arXiv subjects

Theodoros Evrenoglou

Publications and source records attributed to Theodoros Evrenoglou.

8 recordsLinked to original sources

arXiv2026

Distinguishing case-mix from context heterogeneity in prognostic regression model synthesis settings

Prognostic regression models often synthesize data from multiple sites, whether within a multi-site study, across federated settings, or in individual participant data meta-analysis. Here, a site is any data source, such as a hospital, registry, trial, or study, and need not be a physical center. Analysts must then decide whether one regression model represents all sites or whether site-specific models are needed. Established measures such as coefficient-level tau^2 quantify heterogeneity but do not distinguish its source. We focus on diagnosing whether coefficient heterogeneity reflects case-mix or site-specific context effects. Case-mix heterogeneity can arise when linear regression terms approximate multivariable non-linear relationships in populations with different covariate distributions. Contextual heterogeneity arises when comparable patients require different regression relationships across sites. We do this by fitting site-specific local regressions in a dimension-reduced space and partitioning the smoothed coefficient surfaces into a cross-site reference and site-specific deviations. An autoencoder and custom loss structure the latent space around local prognostic relationships. We then project this partition onto the outcome scale to derive observation- and site-level summaries. We demonstrate the approach on a COPD trial with two sites. In the three leading latent slope coordinates, coefficient-surface variation was predominantly contextual. The derived observation-level outcome-scale variance partition was case-mix-leading, whereas its between-site aggregation was concentrated in contextual differences rather than case-mix shifts. A permuted-site negative control assesses whether the contextual summary can arise when site labels carry no signal. This diagnostic distinction can inform whether joint or site-specific regression models should be evaluated.

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arXiv2026

Assessing the Impact of Model Assumptions in Network Meta-Regression: A Simulation Study

Network meta-regression (NMR) extends network meta-analysis (NMA) by synthesizing evidence on multiple treatments while adjusting for potential effect modifiers. By accounting for effect modification, NMR can reduce between-study heterogeneity and improve the validity of relative treatment effects, providing insight regarding characteristics impacting treatment performance. However, choosing between available NMR models is complex, as each model addresses a similar, but unique research question, and the performance of available NMR models under varying network structures, between-study heterogeneity, and interaction assumptions remains unclear. We evaluated the consequences of model misspecification in a simulation study of 120 evidence-network scenarios designed to reflect potential complications in evidence networks introduced by trial design, heterogeneity levels, and interaction assumptions. We compared the standard interaction-free NMA model with four NMR parameterizations differing in across-comparison interaction assumptions (common vs. independent interactions) and interaction consistency assumptions (with or without consistency). Standard NMA models generally overestimated treatment effects when effect modification was present. NMR models with independent across-comparison interactions maintained appropriate confidence interval coverage in dense networks generated with their corresponding consistency assumptions. However, their coverage deteriorated in sparse networks with between-study heterogeneity. Models assuming consistent interactions are advantageous in networks with multi-arm studies. Ignoring effect modification in NMA can lead to biased treatment effect estimates. When effect modification is anticipated, thoughtful alignment between network structure and NMR assumptions can reduce bias and misleading precision, supporting more reliable medical decision making.

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arXiv2026

Learning study similarity to investigate heterogeneity in meta-analysis using LLMs and triplet loss

Meta-analyses of observational studies often show substantial between-study heterogeneity, limiting the interpretability of pooled estimates. Meta-regression can be used to explore heterogeneity, but it is often underpowered to handle multiple effect modifiers. We propose a novel framework that integrates large language models (LLMs) with deep metric learning to infer study-level similarity prior to meta-analysis. Study-level clinical and methodological characteristics were processed by an LLM to generate study triplets (anchor, similar, dissimilar). These triplets were constructed by treating each study as an anchor and comparing it with pairs of other studies to identify, in each instance, the study most similar to the anchor. Then, the triplets were used into an embedding model trained with triplet loss; a deep learning approach that learns an embedding space where clinically and methodologically similar studies are clustered together. We apply our framework to a meta-analysis dataset of 58 observational studies comparing cognitive outcomes between preterm- and term-born children. Subsequently, we fit meta-analysis models within the identified study clusters and compare the results with those of the overall analysis. Results suggested three clusters two of which retained considerable between-study heterogeneity. The remaining cluster comprised the most homogeneous group of studies and exhibited a more extreme pooled effect estimate together with a narrower prediction interval compared with the overall analysis. This work presents a novel approach for exploring heterogeneity in meta-analysis by incorporating study characteristics prior to model fitting. By transforming study information into a similarity space, the framework identifies coherent subgroups and supports more precise inference in heterogeneous real-world evidence.

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arXiv2026

Robust inference methods of diagnostic test accuracy meta-analysis for influential outlying studies via density power divergence

In diagnostic test accuracy meta-analysis (DTA-MA), standard inference methods using bivariate random-effects models for jointly synthesizing sensitivity and specificity can be sensitive to outlying studies and may yield misleading conclusions. In this article, we propose frequentist outlier-robust statistical inference methods for DTA-MA based on density power divergence. The proposed methods automatically downweight influential outlying studies by modifying the estimating function using the robust divergence with a tuning parameter. To achieve robust yet statistically efficient inference in the presence of outlying studies, the proposed methods incorporate practical strategies for selecting the tuning parameter, including a data-adaptive criterion based on the Hyvärinen score. We also quantify the contributions of individual studies to the robust pooled estimates, facilitating interpretation of how outlying studies affect the results. We illustrate the effectiveness of the proposed methods through an application to a DTA-MA of the Mini-Mental State Examination. Simulation studies showed that the proposed methods reduced bias and root mean squared error relative to existing methods and improved coverage probability in the presence of outliers. The proposed methods enable a sensitivity analysis to assess whether the main results obtained using standard methods are driven by outlying studies.

