Browsing by Author "Quinney, Sara"
Now showing 1 - 8 of 8
Results Per Page
Sort Options
Item Analyzing Patterns of Literature-Based Phenotyping Definitions for Text Mining Applications(IEEE, 2018-06) Binkheder, Samar; Wu, Heng-Yi; Quinney, Sara; Li, Lang; BioHealth Informatics, School of Informatics and ComputingPhenotyping definitions are widely used in observational studies that utilize population data from Electronic Health Records (EHRs). Biomedical text mining supports biomedical knowledge discovery. Therefore, we believe that mining phenotyping definitions from the literature can support EHR-based clinical research. However, information about these definitions presented in the literature is inconsistent, diverse, and unknown, especially for text mining usage. Therefore, we aim to analyze patterns of phenotyping definitions as a first step toward developing a text mining application to improve phenotype definition. A set random of observational studies was used for this analysis. Term frequency-inverse document frequency (TF-IDF) and Term Frequency (TF) were used to rank the terms in the 3958 sentences. Finally, we present preliminary results analyzing phenotyping definitions patterns.Item Characterizing the Unfolded Protein Response by Changes in Protein Thermal Stability(2023-09) McCracken, Neil Andrew; Mosley, Amber; Wek, Ron; Evans-Molina, Carmella; Georgiadis, Millie; Quinney, SaraThe Unfolded Protein Response (UPR) protects eukaryotic cells from the threat of excessive protein flux into the Endoplasmic Reticulum (ER). UPR sentries PERK, Ire1 and ATF6 detect unfolded protein in the ER and alert the cell of the condition. Downstream pathways increase translation of select responders while simultaneously decreasing the global protein load in order that toxic protein aggregates do not form in the cell. While this warning system has been characterized over several decades through extensive reporting of UPR impact on transcript and protein abundance, little is known about the biophysical changes that occur to proteins as part of the UPR in the context of the cellular environment. An understanding of how the UPR affects the folding, stability and protein oligomerization is vital for describing subtle but important changes that occur and contribute to maladaptive physiology in diseases including diabetes, cancer, and neurodegeneration. I propose that deficiencies in characterizing the UPR can be overcome by using thermal shifts assays (TSA) that quantify changes in protein stability post stimuli. Findings described herein show the utility of the biophysical thermal shift assay in characterizing the UPR. Thermal shift assays (TSA) measure susceptibility of proteins to denature upon heat treatment and consequently detect changes in protein structure, modification, and interactions in the cellular environment. Previously unobserved protein relationships related to the UPR were detected using TSA. These workflows were improved through more strategic upstream sampling and downstream data analysis through creation of the publicly available InflectSSP program. Observed UPR phenomena during N-linked glycosylation inhibition and UPR induction include protein degradation, changes in stability of N-linked glycosylation enzymes, and transcriptional targets canonical to the UPR. Stability changes in proteins downstream of PERK were also observed in experiments where PERK genetic ablation was combined with UPR induction. Finally, the thermal shift assay was used to develop a “signature” for the UPR that holistically describes the ER stress response. Results described in this dissertation provide an improved perspective of the UPR along with an approach that can be used to identify novel targets for therapeutic intervention of the UPR.Item Cholestasis in the First Trimester Associated with Rare ABCG5/8 Variants: A Case Study(2022-07-28) Ganapaneni, Sruthi; Arul Dhas, Blessed Winston; Vuppalanchi, Raj; Quinney, SaraCholestasis in the First Trimester Associated with Rare ABCG5/8 Variants: A Case Study Sruthi Ganapaneni 1, Blessed Winston Arul Dhas 2, Raj Vuppalanchi 2, Sara Quinney 2,3 1 Indiana University School of Medicine; 2 Indiana University School of Medicine, Department of Medicine; 3 Indiana University School of Medicine, Department of Obstetrics and Gynecology Purpose/Background: Obstetric cholestasis, or intrahepatic cholestasis of pregnancy (ICP), is a liver disease that usually presents in the third trimester of pregnancy. It is characterized by pruritis that is associated with elevated liver enzymes and bile acids. This condition can have