Estimating Long-Term Survival Outcomes for Tumor-Agnostic Therapies: Larotrectinib Case Study.

BACKGROUND: Larotrectinib is a precision oncology treatment for solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Larotrectinib efficacy has been evaluated in single-arm basket trials with limited follow-up and sample sizes at the initial regulatory approval due to the rarity of solid tumors with NTRK gene fusion. OBJECTIVES: We aim to demonstrate that trends in progression-free survival (PFS) and overall survival (OS) in survival data with longer follow-up may be predicted from long-term survival estimates from survival data with shorter follow-up, including predictions for median survival when it is not observed in the trial. METHODS: Patient-level data were pooled from 3 clinical trials (NCT02122913, NCT02576431, and NCT02637687) using the 2018 and 2020 data cuts for the same subset of pediatric and adult patients. The Weibull distribution was selected for survival models. Survival predictions using 2018 data were compared to 2020 Kaplan-Meier (KM) curves. RESULTS: A total of 102 patients representing 15 tumor types were included in the analysis, with a mean age of 37 years. When comparing PFS from the 2018 survival prediction to observed 2020 KM data, the 12-month PFS rate was identical (66.6%). The 36-month PFS rate was lower for the 2018 prediction (35.3%) compared to 2020 KM data (44.4%). The median OS had not yet been reached in either data cut but was predicted to be 90 months using the 2018 data. When comparing OS from the 2018 survival prediction to the observed 2020 KM data, the 12-month OS rate was 89.0% and 86.6% and the 48-month OS rate was 67.2% and 63.0%, respectively. CONCLUSION: Long-term PFS predictions deviated from observed PFS rates due to response differences across tumor types and heavy censoring towards the end of the survival curve. However, for OS, the 48-month survival prediction was consistent with the observed 2020 KM estimate

Designing programs to improve diets for maternal and child health: estimating costs and potential dietary impacts of nutrition-sensitive programs in Ethiopia, Nigeria, and India.

Improving maternal and child nutrition in resource-poor settings requires effective use of limited resources, but priority-setting is constrained by limited information about program costs and impacts, especially for interventions designed to improve diet quality. This study utilized a mixed methods approach to identify, describe and estimate the potential costs and impacts on child dietary intake of 12 nutrition-sensitive programs in Ethiopia, Nigeria and India. These potential interventions included conditional livestock and cash transfers, media and education, complementary food processing and sales, household production and food pricing programs. Components and costs of each program were identified through a novel participatory process of expert regional consultation followed by validation and calibration from literature searches and comparison with actual budgets. Impacts on child diets were determined by estimating of the magnitude of economic mechanisms for dietary change, comprehensive reviews of evaluations and effectiveness for similar programs, and demographic data on each country. Across the 12 programs, total cost per child reached (net present value, purchasing power parity adjusted) ranged very widely: from 0.58 to 2650 USD/year among five programs in Ethiopia; 2.62 to 1919 USD/year among four programs in Nigeria; and 27 to 586 USD/year among three programs in India. When impacts were assessed, the largest dietary improvements were for iron and zinc intakes from a complementary food production program in Ethiopia (increases of 17.7 mg iron/child/day and 7.4 mg zinc/child/day), vitamin A intake from a household animal and horticulture production program in Nigeria (335 RAE/child/day), and animal protein intake from a complementary food processing program in Nigeria (20.0 g/child/day). These results add substantial value to the limited literature on the costs and dietary impacts of nutrition-sensitive interventions targeting children in resource-limited settings, informing policy discussions and serving as critical inputs to future cost-effectiveness analyses focusing on disease outcomes

Priority interventions to improve maternal and child diets in Sub-Saharan Africa and South Asia.

