arXiv subjects

Antonio Remiro-Azócar

Publications and source records attributed to Antonio Remiro-Azócar.

17 recordsLinked to original sources

arXiv2026

Does your cost-effectiveness model answer the question of interest? Marginal versus conditional inputs and transportability across populations

Objectives: There has been increased appreciation of the differences between marginal and conditional estimates and different types of effect measures regarding their applicability to different target populations. This issue of transportability is of concern in model-based cost-effectiveness analysis (CEA) when treatment effects from (international) trials are applied to (country-specific) baseline risk estimates. The objective of this paper is to create awareness regarding the issues that arise when using different types of treatment effect and baseline risk estimates in a model-based CEA to inform health technology assessment (HTA). Methods: We clarify collapsibility, marginal versus conditional estimation, and transportability; derive the ideal modeling approach implied by a marginal cost-effectiveness estimand; and characterize the issues of common modeling approaches, illustrated with a fictitious state-transition model. Results: An individual-level simulation that predicts outcomes from conditional inputs and averages them over the target population targets the marginal cost-effectiveness estimand. Cohort-model approaches that marginalize inputs early, evaluate an outcome regression model at mean covariates, or combine a conditional effect with a marginal baseline (or vice versa) can misstate cost-effectiveness results even with correct-population inputs; inputs from the wrong population add further error. Conclusions: The most rigorous approach is an individual-level simulation that carries conditional inputs (baseline risk, treatment effect, prognostic effects and effect modifiers) and marginalizes late. Cohort approaches instead marginalize early, relying on aggregated inputs, and do not necessarily target the marginal cost-effectiveness estimand of interest for HTA. Model developers should document, for each input, whether it is marginal or conditional and its population.

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arXiv2026

Incorporating estimands into meta-analyses of clinical trials

The estimand framework is increasingly established to pose research questions in confirmatory clinical trials. In evidence synthesis, the uptake of estimands has been modest, and the PICO (Population, Intervention, Comparator, Outcome) framework is more often applied. While PICOs and estimands have overlapping elements, the estimand framework explicitly considers different strategies for intercurrent events. We propose a pragmatic framework for the use of estimands in meta-analyses of clinical trials, highlighting the value of estimands to systematically identify and mitigate key sources of quantitative heterogeneity, and to enhance the applicability or external validity of pooled estimates. Focus is placed on the role of strategies for intercurrent events, within the specific context of meta-analyses for health technology assessment. We apply the estimand framework to a network meta-analysis of clinical trials, comparing the efficacy of semaglutide versus dulaglutide in type 2 diabetes. We explore the impact of a treatment policy strategy for treatment discontinuation or initiation of rescue medication versus a hypothetical strategy for the corresponding intercurrent events. The specification of different target estimands at the meta-analytical level allows us to be explicit about the source of heterogeneity, the intercurrent event strategy, driving any potential differences in results. We advocate for the integration of estimands into the planning of meta-analyses, while acknowledging that potential challenges exist in the absence of subject-level data. Estimands can complement PICOs to strengthen communication between stakeholders about what evidence syntheses seek to demonstrate, and to ensure that the generated evidence is maximally relevant to healthcare decision-makers.

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arXiv2026

Doubly robust augmented weighting estimators for the analysis of externally controlled single-arm trials and unanchored indirect treatment comparisons

Externally controlled single-arm trials are critical to assess treatment efficacy across therapeutic indications for which randomized controlled trials are not feasible. A closely-related research design, the unanchored indirect treatment comparison, is often required for disconnected treatment networks in health technology assessment. We present a unified causal inference framework for both research designs. We develop a novel estimator that augments a popular weighting approach based on entropy balancing -- matching-adjusted indirect comparison (MAIC) -- by fitting a model for the conditional outcome expectation. The predictions of the outcome model are combined with the entropy balancing MAIC weights. While the standard MAIC estimator is singly robust where the outcome model is non-linear, our augmented MAIC approach is doubly robust, providing increased robustness against model misspecification. This is demonstrated in a simulation study with binary outcomes and a logistic outcome model, where the augmented estimator demonstrates its doubly robust property, while exhibiting higher precision than all non-augmented weighting estimators and near-identical precision to G-computation. We describe the extension of our estimator to the setting with unavailable individual participant data for the external control, illustrating it through an applied example. Our findings reinforce the understanding that entropy balancing-based approaches have desirable properties compared to standard ``modeling'' approaches to weighting, but should be augmented to improve protection against bias and guarantee double robustness.

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arXiv2025

Marginal and conditional summary measures: transportability and compatibility across studies

Marginal and conditional summary measures do not generally coincide, have different interpretations and correspond to different decision questions. While these aspects have primarily been recognized for non-collapsible summary measures, they are equally problematic for some collapsible measures in the presence of effect modification. We clarify the interpretation and properties of several marginal and conditional summary measures, considering different types of outcomes and hypothetical outcome-generating mechanisms. We describe implications of the choice of summary measure for transportability, highlighting that covariates not conventionally described as effect modifiers can modify population-level treatment effects. Finally, we illustrate existing summary measure incompatibility issues in the context of evidence synthesis, using the case of covariate adjustment methods for indirect treatment comparisons. Because marginal and conditional summary measures do not generally coincide, their naïve pooling in evidence synthesis can produce bias. Almost invariably, care is needed to ensure that evidence synthesis methods are combining compatible summary measures, and this may be easier to accomplish with full access to individual patient data.

