Forum on immune digital twins: a meeting report.

Medical digital twins are computational models of human biology relevant to a given medical condition, which are tailored to an individual patient, thereby predicting the course of disease and individualized treatments, an important goal of personalized medicine. The immune system, which has a central role in many diseases, is highly heterogeneous between individuals, and thus poses a major challenge for this technology. In February 2023, an international group of experts convened for two days to discuss these challenges related to immune digital twins. The group consisted of clinicians, immunologists, biologists, and mathematical modelers, representative of the interdisciplinary nature of medical digital twin development. A video recording of the entire event is available. This paper presents a synopsis of the discussions, brief descriptions of ongoing digital twin projects at different stages of progress. It also proposes a 5-year action plan for further developing this technology. The main recommendations are to identify and pursue a small number of promising use cases, to develop stimulation-specific assays of immune function in a clinical setting, and to develop a database of existing computational immune models, as well as advanced modeling technology and infrastructure.

Toward mechanistic medical digital twins: some use cases in immunology.

A fundamental challenge for personalized medicine is to capture enough of the complexity of an individual patient to determine an optimal way to keep them healthy or restore their health. This will require personalized computational models of sufficient resolution and with enough mechanistic information to provide actionable information to the clinician. Such personalized models are increasingly referred to as medical digital twins. Digital twin technology for health applications is still in its infancy, and extensive research and development is required. This article focuses on several projects in different stages of development that can lead to specific-and practical-medical digital twins or digital twin modeling platforms. It emerged from a two-day forum on problems related to medical digital twins, particularly those involving an immune system component. Open access video recordings of the forum discussions are available.

A dimensionless number for understanding the evolutionary dynamics of antigenically variable RNA viruses.

Antigenically variable RNA viruses are significant contributors to the burden of infectious disease worldwide. One reason for their ubiquity is their ability to escape herd immunity through rapid antigenic evolution and thereby to reinfect previously infected hosts. However, the ways in which these viruses evolve antigenically are highly diverse. Some have only limited diversity in the long-run, with every emergence of a new antigenic variant coupled with a replacement of the older variant. Other viruses rapidly accumulate antigenic diversity over time. Others still exhibit dynamics that can be considered evolutionary intermediates between these two extremes. Here, we present a theoretical framework that aims to understand these differences in evolutionary patterns by considering a virus's epidemiological dynamics in a given host population. Our framework, based on a dimensionless number, probabilistically anticipates patterns of viral antigenic diversification and thereby quantifies a virus's evolutionary potential. It is therefore similar in spirit to the basic reproduction number, the well-known dimensionless number which quantifies a pathogen's reproductive potential. We further outline how our theoretical framework can be applied to empirical viral systems, using influenza A/H3N2 as a case study. We end with predictions of our framework and work that remains to be done to further integrate viral evolutionary dynamics with disease ecology.

Experiments and Agent Based Models of Zooplankton Movement within Complex Flow Environments.

The movement of plankton is often dictated by local flow patterns, particularly during storms and in environments with strong flows. Reefs, macrophyte beds, and other immersed structures can provide shelter against washout and drastically alter the distributions of plankton as these structures redirect and slow the flows through them. Advection-diffusion and agent-based models are often used to describe the movement of plankton within marine and fresh water environments and across multiple scales. Experimental validation of such models of plankton movement within complex flow environments is challenging because of the difference in both time and spatial scales. Organisms on the scale of 1 mm or less swim by beating their appendages on the order of 1 Hz and are advected meters to kilometers over days, weeks, and months. One approach to study this challenging multiscale problem is to insert actively moving agents within a background flow field. Open source tools to implement this sort of approach are, however, limited. In this paper, we combine experiments and computational fluid dynamics with a newly developed agent-based modeling platform to quantify plankton movement at the scale of tens of centimeters. We use Artemia spp., or brine shrimp, as a model organism given their availability and ease of culturing. The distribution of brine shrimp over time was recorded in a flow tank with simplified physical models of macrophytes. These simplified macrophyte models were 3D-printed arrays of cylinders of varying heights and densities. Artemia nauplii were injected within these arrays, and their distributions over time were recorded with video. The detailed three-dimensional flow fields were quantified using computational fluid dynamics and validated experimentally with particle image velocimetry. To better quantify plankton distributions, we developed an agent-based modeling framework, Planktos, to simulate the movement of plankton immersed within such flow fields. The spatially and temporally varying Artemia distributions were compared across models of varying heights and densities for both the experiments and the agent-based models. The results show that increasing the density of the macrophyte bed drastically increases the average time it takes the plankton to be swept downstream. The height of the macrophyte bed had less of an effect. These effects were easily observed in both experimental studies and in the agent-based simulations.

BIAS IN LINEAR MODEL POWER AND SAMPLE SIZE DUE TO ESTIMATING VARIANCE.

Planning a study using the General Linear Univariate Model often involves sample size calculation based on a variance estimated in an earlier study. Noncentrality, power, and sample size inherit the randomness. Additional complexity arises if the estimate has been censored. Left censoring occurs when only significant tests lead to a power calculation, while right censoring occurs when only non-significant tests lead to a power calculation. We provide simple expressions for straightforward computation of the distribution function, moments, and quantiles of the censored variance estimate, estimated noncentrality, power, and sample size. We also provide convenient approximations and evaluate their accuracy. The results allow demonstrating that ignoring right censoring falsely widens confidence intervals for noncentrality and power, while ignoring left censoring falsely narrows the confidence intervals. The new results allow assessing and avoiding the potentially substantial bias that censoring may create.