David A. Knowles

Andrew Stirn, Hans-Hermann Wessels, Megan Schertzer et al.

Heteroscedastic regression models a Gaussian variable's mean and variance as a function of covariates. Parametric methods that employ neural networks for these parameter maps can capture complex relationships in the data. Yet, optimizing network parameters via log likelihood gradients can yield suboptimal mean and uncalibrated variance estimates. Current solutions side-step this optimization problem with surrogate objectives or Bayesian treatments. Instead, we make two simple modifications to optimization. Notably, their combination produces a heteroscedastic model with mean estimates that are provably as accurate as those from its homoscedastic counterpart (i.e.~fitting the mean under squared error loss). For a wide variety of network and task complexities, we find that mean estimates from existing heteroscedastic solutions can be significantly less accurate than those from an equivalently expressive mean-only model. Our approach provably retains the accuracy of an equally flexible mean-only model while also offering best-in-class variance calibration. Lastly, we show how to leverage our method to recover the underlying heteroscedastic noise variance.

Peter Halmos, Jonathan Pillow, David A. Knowles

The problem of system identification for the Kalman filter, relying on the expectation-maximization (EM) procedure to learn the underlying parameters of a dynamical system, has largely been studied assuming that observations are sampled at equally-spaced time points. However, in many applications this is a restrictive and unrealistic assumption. This paper addresses system identification for the continuous-discrete filter, with the aim of generalizing learning for the Kalman filter by relying on a solution to a continuous-time Itô stochastic differential equation (SDE) for the latent state and covariance dynamics. We introduce a novel two-filter, analytical form for the posterior with a Bayesian derivation, which yields analytical updates which do not require the forward-pass to be pre-computed. Using this analytical and efficient computation of the posterior, we provide an EM procedure which estimates the parameters of the SDE, naturally incorporating irregularly sampled measurements. Generalizing the learning of latent linear dynamical systems (LDS) to continuous-time may extend the use of the hybrid Kalman filter to data which is not regularly sampled or has intermittent missing values, and can extend the power of non-linear system identification methods such as switching LDS (SLDS), which rely on EM for the linear discrete-time Kalman filter as a sub-unit for learning locally linearized behavior of a non-linear system. We apply the method by learning the parameters of a latent, multivariate Fokker-Planck SDE representing a toggle-switch genetic circuit using biologically realistic parameters, and compare the efficacy of learning relative to the discrete-time Kalman filter as the step-size irregularity and spectral-radius of the dynamics-matrix increases.

Daniel H. Um, David A. Knowles, Gail E. Kaiser

This paper demonstrates the utility of organized numerical representations of genes in research involving flat string gene formats (i.e., FASTA/FASTQ5). FASTA/FASTQ files have several current limitations, such as their large file sizes, slow processing speeds for mapping and alignment, and contextual dependencies. These challenges significantly hinder investigations and tasks that involve finding similar sequences. The solution lies in transforming sequences into an alternative representation that facilitates easier clustering into similar groups compared to the raw sequences themselves. By assigning a unique vector embedding to each short sequence, it is possible to more efficiently cluster and improve upon compression performance for the string representations of cDNA libraries. Furthermore, through learning alternative coordinate vector embeddings based on the contexts of codon triplets, we can demonstrate clustering based on amino acid properties. Finally, using this sequence embedding method to encode barcodes and cDNA sequences, we can improve the time complexity of the similarity search by coupling vector embeddings with an algorithm that determines the proximity of vectors in Euclidean space; this allows us to perform sequence similarity searches in a quicker and more modular fashion.

Aaron Zweig, Mingxuan Zhang, David A. Knowles et al.

Trajectory inference investigates how to interpolate paths between observed timepoints of dynamical systems, such as temporally resolved population distributions, with the goal of inferring trajectories at unseen times and better understanding system dynamics. Previous work has focused on continuous geometric priors, utilizing data-dependent spatial features to define a Riemannian metric. In many applications, there exists discrete, directed prior knowledge over admissible transitions (e.g. lineage trees in developmental biology). We introduce a Finsler metric that combines geometry with classification and incorporate both types of priors in trajectory inference, yielding improved performance on interpolation tasks in synthetic and real-world data.

Zaikang Lin, Sei Chang, Aaron Zweig et al.