potentially serious effects on the fetus due to the buildup of serum bile acids resulting from the obstruction of bile flow. Methods/Case Overview: A 28-year-old patient, who was pregnant for the third time, developed pruritis in the first trimester and presented with blood work that showed elevated total bile acids and liver enzymes. A medical history revealed similar symptoms amongst her female relatives during their pregnancies as well as the patient’s own previous pregnancies, suggesting a genetic component in the etiology of the disease. Genetic testing supported this hypothesis and showed variants of unknown significance that indicated a duplication in the ABCG5 and ABCDG8 genes. Results/Discussion: This finding was rather unusual as these genes have not yet been clinically associated with ICP. The ABCG5 and ABCG8 genes code for canicular bile transporters in the liver that transport cholesterol into the bile. Overexpression of these transporters due to the duplication in her genes may result in increased transport of cholesterol into bile, disrupting the regular composition of bile. The resulting increased bile viscosity may cause bile stasis or blockage, and this proposed mechanism can possibly explain the pathophysiology behind this unusual case of cholestasis. Conclusion and Potential Impact: ICP can have potential serious effects on the developing fetus, and its etiology is still being understood. The novel ABCG5/8 gene duplication is a novel variant that may lead to earlier onset of ICP than commonly known variants.Item The Concurrent Initiation of Medications Is Associated with Discontinuation of Buprenorphine Treatment for Opioid Use Disorder(medRxiv, 2020) Zhang, Pengyue; Chiang, Chien-Wei; Quinney, Sara; Donneyong, Macarius; Lu, Bo; Huang, Lei Frank; Cheng, Feixiong; Obstetrics and Gynecology, School of MedicineIntroduction Retention in buprenorphine treatment for opioid use disorder (OUD) yields better opioid abstinence and reduces all-cause mortality for patients with OUD. Despite significant efforts have been made to expand the availability and use of buprenorphine in the United States, its retention rates remain on a low level. The current study examines discontinuation of buprenorphine with respect to concurrent initiation of other medications using real-world evidence. Methods Case-crossover study was conducted to examine discontinuation of buprenorphine using a large-scale longitudinal health dataset including 148,306 commercially-insured individuals initiated on medications for opioid use disorder (MOUD). Odds ratios and Bonferroni adjusted p-values were calculated for medications and therapeutic classes of medications. Results Clonidine was associated with increased discontinuation risk of buprenorphine both using the buprenorphine dataset alone (OR = 1.583 and adjusted p-value = 1.22 × 10−6) and using naltrexone as a comparison drug (OR = 2.706 and adjusted p-value = 4.11 × 10−5). Opioid medications (oxycodone, morphine and fentanyl) and methocarbamol were associated with increased discontinuation risk of buprenorphine using the buprenorphine dataset alone (adjusted p-value < 0.05), but not significant using naltrexone as a comparison drug. 6 drug therapeutic classes were associated with increased discontinuation risk of buprenorphine both using the buprenorphine dataset alone and using naltrexone as a comparison drug (adjusted p-value < 0.05). Conclusion Concurrent initiation of medications is associated with increased discontinuation risk of buprenorphine. Opioid medications are prescribed among patients on MOUD and associated with increased discontinuation risk of buprenorphine. Analgesics is associated with increased discontinuation risk of buprenorphine for patients without previous exposure of pain medications.Item Effect of resistance training on physical function during chemotherapy in colon cancer(Oxford University Press, 2024) Brown, Justin C.; Yang, Shengping; Compton, Stephanie L. E.; Campbell, Kristin L.; Cespedes Feliciano, Elizabeth M.; Quinney, Sara; Sternfeld, Barbara; Caan, Bette J.; Meyerhardt, Jeffrey A.; Schmitz, Kathryn H.; Obstetrics and Gynecology, School of MedicineBackground: The decline of physical function during chemotherapy predicts poor quality of life and premature death. It is unknown if resistance training prevents physical function decline during chemotherapy in colon cancer survivors. Methods: This multicenter trial randomly assigned 181 colon cancer survivors receiving postoperative chemotherapy to home-based resistance training or usual care control. Physical function