Browsing by Author "Zhang, Pengyue"
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Item 83569 Receipt of Pharmacologic Weaning Therapy and Developmental Delay(Cambridge University Press, 2021) Campbell, Angela G.; Zhang, Pengyue; Gharbi, Sami; Wiehe, Sarah; Pediatrics, School of MedicineABSTRACT IMPACT: This study evaluates the long term effects of pharmacologic weaning therapy for opiate exposed infants. OBJECTIVES/GOALS: Infants born to chronic opioid users often suffer from neonatal abstinence syndrome (NAS), a condition characterized by tremors, diarrhea, hyperirritability and an inconsolable high-pitched cry. Symptoms are treated with pharmacologic weaning therapy, but long-term effects of this treatment have not been established. METHODS/STUDY POPULATION: A sample of infants born between 2011-2017 was obtained from a large metropolitan hospital system. All infants who were exposed to opioids and received a Finnegan score were included in the sample (N=1,807). The analysis utilizes three dependent variables to measure developmental delay: motor delay, language delay or any delay, which includes general/non-specific delay in addition to motor and language delay. The treatment is defined as receipt of pharmacologic therapy with methadone or morphine. Maximum Finnegan score was also included as a continuous measure of the extent of the infant’s withdrawal symptoms. Linear models were utilized to determine a relationship between pharmacologic therapy and developmental delay with Maximum Finnegan score as an interaction term. RESULTS/ANTICIPATED RESULTS: In the linear models examining the main effects of weaning therapy on developmental delay, there was no relationship between pharmacologic therapy and motor delay (p=.260), language delay (p=.542) or any developmental delay (p=.176). When maximum Finnegan score was entered into the model as an interaction term the relationships were not significant. DISCUSSION/SIGNIFICANCE OF FINDINGS: These results suggest that while pharmacologic weaning is an appropriate treatment for withdrawal symptoms in infants, it is not a deterrent against developmental delays associated with NAS. This provides support suggest an increased focus on non-pharmacologic interventions such as breastfeeding as the first line of treatment for NAS infants.Item A comprehensive assessment of statin discontinuation among patients who concurrently initiate statins and CYP3A4-inhibitor drugs; a multistate transition model(Wiley, 2023) Donneyong, Macarius M.; Zhu, Yuxi; Zhang, Pengyue; Li, Yiting; Hunold, Katherine M.; Chiang, ChienWei; Unroe, Kathleen; Caterino, Jeffrey M.; Li, Lang; Medicine, School of MedicineAims: The aim of this study was to describe the 1-year direct and indirect transition probabilities to premature discontinuation of statin therapy after concurrently initiating statins and CYP3A4-inhibitor drugs. Methods: A retrospective new-user cohort study design was used to identify (N = 160 828) patients who concurrently initiated CYP3A4 inhibitors (diltiazem, ketoconazole, clarithromycin, others) and CYP3A4-metabolized statins (statin DDI exposed, n = 104 774) vs. other statins (unexposed to statin DDI, n = 56 054) from the MarketScan commercial claims database (2012-2017). The statin DDI exposed and unexposed groups were matched (2:1) through propensity score matching techniques. We applied a multistate transition model to compare the 1-year transition probabilities involving four distinct states (start, adverse drug events [ADEs], discontinuation of CYP3A4-inhibitor drugs, and discontinuation of statin therapy) between those exposed to statin DDIs vs. those unexposed. Statistically significant differences were assessed by comparing the 95% confidence intervals (CIs) of probabilities. Results: After concurrently starting stains and CYP3A, patients exposed to statin DDIs, vs. unexposed, were significantly less likely to discontinue statin therapy (71.4% [95% CI: 71.1, 71.6] vs. 73.3% [95% CI: 72.9, 73.6]) but more likely to experience an ADE (3.4% [95% CI: 3.3, 3.5] vs. 3.2% [95% CI: 3.1, 3.3]) and discontinue with CYP3A4-inhibitor therapy (21.0% [95% CI: 20.8, 21.3] vs. 19.5% [95% CI: 19.2, 19.8]). ADEs did not change these associations because those exposed to statin DDIs, vs. unexposed, were still less