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arXiv2025

Estimands and Their Implications for Evidence Synthesis for Oncology: A Simulation Study of Treatment Switching in Meta-Analysis

The ICH E9(R1) addendum provides guidelines on accounting for intercurrent events in clinical trials using the estimands framework. However, there has been limited attention to the estimands framework for meta-analysis. Using treatment switching, a well-known intercurrent event that occurs frequently in oncology, we conducted a simulation study to explore the bias introduced by pooling together estimates targeting different estimands in a meta-analysis of randomized clinical trials (RCTs) that allowed treatment switching. We simulated overall survival data of a collection of RCTs that allowed patients in the control group to switch to the intervention treatment after disease progression under fixed-effects and random-effects models. For each RCT, we calculated effect estimates for a treatment policy estimand that ignored treatment switching, and a hypothetical estimand that accounted for treatment switching either by fitting rank-preserving structural failure time models or by censoring switchers. Then, we performed random-effects and fixed-effects meta-analyses to pool together RCT effect estimates while varying the proportions of trials providing treatment policy and hypothetical effect estimates. We compared the results of meta-analyses that pooled different types of effect estimates with those that pooled only treatment policy or hypothetical estimates. We found that pooling estimates targeting different estimands results in pooled estimators that do not target any estimand of interest, and that pooling estimates of varying estimands can generate misleading results, even under a random-effects model. Adopting the estimands framework for meta-analysis may improve alignment between meta-analytic results and the clinical research question of interest.

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arXiv2024

Effect modification and non-collapsibility leads to conflicting treatment decisions: a review of marginal and conditional estimands and recommendations for decision-making

Effect modification occurs when a covariate alters the relative effectiveness of treatment compared to control. It is widely understood that, when effect modification is present, treatment recommendations may vary by population and by subgroups within the population. Population-adjustment methods are increasingly used to adjust for differences in effect modifiers between study populations and to produce population-adjusted estimates in a relevant target population for decision-making. It is also widely understood that marginal and conditional estimands for non-collapsible effect measures, such as odds ratios or hazard ratios, do not in general coincide even without effect modification. However, the consequences of both non-collapsibility and effect modification together are little-discussed in the literature. In this paper, we set out the definitions of conditional and marginal estimands, illustrate their properties when effect modification is present, and discuss the implications for decision-making. In particular, we show that effect modification can result in conflicting treatment rankings between conditional and marginal estimates. This is because conditional and marginal estimands correspond to different decision questions that are no longer aligned when effect modification is present. For time-to-event outcomes, the presence of covariates implies that marginal hazard ratios are time-varying, and effect modification can cause marginal hazard curves to cross. We conclude with practical recommendations for decision-making in the presence of effect modification, based on pragmatic comparisons of both conditional and marginal estimates in the decision target population. Currently, multilevel network meta-regression is the only population-adjustment method capable of producing both conditional and marginal estimates, in any decision target population.

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arXiv2024

Broad versus narrow research questions in evidence synthesis: a parallel to (and plea for) estimands

There has been a transition from broad to more specific research questions in the practice of network meta-analysis (NMA). Such convergence is also taking place in the context of individual registrational trials, following the recent introduction of the estimand framework, which is impacting the design, data collection strategy, analysis and interpretation of clinical trials. The language of estimands has much to offer to NMA, particularly given the "narrow" perspective of treatments and target populations taken in health technology assessment.

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arXiv2024

Transportability of model-based estimands in evidence synthesis

In evidence synthesis, effect modifiers are typically described as variables that induce treatment effect heterogeneity at the individual level, through treatment-covariate interactions in an outcome model parametrized at such level. As such, effect modification is defined with respect to a conditional measure, but marginal effect estimates are required for population-level decisions in health technology assessment. For non-collapsible measures, purely prognostic variables that are not determinants of treatment response at the individual level may modify marginal effects, even where there is individual-level treatment effect homogeneity. With heterogeneity, marginal effects for measures that are not directly collapsible cannot be expressed in terms of marginal covariate moments, and generally depend on the joint distribution of conditional effect measure modifiers and purely prognostic variables. There are implications for recommended practices in evidence synthesis. Unadjusted anchored indirect comparisons can be biased in the absence of individual-level treatment effect heterogeneity, or when marginal covariate moments are balanced across studies. Covariate adjustment may be necessary to account for cross-study imbalances in joint covariate distributions involving purely prognostic variables. In the absence of individual patient data for the target, covariate adjustment approaches are inherently limited in their ability to remove bias for measures that are not directly collapsible. Directly collapsible measures would facilitate the transportability of marginal effects between studies by: (1) reducing dependence on model-based covariate adjustment where there is individual-level treatment effect homogeneity or marginal covariate moments are balanced; and (2) facilitating the selection of baseline covariates for adjustment where there is individual-level treatment effect heterogeneity.