outcomes included the short physical performance battery, isometric handgrip strength, and the physical function subscale of the Medical Outcomes Short-Form 36-item questionnaire. Mixed models for repeated measures quantified estimated treatment differences. Results: At baseline, participants had a mean (SD) age of 55.2 (12.8) years; 67 (37%) were 60 years or older, and 29 (16%) had a composite short physical performance battery score of no more than 9. Compared with usual care control, resistance training did not improve the composite short physical performance battery score (estimated treatment difference = -0.01, 95% confidence interval [CI] = -0.32 to 0.31; P = .98) or the short physical performance battery scores for balance (estimated treatment difference = 0.01, 95% CI = -0.10 to 0.11; P = .93), gait speed (estimated treatment difference = 0.08, 95% CI = -0.06 to 0.22; P = .28), and sit-to-stand (estimated treatment difference = -0.08, 95% CI = -0.29 to 0.13; P = .46). Compared with usual care control, resistance training did not improve isometric handgrip strength (estimated treatment difference = 1.50 kg, 95% CI = -1.06 to 4.05; P = .25) or self-reported physical function (estimated treatment difference = -3.55, 95% CI = -10.03 to 2.94); P = .28). The baseline short physical performance battery balance score (r = 0.21, 95% CI = 0.07 to 0.35) and handgrip strength (r = 0.23, 95% CI = 0.09 to 0.36) correlated with chemotherapy relative dose intensity. Conclusion: Among colon cancer survivors with relatively high physical functioning, random assignment to home-based resistance training did not prevent physical function decline during chemotherapy.Item Identifying Racial/Ethnic Differences in Clinical Trial Enrollment, Drug Response, and Genetic Biomarkers of Taxane Induced Peripheral Neuropathy in African American Breast Cancer Patients(2021-08) Shah, Ebony; Skaar, Todd C.; Radovich, Milan; Quinney, Sara; Liu, YunlongMy first aim identified enrollment patterns and variables that predict enrollment in a diverse underserved population and evaluated barriers to enrollment. We analyzed data from the INGENIOUS, (Indiana GENomics Implementation and Opportunity for the UnderServed), pharmacogenomics implementation clinical trial conducted at a community hospital for underserved subjects and a statewide healthcare system. Our main finding revealed, African-Americans were less likely to refuse the study than non-Hispanic Whites (Safety net, OR =0.68, p<0.002; Academic hospital, OR=0.64, p<0.001), using a logistic regression model. The most frequent barriers to enrollment included not being interested, being too busy, transportation, and illness in African-American and non-Hispanic White subjects. In conclusion, improving research awareness, widening the inclusion criteria, and hiring recruiters who represent potential enrollees, should improve enrollment in African-Americans and other diverse populations. My 2nd research aim evaluated racial/ethnic differences in pharmacokinetics, safety, efficacy, and pharmacogenetics in 213 new molecular entities (NMEs). The current approved drug label for NMEs between 2014 to 2018 was updated in the FDA database. A qualitative analysis revealed ~ 9% (n=20/213) of NMEs reported racial/ethnic differences in the approved product label for PK, safety, efficacy, and/or pharmacogenetics. In conclusion, evaluating racial/ethnic differences in drug exposure and response early in the drug development program is essential to providing recommendations for different racial/ethnic subpopulations. My final aim 3, identified genetic biomarkers of Taxane Induced Peripheral Neuropathy (TIPN) in African-American breast cancer patients. We used an innovative computational tool, ALDY, to identify genetic variants in CYP2C8, CYP3A4, and CYP3A5 in 207 breast cancer subjects. TaqMan SNP genotyping for SNP, rs776746 (T>C) was performed in 160 subjects. Subjects were collapsed into three metabolizer groups; normal, intermediate, and poor metabolizer to test the association of peripheral neuropathy, dose reductions and CYP2C8/CYP3A5 metabolizer status. A logistic regression revealed CYP2C8 metabolizer status is associated with grades 3-4 peripheral neuropathy (p=0.04, OR= 2.21). CYP2C8*2 was modestly associated with dose reductions. In conclusion, evaluating pharmacogenetic and pharmacokinetic studies of paclitaxel and CYP2C8 is important. These studies may lead to clinical actionable prescribing of paclitaxel and improve the tolerance and efficacy in African-American breast cancer patients.Item Mining and visualizing high-order