arXiv subjects

Konstantinos Sechidis

Publications and source records attributed to Konstantinos Sechidis.

10 recordsLinked to original sources

arXiv2026

A Workflow for Evaluating Regional Treatment Effect Heterogeneity in Multi-Regional Clinical Trials

Multi-regional clinical trials (MRCTs) enable efficient global drug development by assessing treatment effects across regions within a single protocol. While powered for overall efficacy, MRCTs are typically not designed to provide confirmatory evidence on regional differences, making an assessment of observed regional heterogeneity largely exploratory and susceptible to sampling variability. Despite this challenge, understanding regional heterogeneity remains important for interpretation and regulatory decision-making. This paper proposes a structured, question-driven framework to guide exploratory assessments of regional heterogeneity in MRCTs. We formulate four key questions to clarify the objectives of such analyses and propose a set of statistical methods to address them. Simulation studies evaluate performance under scenarios with no heterogeneity and heterogeneity driven by observed or unobserved treatment effect modifiers, illustrating how a structured approach can support transparent and cautious interpretation.

stat.AP↗

arXiv2025

Data-driven controlled subgroup selection in clinical trials

Subgroup selection in clinical trials is essential for identifying patient groups that react differently to a treatment, thereby enabling personalised medicine. In particular, subgroup selection can identify patient groups that respond particularly well to a treatment or that encounter adverse events more often. However, this is a post-selection inference problem, which may pose challenges for traditional techniques used for subgroup analysis, such as increased Type I error rates and potential biases from data-driven subgroup identification. In this paper, we present two methods for subgroup selection in regression problems: one based on generalised linear modelling and another on isotonic regression. We demonstrate how these methods can be used for data-driven subgroup identification in the analysis of clinical trials, focusing on two distinct tasks: identifying patient groups that are safe from manifesting adverse events and identifying patient groups with high treatment effect, while controlling for Type I error in both cases. A thorough simulation study is conducted to evaluate the strengths and weaknesses of each method, providing detailed insight into the sensitivity of the Type I error rate control to modelling assumptions.

stat.ME↗

arXiv2025

Choosing the nominal level post-hoc with knockoffs using e-values

The knockoff filter is a powerful tool for controlled variable selection with false discovery rate (FDR) control. In this paper, we leverage e-values to allow the nominal FDR level to be switched post-hoc, after looking at the data and applying the knockoff procedure. This approach addresses a significant limitation of standard knockoffs: while frequently used in high-dimensional regressions, they often lack power in low-dimensional and sparse signal settings. One of the main reasons for this is that the knockoff filter requires a minimum number of selections that depends strictly on the nominal FDR level. By utilizing e-values, we can increase the nominal level in cases where the original procedure makes no discoveries, or decrease it to improve precision when discoveries are abundant. These improvements come without any costs, meaning the results of our post-hoc procedure are always more informative than those of the original knockoff filter. We extend this methodology to recently proposed derandomized knockoff procedures and demonstrate its utility in variable selection problems relevant to drug development using real clinical trial data.

stat.ME↗

arXiv2025

Overview and practical recommendations on using Shapley Values for identifying predictive biomarkers via CATE modeling

In recent years, two parallel research trends have emerged in machine learning, yet their intersections remain largely unexplored. On one hand, there has been a significant increase in literature focused on Individual Treatment Effect (ITE) modeling, particularly targeting the Conditional Average Treatment Effect (CATE) using meta-learner techniques. These approaches often aim to identify causal effects from observational data. On the other hand, the field of Explainable Machine Learning (XML) has gained traction, with various approaches developed to explain complex models and make their predictions more interpretable. A prominent technique in this area is Shapley Additive Explanations (SHAP), which has become mainstream in data science for analyzing supervised learning models. However, there has been limited exploration of SHAP application in identifying predictive biomarkers through CATE models, a crucial aspect in pharmaceutical precision medicine. We address inherent challenges associated with the SHAP concept in multi-stage CATE strategies and introduce a surrogate estimation approach that is agnostic to the choice of CATE strategy, effectively reducing computational burdens in high-dimensional data. Using this approach, we conduct simulation benchmarking to evaluate the ability to accurately identify biomarkers using SHAP values derived from various CATE meta-learners and Causal Forest.

stat.ME↗

arXiv2025

Comparing methods to assess treatment effect heterogeneity in general parametric regression models

This paper reviews and compares methods to assess treatment effect heterogeneity in the context of parametric regression models. These methods include the standard likelihood ratio tests, bootstrap likelihood ratio tests, and Goeman's global test motivated by testing whether the random effect variance is zero. We place particular emphasis on tests based on the score-residual of the treatment effect and explore different variants of tests in this class. All approaches are compared in a simulation study, and the approach based on residual scores is illustrated in a clinical trial with time-to-event outcome comparing treatment versus placebo. Our findings demonstrate that score-residual based methods provide practical, flexible and reliable tools for exploring treatment effect heterogeneity and treatment effect modifiers, and can provide useful guidance for decision making around treatment effect heterogeneity.

