Monica Agrawal

Monica Agrawal, Stefan Hegselmann, Hunter Lang et al. · mit

A long-running goal of the clinical NLP community is the extraction of important variables trapped in clinical notes. However, roadblocks have included dataset shift from the general domain and a lack of public clinical corpora and annotations. In this work, we show that large language models, such as InstructGPT, perform well at zero- and few-shot information extraction from clinical text despite not being trained specifically for the clinical domain. Whereas text classification and generation performance have already been studied extensively in such models, here we additionally demonstrate how to leverage them to tackle a diverse set of NLP tasks which require more structured outputs, including span identification, token-level sequence classification, and relation extraction. Further, due to the dearth of available data to evaluate these systems, we introduce new datasets for benchmarking few-shot clinical information extraction based on a manual re-annotation of the CASI dataset for new tasks. On the clinical extraction tasks we studied, the GPT-3 systems significantly outperform existing zero- and few-shot baselines.

Stefan Hegselmann, Alejandro Buendia, Hunter Lang et al. · mit

We study the application of large language models to zero-shot and few-shot classification of tabular data. We prompt the large language model with a serialization of the tabular data to a natural-language string, together with a short description of the classification problem. In the few-shot setting, we fine-tune the large language model using some labeled examples. We evaluate several serialization methods including templates, table-to-text models, and large language models. Despite its simplicity, we find that this technique outperforms prior deep-learning-based tabular classification methods on several benchmark datasets. In most cases, even zero-shot classification obtains non-trivial performance, illustrating the method's ability to exploit prior knowledge encoded in large language models. Unlike many deep learning methods for tabular datasets, this approach is also competitive with strong traditional baselines like gradient-boosted trees, especially in the very-few-shot setting.

Sharon Jiang, Shannon Shen, Monica Agrawal et al. · mit

The large amount of time clinicians spend sifting through patient notes and documenting in electronic health records (EHRs) is a leading cause of clinician burnout. By proactively and dynamically retrieving relevant notes during the documentation process, we can reduce the effort required to find relevant patient history. In this work, we conceptualize the use of EHR audit logs for machine learning as a source of supervision of note relevance in a specific clinical context, at a particular point in time. Our evaluation focuses on the dynamic retrieval in the emergency department, a high acuity setting with unique patterns of information retrieval and note writing. We show that our methods can achieve an AUC of 0.963 for predicting which notes will be read in an individual note writing session. We additionally conduct a user study with several clinicians and find that our framework can help clinicians retrieve relevant information more efficiently. Demonstrating that our framework and methods can perform well in this demanding setting is a promising proof of concept that they will translate to other clinical settings and data modalities (e.g., labs, medications, imaging).

Xuan Yang, Furong Jia, Roy Xie et al.

Current Large Language Model reasoning systems process queries independently, discarding valuable cross-instance signals such as shared reasoning patterns and consistency constraints. We introduce Batch-of-Thought (BoT), a training-free method that processes related queries jointly to enable cross-instance learning. By performing comparative analysis across batches, BoT identifies high-quality reasoning templates, detects errors through consistency checks, and amortizes computational costs. We instantiate BoT within a multi-agent reflection architecture (BoT-R), where a Reflector performs joint evaluation to unlock mutual information gain unavailable in isolated processing. Experiments across three model families and six benchmarks demonstrate that BoT-R consistently improves accuracy and confidence calibration while reducing inference costs by up to 61%. Our theoretical and experimental analysis reveals when and why batch-aware reasoning benefits LLM systems. Our code is available at https://github.com/xuanyang19/BoT

Bohao Yang, Rui Yang, Joshua M. Biro et al.