directional drug interaction effects using the FAERS database(BMC, 2020) Yao, Xiaohui; Tsang, Tiffany; Sun, Qing; Quinney, Sara; Zhang, Pengyue; Ning, Xia; Li, Lang; Shen, Li; Obstetrics and Gynecology, School of MedicineBackground: Adverse drug events (ADEs) often occur as a result of drug-drug interactions (DDIs). The use of data mining for detecting effects of drug combinations on ADE has attracted growing attention and interest, however, most studies focused on analyzing pairwise DDIs. Recent efforts have been made to explore the directional relationships among high-dimensional drug combinations and have shown effectiveness on prediction of ADE risk. However, the existing approaches become inefficient from both computational and illustrative perspectives when considering more than three drugs. Methods: We proposed an efficient approach to estimate the directional effects of high-order DDIs through frequent itemset mining, and further developed a novel visualization method to organize and present the high-order directional DDI effects involving more than three drugs in an interactive, concise and comprehensive manner. We demonstrated its performance by mining the directional DDIs associated with myopathy using a publicly available FAERS dataset. Results: Directional effects of DDIs involving up to seven drugs were reported. Our analysis confirmed previously reported myopathy associated DDIs including interactions between fusidic acid with simvastatin and atorvastatin. Furthermore, we uncovered a number of novel DDIs leading to increased risk for myopathy, such as the co-administration of zoledronate with different types of drugs including antibiotics (ciprofloxacin, levofloxacin) and analgesics (acetaminophen, fentanyl, gabapentin, oxycodone). Finally, we visualized directional DDI findings via the proposed tool, which allows one to interactively select any drug combination as the baseline and zoom in/out to obtain both detailed and overall picture of interested drugs. Conclusions: We developed a more efficient data mining strategy to identify high-order directional DDIs, and designed a scalable tool to visualize high-order DDI findings. The proposed method and tool have the potential to contribute to the drug interaction research and ultimately impact patient health care.Item Recruitment strategies and design considerations in a trial of resistance training to prevent dose-limiting toxicities in colon cancer patients undergoing chemotherapy(Elsevier, 2021) Caan, Bette J.; Meyerhardt, Jeffrey A.; Brown, Justin C.; Campbell, Kristin L.; Cespedes Feliciano, Elizabeth M.; Lee, Catherine; Ross, Michelle C.; Quinney, Sara; Quesenberry, Charles; Sternfeld, Barbara; Schmitz, Kathryn H.; Obstetrics and Gynecology, School of MedicineLow muscle is associated with an increased risk of chemotherapy-related dose limiting toxicities (DLT) in cancer patients. Resistance training (RT) improves muscle mass; however, the effects of RT on preventing DLTs and dose reductions in colon cancer patients has not been investigated. FOcus on Reducing dose-limiting toxicities in Colon cancer with resistance Exercise (FORCE) is a multicenter, randomized clinical trial examining the effects of RT on relative dose intensity (RDI; primary outcome) and moderate and severe chemotoxicities (primary outcome) in non-metastatic colon cancer patients receiving adjuvant chemotherapy. Patients (N = 180) will be recruited from Kaiser Permanente Northern California, Dana-Farber Cancer Institute, and Penn State Cancer Institute. This paper describes recruitment strategies and design considerations. Patients will be randomized in equal numbers to RT intervention or control. Patients have baseline and post completion of chemotherapy visits where information on anthropometry, physical function, body composition, quality of life, physical activity and dietary behaviors, and inflammatory blood markers will be collected. Patient-reported outcomes of chemotherapy side effects will be collected around the time of chemotherapy throughout the duration of the trial. Intervention participants will be prescribed a progressive RT program consisting of 4-6 visits with a certified exercise trainer, delivered either in-person or remotely by video conference, and will be asked to engage twice weekly in-home training sessions. Control patients at the end of the study receive a consult with a FORCE exercise trainer, an online exercise RT training program and a set of resistance bands. Results of this trial will provide information on the benefit of resistance exercise as a treatment to increase RDI.