Superhuman performance of a large language model on the reasoning tasks of a physician

Performance of large language models (LLMs) on medical tasks has traditionally been evaluated using multiple choice question benchmarks. However, such benchmarks are highly constrained, saturated with repeated impressive performance by LLMs, and have an unclear relationship to performance in real clinical scenarios. Clinical reasoning, the process by which physicians employ critical thinking to gather and synthesize clinical data to diagnose and manage medical problems, remains an attractive benchmark for model performance. Prior LLMs have shown promise in outperforming clinicians in routine and complex diagnostic scenarios. We sought to evaluate OpenAI's o1-preview model, a model developed to increase run-time via chain of thought processes prior to generating a response. We characterize the performance of o1-preview with five experiments including differential diagnosis generation, display of diagnostic reasoning, triage differential diagnosis, probabilistic reasoning, and management reasoning, adjudicated by physician experts with validated psychometrics. Our primary outcome was comparison of the o1-preview output to identical prior experiments that have historical human controls and benchmarks of previous LLMs. Significant improvements were observed with differential diagnosis generation and quality of diagnostic and management reasoning. No improvements were observed with probabilistic reasoning or triage differential diagnosis. This study highlights o1-preview's ability to perform strongly on tasks that require complex critical thinking such as diagnosis and management while its performance on probabilistic reasoning tasks was similar to past models. New robust benchmarks and scalable evaluation of LLM capabilities compared to human physicians are needed along with trials evaluating AI in real clinical settings.

Steering Language Model Refusal with Sparse Autoencoders

Responsible practices for deploying language models include guiding models to recognize and refuse answering prompts that are considered unsafe, while complying with safe prompts. Achieving such behavior typically requires updating model weights, which is costly and inflexible. We explore opportunities to steering model activations at inference time, which does not require updating weights. Using sparse autoencoders, we identify and steer features in Phi-3 Mini that mediate refusal behavior. We find that feature steering can improve Phi-3 Minis robustness to jailbreak attempts across various harms, including challenging multi-turn attacks. However, we discover that feature steering can adversely affect overall performance on benchmarks. These results suggest that identifying steerable mechanisms for refusal via sparse autoencoders is a promising approach for enhancing language model safety, but that more research is needed to mitigate feature steerings adverse effects on performance.

From Medprompt to o1: Exploration of Run-Time Strategies for Medical Challenge Problems and Beyond

Run-time steering strategies like Medprompt are valuable for guiding large language models (LLMs) to top performance on challenging tasks. Medprompt demonstrates that a general LLM can be focused to deliver state-of-the-art performance on specialized domains like medicine by using a prompt to elicit a run-time strategy involving chain of thought reasoning and ensembling. OpenAI's o1-preview model represents a new paradigm, where a model is designed to do run-time reasoning before generating final responses. We seek to understand the behavior of o1-preview on a diverse set of medical challenge problem benchmarks. Following on the Medprompt study with GPT-4, we systematically evaluate the o1-preview model across various medical benchmarks. Notably, even without prompting techniques, o1-preview largely outperforms the GPT-4 series with Medprompt. We further systematically study the efficacy of classic prompt engineering strategies, as represented by Medprompt, within the new paradigm of reasoning models. We found that few-shot prompting hinders o1's performance, suggesting that in-context learning may no longer be an effective steering approach for reasoning-native models. While ensembling remains viable, it is resource-intensive and requires careful cost-performance optimization. Our cost and accuracy analysis across run-time strategies reveals a Pareto frontier, with GPT-4o representing a more affordable option and o1-preview achieving state-of-the-art performance at higher cost. Although o1-preview offers top performance, GPT-4o with steering strategies like Medprompt retains value in specific contexts. Moreover, we note that the o1-preview model has reached near-saturation on many existing medical benchmarks, underscoring the need for new, challenging benchmarks. We close with reflections on general directions for inference-time computation with LLMs.