likely to discontinue statin therapy but more likely to discontinue CYP3A4-inhibitor therapy after experiencing an ADE. Conclusion: We did not observe any meaningful clinical differences in the probability of premature statin discontinuation between statin users exposed to statin DDIs and those unexposed.Item A multistate transition model for statin‐induced myopathy and statin discontinuation(Wiley, 2021) Zhu, Yuxi; Chiang, Chien-Wei; Wang, Lei; Brock, Guy; Milks, M. Wesley; Cao, Weidan; Zhang, Pengyue; Zeng, Donglin; Donneyong, Macarius; Li, Lang; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthThe overarching goal of this study was to simultaneously model the dynamic relationships among statin exposure, statin discontinuation, and potentially statin-related myopathic outcomes. We extracted data from the Indiana Network of Patient Care for 134,815 patients who received statin therapy between January 4, 2004, and December 31, 2008. All individuals began statin treatment, some discontinued statin use, and some experienced myopathy and/or rhabdomyolysis while taking the drug or after discontinuation. We developed a militate model to characterize 12 transition probabilities among six different states defined by use or discontinuation of statin and its associated myopathy or rhabdomyolysis. We found that discontinuation of statin therapy was common and frequently early, with 44.4% of patients discontinuing therapy after 1 month, and discontinuation is a strong indicator for statin-induced myopathy (risk ratio, 10.8; p < 0.05). Women more likely than men (p < 0.05) and patients aged 65 years and older had a higher risk than those aged younger than 65 years to discontinue statin use or experience myopathy. In conclusion, we introduce an innovative multistate model that allows clear depiction of the relationship between statin discontinuation and statin-induced myopathy. For the first time, we have successfully demonstrated and quantified the relative risk of myopathy between patients who continued and discontinued statin therapy. Age and sex were two strong risk factors for both statin discontinuation and incident myopathy.Item A Novel Perioperative Multidose Methadone-Based Multimodal Analgesic Strategy in Children Achieved Safe and Low Analgesic Blood Methadone Levels Enabling Opioid-Sparing Sustained Analgesia With Minimal Adverse Effects(Wolters Kluwer, 2021) Sadhasivam, Senthilkumar; Aruldhas, Blessed W.; Packiasabapathy, Senthil; Overholser, Brian R.; Zhang, Pengyue; Zang, Yong; Renschler, Janelle S.; Fitzgerald, Ryan E.; Quinney, Sara K.; Anesthesia, School of MedicineBackground: Intraoperative methadone, a long-acting opioid, is increasingly used for postoperative analgesia, although the optimal methadone dosing strategy in children is still unknown. The use of a single large dose of intraoperative methadone is controversial due to inconsistent reductions in total opioid use in children and adverse effects. We recently demonstrated that small, repeated doses of methadone intraoperatively and postoperatively provided sustained analgesia and reduced opioid use without respiratory depression. The aim of this study was to characterize pharmacokinetics, efficacy, and safety of a multiple small-dose methadone strategy. Methods: Adolescents undergoing posterior spinal fusion (PSF) for idiopathic scoliosis or pectus excavatum (PE) repair received methadone intraoperatively (0.1 mg/kg, maximum 5 mg) and postoperatively every 12 hours for 3-5 doses in a multimodal analgesic protocol. Blood samples were collected up to 72 hours postoperatively and analyzed for R-methadone and S-methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP) metabolites, and alpha-1 acid glycoprotein (AAG), the primary methadone-binding protein. Peak and trough concentrations of enantiomers, total methadone, and AAG levels were correlated with clinical outcomes including pain scores, postoperative nausea and vomiting (PONV), respiratory depression, and QT interval prolongation. Results: The study population included 38 children (10.8-17.9 years): 25 PSF and 13 PE patients. Median total methadone peak plasma concentration was 24.7 (interquartile range [IQR], 19.2-40.8) ng/mL and the median trough was 4.09 (IQR, 2.74-6.4) ng/mL. AAG concentration almost doubled at 48 