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Abstract Standard protocols for meta-analysis of association studies are inadequate for microbiome data due to their complex compositional structure, leading to inaccurate and unstable microbial signature selection. To address this issue, we introduce Melody, a framework that generates, harmonizes, and combines study-specific summary association statistics to powerfully and robustly identify microbial signatures in meta-analysis. Comprehensive and realistic simulations demonstrate that Melody substantially outperforms existing approaches in prioritizing true signatures. In the meta-analyses of five studies on colorectal cancer and eight studies on the gut metabolome, we showcase the superior stability, reliability, and predictive performance of Melody-identified signatures. 

Abstract ObjectiveThis study aims to develop machine learning models that provide both accurate and equitable predictions of 2-year stroke risk for patients with atrial fibrillation across diverse racial groups. Materials and MethodsOur study utilized structured electronic health records (EHR) data from the All of Us Research Program. Machine learning models (LightGBM) were utilized to capture the relations between stroke risks and the predictors used by the widely recognized CHADS2 and CHA2DS2-VASc scores. We mitigated the racial disparity by creating a representative tuning set, customizing tuning criteria, and setting binary thresholds separately for subgroups. We constructed a hold-out test set that not only supports temporal validation but also includes a larger proportion of Black/African Americans for fairness validation. ResultsCompared to the original CHADS2 and CHA2DS2-VASc scores, significant improvements were achieved by modeling their predictors using machine learning models (Area Under the Receiver Operating Characteristic curve from near 0.70 to above 0.80). Furthermore, applying our disparity mitigation strategies can effectively enhance model fairness compared to the conventional cross-validation approach. DiscussionModeling CHADS2 and CHA2DS2-VASc risk factors with LightGBM and our disparity mitigation strategies achieved decent discriminative performance and excellent fairness performance. In addition, this approach can provide a complete interpretation of each predictor. These highlight its potential utility in clinical practice. ConclusionsOur research presents a practical example of addressing clinical challenges through the All of Us Research Program data. The disparity mitigation framework we proposed is adaptable across various models and data modalities, demonstrating broad potential in clinical informatics. 

Abstract Motivation:Clustering patients into subgroups based on their microbial compositions can greatly enhance our understanding of the role of microbes in human health and disease etiology. Distance-based clustering methods, such as partitioning around medoids (PAM), are popular due to their computational efficiency and absence of distributional assumptions. However, the performance of these methods can be suboptimal when true cluster memberships are driven by differences in the abundance of only a few microbes, a situation known as the sparse signal scenario. Results:We demonstrate that classical multidimensional scaling (MDS), a widely used dimensionality reduction technique, effectively denoises microbiome data and enhances the clustering performance of distance-based methods. We propose a two-step procedure that first applies MDS to project high-dimensional microbiome data into a low-dimensional space, followed by distance-based clustering using the low-dimensional data. Our extensive simulations demonstrate that our procedure offers superior performance compared to directly conducting distance-based clustering under the sparse signal scenario. The advantage of our procedure is further showcased in several real data applications. Availability and implementation:The R package MDSMClust is available at https://github.com/wxy929/MDS-project. 

Abstract Microbiome data from sequencing experiments contain the relative abundance of a large number of microbial taxa with their evolutionary relationships represented by a phylogenetic tree. The compositional and high-dimensional nature of the microbiome mediator challenges the validity of standard mediation analyses. We propose a phylogeny-based mediation analysis method called PhyloMed to address this challenge. Unlike existing methods that directly identify individual mediating taxa, PhyloMed discovers mediation signals by analyzing subcompositions defined on the phylogenic tree. PhyloMed produces well-calibrated mediation test p -values and yields substantially higher discovery power than existing methods. 

Individualized treatment rules (ITRs) for treatment recommendation is an important topic for precision medicine as not all beneficial treatments work well for all individuals. Interpretability is a desirable property of ITRs, as it helps practitioners make sense of treatment decisions, yet there is a need for ITRs to be flexible to effectively model complex biomedical data for treatment decision making. Many ITR approaches either focus on linear ITRs, which may perform poorly when true optimal ITRs are nonlinear, or blackbox nonlinear ITRs, which may be hard to interpret and can be overly complex. This dilemma indicates a tension between interpretability and accuracy of treatment decisions. Here we propose an additive model-based nonlinear ITR learning method that balances interpretability and flexibility of the ITR. Our approach aims to strike this balance by allowing both linear and nonlinear terms of the covariates in the final ITR. Our approach is parsimonious in that the nonlinear term is included in the final ITR only when it substantially improves the ITR performance. To prevent overfitting, we combine crossfitting and a specialized information criterion for model selection. Through extensive simulations we show that our methods are data-adaptive to the degree of nonlinearity and can favorably balance ITR interpretability and flexibility. We further demonstrate the robust performance of our methods with an application to a cancer drug sensitive study.