Yejin Kim

Tianhao Li, Sandesh Shetty, Advaith Kamath et al.

Large pre-trained language models (LLMs) have been shown to have significant potential in few-shot learning across various fields, even with minimal training data. However, their ability to generalize to unseen tasks in more complex fields, such as biology, has yet to be fully evaluated. LLMs can offer a promising alternative approach for biological inference, particularly in cases where structured data and sample size are limited, by extracting prior knowledge from text corpora. Our proposed few-shot learning approach uses LLMs to predict the synergy of drug pairs in rare tissues that lack structured data and features. Our experiments, which involved seven rare tissues from different cancer types, demonstrated that the LLM-based prediction model achieved significant accuracy with very few or zero samples. Our proposed model, the CancerGPT (with $\sim$ 124M parameters), was even comparable to the larger fine-tuned GPT-3 model (with $\sim$ 175B parameters). Our research is the first to tackle drug pair synergy prediction in rare tissues with limited data. We are also the first to utilize an LLM-based prediction model for biological reaction prediction tasks.

Kai Zhang, Rui Zhu, Shutian Ma et al.

Drug discovery is a critical task in biomedical natural language processing (NLP), yet explainable drug discovery remains underexplored. Meanwhile, large language models (LLMs) have shown remarkable abilities in natural language understanding and generation. Leveraging LLMs for explainable drug discovery has the potential to improve downstream tasks and real-world applications. In this study, we utilize open-source drug knowledge graphs, clinical trial data, and PubMed publications to construct a comprehensive dataset for the explainable drug discovery task, named \textbf{expRxRec}. Furthermore, we introduce \textbf{KEDRec-LM}, an instruction-tuned LLM which distills knowledge from rich medical knowledge corpus for drug recommendation and rationale generation. To encourage further research in this area, we will publicly release\footnote{A copy is attached with this submission} both the dataset and KEDRec-LM.

Qidi Xu, Nuzha Amjad, Grace Giles et al.

Understanding patients experiences is essential for advancing patient centered care, especially in chronic diseases that require ongoing communication. However, qualitative thematic analysis, the primary approach for exploring these experiences, remains labor intensive, subjective, and difficult to scale. In this study, we developed a multi agent large language model framework that automates qualitative thematic analysis through three agents (Instructor, Thematizer, CodebookGenerator), named Collaborative Theme Identification Agent (CoTI). We applied CoTI to 12 heart failure patient interviews to analyze their perceptions of medication intensity. CoTI identified key phrases, themes, and codebook that were more similar to those of the senior investigator than both junior investigators and baseline NLP models. We also implemented CoTI into a user-facing application to enable AI human interaction in qualitative analysis. However, collaboration between CoTI and junior investigators provided only marginal gains, suggesting they may overrely on CoTI and limit their independent critical thinking.

Pulakesh Upadhyaya, Kai Zhang, Can Li et al.

Causal structure learning refers to a process of identifying causal structures from observational data, and it can have multiple applications in biomedicine and health care. This paper provides a practical review and tutorial on scalable causal structure learning models with examples of real-world data to help health care audiences understand and apply them. We reviewed traditional (combinatorial and score-based methods) for causal structure discovery and machine learning-based schemes. We also highlighted recent developments in biomedicine where causal structure learning can be applied to discover structures such as gene networks, brain connectivity networks, and those in cancer epidemiology. We also compared the performance of traditional and machine learning-based algorithms for causal discovery over some benchmark data sets. Machine learning-based approaches, including deep learning, have many advantages over traditional approaches, such as scalability, including a greater number of variables, and potentially being applied in a wide range of biomedical applications, such as genetics, if sufficient data are available. Furthermore, these models are more flexible than traditional models and are poised to positively affect many applications in the future.

Yaobin Ling, Pulakesh Upadhyaya, Luyao Chen et al.

Developing new drugs for target diseases is a time-consuming and expensive task, drug repurposing has become a popular topic in the drug development field. As much health claim data become available, many studies have been conducted on the data. The real-world data is noisy, sparse, and has many confounding factors. In addition, many studies have shown that drugs effects are heterogeneous among the population. Lots of advanced machine learning models about estimating heterogeneous treatment effects (HTE) have emerged in recent years, and have been applied to in econometrics and machine learning communities. These studies acknowledge medicine and drug development as the main application area, but there has been limited translational research from the HTE methodology to drug development. We aim to introduce the HTE methodology to the healthcare area and provide feasibility consideration when translating the methodology with benchmark experiments on healthcare administrative claim data. Also, we want to use benchmark experiments to show how to interpret and evaluate the model when it is applied to healthcare research. By introducing the recent HTE techniques to a broad readership in biomedical informatics communities, we expect to promote the wide adoption of causal inference using machine learning. We also expect to provide the feasibility of HTE for personalized drug effectiveness.

