arXiv subjects

Boris P. Hejblum

Publications and source records attributed to Boris P. Hejblum.

7 recordsLinked to original sources

arXiv2026

Scalable Dirichlet Process Mixture Models with Unknown Concentration and Adaptive Covariance for High-Dimensional Clustering Applied to Leukemia Transcriptomics

We propose a novel method that performs adaptive clustering with DPMM using collapsed VI, while incorporating weakly-informative priors for DP concentration parameter alpha and base distribution G0. We illustrate the importance of G0 covariance structure and prior choice by considering different parameterisations of the data covariance matrix. On high-dimensional Gaussian simulations, our model demonstrates substantially faster convergence than a state-of-the-art MCMC splice sampler. We further evaluate performances on Negative Binomial simulations and conduct sensitivity analyses to assess robustness on realistic data conditions. Application to a publicly available leukemia transcriptomic data set comprising 72 samples and 2,194 gene expression successfully recovers every known sub-type, all while identifying additional gene expression-based sub-clusters with meaningful biological interpretation.

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arXiv2026

Meta-Analysis of High-Dimensional Surrogate Markers

When direct measurement of a clinically relevant primary endpoint in a clinical trial is infeasible, a surrogate endpoint may be used instead to infer treatment effects. Trial-level surrogates predict the average treatment effect on the primary endpoint and may be evaluated within the meta-analytic framework. However, traditional methods are ill-suited to the complex high-dimensional data now increasingly collected in modern trials, such as omics data. Although methods for high-dimensional surrogate evaluation exist, they have largely been developed for single-trial settings and therefore cannot assess surrogate generalisability. Here, we propose RISE-Meta, an approach for evaluating trial-level surrogate markers in the multi-trial, high-dimensional setting. In the first stage, an existing nonparametric method is applied to individual participant data to derive study-level surrogacy metrics for each candidate marker. Next, random-effects meta-analysis combines these metrics across studies, and equivalence testing provides operational criteria for surrogate validity. Finally, a subset of candidates is combined into a composite signature through a weighting scheme to improve surrogacy relative to any individual candidate. We evaluate RISE-Meta in both simulation studies and real data applications. In an application to high-dimensional data, we analyse gene expression as trial-level surrogate markers for the antibody response to seasonal influenza vaccination, while in a low-dimensional application we compare RISE-Meta to a reference meta-analytic approach and observe strong agreement between the two.

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arXiv2026

Practical limitations for real-life application of data fission and data thinning in post-clustering differential analysis

Post-clustering inference in single-cell RNA sequencing (scRNA-seq) analysis presents significant challenges in controlling Type I error during differential expression analysis. Data fission, a promising approach that aims to split data into two independent parts, relies on strong parametric assumptions of non-mixture distributions that are inherently violated in clustered data. To address this limitation, we introduce conditional data fission, an extension designed to decompose each mixture component into two independent parts. However, we demonstrate that applying such conditional data fission to mixture distributions requires prior knowledge of the clustering structure to ensure valid post-clustering inference. This arises from the need to accurately estimate component-specific scale parameters, which are critical for performing decomposition while maintaining independence. We theoretically quantify how biases in estimating these parameters lead to inflated Type I error rates due to deviations from independence. Given that mixture components are typically unknown in practice, our results underscore the fundamental difficulty of applying data fission in real-world settings, despite its prior proposal as a solution for post-clustering inference.

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arXiv2025

RISE: Two-Stage Rank-Based Identification of High-Dimensional Surrogate Markers Applied to Vaccinology

In vaccine trials with long-term participant follow-up, it is of great importance to identify surrogate markers that accurately infer long-term immune responses. These markers offer practical advantages such as providing early, indirect evidence of vaccine efficacy, and can accelerate vaccine development while identifying potential biomarkers. High-throughput technologies like RNA-sequencing have emerged as promising tools for understanding complex biological systems and informing new treatment strategies. However, these data are high-dimensional, presenting unique statistical challenges for existing surrogate marker identification methods. We introduce Rank-based Identification of high-dimensional SurrogatE Markers (RISE), a novel approach designed for small sample, high-dimensional settings typical in modern vaccine experiments. RISE employs a non-parametric univariate test to screen variables for promising candidates, followed by surrogate evaluation on independent data. Our simulation studies demonstrate RISE's desirable properties, including type one error rate control and empirical power under various conditions. Applying RISE to a clinical trial for inactivated influenza vaccination, we sought to identify genes whose expression could serve as a surrogate for the induced immune response. This analysis revealed a signature of genes appearing to function as a reasonable surrogate for the neutralising antibody response. Pathways related to innate antiviral signalling and interferon stimulation were strongly represented in this derived surrogate, providing a clear immunological interpretation.

