Browsing by Author "Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health"
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Item 79 How do you share documents with collaborators external to your institution?(Cambridge University Press, 2025-04-11) Khalatbari, Shokoufeh; Perkins, Susan; Thurston, Sally; Bugden, Jane; Spino, Cathie; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthObjectives/Goals: Using secure systems for sharing documents with external collaborators is essential for all researchers. These documents may include protected health information (PHI) or sensitive materials like protocols, study reports, DSMB reports, publications, presentations, abstracts, and statistical analysis plans (SAPs). Methods/Study Population: We surveyed the ACTS Biostatistics, Epidemiology, and Research Design Special Interest Group (BERD-SIG) to gather information about the systems they are currently using or have used in the past for document sharing with external collaborators. The survey focused on the security of these systems, particularly in relation to sharing documents containing PHI. In addition, the survey included questions about various system features of interest. These features included version control, simultaneous editing by multiple users, and access rights management, such as the ability to assign different permissions (e.g., read-only, write, and download) to different individuals. We also invited participants to provide feedback on any additional positive or negative aspects of the systems they use. Results/Anticipated Results: We received 28 completed survey responses. Respondents had an option for choosing more than one system. The top current systems reported were Microsoft Teams (OneDrive, SharePoint) (n = 16), Box (n = 11), Google Docs/Drive (n = 10), and Dropbox (n = 6). Among other systems listed individually were Filelocker, REDCap, Slack, Website, Significant Media Shuttle, and Zulip. Notably, 15 responses indicated the respondents were unsure if their system is secure for sharing documents containing PHI. Respondents also offered feedback on both the positive and negative aspects of these systems. For example, a key advantage of Box was its password-controlled access. However, its incompatibility with office tools and the challenges for external collaborators attempting to access the system were noted as drawbacks. Discussion/Significance of Impact: Utilizing secure institutional document-sharing systems and understanding their features significantly affects the effectiveness and security of collaborations among researchers, particularly with external partners. This knowledge is especially crucial when sharing documents containing sensitive patient and study data.Item A Bayesian Phase I/II Design to Determine Subgroup-Specific Optimal Dose for Immunotherapy Sequentially Combined with Radiotherapy(Wiley, 2023) Guo, Beibei; Zang, Yong; Lin, Li-Hsiang; Zhang, Rui; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthSequential administration of immunotherapy following radiotherapy (immunoRT) has attracted much attention in cancer research. Due to its unique feature that radiotherapy upregulates the expression of a predictive biomarker for immunotherapy, novel clinical trial designs are needed for immunoRT to identify patient subgroups and the optimal dose for each subgroup. In this article, we propose a Bayesian phase I/II design for immunotherapy administered after standard-dose radiotherapy for this purpose. We construct a latent subgroup membership variable and model it as a function of the baseline and pre-post radiotherapy change in the predictive biomarker measurements. Conditional on the latent subgroup membership of each patient, we jointly model the continuous immune response and the binary efficacy outcome using plateau models, and model toxicity using the equivalent toxicity score approach to account for toxicity grades. During the trial, based on accumulating data, we continuously update model estimates and adaptively randomize patients to admissible doses. Simulation studies and an illustrative trial application show that our design has good operating characteristics in terms of identifying both patient subgroups and the optimal dose for each subgroup.Item A Comparative Analysis of Oral Health and Self-Rated Health: ‘All of Us Research Program’ vs. ‘Health and Retirement Study’(MDPI, 2024-09-13) Weintraub, Jane A.; Moss, Kevin L.; Finlayson, Tracy L.; Jones, Judith A.; Preisser, John S.