Aniruddh Raghu

Aniruddh Raghu, Divya Shanmugam, Eugene Pomerantsev et al.

Neural network models have demonstrated impressive performance in predicting pathologies and outcomes from the 12-lead electrocardiogram (ECG). However, these models often need to be trained with large, labelled datasets, which are not available for many predictive tasks of interest. In this work, we perform an empirical study examining whether training time data augmentation methods can be used to improve performance on such data-scarce ECG prediction problems. We investigate how data augmentation strategies impact model performance when detecting cardiac abnormalities from the ECG. Motivated by our finding that the effectiveness of existing augmentation strategies is highly task-dependent, we introduce a new method, TaskAug, which defines a flexible augmentation policy that is optimized on a per-task basis. We outline an efficient learning algorithm to do so that leverages recent work in nested optimization and implicit differentiation. In experiments, considering three datasets and eight predictive tasks, we find that TaskAug is competitive with or improves on prior work, and the learned policies shed light on what transformations are most effective for different tasks. We distill key insights from our experimental evaluation, generating a set of best practices for applying data augmentation to ECG prediction problems.

Aniruddh Raghu, Payal Chandak, Ridwan Alam et al.

Self-supervised learning (SSL) for clinical time series data has received significant attention in recent literature, since these data are highly rich and provide important information about a patient's physiological state. However, most existing SSL methods for clinical time series are limited in that they are designed for unimodal time series, such as a sequence of structured features (e.g., lab values and vitals signs) or an individual high-dimensional physiological signal (e.g., an electrocardiogram). These existing methods cannot be readily extended to model time series that exhibit multimodality, with structured features and high-dimensional data being recorded at each timestep in the sequence. In this work, we address this gap and propose a new SSL method -- Sequential Multi-Dimensional SSL -- where a SSL loss is applied both at the level of the entire sequence and at the level of the individual high-dimensional data points in the sequence in order to better capture information at both scales. Our strategy is agnostic to the specific form of loss function used at each level -- it can be contrastive, as in SimCLR, or non-contrastive, as in VICReg. We evaluate our method on two real-world clinical datasets, where the time series contains sequences of (1) high-frequency electrocardiograms and (2) structured data from lab values and vitals signs. Our experimental results indicate that pre-training with our method and then fine-tuning on downstream tasks improves performance over baselines on both datasets, and in several settings, can lead to improvements across different self-supervised loss functions.

Nuria Alina Chandra, Yucen Lily Li, Alan N. Amin et al.

To model discrete sequences such as DNA, proteins, and language using diffusion, practitioners must choose between three major methods: diffusion in discrete space, Gaussian diffusion in Euclidean space, or diffusion on the simplex. Despite their shared goal, these models have disparate algorithms, theoretical structures, and tradeoffs: discrete diffusion has the most natural domain, Gaussian diffusion has more mature algorithms, and diffusion on the simplex in principle combines the strengths of the other two but in practice suffers from a numerically unstable stochastic processes. Ideally we could see each of these models as instances of the same underlying framework, and enable practitioners to switch between models for downstream applications. However previous theories have only considered connections in special cases. Here we build a theory unifying all three methods of discrete diffusion as different parameterizations of the same underlying process: the Wright-Fisher population genetics model. In particular, we find simplicial and Gaussian diffusion as two large-population limits. Our theory formally connects the likelihoods and hyperparameters of these models and leverages decades of mathematical genetics literature to unlock stable simplicial diffusion. Finally, we relieve the practitioner of balancing model trade-offs by demonstrating it is possible to train a single model that can perform diffusion in any of these three domains at test time. Our experiments show that Wright-Fisher simplicial diffusion is more stable and outperforms previous simplicial diffusion models on conditional DNA generation. We also show that we can train models on multiple domains at once that are competitive with models trained on any individual domain.

Meet Shah, Jason Gusdorf, Anil Palepu et al.

