Browsing by Author "Jung, Sin-Ho"
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Item Open Access Bacteremia in solid organ transplant recipients as compared to immunocompetent patients: Acute phase cytokines and outcomes in a prospective, matched cohort study.(American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2021-06) Eichenberger, Emily M; Ruffin, Felicia; Dagher, Michael; Lerebours, Reginald; Jung, Sin-Ho; Sharma-Kuinkel, Batu; Macintyre, Andrew N; Thaden, Joshua T; Sinclair, Matthew; Hale, Lauren; Kohler, Celia; Palmer, Scott M; Alexander, Barbara D; Fowler, Vance G; Maskarinec, Stacey AWe undertook a prospective, matched cohort study of patients with Staphylococcus aureus bacteremia (SAB) and gram-negative bacteremia (GNB) to compare the characteristics, outcomes, and chemokine and cytokine response in transplant recipients to immunocompetent, nontransplant recipients. Fifty-five transplant recipients (GNB n = 29; SAB n = 26) and 225 nontransplant recipients (GNB n = 114; SAB n = 111) were included for clinical analysis. Transplant GNB had a significantly lower incidence of septic shock than nontransplant GNB (10.3% vs 30.7%, p = .03). Thirty-day mortality did not differ significantly between transplant and nontransplant recipients with GNB (10.3% vs 15.8%, p = .57) or SAB (0.0% vs 11.7%, p = .13). Next, transplant patients were matched 1:1 with nontransplant patients for the chemokine and cytokine analysis. Five cytokines and chemokines were significantly lower in transplant GNB vs nontransplant GNB: IL-2 (median [IQR]: 7.1 pg/ml [7.1, 7.1] vs 32.6 pg/ml [7.1, 88.0]; p = .001), MIP-1β (30.7 pg/ml [30.7, 30.7] vs 243.3 pg/ml [30.7, 344.4]; p = .001), IL-8 (32.0 pg/ml [5.6, 53.1] vs 59.1 pg/ml [39.2, 119.4]; p = .003), IL-15 (12.0 pg/ml [12.0, 12.0] vs 12.0 pg/ml [12.0, 126.7]; p = .03), and IFN-α (5.1 pg/mL [5.1, 5.1] vs 5.1 pg/ml [5.1, 26.3]; p = .04). Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES) was higher in transplant SAB vs nontransplant SAB (mean [SD]: 750.2 pg/ml [194.6] vs 656.5 pg/ml [147.6]; p = .046).Item Open Access Decreased Mortality in 1-Year Survivors of Umbilical Cord Blood Transplant vs. Matched Related or Matched Unrelated Donor Transplant in Patients with Hematologic Malignancies.(Transplant Cell Ther, 2021-05-12) Bohannon, Lauren; Tang, Helen; Page, Kristin; Ren, Yi; Jung, Sin-Ho; Artica, Alexandra; Britt, Anne; Islam, Prioty; Siamakpour-Reihani, Sharareh; Giri, Vinay; Lew, Meagan; Kelly, Matthew; Choi, Taewoong; Gasparetto, Cristina; Long, Gwynn; Lopez, Richard; Rizzieri, David; Sarantopoulos, Stefanie; Chao, Nelson; Horwitz, Mitchell; Sung, AnthonyBACKGROUND: Allogeneic hematopoietic stem cell transplantation (HCT) has the potential to cure hematologic malignancies, but is associated with significant morbidity and mortality. While deaths during the first year after transplant are often attributable to treatment toxicities and complications, death after the first year may be due to sequelae of accelerated aging caused by cellular senescence. Cytotoxic therapies and radiation used in cancer treatments and conditioning regimens for HCT can induce aging at the molecular level; HCT patients experience time-dependent effects, such as frailty and aging-associated diseases, more rapidly than people who have not been exposed to these treatments. Consistent with this, recipients of younger cells tend to have decreased markers of aging and improved survival, decreased GVHD, and lower relapse rates. OBJECTIVES: Given that umbilical cord blood (UCB) is the youngest donor source available, we studied the outcomes after the first year of UCB transplant vs. matched related donor (MRD) and matched unrelated donor (MUD) transplant in patients with hematologic malignancies over a 20-year period. STUDY DESIGN: In this single center, retrospective study, we examined the outcomes of all adult patients who underwent their first allogeneic HCT through the Duke Adult Bone Marrow Transplant (ABMT) program from January 1, 1996 to December 31, 2015, to allow for at least 3 years of follow-up. Patients were excluded if they died or were lost to follow-up before day 365 post-HCT; received an allogeneic HCT for a disease other than a hematologic malignancy; or received cells from a haploidentical or mismatched