Calculating the Expected Value of Sample Information using Efficient Nested Monte Carlo: A Tutorial

Objective: The Expected Value of Sample Information (EVSI) quantifies the economic benefit of reducing uncertainty in a health economic model by collecting additional information. This has the potential to improve the allocation of research budgets. Despite this, practical EVSI evaluations are limited, partly due to the computational cost of estimating this value using the "gold-standard" nested simulation methods. Recently, however, Heath et al developed an estimation procedure that reduces the number of simulations required for this "gold-standard" calculation. Up to this point, this new method has been presented in purely technical terms. Study Design: This study presents the practical application of this new method to aid its implementation. We use a worked example to illustrate the key steps of the EVSI estimation procedure before discussing its optimal implementation using a practical health economic model. Methods: The worked example is based on a three parameter linear health economic model. The more realistic model evaluates the cost-effectiveness of a new chemotherapy treatment which aims to reduce the number of side effects experienced by patients. We use a Markov Model structure to evaluate the health economic profile of experiencing side effects. Results: This EVSI estimation method offers accurate estimation within a feasible computation time, seconds compared to days, even for more complex model structures. The EVSI estimation is more accurate if a greater number of nested samples are used, even for a fixed computational cost. Conclusions: This new method reduces the computational cost of estimating the EVSI by nested simulation

Methods for Population Adjustment with Limited Access to Individual Patient Data: A Review and Simulation Study

Population-adjusted indirect comparisons estimate treatment effects when access to individual patient data is limited and there are cross-trial differences in effect modifiers. Popular methods include matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC). There is limited formal evaluation of these methods and whether they can be used to accurately compare treatments. Thus, we undertake a comprehensive simulation study to compare standard unadjusted indirect comparisons, MAIC and STC across 162 scenarios. This simulation study assumes that the trials are investigating survival outcomes and measure continuous covariates, with the log hazard ratio as the measure of effect. MAIC yields unbiased treatment effect estimates under no failures of assumptions. The typical usage of STC produces bias because it targets a conditional treatment effect where the target estimand should be a marginal treatment effect. The incompatibility of estimates in the indirect comparison leads to bias as the measure of effect is non-collapsible. Standard indirect comparisons are systematically biased, particularly under stronger covariate imbalance and interaction effects. Standard errors and coverage rates are often valid in MAIC but the robust sandwich variance estimator underestimates variability where effective sample sizes are small. Interval estimates for the standard indirect comparison are too narrow and STC suffers from bias-induced undercoverage. MAIC provides the most accurate estimates and, with lower degrees of covariate overlap, its bias reduction outweighs the loss in effective sample size and precision under no failures of assumptions. An important future objective is the development of an alternative formulation to STC that targets a marginal treatment effect.Comment: 73 pages (34 are supplementary appendices and references), 8 figures, 2 tables. Full article (following Round 4 of minor revisions). arXiv admin note: text overlap with arXiv:2008.0595

Arab Spring Book Exhibit Bibliography and Call Numbers

An exhibit of books about Arab Spring was held in the William T. Young Library from Oct. 2014 through Feb. 2015 in celebration of the Year of the Middle Year at the University of Kentucky. An annotated bibliography for the exhibit is available by clicking the Download button on the right. Click here to view the online guide about the book exhibit

BCEA: An R Package for Cost-Effectiveness Analysis

We describe in detail how to perform health economic cost-effectiveness analyses (CEA) using the R package $\textbf{BCEA}$ (Bayesian Cost-Effectiveness Analysis). CEA consist of analytic approaches for combining costs and health consequences of intervention(s). These help to understand how much an intervention may cost (per unit of health gained) compared to an alternative intervention, such as a control or status quo. For resource allocation, a decision maker may wish to know if an intervention is cost saving, and if not then how much more would it cost to implement it compared to a less effective intervention. Current guidance for cost-effectiveness analyses advocates the quantification of uncertainties which can be represented by random samples obtained from a probability sensitivity analysis or, more efficiently, a Bayesian model. $\textbf{BCEA}$ can be used to post-process the sampled costs and health impacts to perform advanced analyses producing standardised and highly customisable outputs. We present the features of the package, including its many functions and their practical application. $\textbf{BCEA}$ is valuable for statisticians and practitioners working in the field of health economic modelling wanting to simplify and standardise their workflow, for example in the preparation of dossiers in support of marketing authorisation, or academic and scientific publications

Effect modification in anchored indirect treatment comparisons: Comments on "Matching-adjusted indirect comparisons: Application to time-to-event data"

