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1.  Semiparametric Inference for Data with a Continuous Outcome from a Two-Phase Probability Dependent Sampling Scheme 
Multi-phased designs and biased sampling designs are two of the well recognized approaches to enhance study efficiency. In this paper, we propose a new and cost-effective sampling design, the two-phase probability dependent sampling design (PDS), for studies with a continuous outcome. This design will enable investigators to make efficient use of resources by targeting more informative subjects for sampling. We develop a new semiparametric empirical likelihood inference method to take advantage of data obtained through a PDS design. Simulation study results indicate that the proposed sampling scheme, coupled with the proposed estimator, is more efficient and more powerful than the existing outcome dependent sampling design and the simple random sampling design with the same sample size. We illustrate the proposed method with a real data set from an environmental epidemiologic study.
PMCID: PMC3984585  PMID: 24737947
Empirical likelihood; Missing data; Semiparametric; Probability sample
2.  Cancer Incidence Among Those Initiating Insulin Therapy With Glargine Versus Human NPH Insulin 
Diabetes Care  2013;36(11):3517-3525.
To add to the evidence on comparative long-term effects of insulin analog glargine versus human NPH insulin on the risk for cancer.
We identified cohorts of initiators of glargine and human NPH without an insulin prescription during the prior 19 months among patients covered by the Inovalon Medical Outcomes Research for Effectiveness and Economics Registry (MORE2 Registry) between January 2003 and December 2010. Patients were required to have a second prescription of the same insulin within 180 days and to be free of cancer. We balanced cohorts on risk factors for cancer outcomes based on comorbidities, comedication, and health care use during the prior 12 months using inverse probability of treatment weighting. Incident cancer was defined as having two claims for cancer (any cancer) or the same cancer (breast, prostate, colon) within 2 months. We estimated adjusted hazard ratios (HRs) and their 95% CI using weighted Cox models censoring for stopping, switching, or augmenting insulin treatment, end of enrollment, and mortality.
More patients initiated glargine (43,306) than NPH (9,147). Initiators of glargine (NPH) were followed for 1.2 (1.1) years and 50,548 (10,011) person-years; 993 (178) developed cancer. The overall HR was 1.12 (95% CI 0.95–1.32). Results were consistent for breast cancer, prostate cancer, and colon cancer; various durations of treatment; and sensitivity analyses.
Patients initiating insulin glargine rather than NPH do not seem to be at an increased risk for cancer. While our study contributes significantly to our evidence base for long-term effects, this evidence is very limited mainly based on actual dynamics in insulin prescribing.
PMCID: PMC3816915  PMID: 23877991
3.  Statistical Inference for a Two-Stage Outcome-Dependent Sampling Design with a Continuous Outcome 
Biometrics  2011;67(1):194-202.
The two-stage case-control design has been widely used in epidemiology studies for its cost-effectiveness and improvement of the study efficiency (White, 1982; Breslow and Cain, 1988). The evolution of modern biomedical studies has called for cost-effective designs with a continuous outcome and exposure variables. In this paper, we propose a new two-stage outcome-dependent sampling scheme with a continuous outcome variable, where both the first-stage data and the second-stage data are from outcome-dependent sampling schemes. We develop a semiparametric empirical likelihood estimation for inference about the regression parameters in the proposed design. Simulation studies were conducted to investigate the small sample behavior of the proposed estimator. We demonstrate that, for a given statistical power, the proposed design will require a substantially smaller sample size than the alternative designs. The proposed method is illustrated with an environmental health study conducted at National Institute of Health.
PMCID: PMC4106685  PMID: 20560938
Biased sampling; Empirical likelihood; Outcome dependent; Sample size; Two-stage design
4.  Vitamin E Gamma-tocopherol Reduces Airway Neutrophil Recruitment after Inhaled Endotoxin Challenge in Rats and in Healthy Volunteers 
Free radical biology & medicine  2013;60:10.1016/j.freeradbiomed.2013.02.001.
