We haven't always been right (RIP, Baxter), but we've often been early to spot important areas of progress (we put natural-language processing on our very first list in 2001; today this technology underpins large language models and generative AI tools like ChatGPT). Every year, our reporters and editors nominate technologies that they think deserve a spot, and we spend weeks debating which ones should make the cut. Here are some of the technologies we didn't pick this time--and why we've left them off, for now. Alzmeiher's patients have long lacked treatment options. Several new drugs have now been proved to slow cognitive decline, albeit modestly, by clearing out harmful plaques in the brain.

The incredible capabilities of generative artificial intelligence models have inevitably led to their application in the domain of drug discovery. Within this domain, the vastness of chemical space motivates the development of more efficient methods for identifying regions with molecules that exhibit desired characteristics. In this work, we present a computationally efficient active learning methodology that requires evaluation of only a subset of the generated data in the constructed sample space to successfully align a generative model with respect to a specified objective. We demonstrate the applicability of this methodology to targeted molecular generation by fine-tuning a GPT-based molecular generator toward a protein with FDA-approved small-molecule inhibitors, c-Abl kinase. Remarkably, the model learns to generate molecules similar to the inhibitors without prior knowledge of their existence, and even reproduces two of them exactly. We also show that the methodology is effective for a protein without any commercially available small-molecule inhibitors, the HNH domain of the CRISPR-associated protein 9 (Cas9) enzyme. We believe that the inherent generality of this method ensures that it will remain applicable as the exciting field of in silico molecular generation evolves. To facilitate implementation and reproducibility, we have made all of our software available through the open-source ChemSpaceAL Python package.

Longer timelines and lower success rates of drug candidates limit the productivity of clinical trials in the pharmaceutical industry. Promising de novo drug design techniques help solve this by exploring a broader chemical space, efficiently generating new molecules, and providing improved therapies. However, optimizing for molecular characteristics found in approved oral drugs remains a challenge, limiting de novo usage. In this work, we propose NovoMol, a novel de novo method using recurrent neural networks to mass-generate drug molecules with high oral bioavailability, increasing clinical trial time efficiency. Molecules were optimized for desirable traits and ranked using the quantitative estimate of drug-likeness (QED). Generated molecules meeting QED's oral bioavailability threshold were used to retrain the neural network, and, after five training cycles, 76% of generated molecules passed this strict threshold and 96% passed the traditionally used Lipinski's Rule of Five. The trained model was then used to generate specific drug candidates for the cancer-related PDGFR{\alpha} receptor and 44% of generated candidates had better binding affinity than the current state-of-the-art drug, Imatinib (with a receptor binding affinity of -9.4 kcal/mol), and the best-generated candidate at -12.9 kcal/mol. NovoMol provides a time/cost-efficient AI-based de novo method offering promising drug candidates for clinical trials.

The escalating drug addiction crisis in the United States underscores the urgent need for innovative therapeutic strategies. This study embarked on an innovative and rigorous strategy to unearth potential drug repurposing candidates for opioid and cocaine addiction treatment, bridging the gap between transcriptomic data analysis and drug discovery. We initiated our approach by conducting differential gene expression analysis on addiction-related transcriptomic data to identify key genes. We propose a novel topological differentiation to identify key genes from a protein-protein interaction (PPI) network derived from DEGs. This method utilizes persistent Laplacians to accurately single out pivotal nodes within the network, conducting this analysis in a multiscale manner to ensure high reliability. Through rigorous literature validation, pathway analysis, and data-availability scrutiny, we identified three pivotal molecular targets, mTOR, mGluR5, and NMDAR, for drug repurposing from DrugBank. We crafted machine learning models employing two natural language processing (NLP)-based embeddings and a traditional 2D fingerprint, which demonstrated robust predictive ability in gauging binding affinities of DrugBank compounds to selected targets. Furthermore, we elucidated the interactions of promising drugs with the targets and evaluated their drug-likeness. This study delineates a multi-faceted and comprehensive analytical framework, amalgamating bioinformatics, topological data analysis and machine learning, for drug repurposing in addiction treatment, setting the stage for subsequent experimental validation. The versatility of the methods we developed allows for applications across a range of diseases and transcriptomic datasets.

The significance: These emissions will add up quickly. The generative-AI boom has led big tech companies to integrate powerful AI models into many different products, from email to word processing. They are now used millions, if not billions, of times every single day. The bigger picture: The study shows that while training massive AI models is incredibly energy intensive, it's only one part of the puzzle. Most of their carbon footprint comes from their actual use.

Large Language Models (LLMs) have been driving progress in AI at an unprecedented rate, yet still face challenges in knowledge-intensive domains like biomedicine. Solutions such as pre-training and domain-specific fine-tuning add substantial computational overhead, and the latter require domain-expertise. External knowledge infusion is task-specific and requires model training. Here, we introduce a task-agnostic Knowledge Graph-based Retrieval Augmented Generation (KG-RAG) framework by leveraging the massive biomedical KG SPOKE with LLMs such as Llama-2-13b, GPT-3.5-Turbo and GPT-4, to generate meaningful biomedical text rooted in established knowledge. KG-RAG consistently enhanced the performance of LLMs across various prompt types, including one-hop and two-hop prompts, drug repurposing queries, biomedical true/false questions, and multiple-choice questions (MCQ). Notably, KG-RAG provides a remarkable 71% boost in the performance of the Llama-2 model on the challenging MCQ dataset, demonstrating the framework's capacity to empower open-source models with fewer parameters for domain-specific questions. Furthermore, KG-RAG enhanced the performance of proprietary GPT models, such as GPT-3.5 which exhibited improvement over GPT-4 in context utilization on MCQ data. Our approach was also able to address drug repurposing questions, returning meaningful repurposing suggestions. In summary, the proposed framework combines explicit and implicit knowledge of KG and LLM, respectively, in an optimized fashion, thus enhancing the adaptability of general-purpose LLMs to tackle domain-specific questions in a unified framework.