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arXiv2024

Model-based standardization using multiple imputation

When studying the association between treatment and a clinical outcome, a parametric multivariable model of the conditional outcome expectation is often used to adjust for covariates. The treatment coefficient of the outcome model targets a conditional treatment effect. Model-based standardization is typically applied to average the model predictions over the target covariate distribution, and generate a covariate-adjusted estimate of the marginal treatment effect. The standard approach to model-based standardization involves maximum-likelihood estimation and use of the non-parametric bootstrap. We introduce a novel, general-purpose, model-based standardization method based on multiple imputation that is easily applicable when the outcome model is a generalized linear model. We term our proposed approach multiple imputation marginalization (MIM). MIM consists of two main stages: the generation of synthetic datasets and their analysis. MIM accommodates a Bayesian statistical framework, which naturally allows for the principled propagation of uncertainty, integrates the analysis into a probabilistic framework, and allows for the incorporation of prior evidence. We conduct a simulation study to benchmark the finite-sample performance of MIM in conjunction with a parametric outcome model. The simulations provide proof-of-principle in scenarios with binary outcomes, continuous-valued covariates, a logistic outcome model and the marginal log odds ratio as the target effect measure. When parametric modeling assumptions hold, MIM yields unbiased estimation in the target covariate distribution, valid coverage rates, and similar precision and efficiency than the standard approach to model-based standardization.

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arXiv2023

Methodological considerations for novel approaches to covariate-adjusted indirect treatment comparisons

We examine four important considerations in the development of covariate adjustment methodologies for indirect treatment comparisons. Firstly, we consider potential advantages of weighting versus outcome modeling, placing focus on bias-robustness. Secondly, we outline why model-based extrapolation may be required and useful, in the specific context of indirect treatment comparisons with limited overlap. Thirdly, we describe challenges for covariate adjustment based on data-adaptive outcome modeling. Finally, we offer further perspectives on the promise of doubly-robust covariate adjustment frameworks.

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arXiv2022

Two-stage matching-adjusted indirect comparison

Anchored covariate-adjusted indirect comparisons inform reimbursement decisions where there are no head-to-head trials between the treatments of interest, there is a common comparator arm shared by the studies, and there are patient-level data limitations. Matching-adjusted indirect comparison (MAIC) is the most widely used covariate-adjusted indirect comparison method. MAIC has poor precision and is inefficient when the effective sample size after weighting is small. A modular extension to MAIC, termed two-stage matching-adjusted indirect comparison (2SMAIC), is proposed. This uses two parametric models. One estimates the treatment assignment mechanism in the study with individual patient data (IPD), the other estimates the trial assignment mechanism. The resulting weights seek to balance covariates between treatment arms and across studies. A simulation study provides proof-of-principle in an indirect comparison performed across two randomized trials and explores the use of weight truncation in combination with MAIC for the first time. Despite enforcing randomization and knowing the true treatment assignment mechanism in the IPD trial, 2SMAIC yields improved precision and efficiency with respect to MAIC in all scenarios, while maintaining similarly low levels of bias. The two-stage approach is effective when sample sizes in the IPD trial are low, as it controls for chance imbalances in prognostic baseline covariates between study arms. It is not as effective when overlap between the trials' target populations is poor and the extremity of the weights is high. In these scenarios, truncation leads to substantial precision and efficiency gains but induces considerable bias. The combination of a two-stage approach with truncation produces the highest precision and efficiency improvements.

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arXiv2022

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 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.

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arXiv2022

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 on 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.

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arXiv2022

Target estimands for population-adjusted indirect comparisons

Disagreement remains on what the target estimand should be for population-adjusted indirect treatment comparisons. This debate is of central importance for policy-makers and applied practitioners in health technology assessment. Misunderstandings are based on properties inherent to estimators, not estimands, and on generalizing conclusions based on linear regression to non-linear models. Estimators of marginal estimands need not be unadjusted and may be covariate-adjusted. The population-level interpretation of conditional estimates follows from collapsibility and does not necessarily hold for the underlying conditional estimands. For non-collapsible effect measures, neither conditional estimates nor estimands have a population-level interpretation. Estimators of marginal effects tend to be more precise and efficient than estimators of conditional effects where the measure of effect is non-collapsible. In any case, such comparisons are inconsequential for estimators targeting distinct estimands. Statistical efficiency should not drive the choice of the estimand. On the other hand, the estimand, selected on the basis of relevance to decision-making, should drive the choice of the most efficient estimator. Health technology assessment agencies make reimbursement decisions at the population level. Therefore, marginal estimands are required. Current pairwise population adjustment methods such as matching-adjusted indirect comparison are restricted to target marginal estimands that are specific to the comparator study sample. These may not be relevant for decision-making. Multilevel network meta-regression (ML-NMR) can potentially target marginal estimands in any population of interest. Such population could be characterized by decision-makers using increasingly available "real-world" data sources. Therefore, ML-NMR presents new directions and abundant opportunities for evidence synthesis.

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arXiv2021

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.

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arXiv2021

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.

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arXiv2020

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.

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