adult donor. RESULTS: UCB recipients experienced a better unadjusted overall survival than MRD/MUD recipients (log rank p=0.03, Figure 1, median OS: UCB not reached, MRD/MUD 7.4 years). After adjusting for selected covariates, UCB recipients who survived at least 1 year after HCT had a hazard of death that was 31% lower than that of MRD/MUD recipients (HR: 0.69, 95% CI: 0.47-0.99, p=0.049). This trend held true in a subset analysis of subjects with acute leukemia. UCB recipients also experienced lower rates of moderate or severe chronic graft-versus-host disease (GVHD) and non-relapse mortality, and slower time to relapse. UCB and MRD/MUD recipients experienced similar rates of grade 2-4 acute GVHD, chronic GHVD, secondary malignancy, and subsequent allogeneic HCT. CONCLUSIONS: UCB is already widely used as a donor source in pediatric HCT; however, adult outcomes and adoption have historically lagged behind in comparison. Recent advancements in UCB transplantation such as the implementation of lower-intensity conditioning regimens, double unit transplants, and ex-vivo expansion have improved early mortality, making UCB an increasingly attractive donor source for adults; furthermore, our findings suggest that UCB may actually be a preferred donor source for mitigating late effects of HCT.Item Embargo Design and Inference Methods for Randomized Clinical Trials(2023) Cao, ShiweiTraditionally, phase II trials have employed single-arm designs, recruiting patients exclusively for the experimental therapy, and comparing results with historical controls. Due to the limited sample size and patient heterogeneity, the characteristics of patients in new phase II trials often differ from those in the selected historical controls, leading to potential false positive or false negative conclusions. Randomized phase II trials offer a solution by randomizing patients between an experimental arm and a control arm.In this dissertation, we seek efficient designs for multi-stage randomized clinical trials and develop inference methods for the widely used odds ratio parameter. We propose a two-stage randomized phase II trial design based on Fisher's exact tests. This design includes options for early stopping due to either superiority or futility, aimed at optimizing patient enrollment whether the experimental therapy proves efficacious or not. Furthermore, we introduce a novel criterion, the weighted expected sample size, to define optimal designs for multi-stage clinical trials. We have also developed a Java software tool capable of identifying these optimal designs. Additionally, we present a bias-corrected estimator and an exact conditional confidence interval for the odds ratio in multi-stage randomized clinical trials.
Item Open Access Design and Monitoring of Clinical Trials with Clustered Time-to-Event Endpoint(2020) Li, JianghaoMany clinical trials are involved with clustered data that consists of groups (called clusters) of nested subjects (called subunits). Observations from subunits within each cluster tend to be positively correlated due to shared characteristics. Therefore, analysis of such data needs to account for the dependency between subunits. For clustered time-to-event endpoints, there are only few methods proposed for sample size calculation, especially when the cluster sizes are variable. In this dissertation, we aim to derive sample size formula for clustered survival endpoint based on nonparametric weighted rank tests. First, we propose closed form sample size formulas for cluster randomization trials and subunit randomization trials; accordingly, we derive the intracluster correlation coefficient for clustered time-to-event endpoint. We find that the required number of clusters is affected not only by the mean cluster size, but also by the variance of cluster size distribution. In addition, we prove that in group sequentially monitored cluster randomization studies, the log-rank statistics does not have independent increment property, which is different from the result for independent survival data. We further derive the limiting distribution of sequentially computed log-rank statistics, and develop a group sequential testing procedure based on alpha spending approach, as well as a corresponding sample size calculation method.
