Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing最新文献

{"title":"PGxQA: A Resource for Evaluating LLM Performance for Pharmacogenomic QA Tasks.","authors":"Karl Keat, Rasika Venkatesh, Yidi Huang, Rachit Kumar, Sony Tuteja, Katrin Sangkuhl, Binglan Li, Li Gong, Michelle Whirl-Carrillo, Teri E Klein, Marylyn D Ritchie, Dokyoon Kim","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Pharmacogenetics represents one of the most promising areas of precision medicine, with several guidelines for genetics-guided treatment ready for clinical use. Despite this, implementation has been slow, with few health systems incorporating the technology into their standard of care. One major barrier to uptake is the lack of education and awareness of pharmacogenetics among clinicians and patients. The introduction of large language models (LLMs) like GPT-4 has raised the possibility of medical chatbots that deliver timely information to clinicians, patients, and researchers with a simple interface. Although state-of-the-art LLMs have shown impressive performance at advanced tasks like medical licensing exams, in practice they still often provide false information, which is particularly hazardous in a clinical context. To quantify the extent of this issue, we developed a series of automated and expert-scored tests to evaluate the performance of chatbots in answering pharmacogenetics questions from the perspective of clinicians, patients, and researchers. We applied this benchmark to state-of-the-art LLMs and found that newer models like GPT-4o greatly outperform their predecessors, but still fall short of the standards required for clinical use. Our benchmark will be a valuable public resource for subsequent developments in this space as we work towards better clinical AI for pharmacogenetics.</p>","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"30 ","pages":"229-246"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constructing a multi-ancestry polygenic risk score for uterine fibroids using publicly available data highlights need for inclusive genetic research.","authors":"Jessica L G Winters, Jacqueline A Piekos, Jacklyn N Hellwege, Ozan Dikilitas, Iftikhar J Kullo, Daniel J Schaid, Todd L Edwards, Digna R Velez Edwards","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Uterine leiomyomata, or fibroids, are common gynecological tumors causing pelvic and menstrual symptoms that can negatively affect quality of life and child-bearing desires. As fibroids grow, symptoms can intensify and lead to invasive treatments that are less likely to preserve fertility. Identifying individuals at highest risk for fibroids can aid in access to earlier diagnoses. Polygenic risk scores (PRS) quantify genetic risk to identify those at highest risk for disease. Utilizing the PRS software PRS-CSx and publicly available genome-wide association study (GWAS) summary statistics from FinnGen and Biobank Japan, we constructed a multi-ancestry (META) PRS for fibroids. We validated the META PRS in two cross-ancestry cohorts. In the cross-ancestry Electronic Medical Record and Genomics (eMERGE) Network cohort, the META PRS was significantly associated with fibroid status and exhibited 1.11 greater odds for fibroids per standard deviation increase in PRS (95% confidence interval [CI]: 1.05 - 1.17, p = 5.21x10-5). The META PRS was validated in two BioVU cohorts: one using ICD9/ICD10 codes and one requiring imaging confirmation of fibroid status. In the ICD cohort, a standard deviation increase in the META PRS increased the odds of fibroids by 1.23 (95% CI: 1.15 - 1.32, p = 9.68x10-9), while in the imaging cohort, the odds increased by 1.26 (95% CI: 1.18 - 1.35, p = 2.40x10-11). We subsequently constructed single ancestry PRS for FinnGen (European ancestry [EUR]) and Biobank Japan (East Asian ancestry [EAS]) using PRS-CS and discovered a nominally significant association in the eMERGE cohort within fibroids and EAS PRS but not EUR PRS (95% CI: 1.09 - 1.20, p = 1.64x10-7). These findings highlight the strong predictive power of multi-ancestry PRS over single ancestry PRS. This study underscores the necessity of diverse population inclusion in genetic research to ensure precision medicine benefits all individuals equitably.