Nutrition-sensitive interventions to improve overall diet quality are increasingly needed to improve maternal and child health. This study demonstrates feasibility of a structured process to leverage local expertise in formulating programmes tailored for current circumstances in South Asia and Africa. We assembled 41 stakeholders in 2 regional workshops and followed a prespecified protocol to elicit programme designs listing the human and other resources required, the intervention's mechanism for impact on diets, target foods and nutrients, target populations, and contact information for partners needed to implement the desired programme. Via this protocol, participants described 48 distinct interventions, which we then compared against international recommendations and global goals. Local stakeholders' priorities focused on postharvest food systems to improve access to nutrient-dense products (75% of the 48 programmes) and on production of animal sourced foods (58%), as well as education and social marketing (23%) and direct transfers to meet food needs (12.5%). Each programme included an average of 3.2 distinct elements aligned with those recommended by United Nations system agencies in the Framework for Action produced by the Second International Conference on Nutrition in 2014 and the Compendium of Actions for Nutrition developed for the Renewed Efforts Against Child Hunger initiative in 2016. Our results demonstrate that a participatory process can help local experts identify their own priorities for future investments, as a first step in a novel process of rigorous, transparent, and independent priority setting to improve diets among those at greatest risk of undernutrition

Comparative risk assessment of school food environment policies and childhood diets, childhood obesity, and future cardiometabolic mortality in the United States

Background Promising school policies to improve children’s diets include providing fresh fruits and vegetables (F&V) and competitive food restrictions on sugar-sweetened beverages (SSBs), yet the impact of national implementation of these policies in US schools on cardiometabolic disease (CMD) risk factors and outcomes is not known. Our objective was to estimate the impact of national implementation of F&V provision and SSB restriction in US elementary, middle, and high schools on dietary intake and body mass index (BMI) in children and future CMD mortality. Methods We used comparative risk assessment (CRA) frameworks to model the impacts of these policies with input parameters from nationally representative surveys, randomized-controlled trials, and systematic reviews and meta-analyses. For children ages 5–18 years, this incorporated national data on current dietary intakes and BMI, impacts of these policies on diet, and estimated effects of dietary changes on BMI. In adults ages 25 and older, we further incorporated the sustainability of dietary changes to adulthood, effects of dietary changes on CMD, and national CMD death statistics, modeling effects if these policies had been in place when current US adults were children. Uncertainty across inputs was incorporated using 1000 Monte Carlo simulations. Results National F&V provision would increase daily fruit intake in children by as much as 25.0% (95% uncertainty interval (UI): 15.4, 37.7%), and would have small effects on vegetable intake. SSB restriction would decrease daily SSB intake by as much as 26.5% (95% UI: 6.4, 46.4%), and reduce BMI by as much as 0.7% (95% UI: 0.2, 1.2%). If F&V provision and SSB restriction were nationally implemented, an estimated 22,383 CMD deaths/year (95% UI: 18735, 25930) would be averted. Conclusion National school F&V provision and SSB restriction policies implemented in elementary, middle, and high schools could improve diet and BMI in children and reduce CMD mortality later in life

Quantifying risks and interventions that have affected the burden of diarrhoea among children younger than 5 years : an analysis of the Global Burden of Disease Study 2017

