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Browsing Biostatistics Department Theses and Dissertations by Author "Bakoyannis, Giorgos"
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Item An Analysis of Survival Data when Hazards are not Proportional: Application to a Cancer Treatment Study(2021-12) White, John Benjamin; Yiannoutsos, Constantin; Bakoyannis, Giorgos; Fadel, WilliamThe crossing of Kaplan-Meier survival curves presents a challenge when conducting survival analysis studies, making it unclear whether any of the study groups involved present any significant difference in survival. An approach involving the determination of maximum vertical distance between the curves is considered here as a method to assess whether a survival advantage exists between different groups of patients. The method is illustrated on a dataset containing survival times of patients treated with two cancer treatment regimes, one involving treatment by chemotherapy alone, and the other by treatment with both chemotherapy and radiotherapy.Item Bayesian Adaptive Dose-Finding Clinical Trial Designs with Late-Onset Outcomes(2021-07) Zhang, Yifei; Zhang, Yong; Song, Yiqing; Liu, Hao; Bakoyannis, GiorgosThe late-onset outcome issue is common in early phase dose- nding clinical trials. This problem becomes more intractable in phase I/II clinical trials because both toxicity and e cacy responses are subject to the late-onset outcome issue. The existing methods applying for the phase I trials cannot be used directly for the phase I/II trial due to a lack of capability to model the joint toxicity{e cacy distribution. We propose a conditional weighted likelihood (CWL) method to circumvent this issue. The key idea of the CWL method is to decompose the joint probability into the product of marginal and conditional probabilities and then weight each probability based on each patient's actual follow-up time. We further extend the proposed method to handle more complex situations where the late-onset outcomes are competing risks or semicompeting risks outcomes. We treat the late-onset competing risks/semi-competing risks outcomes as missing data and develop a series of Bayesian data-augmentation methods to e ciently impute the missing data and draw the posterior samples of the parameters of interest. We also propose adaptive dose- nding algorithms to allocate patients and identify the optimal biological dose during the trial. Simulation studies show that the proposed methods yield desirable operating characteristics and outperform the existing methods.Item Building Prediction Models for Dementia: The Need to Account for Interval Censoring and the Competing Risk of Death(2019-08) Marchetti, Arika L.; Bakoyannis, Giorgos; Li, Xiaochun; Gao, Sujuan; Yiannoutsos, ConstantinContext. Prediction models for dementia are crucial for informing clinical decision making in older adults. Previous models have used genotype and age to obtain risk scores to determine risk of Alzheimer’s Disease, one of the most common forms of dementia (Desikan et al., 2017). However, previous prediction models do not account for the fact that the time to dementia onset is unknown, lying between the last negative and the first positive dementia diagnosis time (interval censoring). Instead, these models use time to diagnosis, which is greater than or equal to the true dementia onset time. Furthermore, these models do not account for the competing risk of death which is quite frequent among elder adults. Objectives. To develop a prediction model for dementia that accounts for interval censoring and the competing risk of death. To compare the predictions from this model with the predictions from a naïve analysis that ignores interval censoring and the competing risk of death. Methods. We apply the semiparametric sieve maximum likelihood (SML) approach to simultaneously model the cumulative incidence function (CIF) of dementia and death while accounting for interval censoring (Bakoyannis, Yu, & Yiannoutsos, 2017). The SML is implemented using the R package intccr. The CIF curves of dementia are compared for the SML and the naïve approach using a dataset from the Indianapolis Ibadan Dementia Project. Results. The CIF from the SML and the naïve approach illustrated that for healthier individuals at baseline, the naïve approach underestimated the incidence of dementia compared to the SML, as a result of interval censoring. Individuals with a poorer health condition at baseline have a CIF that appears to be overestimated in the naïve approach. This is due to older individuals with poor health conditions having an elevated risk of death. Conclusions. The SML method that accounts for the competing risk of death along with interval censoring should be used for fitting prediction/prognostic models of dementia to inform clinical decision making in older adults. Without controlling for the competing risk of death and interval censoring, the current models can provide invalid predictions of the CIF of dementia.Item Contemporary Outcomes of Distal Lower Extremity Bypass for Chronic Limb Threatening Ischemia and a Model Based Comparison with Non-surgical Therapies(2021-03) Leckie, Katherin; Bakoyannis, Giorgos; Yiannoutsos, Constantin; Murphy, MichaelObjective: Gold standard therapy for chronic limb threatening ischemia (CLTI) is revascularization but in patients in whom below-the-knee bypass is indicated autologous vein conduit may not be available. Contemporary outcomes of distal bypass with suboptimal conduits have not been well described and recent advances in non-surgical therapies raise the question of whether in some cases there is evidence that these should be considered. Methods: Data was obtained from the Vascular Quality Initiative (VQI) registry as well as from a multi-center, randomized clinical trial of cell therapy. Incidence of major amputation after