arXiv subjects

Kim-Anh Do

Publications and source records attributed to Kim-Anh Do.

13 recordsLinked to original sources

arXiv2026

Multi-Objective Composite Longitudinal Biomarker Scores for Improved Cancer Risk Assessment

Repeated blood-based biomarker measurements can improve cancer risk assessment by capturing longitudinal changes missed by single-time-point analyses. Parametric Empirical Bayes (PEB) incorporates prior measurements to estimate individualized reference values, but existing implementations do not account for the time between measurements and rely on predefined panels with fixed combination rules. We developed improved Parametric Empirical Bayes (iPEB), which accounts for the intervals between serial measurements, adjusts for covariates, and performs feature selection and optimized biomarker combination. iPEB optimizes biomarker weights for specific clinical objectives, such as maximizing sensitivity at a prespecified specificity or diagnostic lead time. We evaluated iPEB through simulations and a real-world application using six protein biomarkers (pro-SFTPB, CEA, CA125, CYFRA 21-1, osteopontin, and HE4) from a case-control study nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The analysis included 324 lung cancer cases and 1,674 controls with at least two serial measurements; six centers were used for model development and four for independent validation. Optimized for sensitivity at 99% specificity, iPEB achieved 24.2% sensitivity in the independent test set, compared with 18.2% for conventional PEB applied to the same four-marker panel. Optimized instead for lead time, iPEB added approximately 50 days of lead time at that stringent operating point. iPEB improved lung cancer risk assessment in independent PLCO data, supporting objective-driven optimization of longitudinal biomarkers for early detection.

stat.ME↗

arXiv2025

Bias in Meta-Analytic Modeling of Surrogate Endpoints in Cancer Screening Trials

In meta-analytic modeling, the functional relationship between a primary and surrogate endpoint is estimated using summary data from a set of completed clinical trials. Parameters in the meta-analytic model are used to assess the quality of the proposed surrogate. Recently, meta-analytic models have been employed to evaluate whether late-stage cancer incidence can serve as a surrogate for cancer mortality in cancer screening trials. A major challenge in meta-analytic models is that uncertainty of trial-level estimates affects the evaluation of surrogacy, since each trial provides only estimates of the primary and surrogate endpoints rather than their true parameter values. In this work, we show via simulation and theory that trial-level estimate uncertainty may bias the results of meta-analytic models towards positive findings of the quality of the surrogate. We focus on cancer screening trials and the late stage incidence surrogate. We reassess correlations between primary and surrogate endpoints in Ovarian cancer screening trials. Our findings indicate that completed trials provide limited information regarding quality of the late-stage incidence surrogate. These results support restricting meta-analytic regression usage to settings where trial-level estimate uncertainty is incorporated into the model.

stat.ME↗

arXiv2025

Robust Learning on Noisy Graphs via Latent Space Constraints with External Knowledge

Graph Neural Networks (GNNs) often struggle with noisy edges. We propose Latent Space Constrained Graph Neural Networks (LSC-GNN) to incorporate external "clean" links and guide embeddings of a noisy target graph. We train two encoders--one on the full graph (target plus external edges) and another on a regularization graph excluding the target's potentially noisy links--then penalize discrepancies between their latent representations. This constraint steers the model away from overfitting spurious edges. Experiments on benchmark datasets show LSC-GNN outperforms standard and noise-resilient GNNs in graphs subjected to moderate noise. We extend LSC-GNN to heterogeneous graphs and validate it on a small protein-metabolite network, where metabolite-protein interactions reduce noise in protein co-occurrence data. Our results highlight LSC-GNN's potential to boost predictive performance and interpretability in settings with noisy relational structures.

cs.LG↗

arXiv2024

Flexible aggregation of compositional predictors with shared effects for microbiome association analysis

Ongoing advancements in microbiome profiling have provided unprecedented insights into the molecular dynamics of microbial communities, sparking a surge of interest in uncovering the microbiome's critical role in human health. Identifying microbial features linked to clinical outcomes, however, remains challenging due to the high-dimensional, sparse, and compositional nature of microbiome data. Additionally, many microbial taxa, although classified as distinct, may share functional roles, complicating traditional variable selection methods. To overcome these obstacles, we introduce Bayesian Regression with Agglomerated Compositional Effects (BRACE), a novel approach using a spike-and-cluster prior combining Bernoulli activity indicators, an Ewens exchangeable partition prior on the finite active set, and a projection-based constrained Gaussian prior on cluster effects to perform data-adaptive clustering and variable selection. The methodological innovation of our work lies in how we combine the Ewens partition prior with a projection-based constrained Gaussian on the cluster atoms to enforce the sum-to-zero constraint. BRACE groups microbial taxa with similar effects on the outcome, yielding more interpretable models while enabling effective dimension reduction. Through comprehensive simulations and a real-world application examining the influence of oral microbiome composition on insulin resistance, we demonstrate BRACE's superior performance over existing methods, particularly in identifying key features with shared effects on outcomes.

