Novel Application of Survival Models for Predicting Microbial Community Transitions with Variable Selection for Environmental DNA.

Survival analysis is a prolific statistical tool in medicine for inferring risk and time to disease-related events. However, it is underutilized in microbiome research to predict microbial community-mediated events, partly due to the sparsity and high-dimensional nature of the data. We advance the application of Cox proportional hazards (Cox PH) survival models to environmental DNA (eDNA) data with feature selection suitable for filtering irrelevant and redundant taxonomic variables. Selection methods are compared in terms of false positives, sensitivity, and survival estimation accuracy in simulation and in a real data setting to forecast harmful cyanobacterial blooms. A novel extension of a method for selecting microbial biomarkers with survival data (SuRFCox) reliably outperforms other methods. We determine that Cox PH models with SuRFCox-selected predictors are more robust to varied signal, noise, and data correlation structure. SuRFCox also yields the most accurate and consistent prediction of blooms according to cross-validated testing by year over eight different bloom seasons. Identification of common biomarkers among validated survival forecasts over changing conditions has clear biological significance. Survival models with such biomarkers inform risk assessment and provide insight into the causes of critical community transitions. IMPORTANCE In this paper, we report on a novel approach of selecting microorganisms for model-based prediction of the time to critical microbially modulated events (e.g., harmful algal blooms, clinical outcomes, community shifts, etc.). Our novel method for identifying biomarkers from large, dynamic communities of microbes has broad utility to environmental and ecological impact risk assessment and public health. Results will also promote theoretical and practical advancements relevant to the biology of specific organisms. To address the unique challenge posed by diverse environmental conditions and sparse microbes, we developed a novel method of selecting predictors for modeling time-to-event data. Competing methods for selecting predictors are rigorously compared to determine which is the most accurate and generalizable. Model forecasts are applied to show suitable predictors can precisely quantify the risk over time of biological events like harmful cyanobacterial blooms.

A highly adaptive microbiome-based association test for survival traits.

BACKGROUND: There has been increasing interest in discovering microbial taxa that are associated with human health or disease, gathering momentum through the advances in next-generation sequencing technologies. Investigators have also increasingly employed prospective study designs to survey survival (i.e., time-to-event) outcomes, but current item-by-item statistical methods have limitations due to the unknown true association pattern. Here, we propose a new adaptive microbiome-based association test for survival outcomes, namely, optimal microbiome-based survival analysis (OMiSA). OMiSA approximates to the most powerful association test in two domains: 1) microbiome-based survival analysis using linear and non-linear bases of OTUs (MiSALN) which weighs rare, mid-abundant, and abundant OTUs, respectively, and 2) microbiome regression-based kernel association test for survival traits (MiRKAT-S) which incorporates different distance metrics (e.g., unique fraction (UniFrac) distance and Bray-Curtis dissimilarity), respectively. RESULTS: We illustrate that OMiSA powerfully discovers microbial taxa whether their underlying associated lineages are rare or abundant and phylogenetically related or not. OMiSA is a semi-parametric method based on a variance-component score test and a re-sampling method; hence, it is free from any distributional assumption on the effect of microbial composition and advantageous to robustly control type I error rates. Our extensive simulations demonstrate the highly robust performance of OMiSA. We also present the use of OMiSA with real data applications. CONCLUSIONS: OMiSA is attractive in practice as the true association pattern is unpredictable in advance and, for survival outcomes, no adaptive microbiome-based association test is currently available.