</p>","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"30 ","pages":"268-280"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Prospective Comparison of Large Language Models for Early Prediction of Sepsis.","authors":"Supreeth P Shashikumar, Shamim Nemati","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We present a comparative study on the performance of two popular open-source large language models for early prediction of sepsis: Llama-3 8B and Mixtral 8x7B. The primary goal was to determine whether a smaller model could achieve comparable predictive accuracy to a significantly larger model in the context of sepsis prediction using clinical data.Our proposed LLM-based sepsis prediction system, COMPOSER-LLM, enhances the previously published COMPOSER model, which utilizes structured EHR data to generate hourly sepsis risk scores. The new system incorporates an LLM-based approach to extract sepsis-related clinical signs and symptoms from unstructured clinical notes. For scores falling within high-uncertainty prediction regions, particularly those near the decision threshold, the system uses the LLM to draw additional clinical context from patient notes; thereby enhancing the model's predictive accuracy in challenging diagnostic scenarios.A total of 2,074 patient encounters admitted to the Emergency Department at two hospitals within the University of California San Diego Health system were used for model evaluation in this study. Our findings reveal that the Llama-3 8B model based system (COMPOSER-LLMLlama) achieved a sensitivity of 70.3%, positive predictive value (PPV) of 32.5%, F-1 score of 44.4% and false alarms per patient hour (FAPH) of 0.0194, closely matching the performance of the larger Mixtral 8x7B model based system (COMPOSER-LLMmixtral) which achieved a sensitivity of 72.1%, PPV of 31.9%, F-1 score of 44.2% and FAPH of 0.020. When prospectively evaluated, COMPOSER-LLMLlama demonstrated similar performance to the COMPOSER-LLMmixtral pipeline, with a sensitivity of 68.7%, PPV of 36.6%, F-1 score of 47.7% and FAPH of 0.019 vs. sensitivity of 70.5%, PPV of 36.3%, F-1 score of 47.9% and FAPH of 0.020. This result indicates that, for extraction of clinical signs and symptoms from unstructured clinical notes to enable early prediction of sepsis, the Llama-3 generation of smaller language models can perform as effectively and more efficiently than larger models. This finding has significant implications for healthcare settings with limited resources.</p>","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"30 ","pages":"109-120"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging Foundational Models in Computational Biology: Validation, Understanding, and Innovation.","authors":"Brett Beaulieu-Jones, Steven Brenner","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Large Language Models (LLMs) have shown significant promise across a wide array of fields, including biomedical research, but face notable limitations in their current applications. While they offer a new paradigm for data analysis and hypothesis generation, their efficacy in computational biology trails other applications such as natural language processing. This workshop addresses the state of the art in LLMs, discussing their challenges and the potential for future development tailored to computational biology. Key issues include difficulties in validating LLM outputs, proprietary model limitations, and the need for expertise in critical evaluation of model failure modes.</p>","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"30 ","pages":"702-705"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated exposomic analysis of lipid phenotypes: Leveraging GE.db in environment by environment interaction studies.","authors":"Andre Luis Garao Rico, Nicole Palmiero, Marylyn D Ritchie, Molly A Hall","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Gene-environment interaction (GxE) studies provide insights into the interplay between genetics and the environment but often overlook multiple environmental factors' synergistic effects. This study encompasses the use of environment by environment interaction (ExE) studies to explore interactions among environmental factors affecting lipid phenotypes (e.g., HDL, LDL, and total cholesterol, and triglycerides), which are crucial for disease risk assessment. We developed a novel curated knowledge base, GE.db, integrating genomic and exposomic interactions. In this study, we filtered NHANES exposure variables (available 1999-2018) to identify significant ExE using GE.db. From 101,316 participants and 77 exposures, we identified 263 statistically significant interactions (FDR p < 0.1) in discovery and replication datasets, with 21 interactions significant for HDL-C (Bonferroni p < 0.05). Notable interactions included docosapentaenoic acid (22:5n-3) (DPA) - arachidic acid (20:0), stearic acid (18:0) - arachidic acid (20:0), and blood 2,5-dimethyfuran - blood benzene associated with HDL-C levels. These findings underscore GE.db's role in enhancing -omics research efficiency and highlight the complex impact of environmental exposures on lipid metabolism, informing future health strategies.