An official website of the United States government
Abstract In this study, we focus on estimating the heterogeneous treatment effect (HTE) for survival outcome. The outcome is subject to censoring and the number of covariates is high-dimensional. We utilize data from both the randomized controlled trial (RCT), considered as the gold standard, and real-world data (RWD), possibly affected by hidden confounding factors. To achieve a more efficient HTE estimate, such integrative analysis requires great insight into the data generation mechanism, particularly the accurate characterization of unmeasured confounding effects/bias. With this aim, we propose a penalized-regression-based integrative approach that allows for the simultaneous estimation of parameters, selection of variables, and identification of the existence of unmeasured confounding effects. The consistency, asymptotic normality, and efficiency gains are rigorously established for the proposed estimate. Finally, we apply the proposed method to estimate the HTE of lobar/sublobar resection on the survival of lung cancer patients. The RCT is a multicenter non-inferiority randomized phase 3 trial, and the RWD comes from a clinical oncology cancer registry in the United States. The analysis reveals that the unmeasured confounding exists and the integrative approach does enhance the efficiency for the HTE estimation.
more »
« less
Microbiome Data Integration via Shared Dictionary Learning
Abstract Data integration is a powerful tool for facilitating a comprehensive and generalizable understanding of microbial communities and their association with outcomes of interest. However, integrating data sets from different studies remains a challenging problem because of severe batch effects, unobserved confounding variables, and high heterogeneity across data sets. We propose a new data integration method called MetaDICT, which initially estimates the batch effects by weighting methods in causal inference literature and then refines the estimation via a novel shared dictionary learning. Compared with existing methods, MetaDICT can better avoid the overcorrection of batch effects and preserve biological variation when there exist unobserved confounding variables or data sets are highly heterogeneous across studies. Furthermore, MetaDICT can generate comparable embedding at both taxa and sample levels that can be used to unravel the hidden structure of the integrated data and improve the integrative analysis. Applications to synthetic and real microbiome data sets demonstrate the robustness and effectiveness of MetaDICT in integrative analysis. Using MetaDICT, we characterize microbial interaction, identify generalizable microbial signatures, and enhance the accuracy of disease prediction in an integrative analysis of colorectal cancer metagenomics studies.
more »
« less
- Award ID(s):
- 2243257
- PAR ID:
- 10595276
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Institution:
- bioRxiv
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Many real-world decision-making tasks require learning causal relationships between a set of variables. Traditional causal discovery methods, however, require that all variables are observed, which is often not feasible in practical scenarios. Without additional assumptions about the unobserved variables, it is not possible to recover any causal relationships from observational data. Fortunately, in many applied settings, additional structure among the confounders can be expected. In particular, pervasive confounding is commonly encountered and has been utilised for consistent causal estimation in linear causal models. In this article, we present a provably consistent method to estimate causal relationships in the nonlinear, pervasive confounding setting. The core of our procedure relies on the ability to estimate the confounding variation through a simple spectral decomposition of the observed data matrix. We derive a DAG score function based on this insight, prove its consistency in recovering a correct ordering of the DAG, and empirically compare it to previous approaches. We demonstrate improved performance on both simulated and real datasets by explicitly accounting for both confounders and nonlinear effects.more » « less
-
Abstract BackgroundA common task in analyzing metatranscriptomics data is to identify microbial metabolic pathways with differential RNA abundances across multiple sample groups. With information from paired metagenomics data, some differential methods control for either DNA or taxa abundances to address their strong correlation with RNA abundance. However, it remains unknown if both factors need to be controlled for simultaneously. ResultsWe discovered that when either DNA or taxa abundance is controlled for, RNA abundance still has a strong partial correlation with the other factor. In both simulation studies and a real data analysis, we demonstrated that controlling for both DNA and taxa abundances leads to superior performance compared to only controlling for one factor. ConclusionsTo fully address the confounding effects in analyzing metatranscriptomics data, both DNA and taxa abundances need to be controlled for in the differential analysis.more » « less
-
Roy, Sushmita (Ed.)Heterogeneity in different genomic studies compromises the performance of machine learning models in cross-study phenotype predictions. Overcoming heterogeneity when incorporating different studies in terms of phenotype prediction is a challenging and critical step for developing machine learning algorithms with reproducible prediction performance on independent datasets. We investigated the best approaches to integrate different studies of the same type of omics data under a variety of different heterogeneities. We developed a comprehensive workflow to simulate a variety of different types of heterogeneity and evaluate the performances of different integration methods together with batch normalization by using ComBat. We also demonstrated the results through realistic applications on six colorectal cancer (CRC) metagenomic studies and six tuberculosis (TB) gene expression studies, respectively. We showed that heterogeneity in different genomic studies can markedly negatively impact the machine learning classifier’s reproducibility. ComBat normalization improved the prediction performance of machine learning classifier when heterogeneous populations are present, and could successfully remove batch effects within the same population. We also showed that the machine learning classifier’s prediction accuracy can be markedly decreased as the underlying disease model became more different in training and test populations. Comparing different merging and integration methods, we found that merging and integration methods can outperform each other in different scenarios. In the realistic applications, we observed that the prediction accuracy improved when applying ComBat normalization with merging or integration methods in both CRC and TB studies. We illustrated that batch normalization is essential for mitigating both population differences of different studies and batch effects. We also showed that both merging strategy and integration methods can achieve good performances when combined with batch normalization. In addition, we explored the potential of boosting phenotype prediction performance by rank aggregation methods and showed that rank aggregation methods had similar performance as other ensemble learning approaches.more » « less
-
We study the problem of learning personalized decision policies from observational data while accounting for possible unobserved confounding in the data-generating process. Unlike previous approaches that assume unconfoundedness, i.e., no unobserved confounders affected both treatment assignment and outcomes, we calibrate policy learning for realistic violations of this unverifiable assumption with uncertainty sets motivated by sensitivity analysis in causal inference. Our framework for confounding-robust policy improvement optimizes the minimax regret of a candidate policy against a baseline or reference "status quo" policy, over an uncertainty set around nominal propensity weights. We prove that if the uncertainty set is well-specified, robust policy learning can do no worse than the baseline, and only improve if the data supports it. We characterize the adversarial subproblem and use efficient algorithmic solutions to optimize over parametrized spaces of decision policies such as logistic treatment assignment. We assess our methods on synthetic data and a large clinical trial, demonstrating that confounded selection can hinder policy learning and lead to unwarranted harm, while our robust approach guarantees safety and focuses on well-evidenced improvement.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Posted Content:
- https://doi.org/10.1101/2024.10.04.616752
