Biostatistics and Health Data Science Works

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https://hdl.handle.net/1805/7162
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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    A Phase I and Pharmacokinetic Trial of Erlotinib in Combination with Weekly Docetaxel in Patients with Taxane-Naive Malignancies
    (American Association of Cancer Research, 2008-02) Chiorean, E. Gabriela; Porter, Jennifer M.; Foster, Anne E.; Omari, Amal S.H. Al; Yoder, Christy A.; Fife, Karen L.; Strother, R. Matthew; Murry, Daryl J.; Yu, Menggang; Jones, David R.; Sweeney, Christopher J.; Biostatistics, School of Public Health
    Purpose: This study aimed to define the maximum tolerated dose of weekly docetaxel combined with daily erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor. Experimental Design: Patients with any solid tumor received 150 mg erlotinib with escalating doses of docetaxel (20, 25, 30, and 35 mg/m2) on days 1, 8, and 15 every 28 days. The pharmacokinetics of docetaxel and erlotinib was determined on cycle 2, day 1. Erlotinib was given for a maximum of 12 cycles and docetaxel was given for up to 6 cycles. Results: Twenty-five patients (17 males and 8 females) were enrolled with a median age of 56 years (range, 34-76); Eastern Cooperative Oncology Group performance status of 0/1 was 20/5. One patient had a dose-limiting toxicity in cycle 1 at the 25 mg/m2 level (grade 3 enterocolitis). At 35 mg/m2 docetaxel dose level, 6 of 10 patients required dose reductions to 30 mg/m2 beyond cycle 1 due to neutropenia (3 patients) and mucositis, increased bilirubin, and diarrhea (1 patient each). The clearance of docetaxel and erlotinib of 61.7 and 8.16 L/h, respectively, did not seem to differ from historical controls. Responses were seen in non–small cell lung cancer, prostate cancer, and hepatobiliary cancers, including a complete response lasting 36+ months in a patient with hepatocellular carcinoma. Conclusion: Although no maximum tolerated dose was reached in cycle 1 with 35 mg/m2 docetaxel, repetitive dosing proved intolerable in a substantial number of patients; thus, the recommended phase II dose of weekly docetaxel is 30 mg/m2 when combined with 150 mg of daily erlotinib.
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    Predicted Functional RNAs within Coding Regions Constrain Evolutionary Rates of Yeast Proteins
    (PLOS, 2008-02-13) Warden, Charles D.; Kim, Seong-Ho; Yi, Soojin V.; Biostatistics, School of Public Health
    Functional RNAs (fRNAs) are being recognized as an important regulatory component in biological processes. Interestingly, recent computational studies suggest that the number and biological significance of functional RNAs within coding regions (coding fRNAs) may have been underestimated. We hypothesized that such coding fRNAs will impose additional constraint on sequence evolution because the DNA primary sequence has to simultaneously code for functional RNA secondary structures on the messenger RNA in addition to the amino acid codons for the protein sequence. To test this prediction, we first utilized computational methods to predict conserved fRNA secondary structures within multiple species alignments of Saccharomyces sensu strico genomes. We predict that as much as 5% of the genes in the yeast genome contain at least one functional RNA secondary structure within their protein-coding region. We then analyzed the impact of coding fRNAs on the evolutionary rate of protein-coding genes because a decrease in evolutionary rate implies constraint due to biological functionality. We found that our predicted coding fRNAs have a significant influence on evolutionary rates (especially at synonymous sites), independent of other functional measures. Thus, coding fRNA may play a role on sequence evolution. Given that coding regions of humans and flies contain many more predicted coding fRNAs than yeast, the impact of coding fRNAs on sequence evolution may be substantial in genomes of higher eukaryotes.
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    Relative sensitivity of magnetic resonance spectroscopy and quantitative magnetic resonance imaging to cognitive function among nondemented individuals infected with HIV
    (Cambridge University Press, 2008-09) Paul, Robert H.; Ernst, Thomas; Brickman, Adam M.; Yiannoutsos, Constantin T.; Tate, David F.; Cohen, Ronald A.; Navia, Bradford A.; Biostatistics, School of Public Health
    In the present study, we examined the relationships among cognitive function, magnetic resonance spectroscopy (MRS) brain metabolite indices measured in the basal ganglia, and quantitative magnetic resonance imaging (MRI) of the caudate nucleus and the putamen in the earliest stages of HIV-related cognitive involvement. Participants included 22 HIV-positive individuals and 20 HIV-negative individuals. HIV-positive individuals performed significantly more poorly than the HIV-negative individuals on several cognitive measures. In addition, the choline/creatine ratio was significantly higher and the N-acetyl aspartate/choline ratio was significantly lower among HIV patients. The caudate and putamen sizes were smaller among HIV-positive patients compared with controls; however, the differences did not reach statistical significance. Correlation analyses revealed associations between cognitive function and select MRS indices. In addition, caudate size was significantly correlated with performances on higher-order thinking tests whereas putamen size was significantly correlated with performances on motor tests. The results suggest that MRS differences are more pronounced than area size differences between seropositive and seronegative individuals in mild stages of HIV-related cognitive impairment. However, basal ganglia size remains an important contributor to cognitive status in this population. Longitudinal studies are needed to determine the evolution of these imaging correlates of HIV-cognitive impairment in HIV.
