Browsing by Author "Department of Biostatistics, School of Public Health"
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Item Cognitive dysfunction and greater visit-to-visit systolic blood pressure variability(Wiley Online Library, 2013-12) Epstein, Noam U.; Lane, Kathleen A.; Farlow, Martin R.; Risacher, Shannon L.; Saykin, Andrew J.; Gao, Sujuan; Department of Biostatistics, School of Public HealthOBJECTIVES: To determine whether variability in blood pressure (BP) is negatively associated with performance on cognitive testing. DESIGN: Multinational, longitudinal, observational cohort study. SETTING: The Alzheimer's Disease Neuroimaging Initiative study. PARTICIPANTS: Individuals with a screening diagnosis of mild cognitive impairment or normal cognition (N=626). MEASUREMENTS: Mean, variance, and maximum BP were calculated based on measures collected from screening to 36 months. Analysis of covariance models were used to determine the association between BP measures and cognitive scores at 36 months after adjusting for covariates. RESULTS: Greater variability in systolic (P<.05) but not diastolic (P>.18) BP was associated with worse global (Modified Alzheimer's Disease Assessment Scale Cognitive Component and Clinical Dementia Rating sum of boxes) and executive (Trail-Making Test Part B, Animal Fluency, and Vegetable Fluency) function and episodic memory (Rey Auditory Verbal Learning Test Total Score). CONCLUSION: There is a clinically significant association between greater systolic BP variability and greater cognitive dysfunction. These results should be verified in other well-characterized cohorts, and the neuroanatomical pathophysiology underlying the observed greater cognitive impairment should be further explored.Item Diabetes-related quality of life and the demands and burdens of diabetes care among emerging adults with type 1 diabetes in the year after high school graduation(Wiley Online Library, 2014-10) Hanna, Kathleen M.; Weaver, Michael T.; Fortenberry, J. Dennis; DiMeglio, Linda A.; Department of Biostatistics, School of Public HealthThe roles of glycemic control, diabetes management, diabetes care responsibility, living independently of parents, and time since high school graduation in predicting diabetes-related quality of life (DQOL) were examined in 184 emerging adults with type 1 diabetes. Data were collected at graduation and 1 year later. Analyses controlling for selected covariates were completed using generalized linear mixed models. Better diabetes management was associated with more positive responses on all four dimensions of DQOL. Impact and worry of DQOL were greater in the presence of depressive symptoms, and life satisfaction was lower. DQOL life satisfaction was lower in those living independently of parents. Young women reported poorer diabetes-related health status than did young men. Time since graduation was not linked to DQOL. Further research is needed on ways to improve DQOL in conjunction with diabetes management and on ways that families can support DQOL when youth live independently.Item GENETIC VARIATION IN CYP4A11 AND BLOOD PRESSURE RESPONSE TO MINERALOCORTICOID RECEPTOR ANTAGONISM OR ENAC INHIBITION: AN EXPLORATORY PILOT STUDY IN AFRICAN AMERICANS(Elsevier, 2014-07) Laffer, Cheryl L.; Elijovich, Fernando; Eckert, George J.; Tu, Wanzhu; Pratt, J. Howard; Brown, Nancy J.; Department of Biostatistics, School of Public HealthBackground An rs3890011 variant of CYP4A11, which is in linkage disequilibrium with the loss-of-function variant rs1126742, is associated with hypertension in humans. In mice, Cyp4a deficiency results in salt-sensitive hypertension through activation of ENaC. We tested the hypothesis that the rs3890011 variant is associated with blood pressure response to drugs acting via the ENaC pathway. Methods and Results African Americans with volume-dependent, resistant hypertension were randomized to treatment with placebo, spironolactone, amiloride, or combination. Blood pressure responses were analyzed by CYP4A11 genotypes. Rs3890011 (GG:GC:CC=20:35:28) and rs1126742 (TT:TC:CC=45:31:7) were in linkage disequilibrium (D′=1, r=0.561). Expected small number of rs1126742 CC homozygotes precluded analysis of the effect of this genotype on treatment responses. Spironolactone reduced blood pressure in rs3890011 GG and GC individuals, but not in CC homozygotes (p=0.002), whereas amiloride reduced blood pressure similarly in all rs3890011 genotypes. The