Item Open Access Initial Clinical Outcome With Bilateral, Dual-Target Deep Brain Stimulation Trial in Parkinson Disease Using Summit RC + S.(Neurosurgery, 2022-04-07) Mitchell, Kyle T; Schmidt, Stephen L; Cooney, Jeffrey W; Grill, Warren M; Peters, Jennifer; Rahimpour, Shervin; Lee, Hui-Jie; Jung, Sin-Ho; Mantri, Sneha; Scott, Burton; Lad, Shivanand P; Turner, Dennis ABackground
Deep brain stimulation (DBS) is an effective therapy in advanced Parkinson disease (PD). Although both subthalamic nucleus (STN) and globus pallidus (GP) DBS show equivalent efficacy in PD, combined stimulation may demonstrate synergism.Objective
To evaluate the clinical benefit of stimulating a combination of STN and GP DBS leads and to demonstrate biomarker discovery for adaptive DBS therapy in an observational study.Methods
We performed a pilot trial (n = 3) of implanting bilateral STN and GP DBS leads, connected to a bidirectional implantable pulse generator (Medtronic Summit RC + S; NCT03815656, IDE No. G180280). Initial 1-year outcome in 3 patients included Unified PD Rating Scale on and off medications, medication dosage, Hauser diary, and recorded beta frequency spectral power.Results
Combined DBS improved PD symptom control, allowing >80% levodopa medication reduction. There was a greater decrease in off-medication motor Unified PD Rating Scale with multiple electrodes activated (mean difference from off stimulation off medications -18.2, range -25.5 to -12.5) than either STN (-12.8, range -20.5 to 0) or GP alone (-9, range -11.5 to -4.5). Combined DBS resulted in a greater reduction of beta oscillations in STN in 5/6 hemispheres than either site alone. Adverse events occurred in 2 patients, including a small cortical hemorrhage and seizure at 24 hours postoperatively, which resolved spontaneously, and extension wire scarring requiring revision at 2 months postoperatively.Conclusion
Patients with PD preferred combined DBS stimulation in this preliminary cohort. Future studies will address efficacy of adaptive DBS as we further define biomarkers and control policy.Item Open Access Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.(Molecular cancer therapeutics, 2023-01) Patel, Rutulkumar; Mowery, Yvonne M; Qi, Yi; Bassil, Alex M; Holbrook, Matt; Xu, Eric S; Hong, Cierra S; Himes, Jonathon E; Williams, Nerissa T; Everitt, Jeffrey; Ma, Yan; Luo, Lixia; Selitsky, Sara R; Modliszewski, Jennifer L; Gao, Junheng; Jung, Sin-Ho; Kirsch, David G; Badea, Cristian TThis study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.Item Open Access Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.(Molecular cancer therapeutics, 2023-01) Patel, Rutulkumar; Mowery, Yvonne M; Qi, Yi; Bassil, Alex M; Holbrook, Matt; Xu, Eric S; Hong, Cierra S; Himes, Jonathon E; Williams, Nerissa T; Everitt, Jeffrey; Ma, Yan; Luo, Lixia; Selitsky, Sara R; Modliszewski, Jennifer L; Gao, Junheng; Jung, Sin-Ho; Kirsch, David G; Badea, Cristian TThis study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.Item Open Access permGPU: Using graphics processing units in RNA microarray association studies.(BMC Bioinformatics, 2010-06-16) Shterev, Ivo D; Jung, Sin-Ho; George, Stephen L; Owzar, KourosBACKGROUND: Many analyses of microarray association studies involve permutation, bootstrap resampling and cross-validation, that are ideally formulated as embarrassingly parallel computing problems. Given that these analyses are computationally intensive, scalable approaches that can take advantage of multi-core processor systems need to be developed. RESULTS: We have developed a CUDA based implementation, permGPU, that employs graphics processing units in microarray association studies. We illustrate the performance and applicability of permGPU within the context of permutation resampling for a number of test statistics. An extensive simulation study demonstrates a dramatic increase in performance when using permGPU on an NVIDIA GTX 280 card compared to an optimized C/C++ solution running on a conventional Linux server. CONCLUSIONS: permGPU is available as an open-source stand-alone application and as an extension package for the R statistical environment. It provides a dramatic increase in performance for permutation resampling analysis in the context of microarray association studies. The current version offers six test statistics for carrying out permutation resampling analyses for binary, quantitative and censored time-to-event traits.Item Open Access Randomised, double-blind, placebo-controlled trial of Probiotics To Eliminate COVID-19 Transmission in Exposed Household Contacts (PROTECT-EHC): a clinical trial protocol.(BMJ open, 2021-05-05) Tang, Helen; Bohannon, Lauren; Lew, Meagan; Jensen, David; Jung, Sin-Ho; Zhao, Aaron; Sung, Anthony D; Wischmeyer, Paul EIntroduction
The COVID-19 pandemic has proven to be an unprecedented challenge to worldwide health, and strategies to mitigate the spread and severity of COVID-19 infection are urgently needed. Emerging evidence suggests that the composition of the gut microbiome and modification of microbial ecology via probiotics can affect susceptibility to a wide range of infections, including respiratory tract infections. In this study, we aim to evaluate the effects of the probiotic Lactobacillus rhamnosus GG (LGG) versus placebo on COVID-19 infection status and the gut microbiome in subjects with a household contact who has tested positive for COVID-19.Methods and analysis