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arXiv2024

On the potential benefits of entropic regularization for smoothing Wasserstein estimators

This paper is focused on the study of entropic regularization in optimal transport as a smoothing method for Wasserstein estimators, through the prism of the classical tradeoff between approximation and estimation errors in statistics. Wasserstein estimators are defined as solutions of variational problems whose objective function involves the use of an optimal transport cost between probability measures. Such estimators can be regularized by replacing the optimal transport cost by its regularized version using an entropy penalty on the transport plan. The use of such a regularization has a potentially significant smoothing effect on the resulting estimators. In this work, we investigate its potential benefits on the approximation and estimation properties of regularized Wasserstein estimators. Our main contribution is to discuss how entropic regularization may reach, at a lower computational cost, statistical performances that are comparable to those of un-regularized Wasserstein estimators in statistical learning problems involving distributional data analysis. To this end, we present new theoretical results on the convergence of regularized Wasserstein estimators. We also study their numerical performances using simulated and real data in the supervised learning problem of proportions estimation in mixture models using optimal transport.

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arXiv2022

CytOpT: Optimal Transport with Domain Adaptation for Interpreting Flow Cytometry data

The automated analysis of flow cytometry measurements is an active research field. We introduce a new algorithm, referred to as CytOpT, using regularized optimal transport to directly estimate the different cell population proportions from a biological sample characterized with flow cytometry measurements. We rely on the regularized Wasserstein metric to compare cytometry measurements from different samples, thus accounting for possible mis-alignment of a given cell population across sample (due to technical variability from the technology of measurements). In this work, we rely on a supervised learning technique based on the Wasserstein metric that is used to estimate an optimal re-weighting of class proportions in a mixture model from a source distribution (with known segmentation into cell sub-populations) to fit a target distribution with unknown segmentation. Due to the high-dimensionality of flow cytometry data, we use stochastic algorithms to approximate the regularized Wasserstein metric to solve the optimization problem involved in the estimation of optimal weights representing the cell population proportions in the target distribution. Several flow cytometry data sets are used to illustrate the performances of CytOpT that are also compared to those of existing algorithms for automatic gating based on supervised learning.

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arXiv2017

Sequential Dirichlet Process Mixtures of Multivariate Skew t-distributions for Model-based Clustering of Flow Cytometry Data

Flow cytometry is a high-throughput technology used to quantify multiple surface and intracellular markers at the level of a single cell. This enables to identify cell sub-types, and to determine their relative proportions. Improvements of this technology allow to describe millions of individual cells from a blood sample using multiple markers. This results in high-dimensional datasets, whose manual analysis is highly time-consuming and poorly reproducible. While several methods have been developed to perform automatic recognition of cell populations, most of them treat and analyze each sample independently. However, in practice, individual samples are rarely independent (e.g. longitudinal studies). Here, we propose to use a Bayesian nonparametric approach with Dirichlet process mixture (DPM) of multivariate skew $t$-distributions to perform model based clustering of flow-cytometry data. DPM models directly estimate the number of cell populations from the data, avoiding model selection issues, and skew $t$-distributions provides robustness to outliers and non-elliptical shape of cell populations. To accommodate repeated measurements, we propose a sequential strategy relying on a parametric approximation of the posterior. We illustrate the good performance of our method on simulated data, on an experimental benchmark dataset, and on new longitudinal data from the DALIA-1 trial which evaluates a therapeutic vaccine against HIV. On the benchmark dataset, the sequential strategy outperforms all other methods evaluated, and similarly, leads to improved performance on the DALIA-1 data. We have made the method available for the community in the R package NPflow.

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