Drausin Wulsin

Aldo Pacchiano, Drausin Wulsin, Robert A. Barton et al. · amazon-science, harvard

The problem of how to genetically modify cells in order to maximize a certain cellular phenotype has taken center stage in drug development over the last few years (with, for example, genetically edited CAR-T, CAR-NK, and CAR-NKT cells entering cancer clinical trials). Exhausting the search space for all possible genetic edits (perturbations) or combinations thereof is infeasible due to cost and experimental limitations. This work provides a theoretically sound framework for iteratively exploring the space of perturbations in pooled batches in order to maximize a target phenotype under an experimental budget. Inspired by this application domain, we study the problem of batch query bandit optimization and introduce the Optimistic Arm Elimination ($\mathrm{OAE}$) principle designed to find an almost optimal arm under different functional relationships between the queries (arms) and the outputs (rewards). We analyze the convergence properties of $\mathrm{OAE}$ by relating it to the Eluder dimension of the algorithm's function class and validate that $\mathrm{OAE}$ outperforms other strategies in finding optimal actions in experiments on simulated problems, public datasets well-studied in bandit contexts, and in genetic perturbation datasets when the regression model is a deep neural network. OAE also outperforms the benchmark algorithms in 3 of 4 datasets in the GeneDisco experimental planning challenge.

Scott Gigante, Varsha G. Raghavan, Amanda M. Robinson et al.

Translating the relevance of preclinical models ($\textit{in vitro}$, animal models, or organoids) to their relevance in humans presents an important challenge during drug development. The rising abundance of single-cell genomic data from human tumors and tissue offers a new opportunity to optimize model systems by their similarity to targeted human cell types in disease. In this work, we introduce SystemMatch to assess the fit of preclinical model systems to an $\textit{in sapiens}$ target population and to recommend experimental changes to further optimize these systems. We demonstrate this through an application to developing $\textit{in vitro}$ systems to model human tumor-derived suppressive macrophages. We show with held-out $\textit{in vivo}$ controls that our pipeline successfully ranks macrophage subpopulations by their biological similarity to the target population, and apply this analysis to rank a series of 18 $\textit{in vitro}$ macrophage systems perturbed with a variety of cytokine stimulations. We extend this analysis to predict the behavior of 66 $\textit{in silico}$ model systems generated using a perturbational autoencoder and apply a $k$-medoids approach to recommend a subset of these model systems for further experimental development in order to fully explore the space of possible perturbations. Through this use case, we demonstrate a novel approach to model system development to generate a system more similar to human biology.

Drausin F. Wulsin, Emily B. Fox, Brian Litt

Patients with epilepsy can manifest short, sub-clinical epileptic "bursts" in addition to full-blown clinical seizures. We believe the relationship between these two classes of events---something not previously studied quantitatively---could yield important insights into the nature and intrinsic dynamics of seizures. A goal of our work is to parse these complex epileptic events into distinct dynamic regimes. A challenge posed by the intracranial EEG (iEEG) data we study is the fact that the number and placement of electrodes can vary between patients. We develop a Bayesian nonparametric Markov switching process that allows for (i) shared dynamic regimes between a variable number of channels, (ii) asynchronous regime-switching, and (iii) an unknown dictionary of dynamic regimes. We encode a sparse and changing set of dependencies between the channels using a Markov-switching Gaussian graphical model for the innovations process driving the channel dynamics and demonstrate the importance of this model in parsing and out-of-sample predictions of iEEG data. We show that our model produces intuitive state assignments that can help automate clinical analysis of seizures and enable the comparison of sub-clinical bursts and full clinical seizures.

Drausin Wulsin, Shane Jensen, Brian Litt

Driven by the multi-level structure of human intracranial electroencephalogram (iEEG) recordings of epileptic seizures, we introduce a new variant of a hierarchical Dirichlet Process---the multi-level clustering hierarchical Dirichlet Process (MLC-HDP)---that simultaneously clusters datasets on multiple levels. Our seizure dataset contains brain activity recorded in typically more than a hundred individual channels for each seizure of each patient. The MLC-HDP model clusters over channels-types, seizure-types, and patient-types simultaneously. We describe this model and its implementation in detail. We also present the results of a simulation study comparing the MLC-HDP to a similar model, the Nested Dirichlet Process and finally demonstrate the MLC-HDP's use in modeling seizures across multiple patients. We find the MLC-HDP's clustering to be comparable to independent human physician clusterings. To our knowledge, the MLC-HDP model is the first in the epilepsy literature capable of clustering seizures within and between patients.