stat.AP↗

arXiv2025

Using Individualized Treatment Effects to Assess Treatment Effect Heterogeneity

Assessing treatment effect heterogeneity (TEH) in clinical trials is crucial, as it provides insights into the variability of treatment responses among patients, influencing important decisions related to drug development. Furthermore, it can lead to personalized medicine by tailoring treatments to individual patient characteristics. This paper introduces novel methodologies for assessing treatment effects using the individual treatment effect as a basis. To estimate this effect, we use a Double Robust (DR) learner to infer a pseudo-outcome that reflects the causal contrast. This pseudo-outcome is then used to perform three objectives: (1) a global test for heterogeneity, (2) ranking covariates based on their influence on effect modification, and (3) providing estimates of the individualized treatment effect. We compare our DR-learner with various alternatives and competing methods in a simulation study, and also use it to assess heterogeneity in a pooled analysis of five Phase III trials in psoriatic arthritis. By integrating these methods with the recently proposed WATCH workflow (Workflow to Assess Treatment Effect Heterogeneity in Drug Development for Clinical Trial Sponsors), we provide a robust framework for analyzing TEH, offering insights that enable more informed decision-making in this challenging area.

stat.AP↗

arXiv2025

WATCH: A Workflow to Assess Treatment Effect Heterogeneity in Drug Development for Clinical Trial Sponsors

This paper proposes a Workflow for Assessing Treatment effeCt Heterogeneity (WATCH) in clinical drug development targeted at clinical trial sponsors. WATCH is designed to address the challenges of investigating treatment effect heterogeneity (TEH) in randomized clinical trials, where sample size and multiplicity limit the reliability of findings. The proposed workflow includes four steps: Analysis Planning, Initial Data Analysis and Analysis Dataset Creation, TEH Exploration, and Multidisciplinary Assessment. The workflow offers a general overview of how treatment effects vary by baseline covariates in the observed data, and guides interpretation of the observed findings based on external evidence and best scientific understanding. The workflow is exploratory and not inferential/confirmatory in nature, but should be pre-planned before data-base lock and analysis start. It is focused on providing a general overview rather than a single specific finding or subgroup with differential effect.

stat.AP↗

arXiv2020

Inferring Causal Direction from Observational Data: A Complexity Approach

At the heart of causal structure learning from observational data lies a deceivingly simple question: given two statistically dependent random variables, which one has a causal effect on the other? This is impossible to answer using statistical dependence testing alone and requires that we make additional assumptions. We propose several fast and simple criteria for distinguishing cause and effect in pairs of discrete or continuous random variables. The intuition behind them is that predicting the effect variable using the cause variable should be `simpler' than the reverse -- different notions of `simplicity' giving rise to different criteria. We demonstrate the accuracy of the criteria on synthetic data generated under a broad family of causal mechanisms and types of noise.

cs.LG↗

arXiv2020

Multi-target regression via output space quantization

Multi-target regression is concerned with the prediction of multiple continuous target variables using a shared set of predictors. Two key challenges in multi-target regression are: (a) modelling target dependencies and (b) scalability to large output spaces. In this paper, a new multi-target regression method is proposed that tries to jointly address these challenges via a novel problem transformation approach. The proposed method, called MRQ, is based on the idea of quantizing the output space in order to transform the multiple continuous targets into one or more discrete ones. Learning on the transformed output space naturally enables modeling of target dependencies while the quantization strategy can be flexibly parameterized to control the trade-off between prediction accuracy and computational efficiency. Experiments on a large collection of benchmark datasets show that MRQ is both highly scalable and also competitive with the state-of-the-art in terms of accuracy. In particular, an ensemble version of MRQ obtains the best overall accuracy, while being an order of magnitude faster than the runner up method.

cs.LG↗

arXiv2016

Ranking Biomarkers Through Mutual Information

We study information theoretic methods for ranking biomarkers. In clinical trials there are two, closely related, types of biomarkers: predictive and prognostic, and disentangling them is a key challenge. Our first step is to phrase biomarker ranking in terms of optimizing an information theoretic quantity. This formalization of the problem will enable us to derive rankings of predictive/prognostic biomarkers, by estimating different, high dimensional, conditional mutual information terms. To estimate these terms, we suggest efficient low dimensional approximations, and we derive an empirical Bayes estimator, which is suitable for small or sparse datasets. Finally, we introduce a new visualisation tool that captures the prognostic and the predictive strength of a set of biomarkers. We believe this representation will prove to be a powerful tool in biomarker discovery.

stat.ML↗