Modern high-throughput biological datasets with thousands of perturbations provide the opportunity for large-scale discovery of causal graphs that represent the regulatory interactions between genes. Differentiable causal graphical models have been proposed to infer a gene regulatory network (GRN) from large scale interventional datasets, capturing the causal gene regulatory relationships from genetic perturbations. However, existing models are limited in their expressivity and scalability while failing to address the dynamic nature of biological processes such as cellular differentiation. We propose PerturbODE, a novel framework that incorporates biologically informative neural ordinary differential equations (neural ODEs) to model cell state trajectories under perturbations and derive the causal GRN from the neural ODE's parameters. We demonstrate PerturbODE's efficacy in trajectory prediction and GRN inference across simulated and real over-expression datasets.

Jiayu Su, David A. Knowles, Raul Rabadan

The success of machine learning models relies heavily on effectively representing high-dimensional data. However, ensuring data representations capture human-understandable concepts remains difficult, often requiring the incorporation of prior knowledge and decomposition of data into multiple subspaces. Traditional linear methods fall short in modeling more than one space, while more expressive deep learning approaches lack interpretability. Here, we introduce Supervised Independent Subspace Principal Component Analysis ($\texttt{sisPCA}$), a PCA extension designed for multi-subspace learning. Leveraging the Hilbert-Schmidt Independence Criterion (HSIC), $\texttt{sisPCA}$ incorporates supervision and simultaneously ensures subspace disentanglement. We demonstrate $\texttt{sisPCA}$'s connections with autoencoders and regularized linear regression and showcase its ability to identify and separate hidden data structures through extensive applications, including breast cancer diagnosis from image features, learning aging-associated DNA methylation changes, and single-cell analysis of malaria infection. Our results reveal distinct functional pathways associated with malaria colonization, underscoring the essentiality of explainable representation in high-dimensional data analysis.

Andrew A. Stirn, David A. Knowles

Widely used deep latent variable models (DLVMs), in particular Variational Autoencoders (VAEs), employ overly simplistic priors on the latent space. To achieve strong clustering performance, existing methods that replace the standard normal prior with a Gaussian mixture model (GMM) require defining the number of clusters to be close to the number of expected ground truth classes a-priori and are susceptible to poor initializations. We leverage VampPrior concepts (Tomczak and Welling, 2018) to fit a Bayesian GMM prior, resulting in the VampPrior Mixture Model (VMM), a novel prior for DLVMs. In a VAE, the VMM attains highly competitive clustering performance on benchmark datasets. Integrating the VMM into scVI (Lopez et al., 2018), a popular scRNA-seq integration method, significantly improves its performance and automatically arranges cells into clusters with similar biological characteristics.

Andrew Stirn, David A. Knowles

Brittle optimization has been observed to adversely impact model likelihoods for regression and VAEs when simultaneously fitting neural network mappings from a (random) variable onto the mean and variance of a dependent Gaussian variable. Previous works have bolstered optimization and improved likelihoods, but fail other basic posterior predictive checks (PPCs). Under the PPC framework, we propose critiques to test predictive mean and variance calibration and the predictive distribution's ability to generate sensible data. We find that our attractively simple solution, to treat heteroscedastic variance variationally, sufficiently regularizes variance to pass these PPCs. We consider a diverse gamut of existing and novel priors and find our methods preserve or outperform existing model likelihoods while significantly improving parameter calibration and sample quality for regression and VAEs.

David A. Knowles

While stochastic variational inference is relatively well known for scaling inference in Bayesian probabilistic models, related methods also offer ways to circumnavigate the approximation of analytically intractable expectations. The key challenge in either setting is controlling the variance of gradient estimates: recent work has shown that for continuous latent variables, particularly multivariate Gaussians, this can be achieved by using the gradient of the log posterior. In this paper we apply the same idea to gamma distributed latent variables given gamma variational distributions, enabling straightforward "black box" variational inference in models where sparsity and non-negativity are appropriate. We demonstrate the method on a recently proposed gamma process model for network data, as well as a novel sparse factor analysis. We outperform generic sampling algorithms and the approach of using Gaussian variational distributions on transformed variables.

