Generalized Venn and Venn-Abers Calibration with Applications in Conformal Prediction

Ensuring model calibration is critical for reliable predictions, yet popular distribution-free methods, such as histogram binning and isotonic regression, provide only asymptotic guarantees. We introduce a unified framework for Venn and Venn-Abers calibration, generalizing Vovk's binary classification approach to arbitrary prediction tasks and loss functions. Venn calibration leverages binning calibrators to construct prediction sets that contain at least one marginally perfectly calibrated point prediction in finite samples, capturing epistemic uncertainty in the calibration process. The width of these sets shrinks asymptotically to zero, converging to a conditionally calibrated point prediction. Furthermore, we propose Venn multicalibration, a novel methodology for finite-sample calibration across subpopulations. For quantile loss, group-conditional and multicalibrated conformal prediction arise as special cases of Venn multicalibration, and Venn calibration produces novel conformal prediction intervals that achieve quantile-conditional coverage. As a separate contribution, we extend distribution-free conditional calibration guarantees of histogram binning and isotonic calibration to general losses.

Limitations of Large Language Models in Clinical Problem-Solving Arising from Inflexible Reasoning

Large Language Models (LLMs) have attained human-level accuracy on medical question-answer (QA) benchmarks. However, their limitations in navigating open-ended clinical scenarios have recently been shown, raising concerns about the robustness and generalizability of LLM reasoning across diverse, real-world medical tasks. To probe potential LLM failure modes in clinical problem-solving, we present the medical abstraction and reasoning corpus (M-ARC). M-ARC assesses clinical reasoning through scenarios designed to exploit the Einstellung effect -- the fixation of thought arising from prior experience, targeting LLM inductive biases toward inflexible pattern matching from their training data rather than engaging in flexible reasoning. We find that LLMs, including current state-of-the-art o1 and Gemini models, perform poorly compared to physicians on M-ARC, often demonstrating lack of commonsense medical reasoning and a propensity to hallucinate. In addition, uncertainty estimation analyses indicate that LLMs exhibit overconfidence in their answers, despite their limited accuracy. The failure modes revealed by M-ARC in LLM medical reasoning underscore the need to exercise caution when deploying these models in clinical settings.

Lifelong Sequential Knowledge Editing without Model Degradation

Prior work in parameter-modifying knowledge editing has shown that large-scale sequential editing leads to significant model degradation. In this paper, we study the reasons behind this and scale sequential knowledge editing to 10,000 sequential edits, while maintaining the downstream performance of the original model. We first show that locate-then-edit knowledge editing methods lead to overfitting on the edited facts. We also show that continuous knowledge editing using these methods leads to disproportionate growth in the norm of the edited matrix. We then provide a crucial insight into the inner workings of locate-then-edit methods. We show that norm-growth is a hidden trick employed by these methods that gives larger importance to the output activations produced from the edited layers. With this "importance hacking", the edited layers provide a much larger contributions to the model's output. To mitigate these issues, we present ENCORE - Early stopping and Norm-Constrained Robust knowledge Editing. ENCORE controls for overfitting and the disproportionate norm-growth to enable long-term sequential editing, where we are able to perform up to 10,000 sequential edits without loss of downstream performance. ENCORE is also 61% faster than MEMIT and 64% faster than AlphaEdit on Llama3-8B.

Conformal Prediction Sets with Improved Conditional Coverage using Trust Scores

Standard conformal prediction offers a marginal guarantee on coverage, but for prediction sets to be truly useful, they should ideally ensure coverage conditional on each test point. Unfortunately, it is impossible to achieve exact, distribution-free conditional coverage in finite samples. In this work, we propose an alternative conformal prediction algorithm that targets coverage where it matters most--in instances where a classifier is overconfident in its incorrect predictions. We start by dissecting miscoverage events in marginally-valid conformal prediction, and show that miscoverage rates vary based on the classifier's confidence and its deviation from the Bayes optimal classifier. Motivated by this insight, we develop a variant of conformal prediction that targets coverage conditional on a reduced set of two variables: the classifier's confidence in a prediction and a nonparametric trust score that measures its deviation from the Bayes classifier. Empirical evaluation on multiple image datasets shows that our method generally improves conditional coverage properties compared to standard conformal prediction, including class-conditional coverage, coverage over arbitrary subgroups, and coverage over demographic groups.

BioAgents: Democratizing Bioinformatics Analysis with Multi-Agent Systems

Creating end-to-end bioinformatics workflows requires diverse domain expertise, which poses challenges for both junior and senior researchers as it demands a deep understanding of both genomics concepts and computational techniques. While large language models (LLMs) provide some assistance, they often fall short in providing the nuanced guidance needed to execute complex bioinformatics tasks, and require expensive computing resources to achieve high performance. We thus propose a multi-agent system built on small language models, fine-tuned on bioinformatics data, and enhanced with retrieval augmented generation (RAG). Our system, BioAgents, enables local operation and personalization using proprietary data. We observe performance comparable to human experts on conceptual genomics tasks, and suggest next steps to enhance code generation capabilities.