Epidemiologic studies suggest that dietary vitamin E is an important candidate intervention for asthma. Our group has shown that daily consumption of vitamin E (gamma tocopherol, γT) has anti-inflammatory actions in both rodent and human phase I studies. The objective of this study was to test whether γT supplementation could mitigate a model of neutrophilic airway inflammation in rats and in healthy human volunteers.
F344/N rats were randomized to oral gavage with γT versus placebo, followed by intranasal LPS (20 ug) challenge. Bronchoalveolar lavage fluid and lung histology were used to assess airway neutrophil recruitment. In a phase IIa clinical study, 13 nonasthmatic subjects completed a double-blinded, placebo controlled crossover study where they consumed either a γT-enriched capsule or a sunflower oil placebo capsule. After 7 days of daily supplementation, they underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 6 hours after inhaled LPS. The effect of γT compared to placebo on airway neutrophils post-LPS was compared using a repeated measures analysis of variance.
In rats, oral γT supplementation significantly reduced tissue infiltration (p<0.05) and accumulation of airway neutrophils (p<0.05) that are elicited by intranasal LPS challenge compared to control rats. In human volunteers, γT treatment significantly decreased induced sputum neutrophils (p=0.03) compared to placebo.
Oral supplementation with γT reduced airway neutrophil recruitment in both rat and human models of inhaled LPS challenge. These results suggest that γT is a potential therapeutic candidate for prevention or treatment of neutrophilic airway inflammation in diseased populations.
PMCID: PMC3654053  PMID: 23402870
Vitamin E; gamma-tocopherol; Endotoxin; Eosinophil; Neutrophil; Induced Sputum; Oxidative Stress; Nitrosative Stress; Rat; LPS
5.  Increase in Speech Recognition due to Linguistic Mismatch Between Target and Masker Speech: Monolingual and Simultaneous Bilingual Performance 
To examine whether improved speech recognition during linguistically mismatched target–masker experiments is due to linguistic unfamiliarity of the masker speech or linguistic dissimilarity between the target and masker speech.
Monolingual English speakers (n = 20) and English–Greek simultaneous bilinguals (n = 20) listened to English sentences in the presence of competing English and Greek speech. Data were analyzed using mixed-effects regression models to determine differences in English recogition performance between the 2 groups and 2 masker conditions.
Results indicated that English sentence recognition for monolinguals and simultaneous English–Greek bilinguals improved when the masker speech changed from competing English to competing Greek speech.
The improvement in speech recognition that has been observed for linguistically mismatched target–masker experiments cannot be simply explained by the masker language being linguistically unknown or unfamiliar to the listeners. Listeners can improve their speech recognition in linguistically mismatched target–masker experiments even when the listener is able to obtain meaningful linguistic information from the masker speech.
PMCID: PMC4043956  PMID: 24167230
informational masking; linguistic masking; simultaneous bilingual
6.  Effect of Broccoli Sprouts on Nasal Response to Live Attenuated Influenza Virus in Smokers: A Randomized, Double-Blind Study 
PLoS ONE  2014;9(6):e98671.
Smokers have increased susceptibility and altered innate host defense responses to influenza virus infection. Broccoli sprouts are a source of the Nrf2 activating agentsulforaphane, and short term ingestion of broccoli sprout homogenates (BSH) has been shown to reduce nasal inflammatory responses to oxidant pollutants.
Assess the effects of BSH on nasal cytokines, virus replication, and Nrf2-dependent enzyme expression in smokers and nonsmokers.
We conducted a randomized, double-blind, placebo-controlled trial comparing the effects of BSH on serially sampled nasal lavage fluid (NLF) cytokines, viral sequence quantity, and Nrf2-dependent enzyme expression in NLF cells and biopsied epithelium. Healthy young adult smokers and nonsmokers ingested BSH or placebo (alfalfa sprout homogenate) for 4 days, designated Days -1, 0, 1, 2. On Day 0 they received standard vaccine dose of live attenuated influenza virus (LAIV) intranasally. Nasal lavage fluids and nasal biopsies were collected serially to assess response to LAIV.
