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Term normalization is the process of mapping a term from free text to a standardized concept and its machine-readable code in an ontology. Accurate normalization of terms that capture phenotypic differences between patients and diseases is critical to the success of precision medicine initiatives. A large language model (LLM), such as GPT-4o, can normalize terms to the Human Phenotype Ontology (HPO), but it may retrieve incorrect HPO IDs. Reported accuracy rates for LLMs on these tasks may be inflated due to imbalanced test datasets skewed towards high-frequency terms. In our study, using a comprehensive dataset of 268,776 phenotype annotations for 12,655 diseases from the HPO, GPT-4o achieved an accuracy of 13.1% in normalizing 11,225 unique terms. However, the accuracy was unevenly distributed, with higher-frequency and shorter terms normalized more accurately than lower-frequency and longer terms. Feature importance analysis, using SHAP and permutation methods, identified low-term frequency as the most significant predictor of normalization errors. These findings suggest that training and evaluation datasets for LLM-based term normalization should balance low- and high-frequency terms to improve model performance, particularly for infrequent terms critical to precision medicine.

Large language models (LLMs) have shown improved accuracy in phenotype term normalization tasks when augmented with retrievers that suggest candidate normalizations based on term definitions. In this work, we introduce a simplified retriever that enhances LLM accuracy by searching the Human Phenotype Ontology (HPO) for candidate matches using contextual word embeddings from BioBERT without the need for explicit term definitions. Testing this method on terms derived from the clinical synopses of Online Mendelian Inheritance in Man (OMIM), we demonstrate that the normalization accuracy of a state-of-the-art LLM increases from a baseline of 62.3% without augmentation to 90.3% with retriever augmentation. This approach is potentially generalizable to other biomedical term normalization tasks and offers an efficient alternative to more complex retrieval methods., Comment: Submitted to Frontiers in Digital Health

High-throughput phenotyping automates the mapping of patient signs to standardized ontology concepts and is essential for precision medicine. This study evaluates the automation of phenotyping of clinical summaries from the Online Mendelian Inheritance in Man (OMIM) database using large language models. Due to their rich phenotype data, these summaries can be surrogates for physician notes. We conduct a performance comparison of GPT-4 and GPT-3.5-Turbo. Our results indicate that GPT-4 surpasses GPT-3.5-Turbo in identifying, categorizing, and normalizing signs, achieving concordance with manual annotators comparable to inter-rater agreement. Despite some limitations in sign normalization, the extensive pre-training of GPT-4 results in high performance and generalizability across several phenotyping tasks while obviating the need for manually annotated training data. Large language models are expected to be the dominant method for automating high-throughput phenotyping of clinical text., Comment: Submitted to IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI), Houston TX

Dimension reduction is increasingly applied to high-dimensional biomedical data to improve its interpretability. When datasets are reduced to two dimensions, each observation is assigned an x and y coordinates and is represented as a point on a scatter plot. A significant challenge lies in interpreting the meaning of the x and y axes due to the complexities inherent in dimension reduction. This study addresses this challenge by using the x and y coordinates derived from dimension reduction to calculate class and feature centroids, which can be overlaid onto the scatter plots. This method connects the low-dimension space to the original high-dimensional space. We illustrate the utility of this approach with data derived from the phenotypes of three neurogenetic diseases and demonstrate how the addition of class and feature centroids increases the interpretability of scatter plots., Comment: Submitted to 46th Annual International Conference of the IEEE Engineering in Medicine and Biology Society