The practice of medicine relies not only upon skillful dialogue but also on the nuanced exchange and interpretation of rich auditory and visual cues between doctors and patients. Building on the low-latency voice and video processing capabilities of Gemini, we introduce AI co-clinician, a first-of-its-kind conversational AI system utilizing continuous streams of audio-visual data from live patient conversations to inform real-time clinical decisions. Its dual-agent architecture balances deep clinical reasoning with the low latency required for natural dialogue. To assess this system, we implemented a video-based interface emulating telemedicine consultations. We crafted 20 standardized outpatient scenarios requiring proactive real-time auditory and visual reasoning and designed "TelePACES" evaluation criteria alongside case-specific rubrics. In a randomized, interface-blinded, crossover simulation study (n = 120 encounters) with 10 internal medicine residents as patient actors, we compared AI co-clinician with primary care physicians (PCPs), GPT-Realtime, and a baseline agent. AI co-clinician approached PCPs in key TelePACES dimensions, including management plans and differential diagnosis, while significantly outperforming GPT-Realtime across all general criteria. While our agent demonstrated parity with PCPs in case-specific triage measures, physicians maintained superior overall performance in case-specific assessments. Although AI co-clinician marks a significant advance in real-time telemedical AI, gaps remain in physical examination and disease-specific reasoning. Our work shows that text-only approaches fail to capture the true challenges of medical consultation and suggests that high-stakes real-time diagnostic AI is most safely advanced in collaborative, triadic models where AI can be a supportive co-clinician for doctors and patients.

Alan Nawzad Amin, Nate Gruver, Yilun Kuang et al.

To build effective therapeutics, biologists iteratively mutate antibody sequences to improve binding and stability. Proposed mutations can be informed by previous measurements or by learning from large antibody databases to predict only typical antibodies. Unfortunately, the space of typical antibodies is enormous to search, and experiments often fail to find suitable antibodies on a budget. We introduce Clone-informed Bayesian Optimization (CloneBO), a Bayesian optimization procedure that efficiently optimizes antibodies in the lab by teaching a generative model how our immune system optimizes antibodies. Our immune system makes antibodies by iteratively evolving specific portions of their sequences to bind their target strongly and stably, resulting in a set of related, evolving sequences known as a clonal family. We train a large language model, CloneLM, on hundreds of thousands of clonal families and use it to design sequences with mutations that are most likely to optimize an antibody within the human immune system. We propose to guide our designs to fit previous measurements with a twisted sequential Monte Carlo procedure. We show that CloneBO optimizes antibodies substantially more efficiently than previous methods in realistic in silico experiments and designs stronger and more stable binders in in vitro wet lab experiments.

Cade Gordon, Aniruddh Raghu, Peyton Greenside et al.

Antibody therapies have been employed to address some of today's most challenging diseases, but must meet many criteria during drug development before reaching a patient. Humanization is a sequence optimization strategy that addresses one critical risk called immunogenicity - a patient's immune response to the drug - by making an antibody more "human-like" in the absence of a predictive lab-based test for immunogenicity. However, existing humanization strategies generally yield very few humanized candidates, which may have degraded biophysical properties or decreased drug efficacy. Here, we re-frame humanization as a conditional generative modeling task, where humanizing mutations are sampled from a language model trained on human antibody data. We describe a sampling process that incorporates models of therapeutic attributes, such as antigen binding affinity, to obtain candidate sequences that have both reduced immunogenicity risk and maintained or improved therapeutic properties, allowing this algorithm to be readily embedded into an iterative antibody optimization campaign. We demonstrate in silico and in lab validation that in real therapeutic programs our generative humanization method produces diverse sets of antibodies that are both (1) highly-human and (2) have favorable therapeutic properties, such as improved binding to target antigens.

Aniruddh Raghu, Sebastian Ober, Maxwell Kazman et al.

Therapeutic antibody candidates often require extensive engineering to improve key functional and developability properties before clinical development. This can be achieved through iterative design, where starting molecules are optimized over several rounds of in vitro experiments. While protein structure can provide a strong inductive bias, it is rarely used in iterative design due to the lack of structural data for continually evolving lead molecules over the course of optimization. In this work, we propose a strategy for iterative antibody optimization that leverages both sequence and structure as well as accumulating lab measurements of binding and developability. Building on prior work, we first train a sequence-structure diffusion generative model that operates on antibody-antigen complexes. We then outline an approach to use this model, together with carefully predicted antibody-antigen complexes, to optimize lead candidates throughout the iterative design process. Further, we describe a guided sampling approach that biases generation toward desirable properties by integrating models trained on experimental data from iterative design. We evaluate our approach in multiple in silico and in vitro experiments, demonstrating that it produces high-affinity binders at multiple stages of an active antibody optimization campaign.

Sebastian W. Ober, Calvin McCarter, Aniruddh Raghu et al.