Clinical communication is central to patient outcomes, yet large-scale human annotation of patient-provider conversation remains labor-intensive, inconsistent, and difficult to scale. Existing approaches based on large language models typically rely on single-task models that lack adaptability, interpretability, and reliability, especially when applied across various communication frameworks and clinical domains. In this study, we developed a Multi-framework Structured Agentic AI system for Clinical Communication (MOSAIC), built on a LangGraph-based architecture that orchestrates four core agents, including a Plan Agent for codebook selection and workflow planning, an Update Agent for maintaining up-to-date retrieval databases, a set of Annotation Agents that applies codebook-guided retrieval-augmented generation (RAG) with dynamic few-shot prompting, and a Verification Agent that provides consistency checks and feedback. To evaluate performance, we compared MOSAIC outputs against gold-standard annotations created by trained human coders. We developed and evaluated MOSAIC using 26 gold standard annotated transcripts for training and 50 transcripts for testing, spanning rheumatology and OB/GYN domains. On the test set, MOSAIC achieved an overall F1 score of 0.928. Performance was highest in the Rheumatology subset (F1 = 0.962) and strongest for Patient Behavior (e.g., patients asking questions, expressing preferences, or showing assertiveness). Ablations revealed that MOSAIC outperforms baseline benchmarking.

Antonio Parziale, Monica Agrawal, Shalmali Joshi et al.

A collection of the extended abstracts that were presented at the 2nd Machine Learning for Health symposium (ML4H 2022), which was held both virtually and in person on November 28, 2022, in New Orleans, Louisiana, USA. Machine Learning for Health (ML4H) is a longstanding venue for research into machine learning for health, including both theoretical works and applied works. ML4H 2022 featured two submission tracks: a proceedings track, which encompassed full-length submissions of technically mature and rigorous work, and an extended abstract track, which would accept less mature, but innovative research for discussion. All the manuscripts submitted to ML4H Symposium underwent a double-blind peer-review process. Extended abstracts included in this collection describe innovative machine learning research focused on relevant problems in health and biomedicine.

Akshay Paruchuri, Maryam Aziz, Rohit Vartak et al. · stanford

People are increasingly seeking healthcare information from large language models (LLMs) via interactive chatbots, yet the nature and inherent risks of these conversations remain largely unexplored. In this paper, we filter large-scale conversational AI datasets to achieve HealthChat-11K, a curated dataset of 11K real-world conversations composed of 25K user messages. We use HealthChat-11K and a clinician-driven taxonomy for how users interact with LLMs when seeking healthcare information in order to systematically study user interactions across 21 distinct health specialties. Our analysis reveals insights into the nature of how and why users seek health information, such as common interactions, instances of incomplete context, affective behaviors, and interactions (e.g., leading questions) that can induce sycophancy, underscoring the need for improvements in the healthcare support capabilities of LLMs deployed as conversational AI. Code and artifacts to retrieve our analyses and combine them into a curated dataset can be found here: https://github.com/yahskapar/HealthChat

Furong Jia, David Sontag, Monica Agrawal

Large language models (LLMs) have performed well across various clinical natural language processing tasks, despite not being directly trained on electronic health record (EHR) data. In this work, we examine how popular open-source LLMs learn clinical information from large mined corpora through two crucial but understudied lenses: (1) their interpretation of clinical jargon, a foundational ability for understanding real-world clinical notes, and (2) their responses to unsupported medical claims. For both use cases, we investigate the frequency of relevant clinical information in their corresponding pretraining corpora, the relationship between pretraining data composition and model outputs, and the sources underlying this data. To isolate clinical jargon understanding, we evaluate LLMs on a new dataset MedLingo. Unsurprisingly, we find that the frequency of clinical jargon mentions across major pretraining corpora correlates with model performance. However, jargon frequently appearing in clinical notes often rarely appears in pretraining corpora, revealing a mismatch between available data and real-world usage. Similarly, we find that a non-negligible portion of documents support disputed claims that can then be parroted by models. Finally, we classified and analyzed the types of online sources in which clinical jargon and unsupported medical claims appear, with implications for future dataset composition.

Sraavya Sambara, Yuan Pu, Ayman Ali et al.