stat.ME↗

arXiv2024

survivalContour: Visualizing predicted survival via colored contour plots

Advances in survival analysis have facilitated unprecedented flexibility in data modeling, yet there remains a lack of tools for graphically illustrating the influence of continuous covariates on predicted survival outcomes. We propose the utilization of a colored contour plot to depict the predicted survival probabilities over time, and provide a Shiny app and R package as implementations of this tool. Our approach is capable of supporting conventional models, including the Cox and Fine-Gray models. However, its capability shines when coupled with cutting-edge machine learning models such as random survival forests and deep neural networks.

stat.AP↗

arXiv2023

Estimating Causal Effects with Hidden Confounding using Instrumental Variables and Environments

Recent works have proposed regression models which are invariant across data collection environments. These estimators often have a causal interpretation under conditions on the environments and type of invariance imposed. One recent example, the Causal Dantzig (CD), is consistent under hidden confounding and represents an alternative to classical instrumental variable estimators such as Two Stage Least Squares (TSLS). In this work we derive the CD as a generalized method of moments (GMM) estimator. The GMM representation leads to several practical results, including 1) creation of the Generalized Causal Dantzig (GCD) estimator which can be applied to problems with continuous environments where the CD cannot be fit 2) a Hybrid (GCD-TSLS combination) estimator which has properties superior to GCD or TSLS alone 3) straightforward asymptotic results for all methods using GMM theory. We compare the CD, GCD, TSLS, and Hybrid estimators in simulations and an application to a Flow Cytometry data set. The newly proposed GCD and Hybrid estimators have superior performance to existing methods in many settings.

stat.ME↗

arXiv2023

CAT: a conditional association test for microbiome data using a leave-out approach

In microbiome analysis, researchers often seek to identify taxonomic features associated with an outcome of interest. However, microbiome features are intercorrelated and linked by phylogenetic relationships, making it challenging to assess the association between an individual feature and an outcome. Researchers have developed global tests for the association of microbiome profiles with outcomes using beta diversity metrics which offer robustness to extreme values and can incorporate information on the phylogenetic tree structure. Despite the popularity of global association testing, most existing methods for follow-up testing of individual features only consider the marginal effect and do not provide relevant information for the design of microbiome interventions. This paper proposes a novel conditional association test, CAT, which can account for other features and phylogenetic relatedness when testing the association between a feature and an outcome. CAT adopts a leave-out method, measuring the importance of a feature in predicting the outcome by removing that feature from the data and quantifying how much the association with the outcome is weakened through the change in the coefficient of determination. By leveraging global tests including PERMANOVA and MiRKAT-based methods, CAT allows association testing for continuous, binary, categorical, count, survival, and correlated outcomes. Our simulation and real data application results illustrate the potential of CAT to inform the design of microbiome interventions aimed at improving clinical outcomes.

stat.ME↗

arXiv2022

Sparse tree-based clustering of microbiome data to characterize microbiome heterogeneity in pancreatic cancer

There is a keen interest in characterizing variation in the microbiome across cancer patients, given increasing evidence of its important role in determining treatment outcomes. Here our goal is to discover subgroups of patients with similar microbiome profiles. We propose a novel unsupervised clustering approach in the Bayesian framework that innovates over existing model-based clustering approaches, such as the Dirichlet multinomial mixture model, in three key respects: we incorporate feature selection, learn the appropriate number of clusters from the data, and integrate information on the tree structure relating the observed features. We compare the performance of our proposed method to existing methods on simulated data designed to mimic real microbiome data. We then illustrate results obtained for our motivating data set, a clinical study aimed at characterizing the tumor microbiome of pancreatic cancer patients.

stat.AP↗

arXiv2022

Causal Models, Prediction, and Extrapolation in Cell Line Perturbation Experiments