This commentary regards a recent simulation study conducted by Aouni, Gaudel-Dedieu and Sebastien, evaluating the performance of different versions of matching-adjusted indirect comparison (MAIC) in an anchored scenario with a common comparator. The simulation study uses survival outcomes and the Cox proportional hazards regression as the outcome model. It concludes that using the LASSO for variable selection is preferable to balancing a maximal set of covariates. However, there are no treatment effect modifiers in imbalance in the study. The LASSO is more efficient because it selects a subset of the maximal set of covariates but there are no cross-study imbalances in effect modifiers inducing bias. We highlight the following points: (1) in the anchored setting, MAIC is necessary where there are cross-trial imbalances in effect modifiers; (2) the standard indirect comparison provides greater precision and accuracy than MAIC if there are no effect modifiers in imbalance; (3) while the target estimand of the simulation study is a conditional treatment effect, MAIC targets a marginal or population-average treatment effect; (4) in MAIC, variable selection is a problem of low dimensionality and sparsity-inducing methods like the LASSO may be problematic. Finally, data-driven approaches do not obviate the necessity for subject matter knowledge when selecting effect modifiers. R code is provided in the Appendix to replicate the analyses and illustrate our points.Comment: 14 pages, minor changes after conditional acceptance by Statistics in Medicine. This is a response to `Matching-adjusted indirect comparisons: Application to time-to-event data' by Aouni, Gaudel-Dedieu and Sebastien (2020

Parametric G-computation for Compatible Indirect Treatment Comparisons with Limited Individual Patient Data

Population adjustment methods such as matching-adjusted indirect comparison (MAIC) are increasingly used to compare marginal treatment effects when there are cross-trial differences in effect modifiers and limited patient-level data. MAIC is based on propensity score weighting, which is sensitive to poor covariate overlap and cannot extrapolate beyond the observed covariate space. Current outcome regression-based alternatives can extrapolate but target a conditional treatment effect that is incompatible in the indirect comparison. When adjusting for covariates, one must integrate or average the conditional estimate over the relevant population to recover a compatible marginal treatment effect. We propose a marginalization method based parametric G-computation that can be easily applied where the outcome regression is a generalized linear model or a Cox model. The approach views the covariate adjustment regression as a nuisance model and separates its estimation from the evaluation of the marginal treatment effect of interest. The method can accommodate a Bayesian statistical framework, which naturally integrates the analysis into a probabilistic framework. A simulation study provides proof-of-principle and benchmarks the method's performance against MAIC and the conventional outcome regression. Parametric G-computation achieves more precise and more accurate estimates than MAIC, particularly when covariate overlap is poor, and yields unbiased marginal treatment effect estimates under no failures of assumptions. Furthermore, the marginalized regression-adjusted estimates provide greater precision and accuracy than the conditional estimates produced by the conventional outcome regression, which are systematically biased because the measure of effect is non-collapsible. This article is protected by copyright. All rights reserved

Conflating marginal and conditional treatment effects: Comments on 'Assessing the performance of population adjustment methods for anchored indirect comparisons: A simulation study'

In this commentary, we highlight the importance of: (1) carefully considering and clarifying whether a marginal or conditional treatment effect is of interest in a population-adjusted indirect treatment comparison; and (2) developing distinct methodologies for estimating the different measures of effect. The appropriateness of each methodology depends on the preferred target of inference.Comment: 6 pages, submitted to Statistics in Medicine. Response to `Assessing the performance of population adjustment methods for anchored indirect comparisons: A simulation study' by Phillippo, Dias, Ades and Welton, published in Statistics in Medicine (2020). Updated after Ph.D. proposal defense/transfer viva comment

Marginalization of Regression-Adjusted Treatment Effects in Indirect Comparisons with Limited Patient-Level Data

Population adjustment methods such as matching-adjusted indirect comparison (MAIC) are increasingly used to compare marginal treatment effects when there are cross-trial differences in effect modifiers and limited patient-level data. MAIC is sensitive to poor covariate overlap and cannot extrapolate beyond the observed covariate space. Current outcome regression-based alternatives can extrapolate but target a conditional treatment effect that is incompatible in the indirect comparison. When adjusting for covariates, one must integrate or average the conditional estimate over the population of interest to recover a compatible marginal treatment effect. We propose a marginalization method based on parametric G-computation that can be easily applied where the outcome regression is a generalized linear model or a Cox model. In addition, we introduce a novel general-purpose method based on multiple imputation, which we term multiple imputation marginalization (MIM) and is applicable to a wide range of models. Both methods can accommodate a Bayesian statistical framework, which naturally integrates the analysis into a probabilistic framework. A simulation study provides proof-of-principle for the methods and benchmarks their performance against MAIC and the conventional outcome regression. The marginalized outcome regression approaches achieve more precise and more accurate estimates than MAIC, particularly when covariate overlap is poor, and yield unbiased marginal treatment effect estimates under no failures of assumptions. Furthermore, the marginalized covariate-adjusted estimates provide greater precision and accuracy than the conditional estimates produced by the conventional outcome regression, which are systematically biased because the measure of effect is non-collapsible.Comment: 86 pages (28 of supplementary appendices and references), 5 figures. Updated after PhD viva comments. arXiv admin note: text overlap with arXiv:2004.1480