Real-world health questions from patients often unintentionally embed false assumptions or premises. In such cases, safe medical communication typically involves redirection: addressing the implicit misconception and then responding to the underlying patient context, rather than the original question. While large language models (LLMs) are increasingly being used by lay users for medical advice, they have not yet been tested for this crucial competency. Therefore, in this work, we investigate how LLMs react to false premises embedded within real-world health questions. We develop a semi-automated pipeline to curate MedRedFlag, a dataset of 1100+ questions sourced from Reddit that require redirection. We then systematically compare responses from state-of-the-art LLMs to those from clinicians. Our analysis reveals that LLMs often fail to redirect problematic questions, even when the problematic premise is detected, and provide answers that could lead to suboptimal medical decision making. Our benchmark and results reveal a novel and substantial gap in how LLMs perform under the conditions of real-world health communication, highlighting critical safety concerns for patient-facing medical AI systems. Code and dataset are available at https://github.com/srsambara-1/MedRedFlag.

Raymond Xiong, Furong Jia, Lionel Wong et al.

Patients are increasingly using large language models (LLMs) to seek answers to their healthcare-related questions. However, benchmarking efforts in LLMs for question answering often focus on medical exam questions, which differ significantly in style and content from the questions patients actually raise in real life. To bridge this gap, we sourced data from Google's People Also Ask feature by querying the top 200 prescribed medications in the United States, curating a dataset of medical questions people commonly ask. A considerable portion of the collected questions contains incorrect assumptions and dangerous intentions. We demonstrate that the emergence of these corrupted questions is not uniformly random and depends heavily on the degree of incorrectness in the history of questions that led to their appearance. Current LLMs that perform strongly on other benchmarks struggle to identify incorrect assumptions in everyday questions.

Niklas Mannhardt, Elizabeth Bondi-Kelly, Barbara Lam et al. · microsoft-research

Large language models (LLMs) have immense potential to make information more accessible, particularly in medicine, where complex medical jargon can hinder patient comprehension of clinical notes. We developed a patient-facing tool using LLMs to make clinical notes more readable by simplifying, extracting information from, and adding context to the notes. We piloted the tool with clinical notes donated by patients with a history of breast cancer and synthetic notes from a clinician. Participants (N=200, healthy, female-identifying patients) were randomly assigned three clinical notes in our tool with varying levels of augmentations and answered quantitative and qualitative questions evaluating their understanding of follow-up actions. Augmentations significantly increased their quantitative understanding scores. In-depth interviews were conducted with participants (N=7, patients with a history of breast cancer), revealing both positive sentiments about the augmentations and concerns about AI. We also performed a qualitative clinician-driven analysis of the model's error modes.

Stefan Hegselmann, Shannon Zejiang Shen, Florian Gierse et al. · mit

Patients often face difficulties in understanding their hospitalizations, while healthcare workers have limited resources to provide explanations. In this work, we investigate the potential of large language models to generate patient summaries based on doctors' notes and study the effect of training data on the faithfulness and quality of the generated summaries. To this end, we release (i) a rigorous labeling protocol for errors in medical texts and (ii) a publicly available dataset of annotated hallucinations in 100 doctor-written and 100 generated summaries. We show that fine-tuning on hallucination-free data effectively reduces hallucinations from 2.60 to 1.55 per summary for Llama 2, while preserving relevant information. We observe a similar effect on GPT-4 (0.70 to 0.40), when the few-shot examples are hallucination-free. We also conduct a qualitative evaluation using hallucination-free and improved training data. We find that common quantitative metrics do not correlate well with faithfulness and quality. Finally, we test GPT-4 for automatic hallucination detection, which clearly outperforms common baselines.

