Iain B. Styles

Samuel Tonks, Cuong Nguyen, Steve Hood et al.

The large volume and variety of imaging data from high-throughput screening (HTS) in the pharmaceutical industry present an excellent resource for training virtual staining models. However, the potential of models trained under one set of experimental conditions to generalize to other conditions remains underexplored. This study systematically investigates whether data from three cell types (lung, ovarian, and breast) and two phenotypes (toxic and non-toxic conditions) commonly found in HTS can effectively train virtual staining models to generalize across three typical HTS distribution shifts: unseen phenotypes, unseen cell types, and the combination of both. Utilizing a dataset of 772,416 paired bright-field, cytoplasm, nuclei, and DNA-damage stain images, we evaluate the generalization capabilities of models across pixel-based, instance-wise, and biological-feature-based levels. Our findings indicate that training virtual nuclei and cytoplasm models on non-toxic condition samples not only generalizes to toxic condition samples but leads to improved performance across all evaluation levels compared to training on toxic condition samples. Generalization to unseen cell types shows variability depending on the cell type; models trained on ovarian or lung cell samples often perform well under other conditions, while those trained on breast cell samples consistently show poor generalization. Generalization to unseen cell types and phenotypes shows good generalization across all levels of evaluation compared to addressing unseen cell types alone. This study represents the first large-scale, data-centric analysis of the generalization capability of virtual staining models trained on diverse HTS datasets, providing valuable strategies for experimental training data generation.

Samuel Tonks, Steve Hood, Ryan Musso et al.

Generative virtual staining (VS) models for high-throughput screening (HTS) can provide an estimated posterior distribution of possible biological feature values for each input and cell. However, when evaluating a VS model, the true posterior is unavailable. Existing evaluation protocols only check the accuracy of the marginal distribution over the dataset rather than the predicted posteriors. We introduce information gain (IG) as a cell-wise evaluation framework that enables direct assessment of predicted posteriors. IG is a strictly proper scoring rule and comes with a sound theoretical motivation allowing for interpretability, and for comparing results across models and features. We evaluate diffusion- and GAN-based models on an extensive HTS dataset using IG and other metrics and show that IG can reveal substantial performance differences other metrics cannot.

Antony R. Lee, Peter Tino, Iain Bruce Styles

Motivated by information geometry, a distance function on the space of stochastic matrices is advocated. Starting with sequences of Markov chains the Bhattacharyya angle is advocated as the natural tool for comparing both short and long term Markov chain runs. Bounds on the convergence of the distance and mixing times are derived. Guided by the desire to compare different Markov chain models, especially in the setting of healthcare processes, a new distance function on the space of stochastic matrices is presented. It is a true distance measure which has a closed form and is efficient to implement for numerical evaluation. In the case of ergodic Markov chains, it is shown that considering either the Bhattacharyya angle on Markov sequences or the new stochastic matrix distance leads to the same distance between models.

Xi Jia, Alexander Thorley, Wei Chen et al.

Data-driven deep learning approaches to image registration can be less accurate than conventional iterative approaches, especially when training data is limited. To address this whilst retaining the fast inference speed of deep learning, we propose VR-Net, a novel cascaded variational network for unsupervised deformable image registration. Using the variable splitting optimization scheme, we first convert the image registration problem, established in a generic variational framework, into two sub-problems, one with a point-wise, closed-form solution while the other one is a denoising problem. We then propose two neural layers (i.e. warping layer and intensity consistency layer) to model the analytical solution and a residual U-Net to formulate the denoising problem (i.e. generalized denoising layer). Finally, we cascade the warping layer, intensity consistency layer, and generalized denoising layer to form the VR-Net. Extensive experiments on three (two 2D and one 3D) cardiac magnetic resonance imaging datasets show that VR-Net outperforms state-of-the-art deep learning methods on registration accuracy, while maintains the fast inference speed of deep learning and the data-efficiency of variational model.

Wenqi Lu, Jinming Duan, Joshua Deepak Veesa et al.

The forward model in diffuse optical tomography (DOT) describes how light propagates through a turbid medium. It is often approximated by a diffusion equation (DE) that is numerically discretized by the classical finite element method (FEM). We propose a nonlocal diffusion equation (NDE) as a new forward model for DOT, the discretization of which is carried out with an efficient graph-based numerical method (GNM). To quantitatively evaluate the new forward model, we first conduct experiments on a homogeneous slab, where the numerical accuracy of both NDE and DE is compared against the existing analytical solution. We further evaluate NDE by comparing its image reconstruction performance (inverse problem) to that of DE. Our experiments show that NDE is quantitatively comparable to DE and is up to 64% faster due to the efficient graph-based representation that can be implemented identically for geometries in different dimensions.

Wenqi Lu, Jinming Duan, David Orive-Miguel et al.

Total variation (TV) is a powerful regularization method that has been widely applied in different imaging applications, but is difficult to apply to diffuse optical tomography (DOT) image reconstruction (inverse problem) due to complex and unstructured geometries, non-linearity of the data fitting and regularization terms, and non-differentiability of the regularization term. We develop several approaches to overcome these difficulties by: i) defining discrete differential operators for unstructured geometries using both finite element and graph representations; ii) developing an optimization algorithm based on the alternating direction method of multipliers (ADMM) for the non-differentiable and non-linear minimization problem; iii) investigating isotropic and anisotropic variants of TV regularization, and comparing their finite element- and graph-based implementations. These approaches are evaluated on experiments on simulated data and real data acquired from a tissue phantom. Our results show that both FEM and graph-based TV regularization is able to accurately reconstruct both sparse and non-sparse distributions without the over-smoothing effect of Tikhonov regularization and the over-sparsifying effect of L$_1$ regularization. The graph representation was found to out-perform the FEM method for low-resolution meshes, and the FEM method was found to be more accurate for high-resolution meshes.