In this double-blinded, randomised, placebo-controlled trial, we will randomise 1132 subjects having a household contact who has recently (≤7 days) tested positive for COVID-19 to daily oral LGG or placebo for 28 days. We hypothesise that taking LGG as a probiotic will protect against COVID-19 infection and reduce the severity of disease in those who become infected (primary endpoint: decreased symptoms), and will be associated with beneficial changes in the composition of the gut microbiome. Stool samples and nasal swabs will be collected to evaluate the microbiome by 16S rRNA sequencing and the presence of SARS-CoV-2 by PCR, respectively. We will also conduct multivariate analysis of demographic, behavioural, temporal, and other variables that may predict development of symptoms and other outcomes.Ethics and dissemination
This trial is conducted under a Food and Drug Administration Investigational New Drug for LGG, has received ethics approval by the institutional review board of Duke University and enrolment has begun. We plan to disseminate the results in peer-reviewed journals and at national and international conferences.Trial registration number
NCT04399252.Item Open Access Robotic Mitral Valve Repair in Older Individuals: An Analysis of The Society of Thoracic Surgeons Database.(The Annals of thoracic surgery, 2018-11) Wang, Alice; Brennan, J Matthew; Zhang, Shuaiqi; Jung, Sin-Ho; Yerokun, Babatunde; Cox, Morgan L; Jacobs, Jeffrey P; Badhwar, Vinay; Suri, Rakesh M; Thourani, Vinod; Halkos, Michael E; Gammie, James S; Gillinov, A Marc; Smith, Peter K; Glower, DonaldBackground
National outcomes of robotic mitral valve repair (rMVr) compared with sternotomy (sMVr) in older patients are currently unknown.Methods
From 2011 to 2014, all patients aged 65 years and older undergoing MVr in The Society of Thoracic Surgeons Adult Cardiac Surgery Database linked to Medicare claims data were identified. Patients who underwent rMVr were propensity matched to patients who underwent sMVr. Standard differences and falsification outcome of baseline characteristics were tested to ensure a balanced match. Cox models were used to calculate 3-year mortality, heart failure readmission, and mitral valve reintervention, adjusting for competing risks where appropriate.Results
After matching, 503 rMVr patients from 65 centers and 503 sMVr from 251 centers were included. There were no significant differences in comorbidities or falsification outcome. Cardiopulmonary bypass and cross-clamp times were longer with rMVr versus sMVr at 125 versus 102 minutes (p < 0.0001) and 85 versus 75 minutes (p < 0.0001), respectively. The rMVr patients had shorter intensive care unit (27 vs 47 hours, p < 0.0001) and hospital stay (5 vs 6 days, p < 0.0001), less frequent transfusion (21% vs 35%, p < 0.0001), and less atrial fibrillation (28% vs 40%, p < 0.0001). Three-year mortality (hazard ratio, 1.21; 95% confidence interval, 0.68 to 2.16; p = 0.52), heart failure readmission (hazard ratio, 1.42; 95% confidence interval, 0.80 to 2.52, p = 0.10), and mitral valve reintervention (hazard ratio, 0.42; 95% confidence interval, 0.15 to 1.18; p = 0.22) did not differ between the groups.Conclusions
The rMVr procedure was associated with less atrial fibrillation, less frequent transfusion requirement, and shorter intensive care unit and hospital stay, without a significant difference in 3-year mortality, heart failure readmission, or mitral valve reintervention. In older patients, rMVr confers short-term advantages without a detriment to midterm outcomes.Item Open Access Robust test method for time-course microarray experiments.(BMC Bioinformatics, 2010-07-22) Sohn, Insuk; Owzar, Kouros; George, Stephen L; Kim, Sujong; Jung, Sin-HoBACKGROUND: In a time-course microarray experiment, the expression level for each gene is observed across a number of time-points in order to characterize the temporal trajectories of the gene-expression profiles. For many of these experiments, the scientific aim is the identification of genes for which the trajectories depend on an experimental or phenotypic factor. There is an extensive recent body of literature on statistical methodology for addressing this analytical problem. Most of the existing methods are based on estimating the time-course trajectories using parametric or non-parametric mean regression methods. The sensitivity of these regression methods to outliers, an issue that is well documented in the statistical literature, should be of concern when analyzing microarray data. RESULTS: In this paper, we propose a robust testing method for identifying genes whose expression time profiles depend on a factor. Furthermore, we propose a multiple testing procedure to adjust for multiplicity. CONCLUSIONS: Through an extensive simulation study, we will illustrate the performance of our method. Finally, we will report the results from applying our method to a case study and discussing potential extensions.