Decision-Focused Uncertainty Quantification

There is increasing interest in ''decision-focused'' machine learning methods which train models to account for how their predictions are used in downstream optimization problems. Doing so can often improve performance on subsequent decision problems. However, current methods for uncertainty quantification do not incorporate any information at all about downstream decisions. We develop a framework based on conformal prediction to produce prediction sets that account for a downstream decision loss function, making them more appropriate to inform high-stakes decision-making. Our approach harnesses the strengths of conformal methods--modularity, model-agnosticism, and statistical coverage guarantees--while incorporating downstream decisions and user-specified utility functions. We prove that our methods retain standard coverage guarantees. Empirical evaluation across a range of datasets and utility metrics demonstrates that our methods achieve significantly lower decision loss compared to standard conformal methods. Additionally, we present a real-world use case in healthcare diagnosis, where our method effectively incorporates the hierarchical structure of dermatological diseases. It successfully generates sets with coherent diagnostic meaning, aiding the triage process during dermatology diagnosis and illustrating how our method can ground high-stakes decision-making on external domain knowledge.

How to Build the Virtual Cell with Artificial Intelligence: Priorities and Opportunities

The cell is arguably the smallest unit of life and is central to understanding biology. Accurate modeling of cells is important for this understanding as well as for determining the root causes of disease. Recent advances in artificial intelligence (AI), combined with the ability to generate large-scale experimental data, present novel opportunities to model cells. Here we propose a vision of AI-powered Virtual Cells, where robust representations of cells and cellular systems under different conditions are directly learned from growing biological data across measurements and scales. We discuss desired capabilities of AI Virtual Cells, including generating universal representations of biological entities across scales, and facilitating interpretable in silico experiments to predict and understand their behavior using Virtual Instruments. We further address the challenges, opportunities and requirements to realize this vision including data needs, evaluation strategies, and community standards and engagement to ensure biological accuracy and broad utility. We envision a future where AI Virtual Cells help identify new drug targets, predict cellular responses to perturbations, as well as scale hypothesis exploration. With open science collaborations across the biomedical ecosystem that includes academia, philanthropy, and the biopharma and AI industries, a comprehensive predictive understanding of cell mechanisms and interactions is within reach.

MedFuzz: Exploring the Robustness of Large Language Models in Medical Question Answering

Large language models (LLM) have achieved impressive performance on medical question-answering benchmarks. However, high benchmark accuracy does not imply that the performance generalizes to real-world clinical settings. Medical question-answering benchmarks rely on assumptions consistent with quantifying LLM performance but that may not hold in the open world of the clinic. Yet LLMs learn broad knowledge that can help the LLM generalize to practical conditions regardless of unrealistic assumptions in celebrated benchmarks. We seek to quantify how well LLM medical question-answering benchmark performance generalizes when benchmark assumptions are violated. Specifically, we present an adversarial method that we call MedFuzz (for medical fuzzing). MedFuzz attempts to modify benchmark questions in ways aimed at confounding the LLM. We demonstrate the approach by targeting strong assumptions about patient characteristics presented in the MedQA benchmark. Successful "attacks" modify a benchmark item in ways that would be unlikely to fool a medical expert but nonetheless "trick" the LLM into changing from a correct to an incorrect answer. Further, we present a permutation test technique that can ensure a successful attack is statistically significant. We show how to use performance on a "MedFuzzed" benchmark, as well as individual successful attacks. The methods show promise at providing insights into the ability of an LLM to operate robustly in more realistic settings.

The Rise of the AI Co-Pilot: Lessons for Design from Aviation and Beyond

The fast pace of advances in AI promises to revolutionize various aspects of knowledge work, extending its influence to daily life and professional fields alike. We advocate for a paradigm where AI is seen as a collaborative co-pilot, working under human guidance rather than as a mere tool. Drawing from relevant research and literature in the disciplines of Human-Computer Interaction and Human Factors Engineering, we highlight the criticality of maintaining human oversight in AI interactions. Reflecting on lessons from aviation, we address the dangers of over-relying on automation, such as diminished human vigilance and skill erosion. Our paper proposes a design approach that emphasizes active human engagement, control, and skill enhancement in the AI partnership, aiming to foster a harmonious, effective, and empowering human-AI relationship. We particularly call out the critical need to design AI interaction capabilities and software applications to enable and celebrate the primacy of human agency. This calls for designs for human-AI partnership that cede ultimate control and responsibility to the human user as pilot, with the AI co-pilot acting in a well-defined supporting role.