hours after surgery (median = 193.9, IQR = 86.3-279.5 µg/mL) from intraoperative levels (median = 87.4, IQR = 70.6-115.8 µg/mL; P < .001), and change of AAG from intraoperative period to 48 hours postoperatively correlated with R-EDDP (P < .001) levels, S-EDDP (P < .001) levels, and pain scores (P = .008). Median opioid usage was minimal, 0.66 (IQR, 0.59-0.75) mg/kg morphine equivalents/d. No respiratory depression (95% Wilson binomial confidence, 0-0.09) or clinically significant QT prolongation (median = 9, IQR = -10 to 28 milliseconds) occurred. PONV occurred in 12 patients and was correlated with morphine equivalent dose (P = .005). Conclusions: Novel multiple small perioperative methadone doses resulted in safe and lower blood methadone levels, <100 ng/mL, a threshold previously associated with respiratory depression. This methadone dosing in a multimodal regimen resulted in lower blood methadone analgesia concentrations than the historically described minimum analgesic concentrations of methadone from an era before multimodal postoperative analgesia without postoperative respiratory depression and prolonged corrected QT (QTc). Larger studies are needed to further study the safety and efficacy of this methadone dosing strategy.Item Alcohol use disorder is associated with higher risks of Alzheimer's and Parkinson's diseases: A study of US insurance claims data(Wiley, 2022-11-21) Zhang, Pengyue; Edenberg, Howard J.; Nurnberger, John; Lai, Dongbing; Cheng, Feixiong; Liu, Yunlong; Biostatistics, School of Public HealthIntroduction: Alcohol use disorder (AUD) is on the ascendancy in the US older adult population. The association between AUD and adverse brain outcomes remains inconclusive. Method: In a retrospective cohort design using US insurance claim data (2007-2020), 129,182 individuals with AUD were matched with 129,182 controls by age, sex, race, and clinical characteristics. We investigated the association between AUD and adverse brain outcomes using Cox analysis, Kaplan-Meier analysis, and log-rank test. Results: After adjusting for covariates, AUD was associated with a higher risk of Alzheimer's disease (female adjusted hazard ratio [HR] = 1.78, 95% confidence interval [CI]: 1.68-1.90, p < 0.001; male adjusted HR = 1.80, 95% CI: 1.71-1.91, p < 0.001) and a higher risk of Parkinson's disease (female adjusted HR = 1.49, 95% CI: 1.32-1.68, p < 0.001; male adjusted HR = 1.42, 95% CI: 1.32-1.52, p < 0.001) in the overall sample. In separate analyses of Black, White, and Hispanic individuals, those with AUD had higher risk of Alzheimer's disease (adjusted HRs ≥1.58; Ps ≤ 0.001). A significantly elevated risk for Parkinson's disease was found only in the White subpopulation (female adjusted HR = 1.55, 95% CI: 1.36-1.77, p < 0.001; male adjusted HR = 1.45, 95% CI: 1.33-1.57, p < 0.001). Conclusions: AUD is associated with Alzheimer's disease. AUD is associated with Parkinson's disease in White people. Cognitive screening and neurological examination among older adults with AUD hold the promise for early detection of Alzheimer's disease and Parkinson's disease. Highlights: Alcohol use disorder is associated with Alzheimer's disease and dementia. Alcohol use disorder is associated with Parkinson's disease in White people.Item Artificial intelligence framework identifies candidate targets for drug repurposing in Alzheimer’s disease(BMC, 2022-01-10) Fang, Jiansong; Zhang, Pengyue; Wang, Quan; Chiang, Chien‑Wei; Zhou, Yadi; Hou, Yuan; Xu, Jielin; Chen, Rui; Zhang, Bin; Lewis, Stephen J.; Leverenz, James B.; Pieper, Andrew A.; Li, Bingshan; Li, Lang; Cummings, Jeffrey; Cheng, Feixiong; Biostatistics and Health Data Science, School of MedicineBackground: Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer's disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. Methods: To address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human protein-protein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and AD transgenic animal models, drug-target networks, and the human protein-protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells. Results: Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that three drugs (pioglitazone, febuxostat, and atenolol) are significantly associated with decreased risk of AD compared with matched control