Biostatistics and Health Data Science Works

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Works authored by scholars from the Department of Biostatistics and Health Data Science, a dual department of the Richard M. Fairbanks School of Public Health and the IU School of Medicine.

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The relationship between cholesterol and cognitive function is homocysteine-dependent
(Dove Press Ltd, 2014-10-23) Cheng, Yibin; Jin, Yinlong; Unverzagt, Frederick W.; Su, Liqin; Yang, Lili; Ma, Feng; Hake, Ann M.; Kettler, Carla; Chen, Chen; Liu, Jingyi; Bian, Jianchao; Li, Ping; Murrell, Jill R.; Hendrie, Hugh C.; Gao, Sujuan; Department of Biostatistics, School of Medicine
Introduction Previous studies have identified hyperlipidemia as a potential risk factor for dementia and Alzheimer’s disease. However, studies on cholesterol measured in late-life and cognitive function have been inconsistent. Few studies have explored nonlinear relationships or considered interactions with other biomarker measures. Methods A cross-sectional sample of 1,889 participants from four rural counties in the People’s Republic of China was included in this analysis. Serum total cholesterol, high-density lipoprotein, triglycerides, and homocysteine levels were measured in fasting blood samples. A composite cognitive score was derived based on nine standardized cognitive test scores. Analysis of covariance models were used to investigate the association between biomarker measures and the composite cognitive scores. Results There was a significant interaction between the homocysteine quartile group and the cholesterol quartile group on cognitive scores (P=0.0478). In participants with normal homocysteine levels, an inverse U-shaped relationship between total cholesterol level and cognitive score was found, indicating that both low and high cholesterol levels were associated with lower cognitive scores. In participants with high homocysteine levels, no significant association between cholesterol and cognition was found. Conclusion The relationship between cholesterol levels and cognitive function depends upon homocysteine levels, suggesting an interactive role between cholesterol and homocysteine on cognitive function in the elderly population. Additional research is required to confirm our findings in other populations, and to explore potential mechanisms underlying the lipid–homocysteine interaction.
Confirmatory test of two factors and four subtypes of bipolar disorder based on lifetime psychiatric comorbidity
(Cambridge, 2015-07) Monahan, Patrick O.; Stump, Timothy; Coryell, William H.; Harezlak, Jaroslaw; Marcoulides, George A.; Liu, Hai; Steeger, Christine M.; Mitchell, Philip B.; Wilcox, Holly C.; Hulvershorn, Leslie A.; Glowinski, Anne L.; Iyer-Eimerbrink, Priya Anapurna; McInnis, Melvin; Nurnberger, John I. Jr.; Department of Biostatistics, IU School of Medicine
Background The first aim was to use confirmatory factor analysis (CFA) to test a hypothesis that two factors (internalizing and externalizing) account for lifetime co-morbid DSM-IV diagnoses among adults with bipolar I (BPI) disorder. The second aim was to use confirmatory latent class analysis (CLCA) to test the hypothesis that four clinical subtypes are detectible: pure BPI; BPI plus internalizing disorders only; BPI plus externalizing disorders only; and BPI plus internalizing and externalizing disorders. Method A cohort of 699 multiplex BPI families was studied, ascertained and assessed (1998–2003) by the National Institute of Mental Health Genetics Initiative Bipolar Consortium: 1156 with BPI disorder (504 adult probands; 594 first-degree relatives; and 58 more distant relatives) and 563 first-degree relatives without BPI. Best-estimate consensus DSM-IV diagnoses were based on structured interviews, family history and medical records. MPLUS software was used for CFA and CLCA. Results The two-factor CFA model fit the data very well, and could not be improved by adding or removing paths. The four-class CLCA model fit better than exploratory LCA models or post-hoc-modified CLCA models. The two factors and four classes were associated with distinctive clinical course and severity variables, adjusted for proband gender. Co-morbidity, especially more than one internalizing and/or externalizing disorder, was associated with a more severe and complicated course of illness. The four classes demonstrated significant familial aggregation, adjusted for gender and age of relatives. Conclusions The BPI two-factor and four-cluster hypotheses demonstrated substantial confirmatory support. These models may be useful for subtyping BPI disorders, predicting course of illness and refining the phenotype in genetic studies.