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arXiv2025

Producing treatment hierarchies in network meta-analysis using probabilistic models and treatment-choice criteria

A key output of network meta-analysis (NMA) is the relative ranking of treatments; nevertheless, it has attracted substantial criticism. Existing ranking methods often lack clear interpretability and fail to adequately account for uncertainty, over-emphasizing small differences in treatment effects. We propose a novel framework to estimate treatment hierarchies in NMA using a probabilistic model, focusing on a clinically relevant treatment-choice criterion (TCC). Initially, we formulate a mathematical expression to define a TCC based on smallest worthwhile differences (SWD), converting NMA relative treatment effects into treatment preference format. This data is then synthesized using a probabilistic ranking model, assigning each treatment a latent 'ability' parameter, representing its propensity to yield clinically important and beneficial true treatment effects relative to the rest of the treatments in the network. Parameter estimation relies on the maximum likelihood theory, with standard errors derived asymptotically from Fisher's information matrix. To facilitate the use of our methods, we launched the R package mtrank. We applied our method to two clinical datasets: one comparing 18 antidepressants for major depression and another comparing 6 antihypertensives for the incidence of diabetes. Our approach provided robust, interpretable treatment hierarchies that account for a concrete TCC. We further examined the agreement between the proposed method and existing ranking metrics in 153 published networks, concluding that the degree of agreement depends on the precision of the NMA estimates. Our framework offers a valuable alternative for NMA treatment ranking, mitigating over-interpretation of minor differences. This enables more reliable and clinically meaningful treatment hierarchies.

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arXiv2024

Meta-analysis models relaxing the random effects normality assumption: methodological systematic review and simulation study

Random effects meta-analysis is widely used for synthesizing studies under the assumption that underlying effects come from a normal distribution. However, under certain conditions the use of alternative distributions might be more appropriate. We conducted a systematic review to identify articles introducing alternative meta-analysis models assuming non-normal between-study distributions. We identified 27 eligible articles suggesting 24 alternative meta-analysis models based on long-tail and skewed distributions, on mixtures of distributions, and on Dirichlet process priors. Subsequently, we performed a simulation study to evaluate the performance of these models and to compare them with the standard normal model. We considered 22 scenarios varying the amount of between-study variance, the shape of the true distribution, and the number of included studies. We compared 15 models implemented in the Frequentist or in the Bayesian framework. We found small differences with respect to bias between the different models but larger differences in the level of coverage probability. In scenarios with large between-study variance, all models were substantially biased in the estimation of the mean treatment effect. This implies that focusing only on the mean treatment effect of random effects meta-analysis can be misleading when substantial heterogeneity is suspected or outliers are present.

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arXiv2023

Sharing information across patient subgroups to draw conclusions from sparse treatment networks

Network meta-analysis (NMA) usually provides estimates of the relative effects with the highest possible precision. However, sparse networks with few available studies and limited direct evidence can arise, threatening the robustness and reliability of NMA estimates. In these cases, the limited amount of available information can hamper the formal evaluation of the underlying NMA assumptions of transitivity and consistency. In addition, NMA estimates from sparse networks are expected to be imprecise and possibly biased as they rely on large sample approximations which are invalid in the absence of sufficient data. We propose a Bayesian framework that allows sharing of information between two networks that pertain to different population subgroups. Specifically, we use the results from a subgroup with a lot of direct evidence (a dense network) to construct informative priors for the relative effects in the target subgroup (a sparse network). This is a two-stage approach where at the first stage we extrapolate the results of the dense network to those expected from the sparse network. This takes place by using a modified hierarchical NMA model where we add a location parameter that shifts the distribution of the relative effects to make them applicable to the target population. At the second stage, these extrapolated results are used as prior information for the sparse network. We illustrate our approach through a motivating example of psychiatric patients. Our approach results in more precise and robust estimates of the relative effects and can adequately inform clinical practice in presence of sparse networks.

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arXiv2021

Network meta-analysis of rare events using penalized likelihood regression

Network meta-analysis (NMA) of rare events has attracted little attention in the literature. Until recently, networks of interventions with rare events were analyzed using the inverse-variance NMA approach. However, when events are rare the normal approximation made by this model can be poor and effect estimates are potentially biased. Other methods for the synthesis of such data are the recent extension of the Mantel-Haenszel approach to NMA or the use of the non-central hypergeometric distribution. In this article, we suggest a new common-effect NMA approach that can be applied even in networks of interventions with extremely low or even zero number of events without requiring study exclusion or arbitrary imputations. Our method is based on the implementation of the penalized likelihood function proposed by Firth for bias reduction of the maximum likelihood estimate to the logistic expression of the NMA model. A limitation of our method is that heterogeneity cannot be taken into account as an additive parameter as in most meta-analytical models. However, we account for heterogeneity by incorporating a multiplicative overdispersion term using a two-stage approach. We show through simulations that our method performs consistently well across all tested scenarios and most often results in smaller bias than other available methods. We also illustrate the use of our method through two clinical examples. We conclude that our "penalized likelihood NMA" approach is promising for the analysis of binary outcomes with rare events especially for networks with very few studies per comparison and very low control group risks.

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