Yan Ding, Xiaoqian Jiang, Yejin Kim

Evaluating the blood-brain barrier (BBB) permeability of drug molecules is a critical step in brain drug development. Traditional methods for the evaluation require complicated in vitro or in vivo testing. Alternatively, in silico predictions based on machine learning have proved to be a cost-efficient way to complement the in vitro and in vivo methods. However, the performance of the established models has been limited by their incapability of dealing with the interactions between drugs and proteins, which play an important role in the mechanism behind the BBB penetrating behaviors. To address this limitation, we employed the relational graph convolutional network (RGCN) to handle the drug-protein interactions as well as the properties of each individual drug. The RGCN model achieved an overall accuracy of 0.872, an AUROC of 0.919 and an AUPRC of 0.838 for the testing dataset with the drug-protein interactions and the Mordred descriptors as the input. Introducing drug-drug similarity to connect structurally similar drugs in the data graph further improved the testing results, giving an overall accuracy of 0.876, an AUROC of 0.926 and an AUPRC of 0.865. In particular, the RGCN model was found to greatly outperform the LightGBM base model when evaluated with the drugs whose BBB penetration was dependent on drug-protein interactions. Our model is expected to provide high-confidence predictions of BBB permeability for drug prioritization in the experimental screening of BBB-penetrating drugs.

Kanglin Hsieh, Yinyin Wang, Luyao Chen et al.

Amid the pandemic of 2019 novel coronavirus disease (COVID-19) infected by SARS-CoV-2, a vast amount of drug research for prevention and treatment has been quickly conducted, but these efforts have been unsuccessful thus far. Our objective is to prioritize repurposable drugs using a drug repurposing pipeline that systematically integrates multiple SARS-CoV-2 and drug interactions, deep graph neural networks, and in-vitro/population-based validations. We first collected all the available drugs (n= 3,635) involved in COVID-19 patient treatment through CTDbase. We built a SARS-CoV-2 knowledge graph based on the interactions among virus baits, host genes, pathways, drugs, and phenotypes. A deep graph neural network approach was used to derive the candidate representation based on the biological interactions. We prioritized the candidate drugs using clinical trial history, and then validated them with their genetic profiles, in vitro experimental efficacy, and electronic health records. We highlight the top 22 drugs including Azithromycin, Atorvastatin, Aspirin, Acetaminophen, and Albuterol. We further pinpointed drug combinations that may synergistically target COVID-19. In summary, we demonstrated that the integration of extensive interactions, deep neural networks, and rigorous validation can facilitate the rapid identification of candidate drugs for COVID-19 treatment. This is a post-peer-review, pre-copyedit version of an article published in Scientific Reports The final authenticated version is available online at: https://www.nature.com/articles/s41598-021-02353-5

Rui Zhang, Luca Giancardo, Danilo A. Pena et al.

In this paper, we studied the association between the change of structural brain volumes to the potential development of Alzheimer's disease (AD). Using a simple abstraction technique, we converted regional cortical and subcortical volume differences over two time points for each study subject into a graph. We then obtained substructures of interest using a graph decomposition algorithm in order to extract pivotal nodes via multi-view feature selection. Intensive experiments using robust classification frameworks were conducted to evaluate the performance of using the brain substructures obtained under different thresholds. The results indicated that compact substructures acquired by examining the differences between patient groups were sufficient to discriminate between AD and healthy controls with an area under the receiver operating curve of 0.72.

Xiaoqian Jiang, Samden Lhatoo, Guo-Qiang Zhang et al.

Existing studies consider Alzheimer's disease (AD) a comorbidity of epilepsy, but also recognize epilepsy to occur more frequently in patients with AD than those without. The goal of this paper is to understand the relationship between epilepsy and AD by studying causal relations among subgroups of epilepsy patients. We develop an approach combining representation learning with tensor factorization to provide an in-depth analysis of the risk factors among epilepsy patients for AD. An epilepsy-AD cohort of ~600,000 patients were extracted from Cerner Health Facts data (50M patients). Our experimental results not only suggested a causal relationship between epilepsy and later onset of AD ( p = 1.92e-51), but also identified five epilepsy subgroups with distinct phenotypic patterns leading to AD. While such findings are preliminary, the proposed method combining representation learning with tensor factorization seems to be an effective approach for risk factor analysis.

Yejin Kim, Xiaoqian Jiang, Luyao Chen et al.

Sleep change is commonly reported in Alzheimer's disease (AD) patients and their brain wave studies show decrease in dreaming and non-dreaming stages. Although sleep disturbance is generally considered as a consequence of AD, it might also be a risk factor of AD as new biological evidence shows. Leveraging National Sleep Research Resource (NSRR), we built a unique cohort of 83 cases and 331 controls with clinical variables and EEG signals. Supervised tensor factorization method was applied for this temporal dataset to extract discriminative sleep patterns. Among the 30 patterns extracted, we identified 5 significant patterns (4 patterns for AD likely and 1 pattern for normal ones) and their visual patterns provide interesting linkage to sleep with repeated wakefulness, insomnia, epileptic seizure, and etc. This study is preliminary but findings are interesting, which is a first step to provide quantifiable evidences to measure sleep as a risk factor of AD.