Marginal and Conditional Distribution Estimation from Double-Sampled Semi-Competing Risks Data
(Wiley, 2015-03) Yu, Menggang; Yiannoutsos, Constantin T.; Department of Biostatistics, IU School of Medicine
Informative dropout is a vexing problem for any biomedical study. Most existing statistical methods attempt to correct estimation bias related to this phenomenon by specifying unverifiable assumptions about the dropout mechanism. We consider a cohort study in Africa that uses an outreach programme to ascertain the vital status for dropout subjects. These data can be used to identify a number of relevant distributions. However, as only a subset of dropout subjects were followed, vital status ascertainment was incomplete. We use semi-competing risk methods as our analysis framework to address this specific case where the terminal event is incompletely ascertained and consider various procedures for estimating the marginal distribution of dropout and the marginal and conditional distributions of survival. We also consider model selection and estimation efficiency in our setting. Performance of the proposed methods is demonstrated via simulations, asymptotic study and analysis of the study data.
Associations of objectively measured and self-reported sleep duration with carotid artery intima media thickness among police officers
(Wiley, 2013-11) Ma, Claudia C.; Burchfiel, Cecil M.; Charles, Luenda E.; Dorn, Joan M.; Andrew, Michael E.; Kook Gu, Ja; Joseph, Parveen Nedra; Fekedulegn, Desta; Slaven, James E.; Hartley, Tara A.; Mnatsakanova, Anna; Violanti, John M.; Biostatistics, School of Medicine
BACKGROUND: We aimed to examine the association of objectively measured and self-reported sleep duration with carotid artery intima media thickness (IMT) among 257 police officers, a group at high risk for cardiovascular disease (CVD). METHODS: Sleep duration was estimated using actigraphic data and through self-reports. The mean maximum IMT was the average of the largest 12 values scanned bilaterally from three angles of the near and far wall of the common carotid, bulb, and internal carotid artery. Linear and quadratic regression models were used to assess the association of sleep duration with IMT. RESULTS: Officers who had fewer than 5 or 8 hr or more of objectively measured sleep duration had significantly higher maximum IMT values, independent of age. Self-reported sleep duration was not associated with either IMT measure. CONCLUSION: Attainment of sufficient sleep duration may be considered as a possible strategy for atherosclerosis prevention among police officers.
Increased lung volume in infants and toddlers at high compared to low altitude
(Wiley, 2013-12) Llapur, Conrado J.; Martínez, Myriam R.; Caram, María Marta; Bonilla, Federico; Cabana, Celia; Yu, Zhansheng; Tepper, Robert S.; Biostatistics, School of Medicine
Children and adults residing at high altitude (HA) compared to low altitude (LA) have larger lung volumes; however, it is unknown whether this response to chronic hypoxia begins early in life. Our objective was to determine whether infants and toddlers at HA have larger lung volumes compared to infants and toddlers at LA. Oxygen saturation (SaO2 ), functional residual capacity (FRC), as well as serum levels of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) were measured in infants and toddlers from HA (N = 50; 3,440 m) and LA (N = 35; 440 m). There were no significant differences in somatic size for HA and LA subjects; however, HA subjects had significantly lower SaO2 (88.5% vs. 96.7%; P < 0.0001). Subjects at HA had significantly greater FRC compared to subjects at LA (group mean: 209 and 157 ml; P < 0.0001), adjusting for body length. Male infants at HA had a significantly greater FRC compared to males at LA (57 ml; P-value < 0.001); however, the increase in FRC for females at HA compared to LA was not significant (20 ml; P-value = 0.101). VEGF and EPO were significantly higher for subjects at HA compared to LA with no gender differences. In summary, infants and toddlers at HA have lower oxygen saturations, higher serum levels of VEGF and EPO, and higher FRC compared to subjects at LA; however, chronic hypoxia appears to generate a more robust response in lung growth in male compared to female infants early in life.