In area under curve analyses, post-LAIV IL-6 responses (P = 0.03) and influenza sequences (P = 0.01) were significantly reduced in NLF from BSH-treated smokers, whileNAD(P)H: quinoneoxidoreductasein NLF cells was significantly increased. In nonsmokers, a similar trend for reduction in virus quantity with BSH did not reach statistical significance.
In smokers, short term ingestion of broccoli sprout homogenates appears to significantly reduce some virus-induced markers of inflammation, as well as reducing virus quantity. Nutritional antioxidant interventions have promise as a safe, low-cost strategy for reducing influenza risk among smokers and other at risk populations.
Trial Registration NCT01269723
PMCID: PMC4049587  PMID: 24910991
7.  Effects of ex vivo Gamma-Tocopherol on Airway Macrophage Function in Healthy and Mild Allergic Asthmatics 
Journal of innate immunity  2013;5(6):613-624.
Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate gamma-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-mediated phagocytosis and expression of cell surface molecules associated with innate and adaptive immunity on sputum-derived macrophages. Cells from non-smoking healthy (n = 6) and mild house dust mite-sensitive (HDM) allergic asthmatics (n = 6) were treated ex vivo with GT (300 μM) or saline (control). Phagocytosis of opsonized Zymosan A bioparticles (S. cerevisiae) and expression of surface molecules associated with innate and adaptive immunity were assessed using flow cytometry. GT caused significantly decreased (P < 0.05) internalization of attached Zymosan bioparticles and decreased (P < 0.05) macrophage expression of CD206, CD36 and CD86 in allergic asthmatics but not in controls. Overall, GT caused down-regulation of both innate and adaptive immune response elements and atopic status appears to be an important factor.
PMCID: PMC3939603  PMID: 23689260
allergy; asthma; macrophages; phagocytosis; flow cytometry; gamma-tocopherol; host defense
8.  Cerebellar modules operate at different frequencies 
eLife  2014;3:e02536.
Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with their expression of the glycolytic enzyme aldolase C or zebrin. Simple spike and complex spike frequencies were significantly higher in Purkinje cells located in zebrin-negative than zebrin-positive modules. The difference in simple spike frequency persisted when the synaptic input to, but not intrinsic activity of, Purkinje cells was manipulated. Blocking TRPC3, the effector channel of a cascade of proteins that have zebrin-like distribution patterns, attenuated the simple spike frequency difference. Our results indicate that zebrin-discriminated cerebellar modules operate at different frequencies, which depend on activation of TRPC3, and that this property is relevant for all cerebellar functions.
eLife digest
The cerebellum, located at the back of the brain underneath the cerebral hemispheres, is best known for its role in the control of movement. Despite its small size, the cerebellum contains more than half of the brain's neurons. These are organized in a repeating pattern in which cells called Purkinje cells receive inputs from two types of fibers: climbing fibers, which ascend into the cerebellum from the brainstem; and parallel fibers, which run perpendicular to the climbing fibers. This gives rise to a characteristic ‘crystalline’ structure.
As a result of this uniform circuitry, it was widely believed was that all Purkinje cells throughout the cerebellum would function the same way. However, the presence of distinct patterns of gene expression in different regions suggests that this is not the case. Molecules called zebrins, for example, are found in some Purkinje cells but not others, and this gives rise to a pattern of zebrin-positive and zebrin-negative stripes. A number of other molecules have similar distributions, suggesting that these differences in molecular machinery could underlie differences in cellular physiology.