Lionel Wong, Ayman Ali, Raymond Xiong et al. · mit

Patients have long sought health information online, and increasingly, they are turning to generative AI to answer their health-related queries. Given the high stakes of the medical domain, techniques like retrieval-augmented generation and citation grounding have been widely promoted as methods to reduce hallucinations and improve the accuracy of AI-generated responses and have been widely adopted into search engines. This paper argues that even when these methods produce literally accurate content drawn from source documents sans hallucinations, they can still be highly misleading. Patients may derive significantly different interpretations from AI-generated outputs than they would from reading the original source material, let alone consulting a knowledgeable clinician. Through a large-scale query analysis on topics including disputed diagnoses and procedure safety, we support our argument with quantitative and qualitative evidence of the suboptimal answers resulting from current systems. In particular, we highlight how these models tend to decontextualize facts, omit critical relevant sources, and reinforce patient misconceptions or biases. We propose a series of recommendations -- such as the incorporation of communication pragmatics and enhanced comprehension of source documents -- that could help mitigate these issues and extend beyond the medical domain.

Divya Shanmugam, Monica Agrawal, Rajiv Movva et al.

The increased capabilities of generative AI have dramatically expanded its possible use cases in medicine. We provide a comprehensive overview of generative AI use cases for clinicians, patients, clinical trial organizers, researchers, and trainees. We then discuss the many challenges -- including maintaining privacy and security, improving transparency and interpretability, upholding equity, and rigorously evaluating models -- which must be overcome to realize this potential, and the open research directions they give rise to.

Hyewon Jeong, Sarah Jabbour, Yuzhe Yang et al. · uw

The third ML4H symposium was held in person on December 10, 2023, in New Orleans, Louisiana, USA. The symposium included research roundtable sessions to foster discussions between participants and senior researchers on timely and relevant topics for the \ac{ML4H} community. Encouraged by the successful virtual roundtables in the previous year, we organized eleven in-person roundtables and four virtual roundtables at ML4H 2022. The organization of the research roundtables at the conference involved 17 Senior Chairs and 19 Junior Chairs across 11 tables. Each roundtable session included invited senior chairs (with substantial experience in the field), junior chairs (responsible for facilitating the discussion), and attendees from diverse backgrounds with interest in the session's topic. Herein we detail the organization process and compile takeaways from these roundtable discussions, including recent advances, applications, and open challenges for each topic. We conclude with a summary and lessons learned across all roundtables. This document serves as a comprehensive review paper, summarizing the recent advancements in machine learning for healthcare as contributed by foremost researchers in the field.

Furong Jia, Yuan Pu, Finn Guo et al.

Large language models (LLMs) excel on multiple-choice clinical diagnosis benchmarks, yet it is unclear how much of this performance reflects underlying probabilistic reasoning. We study this through questions from MedQA, where the task is to select the most likely diagnosis. We introduce the Frequency-Based Probabilistic Ranker (FBPR), a lightweight method that scores options with a smoothed Naive Bayes over concept-diagnosis co-occurrence statistics from a large corpus. When co-occurrence statistics were sourced from the pretraining corpora for OLMo and Llama, FBPR achieves comparable performance to the corresponding LLMs pretrained on that same corpus. Direct LLM inference and FBPR largely get different questions correct, with an overlap only slightly above random chance, indicating complementary strengths of each method. These findings highlight the continued value of explicit probabilistic baselines: they provide a meaningful performance reference point and a complementary signal for potential hybridization. While the performance of LLMs seems to be driven by a mechanism other than simple frequency aggregation, we show that an approach similar to the historically grounded, low-complexity expert systems still accounts for a substantial portion of benchmark performance.

Hunter Lang, Monica Agrawal, Yoon Kim et al.

We demonstrate that co-training (Blum & Mitchell, 1998) can improve the performance of prompt-based learning by using unlabeled data. While prompting has emerged as a promising paradigm for few-shot and zero-shot learning, it is often brittle and requires much larger models compared to the standard supervised setup. We find that co-training makes it possible to improve the original prompt model and at the same time learn a smaller, downstream task-specific model. In the case where we only have partial access to a prompt model (e.g., output probabilities from GPT-3 (Brown et al., 2020)) we learn a calibration model over the prompt outputs. When we have full access to the prompt model's gradients but full finetuning remains prohibitively expensive (e.g., T0 (Sanh et al., 2021)), we learn a set of soft prompt continuous vectors to iteratively update the prompt model. We find that models trained in this manner can significantly improve performance on challenging datasets where there is currently a large gap between prompt-based learning and fully-supervised models.