populations. Pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.916, 95% confidence interval [CI] 0.861-0.974, P = 0.005) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR = 0.921, 95% CI 0.862-0.984, P = 0.0159), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. Conclusions: In summary, we present an integrated, network-based artificial intelligence methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.Item Association Between Tobacco Related Diagnoses and Alzheimer Disease: A Population Study(2022-05) Almalki, Amwaj Ghazi; Zhang, Pengyue; Johnson, Travis; Fadel, WilliamBackground: Tobacco use is associated with an increased risk of developing Alzheimer's disease (AD). 14% of the incidence of AD is associated with various types of tobacco exposure. Additional real-world evidence is warranted to reveal the association between tobacco use and AD in age/gender-specific subpopulations. Method: In this thesis, the relationships between diagnoses related to tobacco use and diagnoses of AD in gender- and age-specific subgroups were investigated, using health information exchange data. The non-parametric Kaplan-Meier method was used to estimate the incidence of AD. Furthermore, the log-rank test was used to compare incidence between individuals with and without tobacco related diagnoses. In addition, we used semi-parametric Cox models to examine the association between tobacco related diagnoses and diagnoses of AD, while adjusting covariates. Results: Tobacco related diagnosis was associated with increased risk of developing AD comparing to no tobacco related diagnosis among individuals aged 60-74 years (female hazard ratio [HR] =1.26, 95% confidence interval [CI]: 1.07 – 1.48, p-value = 0.005; and male HR =1.33, 95% CI: 1.10 - 1.62, p-value =0.004). Tobacco related diagnosis was associated with decreased risk of developing AD comparing to no tobacco related diagnosis among individuals aged 75-100 years (female HR =0.79, 95% CI: 0.70 - 0.89, p-value =0.001; and male HR =0.90, 95% CI: 0.82 - 0.99, p-value =0.023). Conclusion: Individuals with tobacco related diagnoses were associated with an increased risk of developing AD in older adults aged 60-75 years. Among older adults aged 75-100 years, individuals with tobacco related diagnoses were associated with a decreased risk of developing AD.Item Associations Between Neuroinflammation-Related Conditions and Alzheimer’s Disease: A Study of US Insurance Claims Data(Sage, 2024) Xu, Jing; Chen, Yao; Shi, Yi; Sun, Anna; Yang, Yuedi; Boustani, Malaz; Su, Jing; Zhang, Pengyue; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBackground: Early detection of Alzheimer's disease (AD) is a key component for the success of the recently approved lecanemab and aducanumab. Patients with neuroinflammation-related conditions are associated with a higher risk for developing AD. Objective: Investigate the incidence of AD among patients with neuroinflammation-related conditions including epilepsy, hemorrhage stroke, multiple sclerosis (MS), and traumatic brain injury (TBI). Methods: We used Optum's de-identified Clinformatics Data Mart Database (CDM). We derived covariate-matched cohorts including patients with neuroinflammation-related conditions and controls without the corresponding condition. The matched cohorts were: 1) patients with epilepsy and controls (N = 67,825 matched pairs); 2) patients with hemorrhage stroke and controls (N = 81,510 matched pairs); 3) patients with MS and controls (N = 9,853 matched pairs); and 4) patients TBI and controls (N = 104,637 matched pairs). We used the Cox model to investigate the associations between neuroinflammation-related conditions and AD. Results: We identified that epilepsy, hemorrhage stroke, and TBI were associated with increased risks of AD in both males and females (hazard ratios [HRs]≥1.74, p < 0.001), as well as in gender- and race-conscious subpopulations (HRs≥1.64, p < 0.001). We identified that MS was associated with increased risks of AD in both males and females (HRs≥1.47, p≤0.004), while gender- and race-conscious subgroup analysis shown mixed associations. Conclusions: Patients with epilepsy, hemorrhage stroke, MS, and/or TBI are associated with a higher risk of developing AD. More attention on cognitive status should be given to older patients