Bayesian optimization is a natural candidate for the engineering of antibody therapeutic properties, which is often iterative and expensive. However, finding the optimal choice of surrogate model for optimization over the highly structured antibody space is difficult, and may differ depending on the property being optimized. Moreover, to the best of our knowledge, no prior works have attempted to incorporate structural information into antibody Bayesian optimization. In this work, we explore different approaches to incorporating structural information into Bayesian optimization, and compare them to a variety of sequence-only approaches on two different antibody properties, binding affinity and stability. In addition, we propose the use of a protein language model-based ``soft constraint,'' which helps guide the optimization to promising regions of the space. We find that certain types of structural information improve data efficiency in early optimization rounds for stability, but have equivalent peak performance. Moreover, when incorporating the protein language model soft constraint we find that the data efficiency gap is diminished for affinity and eliminated for stability, resulting in sequence-only methods that match the performance of structure-based methods, raising questions about the necessity of structure in Bayesian optimization for antibodies.

Jiayi Xin, Aniruddh Raghu, Nick Bhattacharya et al.

Modern therapeutic antibody design often involves composing multi-part assemblages of individual functional domains, each of which may be derived from a different source or engineered independently. While these complex formats can expand disease applicability and improve safety, they present a significant engineering challenge: the function and stability of individual domains are not guaranteed in the novel format, and the entire molecule may no longer be synthesizable. To address these challenges, we develop a machine learning framework to predict "reformatting success" -- whether converting an antibody from one format to another will succeed or not. Our framework incorporates both antibody sequence and structural context, incorporating an evaluation protocol that reflects realistic deployment scenarios. In experiments on a real-world antibody reformatting dataset, we find the surprising result that large pretrained protein language models (PLMs) fail to outperform simple, domain-tailored, multimodal representations. This is particularly evident in the most difficult evaluation setting, where we test model generalization to a new starting antibody. In this challenging "new antibody, no data" scenario, our best multimodal model achieves high predictive accuracy, enabling prioritization of promising candidates and reducing wasted experimental effort.

Aniruddh Raghu, Jonathan Lorraine, Simon Kornblith et al.

Pre-training (PT) followed by fine-tuning (FT) is an effective method for training neural networks, and has led to significant performance improvements in many domains. PT can incorporate various design choices such as task and data reweighting strategies, augmentation policies, and noise models, all of which can significantly impact the quality of representations learned. The hyperparameters introduced by these strategies therefore must be tuned appropriately. However, setting the values of these hyperparameters is challenging. Most existing methods either struggle to scale to high dimensions, are too slow and memory-intensive, or cannot be directly applied to the two-stage PT and FT learning process. In this work, we propose an efficient, gradient-based algorithm to meta-learn PT hyperparameters. We formalize the PT hyperparameter optimization problem and propose a novel method to obtain PT hyperparameter gradients by combining implicit differentiation and backpropagation through unrolled optimization. We demonstrate that our method improves predictive performance on two real-world domains. First, we optimize high-dimensional task weighting hyperparameters for multitask pre-training on protein-protein interaction graphs and improve AUROC by up to 3.9%. Second, we optimize a data augmentation neural network for self-supervised PT with SimCLR on electrocardiography data and improve AUROC by up to 1.9%.

Aniruddh Raghu, John Guttag, Katherine Young et al.

The impact of machine learning models on healthcare will depend on the degree of trust that healthcare professionals place in the predictions made by these models. In this paper, we present a method to provide people with clinical expertise with domain-relevant evidence about why a prediction should be trusted. We first design a probabilistic model that relates meaningful latent concepts to prediction targets and observed data. Inference of latent variables in this model corresponds to both making a prediction and providing supporting evidence for that prediction. We present a two-step process to efficiently approximate inference: (i) estimating model parameters using variational learning, and (ii) approximating maximum a posteriori estimation of latent variables in the model using a neural network, trained with an objective derived from the probabilistic model. We demonstrate the method on the task of predicting mortality risk for patients with cardiovascular disease. Specifically, using electrocardiogram and tabular data as input, we show that our approach provides appropriate domain-relevant supporting evidence for accurate predictions.

Aniruddh Raghu, Maithra Raghu, Simon Kornblith et al.

Effective training of deep neural networks can be challenging, and there remain many open questions on how to best learn these models. Recently developed methods to improve neural network training examine teaching: providing learned information during the training process to improve downstream model performance. In this paper, we take steps towards extending the scope of teaching. We propose a flexible teaching framework using commentaries, learned meta-information helpful for training on a particular task. We present gradient-based methods to learn commentaries, leveraging recent work on implicit differentiation for scalability. We explore diverse applications of commentaries, from weighting training examples, to parameterising label-dependent data augmentation policies, to representing attention masks that highlight salient image regions. We find that commentaries can improve training speed and/or performance, and provide insights about the dataset and training process. We also observe that commentaries generalise: they can be reused when training new models to obtain performance benefits, suggesting a use-case where commentaries are stored with a dataset and leveraged in future for improved model training.

