Electrical communication between cardiomyocytes can be perturbed during arrhythmia, but these perturbations are not captured by conventional electrocardiographic metrics. We developed a theoretical framework to quantify electrical communication using information theory metrics in two-dimensional cell lattice models of cardiac excitation propagation. The time series generated by each cell was coarse-grained to 1 when excited or 0 when resting. The Shannon entropy for each cell was calculated from the time series during four clinically important heart rhythms: normal heartbeat, anatomical reentry, spiral reentry and multiple reentry. We also used mutual information to perform spatial profiling of communication during these cardiac arrhythmias. We found that information sharing between cells was spatially heterogeneous. In addition, cardiac arrhythmia significantly impacted information sharing within the heart. Entropy localized the path of the drifting core of spiral reentry, which could be an optimal target of therapeutic ablation. We conclude that information theory metrics can quantitatively assess electrical communication among cardiomyocytes. The traditional concept of the heart as a functional syncytium sharing electrical information cannot predict altered entropy and information sharing during complex arrhythmia. Information theory metrics may find clinical application in the identification of rhythm-specific treatments which are currently unmet by traditional electrocardiographic techniques.

SUMMARY Identifying dependency in multivariate data is a common inference task that arises in numerous applications. However, existing nonparametric independence tests typically require computation that scales at least quadratically with the sample size, making it difficult to apply them in the presence of massive sample sizes. Moreover, resampling is usually necessary to evaluate the statistical significance of the resulting test statistics at finite sample sizes, further worsening the computational burden. We introduce a scalable, resampling-free approach to testing the independence between two random vectors by breaking down the task into simple univariate tests of independence on a collection of 2 × 2 contingency tables constructed through sequential coarse-to-fine discretization of the sample space, transforming the inference task into a multiple testing problem that can be completed with almost linear complexity with respect to the sample size. To address increasing dimensionality, we introduce a coarse-to-fine sequential adaptive procedure that exploits the spatial features of dependency structures. We derive a finite-sample theory that guarantees the inferential validity of our adaptive procedure at any given sample size. We show that our approach can achieve strong control of the level of the testing procedure at any sample size without resampling or asymptotic approximation and establish its large-sample consistency. We demonstrate through an extensive simulation study its substantial computational advantage in comparison to existing approaches while achieving robust statistical power under various dependency scenarios, and illustrate how its divide-and-conquer nature can be exploited to not just test independence but to learn the nature of the underlying dependency. Finally, we demonstrate the use of our method through analyzing a dataset from a flow cytometry experiment.

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Flow cytometry (FCM) is the standard multi-parameter assay used to measure single cell phenotype and functionality. It is commonly used to quantify the relative frequencies of cell subsets in blood and disaggregated tissues. A typical analysis of FCM data involves cell classification-that is, the identification of cell subgroups in the sample-and comparisons of the cell subgroups across samples or conditions. While modern experiments often necessitate the collection and processing of samples in multiple batches, analysis of FCM data across batches is challenging because the locations in the marker space of cell subsets may vary across samples due to batch effects. Differences across samples may occur because of true biological variation or technical reasons such as antibody lot effects or instrument optics. An important step in comparative analyses of multi-sample FCM data is cross-sample calibration, whose goal is to align cell subsets across multiple samples in the presence of variations in locations, so that variation due to technical reasons is minimized and true biological variation can be meaningfully compared. We introduce a Bayesian nonparametric hierarchical modeling approach for accomplishing both calibration and cell classification simultaneously in a unified probabilistic manner. Three important features of our method make it particularly effective for analyzing multi-sample FCM data: a nonparametric mixture avoids prespecifying the number of cell clusters; the hierarchical skew normal kernels allow flexibility in the shapes of the cell subsets and cross-sample variation in their locations; and finally the "coarsening" strategy makes inference robust to small departures from the model, a feature that becomes crucial with massive numbers of observations such as those encountered in FCM data. We demonstrate the merits of our approach in simulated examples and carry out a case study in the analysis of two FCM data sets.

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