Russ B. Altman

Kara Liu, Maggie Wang, Russ B. Altman

Selection bias is a common and often unavoidable aspect of real-world data that challenges the generalizability of machine learning models. When models trained on biased data are deployed in the broader target population, poor model generalization may lead to real harm, particularly in high-risk settings such as healthcare. This risk highlights the need for practitioners to reliably assess model generalizability prior to deployment. However, existing methods for predicting model performance rely on unrealistic access to the target distribution or knowledge of the selection mechanism causing bias. To address these limitations, we propose a novel upper bound on the worst-case model performance on the target population under the realistic setting where the selection mechanism and the target population data are only partially observed. We demonstrate the validity and practical utility of our method through experiments on fully synthetic data, semi-synthetic data derived from the All of Us Research Program, and real-world selection bias in MIMIC-IV. Our work offers a principled and practical tool to estimate the impact of selection bias in an otherwise intractable setting, thereby enabling practitioners to build safer and more generalizable models in healthcare and beyond.

Lu Yang, Sheng Wang, Russ B. Altman

Objective For the UK Biobank standardized phenotype codes are associated with patients who have been hospitalized but are missing for many patients who have been treated exclusively in an outpatient setting. We describe a method for phenotype recognition that imputes phenotype codes for all UK Biobank participants. Materials and Methods POPDx (Population-based Objective Phenotyping by Deep Extrapolation) is a bilinear machine learning framework for simultaneously estimating the probabilities of 1,538 phenotype codes. We extracted phenotypic and health-related information of 392,246 individuals from the UK Biobank for POPDx development and evaluation. A total of 12,803 ICD-10 diagnosis codes of the patients were converted to 1,538 Phecodes as gold standard labels. The POPDx framework was evaluated and compared to other available methods on automated multi-phenotype recognition. Results POPDx can predict phenotypes that are rare or even unobserved in training. We demonstrate substantial improvement of automated multi-phenotype recognition across 22 disease categories, and its application in identifying key epidemiological features associated with each phenotype. Conclusions POPDx helps provide well-defined cohorts for downstream studies. It is a general purpose method that can be applied to other biobanks with diverse but incomplete data.

Daniel N. Sosa, Malavika Suresh, Christopher Potts et al.

The COVID-19 pandemic created a deluge of questionable and contradictory scientific claims about drug efficacy -- an "infodemic" with lasting consequences for science and society. In this work, we argue that NLP models can help domain experts distill and understand the literature in this complex, high-stakes area. Our task is to automatically identify contradictory claims about COVID-19 drug efficacy. We frame this as a natural language inference problem and offer a new NLI dataset created by domain experts. The NLI framing allows us to create curricula combining existing datasets and our own. The resulting models are useful investigative tools. We provide a case study of how these models help a domain expert summarize and assess evidence concerning remdisivir and hydroxychloroquine.

Raphael J. L. Townshend, Martin Vögele, Patricia Suriana et al.

Computational methods that operate on three-dimensional molecular structure have the potential to solve important questions in biology and chemistry. In particular, deep neural networks have gained significant attention, but their widespread adoption in the biomolecular domain has been limited by a lack of either systematic performance benchmarks or a unified toolkit for interacting with molecular data. To address this, we present ATOM3D, a collection of both novel and existing benchmark datasets spanning several key classes of biomolecules. We implement several classes of three-dimensional molecular learning methods for each of these tasks and show that they consistently improve performance relative to methods based on one- and two-dimensional representations. The specific choice of architecture proves to be critical for performance, with three-dimensional convolutional networks excelling at tasks involving complex geometries, graph networks performing well on systems requiring detailed positional information, and the more recently developed equivariant networks showing significant promise. Our results indicate that many molecular problems stand to gain from three-dimensional molecular learning, and that there is potential for improvement on many tasks which remain underexplored. To lower the barrier to entry and facilitate further developments in the field, we also provide a comprehensive suite of tools for dataset processing, model training, and evaluation in our open-source atom3d Python package. All datasets are available for download from https://www.atom3d.ai .

Yuanhao Qu, Kaixuan Huang, Ming Yin et al.

The introduction of genome engineering technology has transformed biomedical research, making it possible to make precise changes to genetic information. However, creating an efficient gene-editing system requires a deep understanding of CRISPR technology, and the complex experimental systems under investigation. While Large Language Models (LLMs) have shown promise in various tasks, they often lack specific knowledge and struggle to accurately solve biological design problems. In this work, we introduce CRISPR-GPT, an LLM agent augmented with domain knowledge and external tools to automate and enhance the design process of CRISPR-based gene-editing experiments. CRISPR-GPT leverages the reasoning ability of LLMs to facilitate the process of selecting CRISPR systems, designing guide RNAs, recommending cellular delivery methods, drafting protocols, and designing validation experiments to confirm editing outcomes. We showcase the potential of CRISPR-GPT for assisting non-expert researchers with gene-editing experiments from scratch and validate the agent's effectiveness in a real-world use case. Furthermore, we explore the ethical and regulatory considerations associated with automated gene-editing design, highlighting the need for responsible and transparent use of these tools. Our work aims to bridge the gap between beginner biological researchers and CRISPR genome engineering techniques, and demonstrate the potential of LLM agents in facilitating complex biological discovery tasks. The published version of this draft is available at https://www.nature.com/articles/s41551-025-01463-z.