with these conditions.Item Bayesian Adaptive Designs for Phase II Clinical Trials Evaluating Subgroup-Specific Treatment Effect(2024-12) Shan, Mu; Zang, Yong; Han, Jiali; Tu, Wanzhu; Zhang, PengyueIn Phase II clinical trials, particularly for molecularly targeted agents (MTAs) and biotherapies, there is a critical need to evaluate subgroup-specific treatment effects due to the heterogeneous nature of these therapies. This dissertation introduces two innovative Bayesian adaptive designs for biomarker-guided clinical trials: the Bayesian Order Constrained Adaptive (BOCA) design and the Bayesian Adaptive Marker-Stratified Design Using Calibrated Spike-and-Slab priors (SSS). The BOCA design addresses the limitations of the "one-size-fits-all" approach in non-randomized Phase II trials by efficiently detecting subgroup-specific treatment effects. It combines elements of enrichment and sequential designs, starting with an "all-comers" stage and transitioning to an enrichment stage based on interim analysis results. The decision to continue with either the marker-positive or marker-negative subgroup is guided by two posterior probabilities utilizing inherent ordering constraints. This adaptive approach enhances trial efficiency and cost-effectiveness while managing missing biomarker data. Comprehensive simulation studies show that the BOCA design outperforms conventional designs in detecting subgroup-specific treatment effects, making it a robust tool for Phase II trials. The SSS design improves the efficiency of marker-stratified designs (MSD) by leveraging clinical features of biomarkers and treatments. Patients are classified into marker-positive and marker-negative subgroups and randomized to receive either the MTA or a control treatment. The SSS design uses spike-and-slab priors to dynamically share information on response rates across subgroups, governed by two posterior probabilities that assess similarities in response rates. Additionally, it incorporates a Bayesian multiple imputation method to address missing biomarker profiles. Simulation studies confirm that the SSS design exhibits favorable operational characteristics, surpassing conventional designs in evaluating subgroup-specific treatment effects. Both the BOCA and SSS designs represent significant advancements in Bayesian adaptive methodologies for Phase II trials. By addressing traditional approach limitations, these designs enhance the evaluation of subgroup-specific treatment effects, contributing valuable methodologies to the field of personalized medicine.Item Comparing Nanopore to MethylationEPIC Array and EM-Seq in DNA Methylation Detection(2024-12) Brooks, Steven; Liu, Yunlong; Peng, Gang; Zhang, PengyueDNA Methylation is an important biological process in epigenetics, and many methods have been developed to profile DNA methylation. Recently a growing number of studies use Nanopore long-read sequencing technology in DNA methylation detection, in contrast to widely used Infinium arrays and short-read whole genome sequencing (WGS) methods. In this study, we evaluate the performance of Nanopore sequencing in DNA methylation detection by comparing it to the Illumina MethylationEPIC microarray (EPIC) and Enzymatic Methyl-Sequencing. We first compare Oxford Nanopore Technologies’ Nanopore with MethylationEPIC array. Among the ~850,000 CpG sites covered by both methods, we observed high concordance (R ≥ 0.94 across all four samples). After downsampling Nanopore data from an average coverage of 26.6 reads per site to 10 reads per site, the correlation in CpG methylation remained high (R≥ 0.935). Next, we compare Nanopore with EM-Seq in the context of low coverage. The lower CpG methylation correlation (R ≥ 0.8), can be attributed to reduced coverage of hypomethylated CpG sites by EM-Seq. Furthermore, we highlight Nanopore’s unique capabilities, including native DNA sequencing that can differentiate modification types and the use of long reads for haplotype phasing. Overall, Nanopore demonstrated high concordance with the EPIC array and more uniform coverage across the genome than EM-Seq. This study provides insights for researchers in selecting appropriate DNA methylation detection methods, considering factors such as cost, DNA input, and the complexity of downstream analysis.