Global epistasis and the emergence of function in microbial consortia.

The many functions of microbial communities emerge from a complex web of interactions between organisms and their environment. This poses a significant obstacle to engineering microbial consortia, hindering our ability to harness the potential of microorganisms for biotechnological applications. In this study, we demonstrate that the collective effect of ecological interactions between microbes in a community can be captured by simple statistical models that predict how adding a new species to a community will affect its function. These predictive models mirror the patterns of global epistasis reported in genetics, and they can be quantitatively interpreted in terms of pairwise interactions between community members. Our results illuminate an unexplored path to quantitatively predicting the function of microbial consortia from their composition, paving the way to optimizing desirable community properties and bringing the tasks of predicting biological function at the genetic, organismal, and ecological scales under the same quantitative formalism.

The community-function landscape of microbial consortia.

Quantitatively linking the composition and function of microbial communities is a major aspiration of microbial ecology. Microbial community functions emerge from a complex web of molecular interactions between cells, which give rise to population-level interactions among strains and species. Incorporating this complexity into predictive models is highly challenging. Inspired by a similar problem in genetics of predicting quantitative phenotypes from genotypes, an ecological community-function (or structure-function) landscape could be defined that maps community composition and function. In this piece, we present an overview of our current understanding of these community landscapes, their uses, limitations, and open questions. We argue that exploiting the parallels between both landscapes could bring powerful predictive methodologies from evolution and genetics into ecology, providing a boost to our ability to engineer and optimize microbial consortia.

Global epistasis on fitness landscapes.

Epistatic interactions between mutations add substantial complexity to adaptive landscapes and are often thought of as detrimental to our ability to predict evolution. Yet, patterns of global epistasis, in which the fitness effect of a mutation is well-predicted by the fitness of its genetic background, may actually be of help in our efforts to reconstruct fitness landscapes and infer adaptive trajectories. Microscopic interactions between mutations, or inherent nonlinearities in the fitness landscape, may cause global epistasis patterns to emerge. In this brief review, we provide a succinct overview of recent work about global epistasis, with an emphasis on building intuition about why it is often observed. To this end, we reconcile simple geometric reasoning with recent mathematical analyses, using these to explain why different mutations in an empirical landscape may exhibit different global epistasis patterns-ranging from diminishing to increasing returns. Finally, we highlight open questions and research directions. This article is part of the theme issue 'Interdisciplinary approaches to predicting evolutionary biology'.

Statistically learning the functional landscape of microbial communities.

Microbial consortia exhibit complex functional properties in contexts ranging from soils to bioreactors to human hosts. Understanding how community composition determines function is a major goal of microbial ecology. Here we address this challenge using the concept of community-function landscapes-analogues to fitness landscapes-that capture how changes in community composition alter collective function. Using datasets that represent a broad set of community functions, from production/degradation of specific compounds to biomass generation, we show that statistically inferred landscapes quantitatively predict community functions from knowledge of species presence or absence. Crucially, community-function landscapes allow prediction without explicit knowledge of abundance dynamics or interactions between species and can be accurately trained using measurements from a small subset of all possible community compositions. The success of our approach arises from the fact that empirical community-function landscapes appear to be not rugged, meaning that they largely lack high-order epistatic contributions that would be difficult to fit with limited data. Finally, we show that this observation holds across a wide class of ecological models, suggesting community-function landscapes can be efficiently inferred across a broad range of ecological regimes. Our results open the door to the rational design of consortia without detailed knowledge of abundance dynamics or interactions.

Projecting the number of new HIV infections to formulate the "Getting to Zero" strategy in Illinois, USA.