distal bypass was estimated for the VQI cohort by conduit type using non-parametric survival analysis with death as a competing risk. A cox proportional hazards model was then fit to the pooled data in a stepwise fashion with death as a competing risk, including evaluations for appropriate transformation, time dependency and interactions for each included covariate, and hazard ratios were estimated for the risk of major amputation by treatment. Results: At 365 days, the estimated cumulative incidence of major amputation with death as a competing risk is 25% after distal bypass with non-autologous biologic conduit (0.2499, 95% CI 0.2242 - 0.2785), 13% for prosthetic (0.1276, 95% CI 0.1172 - 0.1389) and 9% for GSV (0.0900, 95% CI 0.0848 - 0.0956). The cox proportional hazards model found a significant interaction between age and treatment. Compared to bypass with non-autogenous biologic, the hazard ratios for bypass with GSV were 0.41 (p<0.0001), 0.41 (p<0.0001), 0.42 (p<0.0001) and 0.42 (p<0.0001) respectively at ages 55, 60, 65 and 70 and for bypass with prosthetic were 0.68 (p=0.0043), 0.67 (p=0.0004), 0.65 (p<0.0001) and 0.64 (p<0.0001) respectively and for autologous cell therapy 0.22 (p=0.0005), 0.34 (p=0.0011), 0.52 (p=0.0196) and 0.76 (p=0.3677) respectively. No significant differences were found between best medical management and distal bypass with non-autologous biologic. Conclusion: The risk of major amputation after distal bypass is lowest in patients with GSV conduit and highest following bypass with non-autologous biologic. Using a semi-parametric model, cell therapy was estimated to significantly decrease the risk of amputation compared to distal bypass with non-autologous biologic conduit in younger patients.Item Dietary Electrolytes and their Influences on Plasma Aldosterone Concentration(2019-06) Ye, Xiaohan; Tu, Wanzhu; Katz, Barry P.; Bakoyannis, Giorgos; Yiannoutsos, Constantin T.Excessive sodium retention is thought to be the main culprit for hypertension. The modern American diet provides an excess of sodium and not sufficient amount of sodium. In this research, we examined the relations among urinary sodium and potassium excretion, and plasma levels of aldosterone, a mineralocorticoid hormone that has been linked to incidence hypertension, in a cohort of healthy children and young adults. We found that higher plasma aldosterone level was associated with lower sodium excretion in the urine, in blacks and whites, suggesting that aldosterone plays a critical role in retaining the sodium from dietary sources. The study highlights the importance of dietary sodium restriction.Item Group Specific Dynamic Models of Time Varying Exposures on a Time-to-Event Outcome(2022-12) Tong, Yan; Gao, Sujuan; Bakoyannis, Giorgos; Tu, Wanzhu; Han, JialiTime-to-event outcomes are widely utilized in medical research. Assessing the cumulative effects of time-varying exposures on time-to-event outcomes poses challenges in statistical modeling. First, exposure status, intensity, or duration may vary over time. Second, exposure effects may be delayed over a latent period, a situation that is not considered in traditional survival models. Third, exposures that occur within a time window may cumulatively in uence an outcome. Fourth, such cumulative exposure effects may be non-linear over exposure latent period. Lastly, exposure-outcome dynamics may differ among groups defined by individuals' characteristics. These challenges have not been adequately addressed in current statistical models. The objective of this dissertation is to provide a novel approach to modeling group-specific dynamics between cumulative timevarying exposures and a time-to-event outcome. A framework of group-specific dynamic models is introduced utilizing functional time-dependent cumulative exposures within an etiologically relevant time window. Penalizedspline time-dependent Cox models are proposed to evaluate group-specific outcome-exposure dynamics through the associations of a time-to-event outcome with functional cumulative exposures and group-by-exposure interactions. Model parameter estimation is achieved by penalized partial likelihood. Hypothesis testing for comparison of group-specific exposure effects is performed by Wald type tests. These models are extended to group-specific non-linear exposure intensity-latency-outcome relationship and group-specific interaction effect from multiple exposures. Extensive simulation studies are conducted and demonstrate satisfactory model performances. The proposed methods are applied to the analyses of group-specific associations between antidepressant use and time to coronary artery disease in a depression-screening cohort using data extracted from electronic medical records.Item The Impact of Social Services on the Utilization of Health Care Services(2018-12) Chen, Mengyan; Zhang, Ying; Tu, Wanzhu; Bakoyannis, Giorgos; Tong, YanThe unnecessary medical care causes a heavy financial burden for the patients themselves and the society, and they also negatively impact the quality of medical care. An estimated 13% to 27% of ED visits in the United States could be managed in physician offices, clinics, and urgent care centers, saving $4.4 billion annually, and 26 percent of hospitalizations were potentially avoidable at a cost of $5.6 billion in 2005. If we can help people become more aware of health care services, it could be a potentially effective way to reduce emergency service overuse. we focused on mental health service and social work service as intervention variable, preventable ED visit, preventable ED visit due to mental health problem and hospitalization due to mental health problem as outcomes to determine the impact of specific social service on utilization of specific health care service adjusting for other characteristics of patients (demographic and utilization history