In cell line perturbation experiments, a collection of cells is perturbed with external agents (e.g. drugs) and responses such as protein expression measured. Due to cost constraints, only a small fraction of all possible perturbations can be tested in vitro. This has led to the development of computational (in silico) models which can predict cellular responses to perturbations. Perturbations with clinically interesting predicted responses can be prioritized for in vitro testing. In this work, we compare causal and non-causal regression models for perturbation response prediction in a Melanoma cancer cell line. The current best performing method on this data set is Cellbox which models how proteins causally effect each other using a system of ordinary differential equations (ODEs). We derive a closed form solution to the Cellbox system of ODEs in the linear case. These analytic results facilitate comparison of Cellbox to regression approaches. We show that causal models such as Cellbox, while requiring more assumptions, enable extrapolation in ways that non-causal regression models cannot. For example, causal models can predict responses for never before tested drugs. We illustrate these strengths and weaknesses in simulations. In an application to the Melanoma cell line data, we find that regression models outperform the Cellbox causal model.

stat.AP↗

arXiv2020

A Framework for Mediation Analysis with Multiple Exposures, Multivariate Mediators, and Non-Linear Response Models

Mediation analysis seeks to identify and quantify the paths by which an exposure affects an outcome. Intermediate variables which are effected by the exposure and which effect the outcome are known as mediators. There exists extensive work on mediation analysis in the context of models with a single mediator and continuous and binary outcomes. However these methods are often not suitable for multi-omic data that include highly interconnected variables measuring biological mechanisms and various types of outcome variables such as censored survival responses. In this article, we develop a general framework for causal mediation analysis with multiple exposures, multivariate mediators, and continuous, binary, and survival responses. We estimate mediation effects on several scales including the mean difference, odds ratio, and restricted mean scale as appropriate for various outcome models. Our estimation method avoids imposing constraints on model parameters such as the rare disease assumption while accommodating continuous exposures. We evaluate the framework and compare it to other methods in extensive simulation studies by assessing bias, type I error and power at a range of sample sizes, disease prevalences, and number of false mediators. Using Kidney Renal Clear Cell Carcinoma data from The Cancer Genome Atlas, we identify proteins which mediate the effect of metabolic gene expression on survival. Software for implementing this unified framework is made available in an R package (https://github.com/longjp/mediateR).

stat.ME↗

arXiv2020

ProgPermute: Progressive permutation for a dynamic representation of the robustness of microbiome discoveries

Identification of features is a critical task in microbiome studies that is complicated by the fact that microbial data are high dimensional and heterogeneous. Masked by the complexity of the data, the problem of separating signals from noise becomes challenging and troublesome. For instance, when performing differential abundance tests, multiple testing adjustments tend to be overconservative, as the probability of a type I error (false positive) increases dramatically with the large numbers of hypotheses. Moreover, the grouping effect of interest can be obscured by heterogeneity. These factors can incorrectly lead to the conclusion that there are no differences in the microbiome compositions. We translate and represent the problem of identifying differential features as a dynamic layout of separating the signal from its random background. We propose progressive permutation as a method to achieve this process and show converging patterns. More specifically, we progressively permute the grouping factor labels of the microbiome samples and perform multiple differential abundance tests in each scenario. We then compare the signal strength of the top features from the original data with their performance in permutations, and observe an apparent decreasing trend if these top features are true positives identified from the data. We have developed this into a user-friendly RShiny tool and R package, which consist of functions that can convey the overall association between the microbiome and the grouping factor, rank the robustness of the discovered microbes, and list the discoveries, their effect sizes, and individual abundances.

stat.ME↗

arXiv2020

aPCoA: Covariate Adjusted Principal Coordinates Analysis

In fields such as ecology, microbiology, and genomics, non-Euclidean distances are widely applied to describe pairwise dissimilarity between samples. Given these pairwise distances, principal coordinates analysis (PCoA) is commonly used to construct a visualization of the data. However, confounding covariates can make patterns related to the scientific question of interest difficult to observe. We provide aPCoA as an easy-to-use tool, available as both an R package and a Shiny app, to improve data visualization in this context, enabling enhanced presentation of the effects of interest.

q-bio.QM↗

arXiv2018

NExUS: Bayesian simultaneous network estimation across unequal sample sizes

Network-based analyses of high-throughput genomics data provide a holistic, systems-level understanding of various biological mechanisms for a common population. However, when estimating multiple networks across heterogeneous sub-populations, varying sample sizes pose a challenge in the estimation and inference, as network differences may be driven by differences in power. We are particularly interested in addressing this challenge in the context of proteomic networks for related cancers, as the number of subjects available for rare cancer (sub-)types is often limited. We develop NExUS (Network Estimation across Unequal Sample sizes), a Bayesian method that enables joint learning of multiple networks while avoiding artefactual relationship between sample size and network sparsity. We demonstrate through simulations that NExUS outperforms existing network estimation methods in this context, and apply it to learn network similarity and shared pathway activity for groups of cancers with related origins represented in The Cancer Genome Atlas (TCGA) proteomic data.

stat.AP↗