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    Diabetes and peripheral arterial disease in men: trends in prevalence, mortality, and effect of concomitant coronary disease
    (Wiley, 2009-08) Kamalesh, Masoor; Shen, Jianzhao; Biostatistics, School of Public Health
    BACKGROUND: Recent data on trends in diabetes mellitus (DM) prevalence and long-term effect on mortality in peripheral arterial disease (PAD) subjects is lacking. METHODS: All subjects discharged from any VA medical center between October 1990 to September 1997 with an International Classification of Diseases (ICD)-9 code for PAD and DM in the discharge summary were retrospectively identified. Demographic data were extracted from the database. Mortality data were obtained from the Beneficiary Information and Resource Locator. Outcome measures were age specific DM prevalence over time, and short-term and long-term mortality. RESULTS: Of 33, 629 patients with PAD, 9474 (29%) had DM. Diabetes mellitus subjects were less likely to be white and had more comorbidities. Mean length of hospital stay was greater for DM (22.3 d vs 18.7 days, P < 0.001). Mortality was higher for DM at 180 days (9.8% vs 8.4%, P < 0.001), 1 year (16.4% vs 13.7%, P < 0.001), and continues to increase at 8 years of follow-up. Logistic regression analysis showed no interaction between DM and coronary artery disease (CAD). CONCLUSIONS: Diabetes mellitus increases all-cause mortality in subjects with PAD starting at 6 months post-discharge and continues to be higher even at 8 years of follow-up. There was a lack of interaction of DM and CAD on mortality in this cohort of subjects with PAD.
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    The Volume-Outcome Relationship in Nursing Home Care: An Examination of Functional Decline Among Long-term Care Residents
    (Wolters Kluwer, 2010) Li, Yue; Cai, Xueya; Mukamel, Dana B.; Glance, Laurent G.; Biostatistics, School of Public Health
    Background: Extensive evidence has demonstrated a relationship between patient volume and improved clinical outcomes in hospital care. This study sought to determine whether a similar association exists between nursing home volume of long-term care residents and rates of decline in physical function. Methods: We conducted retrospective analyses on the 2004 and 2005 Minimum Data Set files that contain 605,433 eligible long-term residents in 9336 nursing homes. The outcome was defined following the federal “Nursing Home Compare” measure that captures changes in 4 basic activities of daily living status between 2 consecutive quarters. Both the outcome measure and nursing home volume were defined on the basis of long-term care residents. We estimated random-effects logistic regression models to quantify the independent impact of volume on functional decline. Results: As volume increased, nursing home’s unadjusted rate of functional decline tended to be lower. After multivariate adjustment for baseline resident characteristics and the nesting of residents within facilities, the odds ratio of activities of daily living decline was 0.82 (95% confidence interval: 0.79–0.86, P < 0.000) for residents in high-volume nursing homes (>101 residents/facility), compared with residents in low-volume facilities (30–51 residents/facility). Conclusions: High volume of long-term care residents in a nursing home is associated with overall less functional decline. Further studies are needed to test other important nursing home outcomes, and explore various institutional, staffing, and resource attributes that underlie this volume-outcome association for long-term care. Understanding how greater experience of high-volume facilities leads to better resident outcome may help guide quality improvement efforts in nursing homes.
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    An empirical Bayes model for gene expression and methylation profiles in antiestrogen resistant breast cancer
    (BMC, 2010-11-25) Jeong, Jaesik; Li, Lang; Liu, Yunlong; Nephew, Kenneth P.; Huang, Tim Hui-Ming; Shen, Changyu; Biostatistics, School of Public Health
    Background The nuclear transcription factor estrogen receptor alpha (ER-alpha) is the target of several antiestrogen therapeutic agents for breast cancer. However, many ER-alpha positive patients do not respond to these treatments from the beginning, or stop responding after being treated for a period of time. Because of the association of gene transcription alteration and drug resistance and the emerging evidence on the role of DNA methylation on transcription regulation, understanding of these relationships can facilitate development of approaches to re-sensitize breast cancer cells to treatment by restoring DNA methylation patterns. Methods We constructed a hierarchical empirical Bayes model to investigate the simultaneous change of gene expression and promoter DNA methylation profiles among wild type (WT) and OHT/ICI resistant MCF7 breast cancer cell lines. Results We found that compared with the WT cell lines, almost all of the genes in OHT or ICI resistant cell lines either do not show methylation change or hypomethylated. Moreover, the correlations between gene expression and methylation are quite heterogeneous across genes, suggesting the involvement of other factors in regulating transcription. Analysis of our results in combination with H3K4me2 data on OHT resistant cell lines suggests a clear interplay between DNA methylation and H3K4me2 in the regulation of gene expression. For hypomethylated genes with alteration of gene expression, most (~80%) are up-regulated, consistent with current view on the relationship between promoter methylation and gene expression. Conclusions We developed an empirical Bayes model to study the association between DNA methylation in the promoter region and gene expression. Our approach generates both global (across all genes) and local (individual gene) views of the interplay. It provides important insight on future effort to develop therapeutic agent to re-sensitize breast cancer cells to treatment.