Monica Agrawal, Hunter Lang, Michael Offin et al.

Label-scarce, high-dimensional domains such as healthcare present a challenge for modern machine learning techniques. To overcome the difficulties posed by a lack of labeled data, we explore an "order-contrastive" method for self-supervised pre-training on longitudinal data. We sample pairs of time segments, switch the order for half of them, and train a model to predict whether a given pair is in the correct order. Intuitively, the ordering task allows the model to attend to the least time-reversible features (for example, features that indicate progression of a chronic disease). The same features are often useful for downstream tasks of interest. To quantify this, we study a simple theoretical setting where we prove a finite-sample guarantee for the downstream error of a representation learned with order-contrastive pre-training. Empirically, in synthetic and longitudinal healthcare settings, we demonstrate the effectiveness of order-contrastive pre-training in the small-data regime over supervised learning and other self-supervised pre-training baselines. Our results indicate that pre-training methods designed for particular classes of distributions and downstream tasks can improve the performance of self-supervised learning.

Luke Murray, Divya Gopinath, Monica Agrawal et al.

Clinical documentation can be transformed by Electronic Health Records, yet the documentation process is still a tedious, time-consuming, and error-prone process. Clinicians are faced with multi-faceted requirements and fragmented interfaces for information exploration and documentation. These challenges are only exacerbated in the Emergency Department -- clinicians often see 35 patients in one shift, during which they have to synthesize an often previously unknown patient's medical records in order to reach a tailored diagnosis and treatment plan. To better support this information synthesis, clinical documentation tools must enable rapid contextual access to the patient's medical record. MedKnowts is an integrated note-taking editor and information retrieval system which unifies the documentation and search process and provides concise synthesized concept-oriented slices of the patient's medical record. MedKnowts automatically captures structured data while still allowing users the flexibility of natural language. MedKnowts leverages this structure to enable easier parsing of long notes, auto-populated text, and proactive information retrieval, easing the documentation burden.

Ariel Levy, Monica Agrawal, Arvind Satyanarayan et al.

Automated decision support can accelerate tedious tasks as users can focus their attention where it is needed most. However, a key concern is whether users overly trust or cede agency to automation. In this paper, we investigate the effects of introducing automation to annotating clinical texts--a multi-step, error-prone task of identifying clinical concepts (e.g., procedures) in medical notes, and mapping them to labels in a large ontology. We consider two forms of decision aid: recommending which labels to map concepts to, and pre-populating annotation suggestions. Through laboratory studies, we find that 18 clinicians generally build intuition of when to rely on automation and when to exercise their own judgement. However, when presented with fully pre-populated suggestions, these expert users exhibit less agency: accepting improper mentions, and taking less initiative in creating additional annotations. Our findings inform how systems and algorithms should be designed to mitigate the observed issues.

Monica Agrawal, Chloe O'Connell, Yasmin Fatemi et al.

Clinical studies often require understanding elements of a patient's narrative that exist only in free text clinical notes. To transform notes into structured data for downstream use, these elements are commonly extracted and normalized to medical vocabularies. In this work, we audit the performance of and indicate areas of improvement for state-of-the-art systems. We find that high task accuracies for clinical entity normalization systems on the 2019 n2c2 Shared Task are misleading, and underlying performance is still brittle. Normalization accuracy is high for common concepts (95.3%), but much lower for concepts unseen in training data (69.3%). We demonstrate that current approaches are hindered in part by inconsistencies in medical vocabularies, limitations of existing labeling schemas, and narrow evaluation techniques. We reformulate the annotation framework for clinical entity extraction to factor in these issues to allow for robust end-to-end system benchmarking. We evaluate concordance of annotations from our new framework between two annotators and achieve a Jaccard similarity of 0.73 for entity recognition and an agreement of 0.83 for entity normalization. We propose a path forward to address the demonstrated need for the creation of a reference standard to spur method development in entity recognition and normalization.