</p>","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"30 ","pages":"535-550"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of An Evolving Regulatory Landscape on the Development of AI and ML in Medicine.","authors":"Nicole Rincon, Sara Gerke, Jennifer K Wagner","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The rapid advancement of artificial intelligence and machine learning (AI/ML) technologies in healthcare presents significant opportunities for enhancing patient care through innovative diagnostic tools, monitoring systems, and personalized treatment plans. However, these innovative advancements might result in regulatory challenges given recent Supreme Court decisions that impact the authority of regulatory agencies like the Food and Drug Administration (FDA). This paper explores the implications of regulatory uncertainty for the healthcare industry related to balancing innovation in biotechnology and biocomputing with ensuring regulatory uniformity and patient safety. We examine key Supreme Court cases, including Loper Bright Enterprises v. Raimondo, Relentless, Inc. v. Department of Commerce, and Corner Post, Inc. v. Board of Governors of the Federal Reserve System, and their impact on the Chevron doctrine. We also discuss other relevant cases to highlight shifts in judicial approaches to agency deference and regulatory authority that might affect how science is handled in regulatory spaces, including how biocomputing and other health sciences are governed, how scientific facts are applied in policymaking, and how scientific expertise guides decision making. Through a detailed analysis, we assess the potential impact of regulatory uncertainty in healthcare. Additionally, we provide recommendations for the medical community on navigating these challenges.</p>","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"30 ","pages":"154-166"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma protein-based and polygenic risk scores serve complementary roles in predicting inflammatory bowel disease.","authors":"Jakob Woerner, Thomas Westbrook, Seokho Jeong, Manu Shivakumar, Allison R Greenplate, Sokratis A Apostolidis, Seunggeun Lee, Yonghyun Nam, Dokyoon Kim","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), has a significant genetic component and is increasingly prevalent due to environmental factors. Current polygenic risk scores (PRS) have limited predictive power and cannot inform time of symptom onset. Circulating proteomics profiling offers a novel, non-invasive approach for understanding the inflammatory state of complex diseases, enabling the creation of proteomic risk scores (ProRS). This study utilizes data from 51,772 individuals in the UK Biobank to evaluate the unique and combined contributions of PRS and ProRS to IBD risk prediction. We developed ProRS models for CD and UC, assessed their predictive performance over time, and examined the benefits of integrating PRS and ProRS for enhanced risk stratification. Our findings are the first to demonstrate that combining genetic and proteomic data improves IBD incidence prediction, with ProRS providing time-sensitive predictions and PRS offering additional long-term predictive value. We also show that the ProRS achieves better predictive performance among individuals with high PRS. This integrated approach highlights the potential for multi-omic data in precision medicine for IBD.</p>","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"30 ","pages":"522-534"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Pathway-Level Information ExtractoR (PLIER) framework to gain mechanistic insights into obesity in Down syndrome.","authors":"Sutanu Nandi, Yuehua Zhu, Lucas A Gillenwater, Marc Subirana-Granés, Haoyu Zhang, Negar Janani, Casey Greene, Milton Pividori, Maria Chikina, James C Costello","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Down syndrome (DS), caused by the triplication of chromosome 21 (T21), is a prevalent genetic disorder with a higher incidence of obesity. Traditional approaches have struggled to differentiate T21-specific molecular dysregulation from general obesity-related processes. This study introduces the omni-PLIER framework, combining the Pathway-Level Information ExtractoR (PLIER) with the omnigenic model, to uncover molecular mechanisms underlying obesity in DS. The PLIER framework aligns gene expression data with biological pathways, facilitating the identification of relevant molecular patterns. Using RNA sequencing data from the Human Trisome Project, omni-PLIER identified latent variables (LVs) significantly associated with both T21 and body mass index (BMI). Elastic net regression and causal mediation analysis revealed LVs mediating the effect of karyotype on BMI. Notably, LVs involving glutathione peroxidase-1 (GPX1) and MCL1 apoptosis regulator, BCL2 family members emerged as crucial mediators. These findings provide insights into the molecular interplay between DS and obesity. The omni-PLIER model offers a robust methodological advancement for dissecting complex genetic disorders, with implications for understanding obesity-related processes in both DS and the general population.