Veridical Data Science for Medical Foundation Models

The advent of foundation models (FMs) such as large language models (LLMs) has led to a cultural shift in data science, both in medicine and beyond. This shift involves moving away from specialized predictive models trained for specific, well-defined domain questions to generalist FMs pre-trained on vast amounts of unstructured data, which can then be adapted to various clinical tasks and questions. As a result, the standard data science workflow in medicine has been fundamentally altered; the foundation model lifecycle (FMLC) now includes distinct upstream and downstream processes, in which computational resources, model and data access, and decision-making power are distributed among multiple stakeholders. At their core, FMs are fundamentally statistical models, and this new workflow challenges the principles of Veridical Data Science (VDS), hindering the rigorous statistical analysis expected in transparent and scientifically reproducible data science practices. We critically examine the medical FMLC in light of the core principles of VDS: predictability, computability, and stability (PCS), and explain how it deviates from the standard data science workflow. Finally, we propose recommendations for a reimagined medical FMLC that expands and refines the PCS principles for VDS including considering the computational and accessibility constraints inherent to FMs.

Generative AI Enables Medical Image Segmentation in Ultra Low-Data Regimes

Semantic segmentation of medical images is pivotal in applications like disease diagnosis and treatment planning. While deep learning has excelled in automating this task, a major hurdle is the need for numerous annotated segmentation masks, which are resource-intensive to produce due to the required expertise and time. This scenario often leads to ultra low-data regimes, where annotated images are extremely limited, posing significant challenges for the generalization of conventional deep learning methods on test images. To address this, we introduce a generative deep learning framework, which uniquely generates high-quality paired segmentation masks and medical images, serving as auxiliary data for training robust models in data-scarce environments. Unlike traditional generative models that treat data generation and segmentation model training as separate processes, our method employs multi-level optimization for end-to-end data generation. This approach allows segmentation performance to directly influence the data generation process, ensuring that the generated data is specifically tailored to enhance the performance of the segmentation model. Our method demonstrated strong generalization performance across 9 diverse medical image segmentation tasks and on 16 datasets, in ultra-low data regimes, spanning various diseases, organs, and imaging modalities. When applied to various segmentation models, it achieved performance improvements of 10-20\% (absolute), in both same-domain and out-of-domain scenarios. Notably, it requires 8 to 20 times less training data than existing methods to achieve comparable results. This advancement significantly improves the feasibility and cost-effectiveness of applying deep learning in medical imaging, particularly in scenarios with limited data availability.

Large Language Models as Co-Pilots for Causal Inference in Medical Studies

The validity of medical studies based on real-world clinical data, such as observational studies, depends on critical assumptions necessary for drawing causal conclusions about medical interventions. Many published studies are flawed because they violate these assumptions and entail biases such as residual confounding, selection bias, and misalignment between treatment and measurement times. Although researchers are aware of these pitfalls, they continue to occur because anticipating and addressing them in the context of a specific study can be challenging without a large, often unwieldy, interdisciplinary team with extensive expertise. To address this expertise gap, we explore the use of large language models (LLMs) as co-pilot tools to assist researchers in identifying study design flaws that undermine the validity of causal inferences. We propose a conceptual framework for LLMs as causal co-pilots that encode domain knowledge across various fields, engaging with researchers in natural language interactions to provide contextualized assistance in study design. We provide illustrative examples of how LLMs can function as causal co-pilots, propose a structured framework for their grounding in existing causal inference frameworks, and highlight the unique challenges and opportunities in adapting LLMs for reliable use in epidemiological research.

Mean-field Chaos Diffusion Models

In this paper, we introduce a new class of score-based generative models (SGMs) designed to handle high-cardinality data distributions by leveraging concepts from mean-field theory. We present mean-field chaos diffusion models (MF-CDMs), which address the curse of dimensionality inherent in high-cardinality data by utilizing the propagation of chaos property of interacting particles. By treating high-cardinality data as a large stochastic system of interacting particles, we develop a novel score-matching method for infinite-dimensional chaotic particle systems and propose an approximation scheme that employs a subdivision strategy for efficient training. Our theoretical and empirical results demonstrate the scalability and effectiveness of MF-CDMs for managing large high-cardinality data structures, such as 3D point clouds.

Prediction-powered Generalization of Causal Inferences

Causal inferences from a randomized controlled trial (RCT) may not pertain to a target population where some effect modifiers have a different distribution. Prior work studies generalizing the results of a trial to a target population with no outcome but covariate data available. We show how the limited size of trials makes generalization a statistically infeasible task, as it requires estimating complex nuisance functions. We develop generalization algorithms that supplement the trial data with a prediction model learned from an additional observational study (OS), without making any assumptions on the OS. We theoretically and empirically show that our methods facilitate better generalization when the OS is high-quality, and remain robust when it is not, and e.g., have unmeasured confounding.