Divya Gopinath, Monica Agrawal, Luke Murray et al.

We present a system that uses a learned autocompletion mechanism to facilitate rapid creation of semi-structured clinical documentation. We dynamically suggest relevant clinical concepts as a doctor drafts a note by leveraging features from both unstructured and structured medical data. By constraining our architecture to shallow neural networks, we are able to make these suggestions in real time. Furthermore, as our algorithm is used to write a note, we can automatically annotate the documentation with clean labels of clinical concepts drawn from medical vocabularies, making notes more structured and readable for physicians, patients, and future algorithms. To our knowledge, this system is the only machine learning-based documentation utility for clinical notes deployed in a live hospital setting, and it reduces keystroke burden of clinical concepts by 67% in real environments.

Alexander K. Lew, Monica Agrawal, David Sontag et al.

Data cleaning is naturally framed as probabilistic inference in a generative model of ground-truth data and likely errors, but the diversity of real-world error patterns and the hardness of inference make Bayesian approaches difficult to automate. We present PClean, a probabilistic programming language (PPL) for leveraging dataset-specific knowledge to automate Bayesian cleaning. Compared to general-purpose PPLs, PClean tackles a restricted problem domain, enabling three modeling and inference innovations: (1) a non-parametric model of relational database instances, which users' programs customize; (2) a novel sequential Monte Carlo inference algorithm that exploits the structure of PClean's model class; and (3) a compiler that generates near-optimal SMC proposals and blocked-Gibbs rejuvenation kernels based on the user's model and data. We show empirically that short (< 50-line) PClean programs can: be faster and more accurate than generic PPL inference on data-cleaning benchmarks; match state-of-the-art data-cleaning systems in terms of accuracy and runtime (unlike generic PPL inference in the same runtime); and scale to real-world datasets with millions of records.

Benjamin Birnbaum, Nathan Nussbaum, Katharina Seidl-Rathkopf et al.

Objective Electronic health records (EHRs) are a promising source of data for health outcomes research in oncology. A challenge in using EHR data is that selecting cohorts of patients often requires information in unstructured parts of the record. Machine learning has been used to address this, but even high-performing algorithms may select patients in a non-random manner and bias the resulting cohort. To improve the efficiency of cohort selection while measuring potential bias, we introduce a technique called Model-Assisted Cohort Selection (MACS) with Bias Analysis and apply it to the selection of metastatic breast cancer (mBC) patients. Materials and Methods We trained a model on 17,263 patients using term-frequency inverse-document-frequency (TF-IDF) and logistic regression. We used a test set of 17,292 patients to measure algorithm performance and perform Bias Analysis. We compared the cohort generated by MACS to the cohort that would have been generated without MACS as reference standard, first by comparing distributions of an extensive set of clinical and demographic variables and then by comparing the results of two analyses addressing existing example research questions. Results Our algorithm had an area under the curve (AUC) of 0.976, a sensitivity of 96.0%, and an abstraction efficiency gain of 77.9%. During Bias Analysis, we found no large differences in baseline characteristics and no differences in the example analyses. Conclusion MACS with bias analysis can significantly improve the efficiency of cohort selection on EHR data while instilling confidence that outcomes research performed on the resulting cohort will not be biased.

Irene Y. Chen, Monica Agrawal, Steven Horng et al.

Increasingly large electronic health records (EHRs) provide an opportunity to algorithmically learn medical knowledge. In one prominent example, a causal health knowledge graph could learn relationships between diseases and symptoms and then serve as a diagnostic tool to be refined with additional clinical input. Prior research has demonstrated the ability to construct such a graph from over 270,000 emergency department patient visits. In this work, we describe methods to evaluate a health knowledge graph for robustness. Moving beyond precision and recall, we analyze for which diseases and for which patients the graph is most accurate. We identify sample size and unmeasured confounders as major sources of error in the health knowledge graph. We introduce a method to leverage non-linear functions in building the causal graph to better understand existing model assumptions. Finally, to assess model generalizability, we extend to a larger set of complete patient visits within a hospital system. We conclude with a discussion on how to robustly extract medical knowledge from EHRs.