Kristy A. Carpenter, Issah A. Samori, Mathew V. Kiang et al.

Social media text shows promise for monitoring trends in the opioid overdose crisis; however, the overwhelming majority of social media text is unrelated to opioids. When leveraging social media text to monitor trends in the ongoing opioid overdose crisis, a common strategy for identifying relevant content is to use a lexicon of opioid-related terms as inclusion criteria. However, many slang terms for opioids, such as "smack" or "blues," have common non-opioid meanings, making them ambiguous. The advanced textual reasoning capability of large language models (LLMs) presents an opportunity to disambiguate these slang terms at scale. We present three tasks on which to evaluate four state-of-the-art LLMs (GPT-4, GPT-5, Gemini 2.5 Pro, and Claude Sonnet 4.5): a lexicon-based setting, in which the LLM must disambiguate a specific term within the context of a given post; a lexicon-free setting, in which the LLM must identify opioid-related posts from context without a lexicon; and an emergent slang setting, in which the LLM must identify opioid-related posts with simulated new slang terms. All four LLMs showed excellent performance across all tasks. In both subtasks of the lexicon-based setting, LLM F1 scores ("fenty" subtask: 0.824-0.972; "smack" subtask: 0.540-0.862) far exceeded those of the best lexicon strategy (0.126 and 0.009, respectively). In the lexicon-free task, LLM F1 scores (0.544-0.769) surpassed those of lexicons (0.080-0.540), and LLMs demonstrated uniformly higher recall. On emergent slang, all LLMs had higher accuracy (average: 0.784), F1 score (average: 0.712), precision (average: 0.981), and recall (average: 0.587) than the two lexicons assessed. Our results show that LLMs can be used to identify relevant content for low-prevalence topics, including but not limited to opioid references, enhancing data provided to downstream analyses and predictive models.

Aloysius Ochasi, Abdoul Jalil Djiberou Mahamadou, Russ B. Altman

There is an ongoing debate on balancing the benefits and risks of artificial intelligence (AI) as AI is becoming critical to improving healthcare delivery and patient outcomes. Such improvements are essential in resource-constrained settings where millions lack access to adequate healthcare services, such as in Africa. AI in such a context can potentially improve the effectiveness, efficiency, and accessibility of healthcare services. Nevertheless, the development and use of AI-driven healthcare systems raise numerous ethical, legal, and socio-economic issues. Justice is a major concern in AI that has implications for amplifying social inequities. This paper discusses these implications and related justice concepts such as solidarity, Common Good, sustainability, AI bias, and fairness. For Africa to effectively benefit from AI, these principles should align with the local context while balancing the risks. Compared to mainstream ethical debates on justice, this perspective offers context-specific considerations for equitable healthcare AI development in Africa.

Abdoul Jalil Djiberou Mahamadou, Aloysius Ochasi, Russ B. Altman

Data are essential in developing healthcare artificial intelligence (AI) systems. However, patient data collection, access, and use raise ethical concerns, including informed consent, data bias, data protection and privacy, data ownership, and benefit sharing. Various ethical frameworks have been proposed to ensure the ethical use of healthcare data and AI, however, these frameworks often align with Western cultural values, social norms, and institutional contexts emphasizing individual autonomy and well-being. Ethical guidelines must reflect political and cultural settings to account for cultural diversity, inclusivity, and historical factors such as colonialism. Thus, this paper discusses healthcare data ethics in the AI era in Africa from the Ubuntu philosophy perspective. It focuses on the contrast between individualistic and communitarian approaches to data ethics. The proposed framework could inform stakeholders, including AI developers, healthcare providers, the public, and policy-makers about healthcare data ethical usage in AI in Africa.

Russ B. Altman

We have developed a general Bayesian algorithm for determining the coordinates of points in a three-dimensional space. The algorithm takes as input a set of probabilistic constraints on the coordinates of the points, and an a priori distribution for each point location. The output is a maximum-likelihood estimate of the location of each point. We use the extended, iterated Kalman filter, and add a search heuristic for optimizing its solution under nonlinear conditions. This heuristic is based on the same principle as the simulated annealing heuristic for other optimization problems. Our method uses any probabilistic constraints that can be expressed as a function of the point coordinates (for example, distance, angles, dihedral angles, and planarity). It assumes that all constraints have Gaussian noise. In this paper, we describe the algorithm and show its performance on a set of synthetic data to illustrate its convergence properties, and its applicability to domains such ng molecular structure determination.

Russ B. Altman, Cheng C. Chen, William B. Poland et al.

We have previously reported a Bayesian algorithm for determining the coordinates of points in three-dimensional space from uncertain constraints. This method is useful in the determination of biological molecular structure. It is limited, however, by the requirement that the uncertainty in the constraints be normally distributed. In this paper, we present an extension of the original algorithm that allows constraint uncertainty to be represented as a mixture of Gaussians, and thereby allows arbitrary constraint distributions. We illustrate the performance of this algorithm on a problem drawn from the domain of molecular structure determination, in which a multicomponent constraint representation produces a much more accurate solution than the old single component mechanism. The new mechanism uses mixture distributions to decompose the problem into a set of independent problems with unimodal constraint uncertainty. The results of the unimodal subproblems are periodically recombined using Bayes' law, to avoid combinatorial explosion. The new algorithm is particularly suited for parallel implementation.