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    Adjusting Mortality for Loss to Follow-Up: Analysis of Five ART Programmes in Sub-Saharan Africa
    (Public Library of Science, 2010-11-30) Brinkhof, Martin W. G.; Spycher, Ben D.; Yiannoutsos, Constantin; Weigel, Ralf; Wood, Robin; Messou, Eugène; Boulle, Andrew; Egger, Matthias; Sterne, Jonathan A. C.; Biostatistics, School of Public Health
    Evaluation of antiretroviral treatment (ART) programmes in sub-Saharan Africa is difficult because many patients are lost to follow-up. Outcomes in these patients are generally unknown but studies tracing patients have shown mortality to be high. We adjusted programme-level mortality in the first year of antiretroviral treatment (ART) for excess mortality in patients lost to follow-up. Methods and Findings Treatment-naïve patients starting combination ART in five programmes in Côte d'Ivoire, Kenya, Malawi and South Africa were eligible. Patients whose last visit was at least nine months before the closure of the database were considered lost to follow-up. We filled missing survival times in these patients by multiple imputation, using estimates of mortality from studies that traced patients lost to follow-up. Data were analyzed using Weibull models, adjusting for age, sex, ART regimen, CD4 cell count, clinical stage and treatment programme. A total of 15,915 HIV-infected patients (median CD4 cell count 110 cells/µL, median age 35 years, 68% female) were included; 1,001 (6.3%) were known to have died and 1,285 (14.3%) were lost to follow-up in the first year of ART. Crude estimates of mortality at one year ranged from 5.7% (95% CI 4.9–6.5%) to 10.9% (9.6–12.4%) across the five programmes. Estimated mortality hazard ratios comparing patients lost to follow-up with those remaining in care ranged from 6 to 23. Adjusted estimates based on these hazard ratios ranged from 10.2% (8.9–11.6%) to 16.9% (15.0–19.1%), with relative increases in mortality ranging from 27% to 73% across programmes. Conclusions Naïve survival analysis ignoring excess mortality in patients lost to follow-up may greatly underestimate overall mortality, and bias ART programme evaluations. Adjusted mortality estimates can be obtained based on excess mortality rates in patients lost to follow-up.
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    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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    Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension
    (Elsevier, 2012-01) Gabler, Nicole B.; French, Benjamin; Strom, Brian L.; Liu, Ziyue; Palevsky, Harold I.; Taichman, Darren B.; Kawut, Steven M.; Halpern, Scott D.; Biostatistics, School of Public Health
    Background Recently studied therapies for pulmonary arterial hypertension (PAH) have improved outcomes among populations of patients, but little is known about which patients are most likely to respond to specific treatments. Differences in endothelin-1 biology between sexes and between whites and blacks may lead to differences in patients' responses to treatment with endothelin receptor antagonists (ERAs). Methods We conducted pooled analyses of deidentified, patient-level data from six randomized placebo-controlled trials of ERAs submitted to the US Food and Drug Administration to elucidate heterogeneity in treatment response. We estimated the interaction between treatment assignment (ERA vs placebo) and sex and between treatment and white or black race in terms of the change in 6-min walk distance from baseline to 12 weeks. Results Trials included 1,130 participants with a mean age of 49 years; 21% were men, 74% were white, and 6% were black. The placebo-adjusted response to ERAs was 29.7 m (95% CI, 3.7-55.7 m) greater in women than in men (P = .03). The placebo-adjusted response was 42.2 m for whites and −1.4 m for blacks, a difference of 43.6 m (95% CI, −3.5-90.7 m) (P = .07). Similar results were found in sensitivity analyses and in secondary analyses using the outcome of absolute distance walked. Conclusions Women with PAH obtain greater responses to ERAs than do men, and whites may experience a greater treatment benefit than do blacks. This heterogeneity in treatment-response may reflect pathophysiologic differences between sexes and races or distinct disease phenotypes.