</p>","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"30 ","pages":"412-425"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spherical Manifolds Capture Drug-Induced Changes in Tumor Cell Cycle Behavior.","authors":"Olivia Wen, Samuel C Wolff, Wayne Stallaert, Didong Li, Jeremy E Purvis, Tarek M Zikry","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>CDK4/6 inhibitors such as palbociclib block cell cycle progression and improve outcomes for many ER+/HER2- breast cancer patients. Unfortunately, many patients are initially resistant to the drug or develop resistance over time in part due to heterogeneity among individual tumor cells. To better understand these mechanisms of resistance, we used multiplex, single-cell imaging to profile cell cycle proteins in ER+ breast tumor cells under increasing palbociclib concentrations. We then applied spherical principal component analysis (SPCA), a dimensionality reduction method that leverages the inherently cyclical nature of the high-dimensional imaging data, to look for changes in cell cycle behavior in resistant cells. SPCA characterizes data as a hypersphere and provides a framework for visualizing and quantifying differences in cell cycles across treatment-induced perturbations. The hypersphere representations revealed shifts in the mean cell state and population heterogeneity. SPCA validated expected trends of CDK4/6 inhibitor response such as decreased expression of proliferation markers (Ki67, pRB), but also revealed potential mechanisms of resistance including increased expression of cyclin D1 and CDK2. Understanding the molecular mechanisms that allow treated tumor cells to evade arrest is critical for identifying targets of future therapies. Ultimately, we seek to further SPCA as a tool of precision medicine, targeting treatments by individual tumors, and extending this computational framework to interpret other cyclical biological processes represented by high-dimensional data.</p>","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"30 ","pages":"473-487"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocyte Reactivity Polygenic Risk Score May Predict Cognitive Decline in Alzheimer's Disease.","authors":"Jared M Phillips, Julie A Schneider, David A Bennett, Paul K Crane, Shannon L Risacher, Andrew J Saykin, Logan C Dumitrescu, Timothy J Hohman","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a polygenic disorder with a prolonged prodromal phase, complicating early diagnosis. Recent research indicates that increased astrocyte reactivity is associated with a higher risk of pathogenic tau accumulation, particularly in amyloid-positive individuals. However, few clinical tools are available to predict which individuals are likely to exhibit elevated astrocyte activation and, consequently, be susceptible to hyperphosphorylated tau-induced neurodegeneration. Polygenic risk scores (PRS) aggregate the effects of multiple genetic loci to provide a single, continuous metric representing an individual's genetic risk for a specific phenotype. We hypothesized that an astrocyte activation PRS could aid in the early detection of faster clinical decline. Therefore, we constructed an astrocyte activation PRS and assessed its predictive value for cognitive decline and AD biomarkers (i.e., cerebrospinal fluid [CSF] levels of Aβ1-42, total tau, and p-tau181) in a cohort of 791 elderly individuals. The astrocyte activation PRS showed significant main effects on cross-sectional memory (β = -0.07, p = 0.03) and longitudinal executive function (β = -0.01, p = 0.03). Additionally, the PRS interacted with amyloid positivity (p.intx = 0.02), whereby indicating that amyloid burden modifies the association between the PRS and annual rate of language decline. Furthermore, the PRS was negatively associated with CSF Aβ1-42 levels (β = -3.4, p = 0.07) and interacted with amyloid status, such that amyloid burden modifies the association between the PRS and CSF phosphorylated tau levels (p.intx = 0.08). These findings suggest that an astrocyte activation PRS could be a valuable tool for early disease risk prediction, potentially enabling intervention during the interval between pathogenic amyloid and tau accumulation.</p>","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"30 ","pages":"488-503"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}