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Levine, K. S.

Publications and source records attributed to Levine, K. S..

3 recordsLinked to original sources

CARDBiomedBench: A Benchmark for Evaluating Large Language Model Performance in Biomedical Research

BackgroundsBiomedical research requires sophisticated understanding and reasoning across multiple specializations. While large language models (LLMs) show promise in scientific applications, their capability to safely and accurately support complex biomedical research remains uncertain. MethodsWe present CARDBiomedBench, a novel question-and-answer benchmark for evaluating LLMs in biomedical research. For our pilot implementation, we focus on neurodegenerative diseases (NDDs), a domain requiring integration of genetic, molecular, and clinical knowledge. The benchmark combines expert-annotated question-answer (Q/A) pairs with semi-automated data augmentation, drawing from authoritative public resources including drug development data, genome-wide association studies (GWAS), and Summary-data based Mendelian Randomization (SMR) analyses. We evaluated seven private and open-source LLMs across ten biological categories and nine reasoning skills, using novel metrics to assess both response quality and safety. ResultsOur benchmark comprises over 68,000 Q/A pairs, enabling robust evaluation of LLM performance. Current state-of-the-art models show significant limitations: models like Claude-3.5-Sonnet demonstrates excessive caution (Response Quality Rate: 25% [95% CI: 25% {+/-} 1], Safety Rate: 76% {+/-} 1), while others like ChatGPT-4o exhibits both poor accuracy and unsafe behavior (Response Quality Rate: 37% {+/-} 1, Safety Rate: 31% {+/-} 1). These findings reveal fundamental gaps in LLMs ability to handle complex biomedical information. ConclusionCARDBiomedBench establishes a rigorous standard for assessing LLM capabilities in biomedical research. Our pilot evaluation in the NDD domain reveals critical limitations in current models ability to safely and accurately process complex scientific information. Future iterations will expand to other biomedical domains, supporting the development of more reliable AI systems for accelerating scientific discovery.

bioinformatics↗

Monovalent XBB.1.5 mRNA Vaccine Recalls a More Durable and Coordinated Antibody Response to SARS-CoV-2 Spike than the Bivalent WT/BA.5 mRNA Vaccine

In the fall of 2023, the monovalent XBB.1.5 mRNA vaccine for COVID-19 became available. However, the comparative magnitude, durability, and functionality of antibody responses induced by the XBB.1.5 vaccine compared with the 2022-2023 bivalent wildtype (WT) + Omicron BA.5 vaccine remains to be fully determined. In this study, we compared antibody profiles generated by these two vaccines in healthcare workers. We show that the monovalent XBB.1.5 vaccine induced higher magnitude binding, neutralizing, and Fc-gamma receptor (Fc{gamma}R) binding antibodies to the XBB.1.5 spike compared with the bivalent vaccine against the WT and BA.5 spikes, both at both peak immunogenicity and at 6 months post-vaccination. Moreover, antibody interaction architectures and correlations remained more robust at 6 months post-vaccination with the XBB.1.5 vaccine, whereas these correlations were largely lost at 6 months with the bivalent vaccine. Our results suggest that the XBB.1.5 vaccine led to a more durable and functionally coordinated antibody response compared to the bivalent vaccine.

immunology↗

iSCORE-PD: an isogenic stem cell collection to research Parkinson Disease

Parkinsons disease (PD) is a neurodegenerative disorder caused by complex genetic and environmental factors. Genome-edited human pluripotent stem cells (hPSCs) offer a unique experimental platform to advance our understanding of PD etiology by enabling the generation of disease-relevant cell types carrying patient mutations along with isogenic control cells. To facilitate this approach, we generated a collection of 65 human stem cell lines genetically engineered to harbor high risk or causal variants in genes associated with PD (SNCA A53T, SNCA A30P, PRKN Ex3del, PINK1 Q129X, DJ1/PARK7 Ex1-5del, LRRK2 G2019S, ATP13A2 FS, FBXO7 R498X/FS, DNAJC6 c.801 A>G/FS, SYNJ1 R258Q/FS, VPS13C A444P/FS, VPS13C W395C/FS, GBA1 IVS2+1/FS). All mutations were introduced into a fully characterized and sequenced female human embryonic stem cell (hESC) line (WIBR3; NIH approval number NIHhESC-10-0079) using different genome editing techniques. To ensure the genetic integrity of these cell lines, we implemented rigorous quality controls, including whole-genome sequencing of each line. Our analysis of the genetic variation in this cell line collection revealed that while genome editing, particularly using CRISPR/Cas9, can introduce rare off-target mutations, the predominant source of genetic variants arises from routine cell culture and are fixed in cell lines during clonal isolation. The observed genetic variation was minimal compared to that typically found in patient-derived iPSC experiments and predominantly affected non-coding regions of the genome. Importantly, our analysis outlines strategies for effectively managing genetic variation through stringent quality control measures and careful experimental design. This systematic approach ensures the high quality of our stem cell collection, highlights advantages of prime editing over conventional CRISPR/Cas9 methods and provides a roadmap for the generation of gene-edited hPSC collections at scale in an academic setting. Our iSCORE-PD collection represents an easily accessible and valuable platform to study PD, which can be used by investigators to understand the molecular pathophysiology of PD in a human cellular setting.

neuroscience↗