Design of a Splicing Promiscuity Model Capable of Predicting Treatment Response of Immune Checkpoint Blockade Treatments; The Implementation of Spiritual Care Within Cancer Treatment Plans and its Potential Within Standard Medical Care

McKey, Samuel, School of Engineering and Applied Science, University of Virginia
Haddox, Samuel, Biochemistry and Molecular Genetics, University of Virginia
Li, Hui, Pathology, University of Virginia
Francisco, Pedro Augusto, Engineering and Society, University of Virginia

Background for Sociotechnical & Technical Research:
Scientific exploration has driven the advancement of modern medicine. We sit on the forefront of new discoveries, continuously probing human biology to heal and empower patients with a weapon to fight against disease. This pursuit for knowledge has led to the development of immunotherapy, a tool that utilizes a human’s unique immune system to recognize and fight against cancer. Although its utility shows great promise in treating cancer patients, it lacks a reliable biomarker that can properly predict treatment response. As such, my team and I have sought to develop a complementary biomarker to enhance existing approaches in predicting treatment outcomes. To better understand the treatment and recovery journey that cancer patients endure as well as their sociotechnical interactions with current medical regimens, I have attempted to identify an underrepresented facet of medical care that might improve the overall well-being of cancer patients. I have chosen to investigate spirituality’s unique relationship with human biology to determine if the implementation of spiritual care within cancer treatment plans could act as an additional crutch for patients to use as they persevere through their cancer journey. These technical and sociotechnical topics share the pursuit to improve the lives of cancer patients and equip patients with additional tools- one focusing on cognitive support and the other on physical aid- that help to fight back against cancer and maintain resilience.

Technical Research:
Within the field of immunotherapy, advanced genomic testing has provided scientists with the ability to analyze cancerous DNA. This analysis has given rise to a biomarker known as Tumor Mutation Burden (TMB). Medical professionals currently use this biomarker as an indicator to gauge whether a patient will respond favorably or unfavorably to immunotherapy. However, in a subset of patients, TMB has shown to be inaccurate in properly predicting treatment response, revealing its limitations as a comprehensive assessment tool. This underscores the necessity of complementing TMB with a new biomarker for a more thorough evaluation. As such, my team and I sought to develop a complementary biomarker to TMB by investigating the dysregulation of splicing events within alternatively spliced transcripts often associated with cancerous cells. This research led to the development of a splice promiscuity model capable of detecting splice donor and acceptor promiscuity associations with treatment response.
Initial testing of simulated RNA sequencing data within our BASH pipeline revealed that sequences with different read lengths were unable to be compared. However, it was found that sequences with differing read depths were comparable after normalization of the reads. Following this, our model successfully quantified splice promiscuity when analyzing the alternative splicing options in simulated data with a single isoform versus multiple isoforms. Additionally, validation of our model was successful when comparing the promiscuity score distributions of blood and testis tissue data from GTEx. Using our Kolmogorov-Smirnov (KS) and Ratio normalization methods, a significant p-value of 1.38E-68 and 7.97E-47 respectively was computed when comparing the promiscuity scores between the datasets. Upon applying our model to data from non-small cell lung cancer patients who underwent ICB treatment, the KS method was found to be the best at showing a difference in promiscuity indexes across treatment responses. Although our model successfully quantified splice promiscuity, additional data is needed to further explore the promiscuity indexes associated with each treatment response. In future work, deep learning and machine learning algorithms will be utilized to investigate the individual slice sites.

Sociotechnical Research:
Technological advancements within the medical field continue to push the boundaries of what we once thought possible to heal physical ailments. These advancements have revolutionized the treatments available to cancer patients. Still, despite this, we have failed to provide patients with a holistic treatment plan that addresses not only their physical ailment but also their cognitive well-being. In particular, one of the unaddressed biological domains that uniquely contributes to the patient’s battle with cancer is their spiritual well-being. This need for spiritual care while undergoing treatment is often left unfulfilled as the medical infrastructure to provide this care has not yet been established. As such, I will be conducting a systematic review of the current research on spirituality’s effects on patient well-being as well as its implementation within medical treatments thus far. In this investigation I aim to ascertain whether or not spiritual care would have a positive impact on patient well-being and if so, how spiritual care should be implemented into current medical treatment plans.
Surveys used to question hospital inpatients on their spirituality and unmet needs during treatment revealed that a large percentage of patients feel that their spiritual needs were overlooked or neglected. Additionally, many of these patients reported that their spirituality was one of the most influential when making treatment decisions, yet this aspect was seldom addressed. Extensive research into spirituality’s effects on mental health, particularly for patients, has highlighted spirituality’s positive role in alleviating depression and anxiety. Furthermore, spirituality acts as a powerful coping mechanism for patients grappling with the physical and mental strains that they often endure while undergoing treatment. Psychoneuroimmunology research into the effects of spirituality on the human body has unveiled its capacity to modulate patient immunity, bolster biological resilience, and expedite recovery. Implementation of spiritual care practices within patient treatment plans has demonstrated alterations in cortisol levels, reductions in epinephrine and norepinephrine, decreases in inflammatory markers such as IL-6 and TNF-alpha, and improvements in natural killer and leukocyte cells. As it stands, there is still a great deal of research that is required to truly understand spirituality’s potential role within medical care. Initial results into the implementation of spiritual care within medical treatment plans and its overall benefits for patients highlight its utility in medical care.

BS (Bachelor of Science)
Immunotherapy, Immune checkpoint blockade (ICB), Alternative splicing, Tumor Mutation Burden, Biomarker, Spirituality , Cancer

School of Engineering and Applied Science

Bachelor of Science in Biomedical Engineering

Technical Advisor: Dr. Hui Li, Samuel Haddox

STS Advisor: Pedro Augusto Francisco

Technical Team Members: Ningxi Huang

All rights reserved (no additional license for public reuse)
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