antihypertensive effects of spironolactone and amiloride were comparable in GG and GC participants, but only amiloride reduced pressure in CC homozygotes (−6.3±7.3/−3.2±4.0 versus +6.8±7.9/+4.8±8.6 mmHg, p<0.01/<0.05). The aldosterone response to spironolactone was also blunted in the CC genotype. Conclusions In individuals homozygous for the CYP4A11 rs3890011 C allele, blood pressure is resistant to mineralocorticoid receptor antagonism, but sensitive to ENaC inhibition, consistent with ENaC activation. Studies in a larger population are needed to replicate these findings.Item Impact of and Correction for Outcome Misclassification in Cumulative Incidence Estimation(Public Library of Science, 2015) Bakoyannis, Giorgos; Yiannoutsos, Constantin T.; Department of Biostatistics, School of Public HealthCohort studies and clinical trials may involve multiple events. When occurrence of one of these events prevents the observance of another, the situation is called "competing risks". A useful measure in such studies is the cumulative incidence of an event, which is useful in evaluating interventions or assessing disease prognosis. When outcomes in such studies are subject to misclassification, the resulting cumulative incidence estimates may be biased. In this work, we study the mechanism of bias in cumulative incidence estimation due to outcome misclassification. We show that even moderate levels of misclassification can lead to seriously biased estimates in a frequently unpredictable manner. We propose an easy to use estimator for correcting this bias that is uniformly consistent. Extensive simulations suggest that this method leads to unbiased estimates in practical settings. The proposed method is useful, both in settings where misclassification probabilities are known by historical data or can be estimated by other means, and for performing sensitivity analyses when the misclassification probabilities are not precisely known.Item Impact of dependent left truncation in semiparametric competing risks methods: A simulation study(Taylor & Francis, 2017) Bakoyannis, Giorgos; Touloumi, Giota; Department of Biostatistics, School of Public HealthIn this study, we investigated the robustness of the methods that account for independent left truncation when applied to competing risks settings with dependent left truncation. We specifically focused on the methods for the proportional cause-specific hazards model and the Fine–Gray model. Simulation experiments showed that these methods are not in general robust against dependent left truncation. The magnitude of the bias was analogous to the strength of the association between left truncation and failure times, the effect of the covariate on the competing cause of failure, and the baseline hazard of left truncation time.Item Is There an Association of Physical Activity with Brain Volume, Behavior, and Day-to-day Functioning? A Cross Sectional Design in Prodromal and Early Huntington Disease(PLOS, 2016-03) Wallace, McKenzie; Downing, Nancy; Lourens, Spencer; Mills, James; Kim, Ji-in; Long, Jeffrey; Paulsen, Jane; Department of Biostatistics, School of Public HealthBackground: Huntington disease (HD) is a genetic neurodegenerative disease leading to progressive motor, cognitive, and behavioral decline. Subtle changes in these domains are detectable up to 15 years before a definitive motor diagnosis is made. This period, called prodromal HD, provides an opportunity to examine lifestyle behaviors that may impact disease progression. Theoretical Framework: Physical activity relates to decreased rates of brain atrophy and improved cognitive and day-to-day functioning in Alzheimer disease and healthy aging populations. Previous research has yielded mixed results regarding the impact of physical activity on disease progression in HD and paid little attention to the prodromal phase. Methods: We conducted analyses of associations among current physical activity level, current and retrospective rate of change for hippocampus and striatum volume, and cognitive, motor, and day-to-day functioning variables. Participants were 48 gene-expanded cases with prodromal and early-diagnosed HD and 27 nongene-expanded control participants. Participants wore Fitbit Ultra activity monitors for three days and completed the self-reported International Physical Activity Questionnaire (IPAQ). Hippocampal and striatal white matter volumes were measured using magnetic resonance imaging. Cognitive