Background Many countries have shown marked declines in diarrhoea! disease mortality among children younger than 5 years. With this analysis, we provide updated results on diarrhoeal disease mortality among children younger than 5 years from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) and use the study's comparative risk assessment to quantify trends and effects of risk factors, interventions, and broader sociodemographic development on mortality changes in 195 countries and territories from 1990 to 2017. Methods This analysis for GBD 2017 had three main components. Diarrhoea mortality was modelled using vital registration data, demographic surveillance data, and verbal autopsy data in a predictive, Bayesian, ensemble modelling tool; and the attribution of risk factors and interventions for diarrhoea were modelled in a counterfactual framework that combines modelled population-level prevalence of the exposure to each risk or intervention with the relative risk of diarrhoea given exposure to that factor. We assessed the relative and absolute change in diarrhoea mortality rate between 1990 and 2017, and used the change in risk factor exposure and sociodemographic status to explain differences in the trends of diarrhoea mortality among children younger than 5 years. Findings Diarrhoea was responsible for an estimated 533 768 deaths (95% uncertainty interval 477 162-593 145) among children younger than 5 years globally in 2017, a rate of 78.4 deaths (70.1-87.1) per 100 000 children. The diarrhoea mortality rate ranged between countries by over 685 deaths per 100 000 children. Diarrhoea mortality per 100 000 globally decreased by 69.6% (63.1-74.6) between 1990 and 2017. Among the risk factors considered in this study, those responsible for the largest declines in the diarrhoea mortality rate were reduction in exposure to unsafe sanitation (13.3% decrease, 11.2-15.5), childhood wasting (9.9% decrease, 9.6-10.2), and low use of oral rehydration solution (6.9% decrease, 4-8-8-4). Interpretation Diarrhoea mortality has declined substantially since 1990, although there are variations by country. Improvements in sociodemographic indicators might explain some of these trends, but changes in exposure to risk factors-particularly unsafe sanitation, childhood growth failure, and low use of oral rehydration solution-appear to be related to the relative and absolute rates of decline in diarrhoea mortality. Although the most effective interventions might vary by country or region, identifying and scaling up the interventions aimed at preventing and protecting against diarrhoea that have already reduced diarrhoea mortality could further avert many thousands of deaths due to this illness. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.Peer reviewe

The HIV cure research agenda: the role of mathematical modelling and cost-effectiveness analysis

Abstract The research agenda towards an HIV cure is building rapidly. In this article, we discuss the reasons for and methodological approach to using mathematical modelling and cost-effectiveness analysis in this agenda. We provide a brief description of the proof of concept for cure and the current directions of cure research. We then review the types of clinical economic evaluations, including cost analysis, cost-benefit analysis and cost-effectiveness analysis. We describe the use of mathematical modelling and cost-effectiveness analysis early in the HIV epidemic as well as in the era of combination antiretroviral therapy. We then highlight the novel methodology of Value of Information (VOI) analysis and its potential role in the planning of clinical trials. We close with recommendations for modelling and cost-effectiveness analysis in the HIV cure agenda

Estimated cardiometabolic deaths averted associated with F&V provision and SSB restriction in US schools¹.

<p>Estimated cardiometabolic deaths averted associated with F&V provision and SSB restriction in US schools<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200378#t003fn002" target="_blank">¹</a>.</p

Estimated annual cardiometabolic deaths averted from implementation of national school policies on F&V provision and SSB restriction, separately and jointly, in US elementary, middle, and high schools.

<p>Bars represent the median values from 1,000 Monte Carlo simulations in a comparative risk assessment framework; and error bars, the 95% uncertainty intervals. Health effects are estimated for the current US adult population if exposed to these school environment policies during their childhood in elementary, middle, and high school. Panel (<b>A)</b> assumes that 25% of the dietary changes achieved in childhood are sustained into adulthood; panel (<b>B)</b>, that 35% of dietary changes are sustained; and panel (<b>C)</b> that 50% of dietary changes are sustained.</p

Select model inputs and estimated changes in child diet and child BMI associated with F&V provision and SSB restriction in US schools¹.

<p>Select model inputs and estimated changes in child diet and child BMI associated with F&V provision and SSB restriction in US schools<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200378#t001fn002" target="_blank">¹</a>.</p

Current and estimated changes in dietary intakes associated with national school policies on F&V provision and SSB restriction among US children by age.

<p>Current intakes are based on NHANES 2009–10 and 2011–12 (N = 4,165 children age 5–18 years), where bars represent the mean and error bars, the 95% confidence intervals. Estimates for dietary intake with policies are based on a comparative risk assessment framework incorporating policy effects from intervention studies, where bars represent the median values from 1,000 Monte Carlo simulations and error bars, the 95% uncertainty intervals.</p