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthPoor oral health can impact overall health. This study assessed the association between dental factors (dentate status and dental utilization) and self-rated health (S-RH) among older adults in two cross-sectional datasets: (1) NIH "All of Us (AoU) Research Program" (May 2018-July 2022 release) and (2) U.S. nationally representative "Health and Retirement Study" (HRS) 2018 wave. Participants aged ≥ 51 years were included in these analyses if (1) from AoU, they had clinical dental and medical data from electronic health records (EHRs) and surveys (n = 5480), and (2) from HRS, they had dental and socio-demographic survey data (n = 14,358). S-RH was dichotomized (fair/poor vs. better) and analyzed with logistic regression. Sample survey weights for HRS and stratification and averaging AoU results used the weighted HRS race-ethnicity and age distribution standardized respective analyses to the U.S. population. Fair/poor S-RH was reported by 32.6% in AoU and 28.6% in HRS. Dentate status information was available from 7.7% of AoU EHRs. In population-standardized analyses, lack of dental service use increased odds of fair/poor S-RH in AoU, OR (95% CI) = 1.28 (1.11-1.48), and in HRS = 1.45 (1.09-1.94), as did having diabetes, less education, and ever being a smoker. Having no natural teeth was not statistically associated with fair/poor S-RH. Lack of dental service was positively associated with fair/poor S-RH in both datasets. More and better oral health information in AoU and HRS are needed.Item A Consideration of Genetic Mechanisms Behind the Development of Hypertension in Blacks(Springer, 2013) Tu, Wanzhu; Pratt, J. Howard; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthHypertension is a more serious disease in blacks. The determinants of the blood pressure (BP) may be uniquely different from those in whites. The characteristic low-renin, salt-sensitive hypertension of blacks is consistent with the kidney reabsorbing additional sodium (Na), which leads to an expanded plasma volume that drives the BP. Mechanisms considered are genetically based. These include: (1) the intra-renal renin-angiotensin system (RAS), one based on molecular variations in angiotensinogen; (2) the Na, K, 2Cl cotransporter (NKCC2) and its regulators in the thick ascending limb, which are associated with a variety of phenotypes consistent with a more active cotransporter in blacks; and (3) the genes for MYH9 and APOL 1, which have been associated with kidney disease in blacks. To achieve a state of hypertension, an increase in Na uptake in proximal nephron regions may require a distal nephron that does not fully adjust due to less than adequate suppression of aldosterone production.Item A generalized phase 1-2-3 design integrating dose optimization with confirmatory treatment comparison(Oxford University Press, 2024) Zang, Yong; Thall, Peter F.; Yuan, Ying; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthA generalized phase 1-2-3 design, Gen 1-2-3, that includes all phases of clinical treatment evaluation is proposed. The design extends and modifies the design of Chapple and Thall (2019), denoted by CT. Both designs begin with a phase 1-2 trial including dose acceptability and optimality criteria, and both select an optimal dose for phase 3. The Gen 1-2-3 design has the following key differences. In stage 1, it uses phase 1-2 criteria to identify a set of candidate doses rather than 1 dose. In stage 2, which is intermediate between phase 1-2 and phase 3, it randomizes additional patients fairly among the candidate doses and an active control treatment arm and uses survival time data from both stage 1 and stage 2 patients to select an optimal dose. It then makes a Go/No Go decision of whether or not to conduct phase 3 based on the predictive probability that the selected optimal dose will provide a specified substantive improvement in survival time over the control. A simulation study shows that the Gen 1-2-3 design has desirable operating characteristics compared to the CT design and 2 conventional designs.Item A genetically informed brain atlas for enhancing brain imaging genomics(Springer Nature, 2025-04-14) Bao, Jingxuan; Wen, Junhao; Chang, Changgee; Mu, Shizhuo; Chen, Jiong; Shivakumar, Manu; Cui, Yuhan; Erus, Guray; Yang, Zhijian; Yang, Shu; Wen, Zixuan; The Alzheimer’s Disease Neuroimaging Initiative; Zhao, Yize; Kim, Dokyoon; Duong-Tran, Duy; Saykin, Andrew J.; Zhao, Bingxin; Davatzikos, Christos; Long, Qi; Shen, Li; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBrain imaging genomics has manifested considerable potential in illuminating the genetic determinants of human brain structure and function. This has propelled us to develop the GIANT (Genetically Informed brAiN aTlas) that accounts for genetic and neuroanatomical variations simultaneously. Integrating voxel-wise heritability and spatial proximity, GIANT clusters brain voxels into genetically informed regions, while retaining fundamental anatomical knowledge. Compared to conventional (non-genetics) brain atlases, GIANT exhibits smaller intra-region variations and larger inter-region variations in terms of voxel-wise heritability. As a result, GIANT yields increased regional SNP heritability, enhanced polygenicity, and its polygenic risk score explains more brain volumetric variation than traditional neuroanatomical brain atlases. We provide extensive validation to GIANT and