Can Generalist Foundation Models Outcompete Special-Purpose Tuning? Case Study in Medicine

Generalist foundation models such as GPT-4 have displayed surprising capabilities in a wide variety of domains and tasks. Yet, there is a prevalent assumption that they cannot match specialist capabilities of fine-tuned models. For example, most explorations to date on medical competency benchmarks have leveraged domain-specific training, as exemplified by efforts on BioGPT and Med-PaLM. We build on a prior study of GPT-4's capabilities on medical challenge benchmarks in the absence of special training. Rather than using simple prompting to highlight the model's out-of-the-box capabilities, we perform a systematic exploration of prompt engineering. We find that prompting innovation can unlock deeper specialist capabilities and show that GPT-4 easily tops prior leading results for medical benchmarks. The prompting methods we explore are general purpose, and make no specific use of domain expertise, removing the need for expert-curated content. Our experimental design carefully controls for overfitting during the prompt engineering process. We introduce Medprompt, based on a composition of several prompting strategies. With Medprompt, GPT-4 achieves state-of-the-art results on all nine of the benchmark datasets in the MultiMedQA suite. The method outperforms leading specialist models such as Med-PaLM 2 by a significant margin with an order of magnitude fewer calls to the model. Steering GPT-4 with Medprompt achieves a 27% reduction in error rate on the MedQA dataset over the best methods to date achieved with specialist models and surpasses a score of 90% for the first time. Beyond medical problems, we show the power of Medprompt to generalize to other domains and provide evidence for the broad applicability of the approach via studies of the strategy on exams in electrical engineering, machine learning, philosophy, accounting, law, nursing, and clinical psychology.

Frontier AI Regulation: Managing Emerging Risks to Public Safety

Advanced AI models hold the promise of tremendous benefits for humanity, but society needs to proactively manage the accompanying risks. In this paper, we focus on what we term "frontier AI" models: highly capable foundation models that could possess dangerous capabilities sufficient to pose severe risks to public safety. Frontier AI models pose a distinct regulatory challenge: dangerous capabilities can arise unexpectedly; it is difficult to robustly prevent a deployed model from being misused; and, it is difficult to stop a model's capabilities from proliferating broadly. To address these challenges, at least three building blocks for the regulation of frontier models are needed: (1) standard-setting processes to identify appropriate requirements for frontier AI developers, (2) registration and reporting requirements to provide regulators with visibility into frontier AI development processes, and (3) mechanisms to ensure compliance with safety standards for the development and deployment of frontier AI models. Industry self-regulation is an important first step. However, wider societal discussions and government intervention will be needed to create standards and to ensure compliance with them. We consider several options to this end, including granting enforcement powers to supervisory authorities and licensure regimes for frontier AI models. Finally, we propose an initial set of safety standards. These include conducting pre-deployment risk assessments; external scrutiny of model behavior; using risk assessments to inform deployment decisions; and monitoring and responding to new information about model capabilities and uses post-deployment. We hope this discussion contributes to the broader conversation on how to balance public safety risks and innovation benefits from advances at the frontier of AI development.

Accurate Measures of Vaccination and Concerns of Vaccine Holdouts from Web Search Logs

To design effective vaccine policies, policymakers need detailed data about who has been vaccinated, who is holding out, and why. However, existing data in the US are insufficient: reported vaccination rates are often delayed or missing, and surveys of vaccine hesitancy are limited by high-level questions and self-report biases. Here, we show how large-scale search engine logs and machine learning can be leveraged to fill these gaps and provide novel insights about vaccine intentions and behaviors. First, we develop a vaccine intent classifier that can accurately detect when a user is seeking the COVID-19 vaccine on search. Our classifier demonstrates strong agreement with CDC vaccination rates, with correlations above 0.86, and estimates vaccine intent rates to the level of ZIP codes in real time, allowing us to pinpoint more granular trends in vaccine seeking across regions, demographics, and time. To investigate vaccine hesitancy, we use our classifier to identify two groups, vaccine early adopters and vaccine holdouts. We find that holdouts, compared to early adopters matched on covariates, are 69% more likely to click on untrusted news sites. Furthermore, we organize 25,000 vaccine-related URLs into a hierarchical ontology of vaccine concerns, and we find that holdouts are far more concerned about vaccine requirements, vaccine development and approval, and vaccine myths, and even within holdouts, concerns vary significantly across demographic groups. Finally, we explore the temporal dynamics of vaccine concerns and vaccine seeking, and find that key indicators emerge when individuals convert from holding out to preparing to accept the vaccine.