Effective and rapid decision-making from randomized controlled trials (RCTs) requires unbiased and precise treatment effect inferences. Two strategies to address this requirement are to adjust for covariates that are highly correlated with the outcome, and to leverage historical control information via Bayes' theorem. We propose a new Bayesian prognostic covariate adjustment methodology, referred to as Bayesian PROCOVA, that combines these two strategies. Covariate adjustment in Bayesian PROCOVA is based on generative artificial intelligence (AI) algorithms that construct a digital twin generator (DTG) for RCT participants. The DTG is trained on historical control data and yields a digital twin (DT) probability distribution for each RCT participant's outcome under the control treatment. The expectation of the DT distribution, referred to as the prognostic score, defines the covariate for adjustment. Historical control information is leveraged via an additive mixture prior with two components: an informative prior probability distribution specified based on historical control data, and a weakly informative prior distribution. The mixture weight determines the extent to which posterior inferences are drawn from the informative component, versus the weakly informative component. This weight has a prior distribution as well, and so the entire additive mixture prior is completely pre-specifiable without involving any RCT information. We establish an efficient Gibbs algorithm for sampling from the posterior distribution, and derive closed-form expressions for the posterior mean and variance of the treatment effect parameter conditional on the weight, in Bayesian PROCOVA. We evaluate efficiency gains of Bayesian PROCOVA via its bias control and variance reduction compared to frequentist PROCOVA in simulation studies that encompass different discrepancies. These gains translate to smaller RCTs.

This study concentrates on evaluating the efficacy of Large Language Models (LLMs) in healthcare, with a specific focus on their application in personal anomalous health monitoring. Our research primarily investigates the capabilities of LLMs in interpreting and analyzing physiological data obtained from FDA-approved devices. We conducted an extensive analysis using anomalous physiological data gathered in a simulated low-air-pressure plateau environment. This allowed us to assess the precision and reliability of LLMs in understanding and evaluating users' health status with notable specificity. Our findings reveal that LLMs exhibit exceptional performance in determining medical indicators, including a Mean Absolute Error (MAE) of less than 1 beat per minute for heart rate and less than 1% for oxygen saturation (SpO2). Furthermore, the Mean Absolute Percentage Error (MAPE) for these evaluations remained below 1%, with the overall accuracy of health assessments surpassing 85%. In image analysis tasks, such as interpreting photoplethysmography (PPG) data, our specially adapted GPT models demonstrated remarkable proficiency, achieving less than 1 bpm error in cycle count and 7.28 MAE for heart rate estimation. This study highlights LLMs' dual role as health data analysis tools and pivotal elements in advanced AI health assistants, offering personalized health insights and recommendations within the future health assistant framework.

After a machine learning (ML)-based system is deployed in clinical practice, performance monitoring is important to ensure the safety and effectiveness of the algorithm over time. The goal of this work is to highlight the complexity of designing a monitoring strategy and the need for a systematic framework that compares the multitude of monitoring options. One of the main decisions is choosing between using real-world (observational) versus interventional data. Although the former is the most convenient source of monitoring data, it exhibits well-known biases, such as confounding, selection, and missingness. In fact, when the ML algorithm interacts with its environment, the algorithm itself may be a primary source of bias. On the other hand, a carefully designed interventional study that randomizes individuals can explicitly eliminate such biases, but the ethics, feasibility, and cost of such an approach must be carefully considered. Beyond the decision of the data source, monitoring strategies vary in the performance criteria they track, the interpretability of the test statistics, the strength of their assumptions, and their speed at detecting performance decay. As a first step towards developing a framework that compares the various monitoring options, we consider a case study of an ML-based risk prediction algorithm for postoperative nausea and vomiting (PONV). Bringing together tools from causal inference and statistical process control, we walk through the basic steps of defining candidate monitoring criteria, describing potential sources of bias and the causal model, and specifying and comparing candidate monitoring procedures. We hypothesize that these steps can be applied more generally, as causal inference can address other sources of biases as well.

This study introduces a novel, rich dataset obtained from home sleep apnea tests using the FDA-approved WatchPAT-300 device, collected from 7,077 participants over 21,412 nights. The dataset comprises three levels of sleep data: raw multi-channel time-series from sensors, annotated sleep events, and computed summary statistics, which include 447 features related to sleep architecture, sleep apnea, and heart rate variability (HRV). We present reference values for Apnea/Hypopnea Index (AHI), sleep efficiency, Wake After Sleep Onset (WASO), and HRV sample entropy, stratified by age and sex. Moreover, we demonstrate that the dataset improves the predictive capability for various health related traits, including body composition, bone density, blood sugar levels and cardiovascular health. These results illustrate the dataset's potential to advance sleep research, personalized healthcare, and machine learning applications in biomedicine.