demonstrate its neuroanatomical validity, confirming its generalizability across populations with diverse genetic ancestries and various brain conditions. Furthermore, we present a comprehensive genetic architecture of the GIANT regions, covering their functional annotation at the molecular levels, their associations with other complex traits/diseases, and the genetic and phenotypic correlations among GIANT-defined imaging endophenotypes. In summary, GIANT constitutes a brain atlas that captures the complexity of genetic and neuroanatomical heterogeneity, thereby enhancing the discovery power and applicability of imaging genomics investigations in biomedical science.Item A Multi-Center, Single Arm, Phase Ib study of Pembrolizumab (MK-3475) in Combination with Chemotherapy for Patients with Advanced Colorectal Cancer: HCRN GI14-186(Springer, 2021) Herting, Cameron J.; Farren, Matthew R.; Tong, Yan; Liu, Ziyue; O’Neil, Bert; Bekaii-Saab, Tanios; Noonan, Anne; McQuinn, Christopher; Mace, Thomas A.; Shaib, Walid; Wu, Christina; El-Rayes, Bassel F.; Shahda, Safi; Lesinski, Gregory B.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthModified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression-free survival (mPFS), with secondary objectives including median overall survival, safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients, respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.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 New Method of Peak Detection for Analysis of Comprehensive Two-Dimensional Gas Chromatography Mass Spectrometry Data(Duke University Press, 2014) Kim, Seongho; Ouyang, Ming; Jeong, Jaesik; Shen, Changyu; Zhang, Xiang; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthWe develop a novel peak detection algorithm for the analysis of comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOF MS) data using normal-exponential-Bernoulli (NEB) and mixture probability models. The algorithm first performs baseline correction and denoising simultaneously using the NEB model, which also defines peak regions. Peaks are then picked using a mixture of probability distribution to deal with the co-eluting peaks. Peak merging is further carried out based on the mass spectral similarities among the peaks within the same peak group. The algorithm is evaluated using experimental data to study the effect of different cut-offs of the conditional Bayes factors and the effect of different mixture models including Poisson, truncated Gaussian, Gaussian, Gamma, and exponentially modified Gaussian (EMG) distributions, and the optimal version is introduced using a trial-and-error approach. We then compare the new algorithm with two existing algorithms in terms of compound identification. Data analysis shows that the developed algorithm can detect the peaks with lower false discovery rates than the existing algorithms, and a less complicated peak picking model is a promising alternative to the more complicated and widely used EMG mixture models.Item A phase II study evaluating safety and efficacy of niraparib in patients with previously treated homologous recombination defective metastatic esophageal/gastroesophageal junction/proximal gastric adenocarcinoma(Frontiers Media, 2024-11-21) Khalid, Ahmed Bilal; Fountzilas, Christos; Burney, Heather N.; Mamdani, Hirva; Schneider, Bryan P.; Fausel, Christopher; Perkins, Susan M.; Jalal, Shadia; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthIntroduction: Esophageal adenocarcinoma (EAC) remains a devastating disease and second line treatment options in the metastatic space are limited. Homologous recombination (HR) defects have been described in EAC in up to 40% of patients. Poly (ADP-ribose) polymerase (PARP)1 and PARP2 inhibitors have shown efficacy in HR defective prostate and ovarian cancers. Here, we describe the activity of the PARP inhibitor niraparib in metastatic EAC with HR defects. Methods: In this single arm Simon two-stage Phase II study, we assessed the safety and efficacy of niraparib in patients with metastatic EAC previously treated with platinum containing chemotherapy harboring defective HR. Defective HR was defined as deleterious alterations in the following HR genes: BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A and GEN1. Results: 14 patients were enrolled in this study. The trial was stopped early due to slow accrual. 3 patients did not have post-treatment scans because of rapid clinical decline. The overall response rate (ORR) (95% exact CI) was 0/11 = 0% (0%, 28.49%). The disease control rate (DCR) (95% exact CI) was 2/11 = 18.2% (2.3%, 51.8%). The median PFS was 1.8 months (95% CI = 1.0-3.7). The median OS for evaluable patients was 6.6 months (95% CI =2.7-11.4) and 5.7 months for all patients (95% CI =2.7-10.1). The most common adverse events seen were anemia, fatigue, and thrombocytopenia. Conclusion: In patients with metastatic EAC, single agent niraparib as second line therapy is not an effective option.