OBJECTIVES: Getting to Zero (GTZ) initiatives focus on expanding use of antiretroviral treatment (ART) and pre-exposure prophylaxis (PrEP) to eliminate new HIV infections. Computational models help inform policies for implementation of ART and PrEP continuums. Such models, however, vary in their design, and may yield inconsistent predictions. Using multiple approaches can help assess the consistency in results obtained from varied modeling frameworks, and can inform optimal implementation strategies. METHODS: A study using three different modeling approaches is conducted. Two approaches use statistical time series analysis techniques that incorporate temporal HIV incidence data. A third approach uses stochastic stimulation, conducted using an agent-based network model (ABNM). All three approaches are used to project HIV incidence among a key population, young Black MSM (YBMSM), over the course of the GTZ implementation period (2016-2030). RESULTS: All three approaches suggest that simultaneously increasing PrEP and ART uptake is likely to be more effective than increasing only one, but increasing ART and PrEP by 20% points may not eliminate new HIV infections among YBMSM. The results further suggest that a 20% increase in ART is likely to be more effective than a 20% increase in PrEP. All three methods consistently project that increasing ART and PrEP by 30% simultaneously can help reach GTZ goals. CONCLUSIONS: Increasing PrEP and ART uptake by about 30% might be necessary to accomplish GTZ goals. Such scale-up may require addressing psychosocial and structural barriers to engagement in HIV and PrEP care continuums. ABNMs and other flexible modeling approaches can be extended to examine specific interventions that address these barriers and may provide important data to guide the successful intervention implementation.

Leveraging system sciences methods in clinical trial evaluation: An example concerning African American women diagnosed with breast cancer via the Patient Navigation in Medically Underserved Areas study.

BACKGROUND: Systems science methodologies offer a promising assessment approach for clinical trials by: 1) providing an in-silico laboratory to conduct investigations where purely empirical research may be infeasible or unethical; and, 2) offering a more precise measurement of intervention benefits across individual, network, and population levels. We propose to assess the potential of systems sciences methodologies by quantifying the spillover effects of randomized controlled trial via empirical social network analysis and agent-based models (ABM). DESIGN/METHODS: We will evaluate the effects of the Patient Navigation in Medically Underserved Areas (PNMUA) study on adult African American participants diagnosed with breast cancer and their networks through social network analysis and agent-based modeling. First, we will survey 100 original trial participants (50 navigated, 50 non-navigated) and 150 of members of their social networks (75 from navigated, 75 non-navigated) to assess if navigation results in: 1) greater dissemination of breast health information and breast healthcare utilization throughout the trial participants' networks; and, 2) lower incremental costs, when incorporating navigation effects on trial participants and network members. Second, we will compare cost-effectiveness models, using a provider perspective, incorporating effects on trial participants versus trial participants and network members. Third, we will develop an ABM platform, parameterized using published data sources and PNMUA data, to examine if navigation increases the proportion of early stage breast cancer diagnoses. DISCUSSION: Our study results will provide promising venues for leveraging systems science methodologies in clinical trial evaluation.

A modeling framework to inform preexposure prophylaxis initiation and retention scale-up in the context of 'Getting to Zero' initiatives.

OBJECTIVE(S): 'Getting to Zero' (GTZ) initiatives aim to eliminate new HIV infections over a projected time frame. Increased preexposure prophylaxis (PrEP) uptake among populations with the highest HIV incidence, such as young Black MSM, is necessary to accomplish this aim. Agent-based network models (ABNMs) can help guide policymakers on strategies to increase PrEP uptake. DESIGN: Effective PrEP implementation requires a model that incorporates the dynamics of interventions and dynamic feedbacks across multiple levels including virus, host, behavior, networks, and population. ABNMs are a powerful tool to incorporate these processes. METHODS: An ABNM, designed for and parameterized using data for young Black MSM in Illinois, was used to compare the impact of PrEP initiation and retention interventions on HIV incidence after 10 years, consistent with GTZ timelines. Initiation interventions selected individuals in serodiscordant partnerships, or in critical sexual network positions, and compared with a controlled setting where PrEP initiators were randomly selected. Retention interventions increased the mean duration of PrEP use. A combination intervention modeled concurrent increases in PrEP initiation and retention. RESULTS: Selecting HIV-negative individuals for PrEP initiation in serodiscordant partnerships resulted in the largest HIV incidence declines, relative to other interventions. For a given PrEP uptake level, distributing effort between increasing PrEP initiation and retention in combination was approximately as effective as increasing only one exclusively. CONCLUSION: Simulation results indicate that expanded PrEP interventions alone may not accomplish GTZ goals within a decade, and integrated scale-up of PrEP, antiretroviral therapy, and other interventions might be necessary.