Amar Shah, David A. Knowles, Zoubin Ghahramani

Stochastic variational inference (SVI) is emerging as the most promising candidate for scaling inference in Bayesian probabilistic models to large datasets. However, the performance of these methods has been assessed primarily in the context of Bayesian topic models, particularly latent Dirichlet allocation (LDA). Deriving several new algorithms, and using synthetic, image and genomic datasets, we investigate whether the understanding gleaned from LDA applies in the setting of sparse latent factor models, specifically beta process factor analysis (BPFA). We demonstrate that the big picture is consistent: using Gibbs sampling within SVI to maintain certain posterior dependencies is extremely effective. However, we find that different posterior dependencies are important in BPFA relative to LDA. Particularly, approximations able to model intra-local variable dependence perform best.

Creighton Heaukulani, David A. Knowles, Zoubin Ghahramani

We define the beta diffusion tree, a random tree structure with a set of leaves that defines a collection of overlapping subsets of objects, known as a feature allocation. A generative process for the tree structure is defined in terms of particles (representing the objects) diffusing in some continuous space, analogously to the Dirichlet diffusion tree (Neal, 2003), which defines a tree structure over partitions (i.e., non-overlapping subsets) of the objects. Unlike in the Dirichlet diffusion tree, multiple copies of a particle may exist and diffuse along multiple branches in the beta diffusion tree, and an object may therefore belong to multiple subsets of particles. We demonstrate how to build a hierarchically-clustered factor analysis model with the beta diffusion tree and how to perform inference over the random tree structures with a Markov chain Monte Carlo algorithm. We conclude with several numerical experiments on missing data problems with data sets of gene expression microarrays, international development statistics, and intranational socioeconomic measurements.

Konstantina Palla, David A. Knowles, Zoubin Ghahramani

We present a nonparametric prior over reversible Markov chains. We use completely random measures, specifically gamma processes, to construct a countably infinite graph with weighted edges. By enforcing symmetry to make the edges undirected we define a prior over random walks on graphs that results in a reversible Markov chain. The resulting prior over infinite transition matrices is closely related to the hierarchical Dirichlet process but enforces reversibility. A reinforcement scheme has recently been proposed with similar properties, but the de Finetti measure is not well characterised. We take the alternative approach of explicitly constructing the mixing measure, which allows more straightforward and efficient inference at the cost of no longer having a closed form predictive distribution. We use our process to construct a reversible infinite HMM which we apply to two real datasets, one from epigenomics and one ion channel recording.

Novi Quadrianto, Viktoriia Sharmanska, David A. Knowles et al.

We propose a probabilistic model to infer supervised latent variables in the Hamming space from observed data. Our model allows simultaneous inference of the number of binary latent variables, and their values. The latent variables preserve neighbourhood structure of the data in a sense that objects in the same semantic concept have similar latent values, and objects in different concepts have dissimilar latent values. We formulate the supervised infinite latent variable problem based on an intuitive principle of pulling objects together if they are of the same type, and pushing them apart if they are not. We then combine this principle with a flexible Indian Buffet Process prior on the latent variables. We show that the inferred supervised latent variables can be directly used to perform a nearest neighbour search for the purpose of retrieval. We introduce a new application of dynamically extending hash codes, and show how to effectively couple the structure of the hash codes with continuously growing structure of the neighbourhood preserving infinite latent feature space.

Konstantina Palla, David A. Knowles, Zoubin Ghahramani

The fundamental aim of clustering algorithms is to partition data points. We consider tasks where the discovered partition is allowed to vary with some covariate such as space or time. One approach would be to use fragmentation-coagulation processes, but these, being Markov processes, are restricted to linear or tree structured covariate spaces. We define a partition-valued process on an arbitrary covariate space using Gaussian processes. We use the process to construct a multitask clustering model which partitions datapoints in a similar way across multiple data sources, and a time series model of network data which allows cluster assignments to vary over time. We describe sampling algorithms for inference and apply our method to defining cancer subtypes based on different types of cellular characteristics, finding regulatory modules from gene expression data from multiple human populations, and discovering time varying community structure in a social network.

Tim Salimans, David A. Knowles

We propose a general algorithm for approximating nonstandard Bayesian posterior distributions. The algorithm minimizes the Kullback-Leibler divergence of an approximating distribution to the intractable posterior distribution. Our method can be used to approximate any posterior distribution, provided that it is given in closed form up to the proportionality constant. The approximation can be any distribution in the exponential family or any mixture of such distributions, which means that it can be made arbitrarily precise. Several examples illustrate the speed and accuracy of our approximation method in practice.