Monica Agrawal, Griffin Adams, Nathan Nussbaum et al.

Oral drugs are becoming increasingly common in oncology care. In contrast to intravenous chemotherapy, which is administered in the clinic and carefully tracked via structure electronic health records (EHRs), oral drug treatment is self-administered and therefore not tracked as well. Often, the details of oral cancer treatment occur only in unstructured clinic notes. Extracting this information is critical to understanding a patient's treatment history. Yet, this a challenging task because treatment intervals must be inferred longitudinally from both explicit mentions in the text as well as from document timestamps. In this work, we present TIFTI (Temporally Integrated Framework for Treatment Intervals), a robust framework for extracting oral drug treatment intervals from a patient's unstructured notes. TIFTI leverages distinct sources of temporal information by breaking the problem down into two separate subtasks: document-level sequence labeling and date extraction. On a labeled dataset of metastatic renal-cell carcinoma (RCC) patients, it exactly matched the labeled start date in 46% of the examples (86% of the examples within 30 days), and it exactly matched the labeled end date in 52% of the examples (78% of the examples within 30 days). Without retraining, the model achieved a similar level of performance on a labeled dataset of advanced non-small-cell lung cancer (NSCLC) patients.

Marinka Zitnik, Monica Agrawal, Jure Leskovec

The use of drug combinations, termed polypharmacy, is common to treat patients with complex diseases and co-existing conditions. However, a major consequence of polypharmacy is a much higher risk of adverse side effects for the patient. Polypharmacy side effects emerge because of drug-drug interactions, in which activity of one drug may change if taken with another drug. The knowledge of drug interactions is limited because these complex relationships are rare, and are usually not observed in relatively small clinical testing. Discovering polypharmacy side effects thus remains an important challenge with significant implications for patient mortality. Here, we present Decagon, an approach for modeling polypharmacy side effects. The approach constructs a multimodal graph of protein-protein interactions, drug-protein target interactions, and the polypharmacy side effects, which are represented as drug-drug interactions, where each side effect is an edge of a different type. Decagon is developed specifically to handle such multimodal graphs with a large number of edge types. Our approach develops a new graph convolutional neural network for multirelational link prediction in multimodal networks. Decagon predicts the exact side effect, if any, through which a given drug combination manifests clinically. Decagon accurately predicts polypharmacy side effects, outperforming baselines by up to 69%. We find that it automatically learns representations of side effects indicative of co-occurrence of polypharmacy in patients. Furthermore, Decagon models particularly well side effects with a strong molecular basis, while on predominantly non-molecular side effects, it achieves good performance because of effective sharing of model parameters across edge types. Decagon creates opportunities to use large pharmacogenomic and patient data to flag and prioritize side effects for follow-up analysis.

Monica Agrawal, Marinka Zitnik, Jure Leskovec

Discovering disease pathways, which can be defined as sets of proteins associated with a given disease, is an important problem that has the potential to provide clinically actionable insights for disease diagnosis, prognosis, and treatment. Computational methods aid the discovery by relying on protein-protein interaction (PPI) networks. They start with a few known disease-associated proteins and aim to find the rest of the pathway by exploring the PPI network around the known disease proteins. However, the success of such methods has been limited, and failure cases have not been well understood. Here we study the PPI network structure of 519 disease pathways. We find that 90% of pathways do not correspond to single well-connected components in the PPI network. Instead, proteins associated with a single disease tend to form many separate connected components/regions in the network. We then evaluate state-of-the-art disease pathway discovery methods and show that their performance is especially poor on diseases with disconnected pathways. Thus, we conclude that network connectivity structure alone may not be sufficient for disease pathway discovery. However, we show that higher-order network structures, such as small subgraphs of the pathway, provide a promising direction for the development of new methods.