trials. Data from both studies were pooled and stratified by study for postmenopausal models; premenopausal models were fit only on RxPONDER data. Absolute CET benefit across combination of covariate values was estimated as the difference between ET and CET risk estimates. Validation of RSClin N+ was performed in 592 Nmic/N1 patients in the Clalit registry real-world dataset. Results: For pre- and postmenopausal patients, RSClin N+ provided significantly more prognostic information for iDFS than RS or clinicopathologic factors alone (LR Chi-square p&lt;0.05). In postmenopausal patients, RS and clinicopathologic factors were independently prognostic, but only RS showed interaction with CET benefit (p=0.016). Absolute CET benefit for iDFS ranged from &lt;0.1% to 21.5% as the RS increased from 0 to 50. Table shows examples of risk stratification and predicted benefit by RS within clinical low and high risk patients. In premenopausal patients, both RS and clinicopathologic factors remained prognostic but no interaction was observed between RS and CET.In external validation, RSClin N+ risk estimates were concordant with (Lin’s concordance=0.92) and prognostic for observed risk (HR 1.75; 95% CI 1.38 to 2.20). Conclusions: The RSClin N+ model provides improved estimates of prognostic risk and absolute CET benefit than clinical or genomic data alone in node-positive, HR+/HER2- breast cancer and could be used in patient counseling. [Table: see text]