Longitudinal analysis of multivariate individual-specific microbiome profiles over time or across conditions remains dauntin. Most statistical tools and methods that are available to study microbiomes are based on cross-sectional data. Over the past few years, several attempts have been made to model the dynamics of bacterial species over time or across conditions. However, the field needs novel views on handling microbial interactions in temporal analyses. This study proposes a novel data analysis framework, MNDA, that combines representation learning and individual-specific microbial co-occurrence networks to uncover taxon neighborhood dynamics. As a use case, we consider a cohort of newborns with microbiomes available at 6 and 9 months after birth, and extraneous data available on the mode of delivery and diet changes between the considered time points. Our results show that prediction models for these extraneous outcomes based on an MNDA measure of local neighborhood dynamics for each taxon outperform traditional prediction models solely based on individual-specific microbial abundances. Furthermore, our results show that unsupervised similarity analysis of newborns in the study, again using the notion of a taxon's dynamic neighborhood derived from time-matched individual-specific microbial networks, can reveal different subpopulations of individuals, compared to standard microbiome-based clustering, with potential relevance to clinical practice. This study highlights the complementarity of microbial interactions and abundances in downstream analyses and opens new avenues to personalized prediction or stratified medicine with temporal microbiome data.
Background Recent advances in biotechnology enable the acquisition of high-dimensional data on individuals, posing challenges for prediction models which traditionally use covariates such as clinical patient characteristics. Alternative forms of covariate representations for the features derived from these modern data modalities should be considered that can utilize their intrinsic interconnection. The connectivity information between these features can be represented as an individual-specific network defined by a set of nodes and edges, the strength of which can vary from individual to individual. Global or local graph-theoretical features describing the network may constitute potential prognostic biomarkers instead of or in addition to traditional covariates and may replace the often unsuccessful search for individual biomarkers in a high-dimensional predictor space. Methods We conducted a scoping review to identify, collate and critically appraise the state-of-art in the use of individual-specific networks for prediction modelling in medicine and applied health research, published during 2000–2020 in the electronic databases PubMed, Scopus and Embase. Results Our scoping review revealed the main application areas namely neurology and pathopsychology, followed by cancer research, cardiology and pathology (N = 148). Network construction was mainly based on Pearson correlation coefficients of repeated measurements, but also alternative approaches (e.g. partial correlation, visibility graphs) were found. For covariates measured only once per individual, network construction was mostly based on quantifying an individual’s contribution to the overall group-level structure. Despite the multitude of identified methodological approaches for individual-specific network inference, the number of studies that were intended to enable the prediction of clinical outcomes for future individuals was quite limited, and most of the models served as proof of concept that network characteristics can in principle be useful for prediction. Conclusion The current body of research clearly demonstrates the value of individual-specific network analysis for prediction modelling, but it has not yet been considered as a general tool outside the current areas of application. More methodological research is still needed on well-founded strategies for network inference, especially on adequate network sparsification and outcome-guided graph-theoretical feature extraction and selection, and on how networks can be exploited efficiently for prediction modelling.
Background: Longitudinal analysis of multivariate individual-specific microbiome profiles over time or across conditions remains a daunting task. The vast majority of statistical tools and methods available to study the microbiota are based upon cross-sectional data. Over the past few years, several attempts have been made to model the dynamics of bacterial species over time or across conditions. However, the field needs novel views on how to incorporate individual-specific microbial associations in temporal analyses when the focus lies on microbial interactions. Results: Here, we propose a novel data analysis framework, called MNDA, to uncover taxon neighbourhood dynamics that combines representation learning and individual-specific microbiome co-occurrence networks. We show that tracking local neighbourhood dynamics in microbiome interaction or co-occurrence networks can yield complementary information to standard approaches that only use microbial abundances or pairwise microbial interactions. We use cohort data on infants for whom microbiome data was available at 6 and 9 months after birth, as well as information on mode of delivery and diet changes over time. In particular, MNDA-based prediction models outperform traditional prediction models based on individual-specific abundances, and enable the detection of microbes whose neighbourhood dynamics are informative of clinical variables. We further show that similarity analyses of individuals based on microbial neighbourhood dynamics can be used to find subpopulations of individuals with potential relevance to clinical practice. The annotated source code for the MNDA framework can be downloaded from: https://github.com/H2020TranSYS/microbiome\_dynamics Conclusions: MNDA extracts information from matched microbiome profiles and opens new avenues to personalized prediction or stratified medicine with temporal microbiome data.
Individual-specific networks, defined as networks of nodes and connecting edges that are specific to an individual, are promising tools for precision medicine. When such networks are biological, interpretation of functional modules at an individual level becomes possible. An under-investigated problem is relevance or ”significance” assessment of each individual-specific network. This paper proposes novel edge and module significance assessment procedures for weighted and unweighted individual-specific networks. Specifically, we propose a modular Cook’s distance using a method that involves iterative modeling of one edge versus all the others within a module. Two procedures assessing changes between using all individuals and using all individuals but leaving one individual out (LOO) are proposed as well (LOO-ISN, MultiLOO-ISN), relying on empirically derived edges. We compare our proposals to competitors, including adaptions of OPTICS, kNN, and Spoutlier methods, by an extensive simulation study, templated on real-life scenarios for gene co-expression and microbial interaction networks. Results show the advantages of performing modular versus edge-wise significance assessments for individual-specific networks. Furthermore, modular Cook’s distance is among the top performers across all considered simulation settings. Finally, the identification of outlying individuals regarding their individual-specific networks, is meaningful for precision medicine purposes, as confirmed by network analysis of microbiome abundance profiles.
Multi-view data offer advantages over single-view data for characterizing individuals, which is crucial in precision medicine toward personalized prevention, diagnosis, or treatment follow-up. Here, we develop a network-guided multi-view clustering framework named netMUG to identify actionable subgroups of individuals. This pipeline first adopts sparse multiple canonical correlation analysis to select multi-view features possibly informed by extraneous data, which are then used to construct individual-specific networks (ISNs). Finally, the individual subtypes are automatically derived by hierarchical clustering on these network representations. We applied netMUG to a dataset containing genomic data and facial images to obtain BMI-informed multi-view strata and showed how it could be used for a refined obesity characterization. Benchmark analysis of netMUG on synthetic data with known strata of individuals indicated its superior performance compared with both baseline and benchmark methods for multi-view clustering. In addition, the real-data analysis revealed subgroups strongly linked to BMI and genetic and facial determinants of these classes. NetMUG provides a powerful strategy, exploiting individual-specific networks to identify meaningful and actionable strata. Moreover, the implementation is easy to generalize to accommodate heterogeneous data sources or highlight data structures.
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