tests included the Stroop Color and Word Test, and the Symbol Digit Modalities Test (SDMT). Motor function was assessed using the Unified Huntington’s Disease Rating Scale total motor score (TMS). Day-to-day functioning was measured using the World Health Organization Disability Assessment Schedule (WHODAS) version 2.0. Results: Higher Fitbit activity scores were significantly related to better scores on the SDMT and WHODAS in case participants but not in controls. Fitbit activity scores tracked better with TMS scores in the group as a whole, though the association did not reach statistical significance in the case participants. Higher Fitbit activity scores related to less day-to-day functioning decline in retrospective slope analyses. Fitbit activity scores did not differ significantly between cases and controls. Conclusions: This is the first known study examining the associations between activity level and imaging, motor, cognitive, and day-to-day functioning outcomes in prodromal and early HD. Preliminary results suggest physical activity positively correlates with improved cognitive and day-to-day functioning and possibly motor function in individuals in the prodromal and early phase of the condition.Item Longitudinal Beta-Binomial Modeling using GEE for Over-Dispersed Binomial Data(Wiley, 2017-03) Wu, Hongqian; Zhang, Ying; Long, Jeffrey D.; Department of Biostatistics, School of Public HealthLongitudinal binomial data are frequently generated from multiple questionnaires and assessments in various scientific settings for which the binomial data are often overdispersed. The standard generalized linear mixed effects model may result in severe underestimation of standard errors of estimated regression parameters in such cases and hence potentially bias the statistical inference. In this paper, we propose a longitudinal beta-binomial model for overdispersed binomial data and estimate the regression parameters under a probit model using the generalized estimating equation method. A hybrid algorithm of the Fisher scoring and the method of moments is implemented for computing the method. Extensive simulation studies are conducted to justify the validity of the proposed method. Finally, the proposed method is applied to analyze functional impairment in subjects who are at risk of Huntington disease from a multisite observational study of prodromal Huntington disease.Item Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice(American Society of Hematology, 2014-01-23) Wang, Jiapeng; Li, Zhaomin; He, Yongzheng; Pan, Feng; Chen, Shi; Rhodes, Steven; Nguyen, Lihn; Yuan, Jin; Jiang, Li; Yang, Xianlin; Weeks, Ophelia; Liu, Ziyue; Zhou, Jiehao; Ni, Hongyu; Cai, Chen-Leng; Xu, Mingjiang; Yang, Feng-Chun; Department of Biostatistics, School of Public HealthASXL1 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies, and its alterations are associated with poor prognosis. De novo ASXL1 mutations cause Bohring-Opitz syndrome characterized by multiple congenital malformations. We show that Asxl1 deletion in mice led to developmental abnormalities including dwarfism, anophthalmia, and 80% embryonic lethality. Surviving Asxl1(-/-) mice lived for up to 42 days and developed features of myelodysplastic syndrome (MDS), including dysplastic neutrophils and multiple lineage cytopenia. Asxl1(-/-) mice had a reduced hematopoietic stem cell (HSC) pool, and Asxl1(-/-) HSCs exhibited decreased hematopoietic repopulating capacity, with skewed cell differentiation favoring granulocytic lineage. Asxl1(+/-) mice also developed mild MDS-like disease, which could progress to MDS/myeloproliferative neoplasm, demonstrating a haploinsufficient effect of Asxl1 in the pathogenesis of myeloid malignancies. Asxl1 loss led to an increased apoptosis and mitosis in Lineage(-)c-Kit(+) (Lin(-)c-Kit(+)) cells, consistent with human MDS. Furthermore, Asxl1(-/-) Lin(-)c-Kit(+) cells exhibited decreased global levels of H3K27me3 and H3K4me3 and altered expression of genes regulating apoptosis (Bcl2, Bcl2l12, Bcl2l13). Collectively, we report a novel ASXL1 murine model that recapitulates human myeloid malignancies, implying that Asxl1 functions as a tumor suppressor to maintain hematopoietic cell homeostasis. Future work is necessary to clarify the contribution of microenvironment to the hematopoietic phenotypes observed in the constitutional Asxl1(-/-) mice.Item Mild Cognitive Impairment, Incidence, Progression, and Reversion: Findings from a