Aniruddh Raghu, Maithra Raghu, Samy Bengio et al.

An important research direction in machine learning has centered around developing meta-learning algorithms to tackle few-shot learning. An especially successful algorithm has been Model Agnostic Meta-Learning (MAML), a method that consists of two optimization loops, with the outer loop finding a meta-initialization, from which the inner loop can efficiently learn new tasks. Despite MAML's popularity, a fundamental open question remains -- is the effectiveness of MAML due to the meta-initialization being primed for rapid learning (large, efficient changes in the representations) or due to feature reuse, with the meta initialization already containing high quality features? We investigate this question, via ablation studies and analysis of the latent representations, finding that feature reuse is the dominant factor. This leads to the ANIL (Almost No Inner Loop) algorithm, a simplification of MAML where we remove the inner loop for all but the (task-specific) head of a MAML-trained network. ANIL matches MAML's performance on benchmark few-shot image classification and RL and offers computational improvements over MAML. We further study the precise contributions of the head and body of the network, showing that performance on the test tasks is entirely determined by the quality of the learned features, and we can remove even the head of the network (the NIL algorithm). We conclude with a discussion of the rapid learning vs feature reuse question for meta-learning algorithms more broadly.

Aniruddh Raghu, Matthieu Komorowski, Sumeetpal Singh

Sepsis is a dangerous condition that is a leading cause of patient mortality. Treating sepsis is highly challenging, because individual patients respond very differently to medical interventions and there is no universally agreed-upon treatment for sepsis. In this work, we explore the use of continuous state-space model-based reinforcement learning (RL) to discover high-quality treatment policies for sepsis patients. Our quantitative evaluation reveals that by blending the treatment strategy discovered with RL with what clinicians follow, we can obtain improved policies, potentially allowing for better medical treatment for sepsis.

Aniruddh Raghu, Omer Gottesman, Yao Liu et al.

In this work, we consider the problem of estimating a behaviour policy for use in Off-Policy Policy Evaluation (OPE) when the true behaviour policy is unknown. Via a series of empirical studies, we demonstrate how accurate OPE is strongly dependent on the calibration of estimated behaviour policy models: how precisely the behaviour policy is estimated from data. We show how powerful parametric models such as neural networks can result in highly uncalibrated behaviour policy models on a real-world medical dataset, and illustrate how a simple, non-parametric, k-nearest neighbours model produces better calibrated behaviour policy estimates and can be used to obtain superior importance sampling-based OPE estimates.

Yao Liu, Omer Gottesman, Aniruddh Raghu et al.

We study the problem of off-policy policy evaluation (OPPE) in RL. In contrast to prior work, we consider how to estimate both the individual policy value and average policy value accurately. We draw inspiration from recent work in causal reasoning, and propose a new finite sample generalization error bound for value estimates from MDP models. Using this upper bound as an objective, we develop a learning algorithm of an MDP model with a balanced representation, and show that our approach can yield substantially lower MSE in common synthetic benchmarks and a HIV treatment simulation domain.

Aniruddh Raghu, Matthieu Komorowski, Imran Ahmed et al.

Sepsis is a leading cause of mortality in intensive care units and costs hospitals billions annually. Treating a septic patient is highly challenging, because individual patients respond very differently to medical interventions and there is no universally agreed-upon treatment for sepsis. In this work, we propose an approach to deduce treatment policies for septic patients by using continuous state-space models and deep reinforcement learning. Our model learns clinically interpretable treatment policies, similar in important aspects to the treatment policies of physicians. The learned policies could be used to aid intensive care clinicians in medical decision making and improve the likelihood of patient survival.

Aniruddh Raghu, Matthieu Komorowski, Leo Anthony Celi et al.

Sepsis is a leading cause of mortality in intensive care units (ICUs) and costs hospitals billions annually. Treating a septic patient is highly challenging, because individual patients respond very differently to medical interventions and there is no universally agreed-upon treatment for sepsis. Understanding more about a patient's physiological state at a given time could hold the key to effective treatment policies. In this work, we propose a new approach to deduce optimal treatment policies for septic patients by using continuous state-space models and deep reinforcement learning. Learning treatment policies over continuous spaces is important, because we retain more of the patient's physiological information. Our model is able to learn clinically interpretable treatment policies, similar in important aspects to the treatment policies of physicians. Evaluating our algorithm on past ICU patient data, we find that our model could reduce patient mortality in the hospital by up to 3.6% over observed clinical policies, from a baseline mortality of 13.7%. The learned treatment policies could be used to aid intensive care clinicians in medical decision making and improve the likelihood of patient survival.