Zhou, Lin et al. have now provided one of the first direct demonstrations of such physiological differences by showing that zebrin-positive cells generate action potentials at lower frequencies than zebrin-negative cells. This pattern is seen throughout the cerebellum, and is evident even when the positive and negative cells are neighbors, which indicates that these differences do not simply reflect differences in the locations of the cells or differences in the inputs they receive from parallel fibers. Additional experiments revealed that the distinct firing rates are likely not generated by zebrin itself, but rather by proteins that are expressed alongside zebrin, most notably those that work through an ion channel called TRPC3.
By showing that cells arranged in the same type of circuit can nevertheless have distinct firing rates, the work of Zhou, Lin et al. has revealed an additional level of complexity in the physiology of the cerebellum. In addition to improving our understanding of how the brain controls movement, these findings might also be of interest to researchers studying the increasing number of neurological and psychiatric disorders in which cerebellar dysfunction has been implicated.
PMCID: PMC4049173  PMID: 24843004
cerebellum; cerebellar modules; Purkinje cells; zebrin II; TRPC3; mouse
This article presents a multiple imputation method for sensitivity analyses of time-to-event data with possibly informative censoring. The imputed time for censored values is drawn from the failure time distribution conditional on the time of follow-up discontinuation. A variety of specifications regarding the post-discontinuation tendency of having events can be incorporated in the imputation through a hazard ratio parameter for discontinuation versus continuation of follow-up. Multiple-imputed data sets are analyzed with the primary analysis method, and the results are then combined using the methods of Rubin. An illustrative example is provided.
PMCID: PMC4009741  PMID: 24605967
Multiple imputation; Sensitivity analysis; Time-to-event data
10.  Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis 
The Journal of Clinical Investigation  2014;124(4):1552-1567.
Familial Alzheimer’s disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A–associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration.
PMCID: PMC3973081  PMID: 24569455
11.  The Glutathione-S-Transferase null genotype and increased neutrophil response to low level ozone (0.06 ppm) 
PMCID: PMC3509264  PMID: 22921799
GSTM1null genotype; PMN responsiveness; ozone; innate immune phenotypes
12.  Inference for Seemingly Unrelated Varying-Coefficient Nonparametric Regression Models 
This paper is concerned with the inference of seemingly unrelated (SU) varying-coefficient nonparametric regression models. We propose an estimation for the unknown coefficient functions, which is an extension of the two-stage procedure proposed by Linton, et al. (2004) in the longitudinal data framework where they focused on purely nonparametric regression. We show the resulted estimators are asymptotically normal and more efficient than those based on only the individual regression equation even when the error covariance matrix is homogeneous. Another focus of this paper is to extend the generalized likelihood ratio technique developed by Fan, Zhang and Zhang (2001) for testing the goodness of fit of models to the setting of SU regression. A wild block bootstrap based method is used to compute p-value of the test. Some simulation studies are given in support of the asymptotics. A real data set from an ongoing environmental epidemiologic study is used to illustrate the proposed procedures.
PMCID: PMC3893667  PMID: 24453433
Seemingly unrelated regression; Varying-coefficient model; Two-stage estimation; Asymptotic normality
13.  Nasal PMN response to repeated challenge with endotoxin in healthy volunteers 
Inhalation toxicology  2011;23(3):10.3109/08958378.2011.553247.
We have employed nasal challenge with lipopolysaccharide (LPS) followed by nasal lavage (NL) to experimentally induce and examine upper airway inflammation in human volunteers. It is unclear however whether adaptation within individuals occurs following repeated nasal challenge. This was a pilot study to determine if repeated nasal LPS challenge yields attenuation of markers of inflammation (primarily neutrophil response) in the NL fluid of healthy humans.
We employed a 3-day nasal LPS challenge protocol with NL using a “split nose” design. The control and LPS nares received two consecutive day saline (0.9% saline/day) and LPS (2 μg LPS/day) challenges, respectively followed by an LPS (2 μg/day) challenge to each nare on Day 3. NL was performed immediately pre Day 1 challenges and 6-h post nasal LPS challenges on both Days 1 and 3. Markers of inflammation (PMNs/mg, cytokines) were assessed in NL and the inflammatory response to LPS (measured as the difference between pre and post challenge) was evaluated in both nares on Day 3 and compared to Day 1.