Community-based Cohort of Elderly African Americans(Elsevier, 2014-07) Gao, Sujuan; Unverzagt, Frederick W.; Hall, Kathleen S.; Lane, Kathleen A.; Murrell, Jill R.; Hake, Ann M.; Smith-Gamble, Valerie; Hendrie, Hugh C.; Department of Biostatistics, School of Public HealthObjective To examine the long-term outcomes of community-based elderly African Americans by following their transitions from normal cognition to mild cognitive impairment (MCI), and to dementia. Methods Participants were from the community-based Indianapolis Dementia Project. A total of 4104 African Americans were enrolled in 1992 or 2001 and followed until 2009 with regularly scheduled evaluation of cognitive assessment. A two-stage sampling was used at each evaluation to select individuals for extensive clinical assessment following the results of stage one cognitive testing. Age and gender specific incidence, progression and reversion rates for MCI were derived using the person-year method in a dynamic cohort and predicted probabilities from weighted multinomial logistic models of transitional probabilities among normal cognition, MCI and dementia. Results Annual overall incidence rate for MCI is 5.6% (95% CI: 4.6–6.6%). Annual progression rate from MCI to dementia is 5.9% (95% CI: 5.3–6.5%) and annual reversion rate from MCI to normal is 18.6% (95% CI: 16.7–20.4%). Both MCI incidence rates and MCI to dementia progression rates increase with age, while reversion rates from MCI to normal decrease with age. Conclusion MCI progression to dementia is much more frequent in the older age groups than in the younger participants where reversion to normal cognition is more common. Future research is needed to determine factors related to the heterogeneous outcomes in MCI individuals.Item Optimizing strategies for population-based chlamydia infection screening among young women: an age-structured system dynamics approach(Springer (Biomed Central Ltd.), 2015) Teng, Yu; Kong, Nan; Tu, Wanzhu; Department of Biostatistics, School of Public HealthBACKGROUND: Chlamydia infection (CT) is one of the most commonly reported sexually transmitted diseases. It is often referred to as a "silent" disease with the majority of infected people having no symptoms. Without early detection, it can progress to serious reproductive and other health problems. Economical identification of asymptomatically infected is a key public health challenge. Increasing evidence suggests that CT infection risk varies over the range of adolescence. Hence, age-dependent screening strategies with more frequent testing for certain age groups of higher risk may be cost-saving in controlling the disease. METHODS: We study the optimization of age-dependent screening strategies for population-based chlamydia infection screening among young women. We develop an age-structured compartment model for CT natural progress, screening, and treatment. We apply parameter optimization on the resultant PDE-based system dynamical models with the objective of minimizing the total care spending, including screening and treatment costs during the program period and anticipated costs of treating the sequelae afterwards). For ease of practical implementation, we also search for the best screening initiation age for strategies with a constant screening frequency. RESULTS: The optimal age-dependent strategies identified outperform the current CDC recommendations both in terms of total care spending and disease prevalence at the termination of the program. For example, the age-dependent strategy that allows monthly screening rate changes can save about 5% of the total spending. Our results suggest early initiation of CT screening is likely beneficial to the cost saving and prevalence reduction. Finally, our results imply that the strategy design may not be sensitive to accurate quantification of the age-specific CT infection risk if screening initiation age and screening rate are the only decisions to make. CONCLUSIONS: Our research demonstrates the potential economic benefit of age-dependent screening strategy design for population-based screening programs. It also showcases the applicability of age-structured system dynamical modeling to infectious disease control with increasing evidence on the age differences in infection risk. The research can be further improved with consideration of the difference between first-time infection and reinfection, as well as population heterogeneity in sexual partnership.