information). The data which involved 24074 patients was provided from and managed by the Regenstrief Institute. The date of having the specific service and the frequency of using the specific health care service per year from 2011 to 2014 for each patient was recorded as well as the baseline information including gender, age, race, primary care visit per year before 2011, ACG risk score at 2011, ED visit per year before 2011. For each of preventable ED visit, preventable ED visit due to mental health problem and hospitalization due to mental health problem, we fitted a multiple linear regression model to ascertain the effects of mental health service and social work service adjusted for the baseline information. There was a significant relationship between preventable ED visit & mental health service, hospitalization due to mental health problems & mental health service, as well as hospitalization due to mental health problems & social work service. We found that in most situation, social services were positively associated with health care service. But in the second model which described the impact of mental health service on utilization of hospitalization due to mental health problem, receiving one mental health service can reduce the utilization of hospitalization due to mental health problem, which is as our expectation. According to our study, appropriate amount of services appears helpful on reducing the overuse of ED and hospitalization due to mental health problem. However, people who overused ED or hospitalization in the past were also more likely to be frequent service users, and they tended to continue overuse ED or Incur more hospitalization. There is a group of people who overuse ED or hospitalization without having any service. ED or hospitalization may be their first choice because of their financial condition or other factors, which makes them have no interest to take services.Item Innovative Bayesian Designs for Clinical Trials(2022-10) He, Tian; Zang, Yong; Liu, Hao; Bakoyannis, Giorgos; Zhao, Yi; Hasan, MohammadTraditional clinical trial designs are generally based on the doctrine of studying one drug for one disease at a time, which may be slow and inefficient. With a high failure rate in drug development, there is a great need to speed up the process of drug development and minimize the cost. Novel trial designs have been proposed, such as the master protocol approach, which has expanded the trial design horizon to umbrella, basket, and platform trials. Compared to traditional clinical protocols, the master protocol enables investigators to evaluate multiple drugs and diverse disease populations simultaneously in a single protocol with the capacity to modify the protocol based on the observed trial data and new drugs. While many statistical methods for trial designs have been proposed for umbrella, basket, and platform trials in the literature, most of the designs are based on a binary or continuous endpoint. However, in the context of oncology trials, there is a great need to develop novel methods for survival endpoints. In this dissertation, we propose three novel Bayesian statistical methods for three distinctive trial design problems, respectively: 1) an optimal Bayesian design for platform trials with multiple endpoints; 2) a novel Bayesian design for basket trials with survival outcomes; 3) an adaptive Bayesian design for seamless phase II/III platform trials with survival endpoints. Extensive simulation studies are performed to evaluate the operating characteristics of the proposed designs under various scenarios.Item Insights in Response to Statewide COVID-19 Sampling in Indiana(2023-05) Shields, David William, Jr.; Yiannoutsos, Constantin; Fadel, William; Bakoyannis, GiorgosDuring 2020, the Indiana State Department of Health conducted a longitudinal study of novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus, the cause of COVID-19 disease, to understand the number of past and current infections as well as the prevalence of disease in the State of Indiana by conducting a survey to participants as well as administering testing for exposure to SARS-COV-2. The study consisted of 3 waves of testing, each spread months apart, consisting of a random sample and a non-random sample. The non-random sample was used to ensure the sample population was representative of the state of Indiana and was used as stratum in the logistic regression model, allowing for the adjustment for nonresponse. These finding indicate that persons of non-White race and persons of Hispanic ethnicity had highest risk of exposure to the virus. Understanding the disparity in health in various racial and ethnic populations and addressing how different communities are impacted by the pandemic, as well as working with the community is paramount when attempting to mitigate a pandemic. In addition, understanding the data from the ambient pandemic when instituting measures to mitigate the spread of viruses is also extremely important for managing health emergencies such as the COVID-19 pandemic.Item A Longitudinal Analysis to Compare a Tailored Web-Based Intervention and Tailored Phone Counseling to Usual Care for Improving Beliefs of Colorectal Cancer Screening(2018-07) Dorman, Hannah Louise; Monahan, Patrick; Stump, Timothy; Bakoyannis, Giorgos; Lourens, SpencerAn analysis of longitudinal data collected about beliefs regarding colorectal cancer (CRC) screenings at three-time points was analyzed to determine whether the beliefs improved from either the Web-Based, Phone-Based, or Web + Phone interventions compared to Usual Care. A mixed linear model adjusting for baseline and controlling for covariates was used to determine the effects of the intervention; Web-Based intervention was the most efficacious in improving beliefs, and phone intervention was also efficacious for several beliefs, compared to usual care.