Inverse probability weighting for covariate adjustment in randomized studies
(Wiley, 2014-02) Shen, Changyu; Li, Xiaochun; Li, Lingling; Biostatistics, School of Medicine
Covariate adjustment in randomized clinical trials has the potential benefit of precision gain. It also has the potential pitfall of reduced objectivity as it opens the possibility of selecting a 'favorable' model that yields strong treatment benefit estimate. Although there is a large volume of statistical literature targeting on the first aspect, realistic solutions to enforce objective inference and improve precision are rare. As a typical randomized trial needs to accommodate many implementation issues beyond statistical considerations, maintaining the objectivity is at least as important as precision gain if not more, particularly from the perspective of the regulatory agencies. In this article, we propose a two-stage estimation procedure based on inverse probability weighting to achieve better precision without compromising objectivity. The procedure is designed in a way such that the covariate adjustment is performed before seeing the outcome, effectively reducing the possibility of selecting a 'favorable' model that yields a strong intervention effect. Both theoretical and numerical properties of the estimation procedure are presented. Application of the proposed method to a real data example is presented.
Choosing profile double-sampling designs for survival estimation with application to PEPFAR evaluation
(Wiley, 2014-05) An, Ming-Wen; Frangakis, Constantine E.; Yiannoutsos, Constantin T.; Biostatistics, School of Medicine
Most studies that follow subjects over time are challenged by having some subjects who dropout. Double sampling is a design that selects and devotes resources to intensively pursue and find a subset of these dropouts, then uses data obtained from these to adjust naïve estimates, which are potentially biased by the dropout. Existing methods to estimate survival from double sampling assume a random sample. In limited-resource settings, however, generating accurate estimates using a minimum of resources is important. We propose using double-sampling designs that oversample certain profiles of dropouts as more efficient alternatives to random designs. First, we develop a framework to estimate the survival function under these profile double-sampling designs. We then derive the precision of these designs as a function of the rule for selecting different profiles, in order to identify more efficient designs. We illustrate using data from the United States President's Emergency Plan for AIDS Relief-funded HIV care and treatment program in western Kenya. Our results show why and how more efficient designs should oversample patients with shorter dropout times. Further, our work suggests generalizable practice for more efficient double-sampling designs, which can help maximize efficiency in resource-limited settings.
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 Health
Objective 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.
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 Health
Background 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.
Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies
(Springer US, 2011-08) Tate, David F.; Sampat, Mehul; Harezlak, Jaroslaw; Fiecas, Mark; Hogan, Joseph; Dewey, Jeffrey; McCaffrey, Daniel; Branson, Daniel; Russell, Troy; Conley, Jared; Taylor, Michael; Schifitto, Giavoni; Zhong, J.; Daar, Eric S.; Alger, Jeffrey; Brown, Mark; Singer, Elyse; Campbell, T.; McMahon, D.; Tso, Y.; Matesan, Janetta; Letendre, Scott; Paulose, S.; Gaugh, Michelle; Tripoli, C.; Yiannoutsos, Constantine; Bigler, Erin D.; Cohen, Ronald A.; Guttmann, Charles R. G.; Navia, Bradford; HIV Neuroimaging Consortium; Department of Biostatistics, Richard M. Fairbanks School of Public Health
Recent reports suggest that a growing number of human immunodeficiency virus (HIV)-infected persons show signs of persistent cognitive impairment even in the context of combination antiretroviral therapies (cART). The basis for this finding remains poorly understood as there are only a limited number of studies examining the relationship between CNS injury, measures of disease severity, and cognitive function in the setting of stable disease. This study examined the effects of HIV infection on cerebral white matter using quantitative morphometry of the midsagittal corpus callosum (CC) in 216 chronically infected participants from the multisite HIV Neuroimaging Consortium study currently receiving cART and 139 controls. All participants underwent MRI assessment, and HIV-infected subjects also underwent measures of cognitive function and disease severity. The midsagittal slice of the CC was quantified using two semi-automated procedures. Group comparisons were accomplished using ANOVA, and the relationship between CC morphometry and clinical covariates (current CD4, nadir CD4, plasma and CSF HIV RNA, duration of HIV infection, age, and ADC stage) was assessed using linear regression models. HIV-infected patients showed significant reductions in both the area and linear widths for several regions of the CC. Significant relationships were found with ADC stage and nadir CD4 cell count, but no other clinical variables. Despite effective treatment, significant and possibly irreversible structural loss of the white matter persists in the setting of chronic HIV disease. A history of advanced immune suppression is a strong predictor of this complication and suggests that antiretroviral intervention at earlier stages of infection may be warranted.

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