Significant (p < 0.05) blunting of the LPS-induced polymorphonuclear leukocyte (PMN) response was observed in the nare that received repeated LPS challenges as compared to the control nare (67.60 ± 22.39 vs. 157.8 ± 76.04 PMN/mg) and initial LPS challenge on Day 1 (121 ± 32 PMN/mg). Decreased soluble CD14 and significantly decreased interleukin-8 were also found in the repeat LPS-treated nare. In the LPS-treated nare, the blunted PMN response on Day 3 correlated well with the observed PMN response on Day1 (r = 0.58, p = 0.02).
We show attenuation of PMN response to repeated LPS in the nasal airways in healthy humans. Effect of repeat endotoxin exposure prior to allergen delivery on local airway inflammation in both healthy and atopic subjects can be studied.
PMCID: PMC3808958  PMID: 21391782
Airway inflammation; neutrophils; adaptation; lipopolysaccharide (LPS, endotoxin)
14.  Enhancement of systemic and sputum granulocyte response to inhaled endotoxin in people with the GSTM1 null genotype 
Occupational and environmental medicine  2011;68(10):10.1136/oem.2010.061747.
To determine if the GSTM1 null genotype is a risk factor for increased inflammatory response to inhaled endotoxin.
35 volunteers who had undergone inhalation challenge with a 20 000 endotoxin unit dose of Clinical Center Reference Endotoxin (CCRE) were genotyped for the GSTM1 null polymorphism. Parameters of airway and systemic inflammation observed before and after challenge were compared in GSTM1 null (n=17) and GSTM1 (n=18) sufficient volunteers.
GSTM1 null volunteers had significantly increased circulating white blood cells (WBCs), polymorphonuclear neutrophils (PMNs), platelets and sputum PMNs (% sputum PMNs and PMNs/mg sputum) after CCRE challenge. GSTM1 sufficient volunteers had significant, but lower increases in circulating WBCs, PMNs and % sputum PMNs, and no increase in platelets or PMNs/mg sputum. Linear regression analysis adjusted for baseline values of the entire cohort revealed that the GSTM1 null genotype significantly increased circulating WBCs, platelets and % sputum PMNs after challenge
These data support the hypothesis that the GSTM1 null genotype is a risk factor for increased acute respiratory and systemic inflammatory response to inhaled CCRE. These data are consistent with other observations that the GSTM1 null genotype is associated with increased respiratory, systemic and cardiovascular effects linked to ambient air particulate matter exposure and indicate that the GSTM1 null genotype should be considered a risk factor for adverse health effects associated with exposure to environmental endotoxin.
PMCID: PMC3808962  PMID: 21441173
15.  Atopic asthmatic patients have reduced airway inflammatory cell recruitment after inhaled endotoxin challenge compared with healthy volunteers 
Atopic asthmatic patients are reported to be more sensitive to the effects of environmental endotoxin (LPS) than healthy volunteers (HVs). It is unknown whether this sensitivity is due to dysregulated inflammatory responses after LPS exposure in atopic asthmatic patients.
We sought to test the hypothesis that atopic asthmatic patients respond differentially to inhaled LPS challenge compared with HVs.
Thirteen allergic asthmatic (AA) patients and 18 nonallergic nonasthmatic subjects (healthy volunteers [HVs]) underwent an inhalation challenge to 20,000 endotoxin units of Clinical Center Reference Endotoxin (LPS). Induced sputum and peripheral blood were obtained at baseline and 6 hours after inhaled LPS challenge. Sputum and blood samples were assayed for changes in inflammatory cell numbers and cytokine and cell-surface marker levels on monocytes and macrophages.
The percentage of neutrophils in sputum (%PMN) in induced sputum similarly and significantly increased in both HVs and AA patients after inhaled LPS challenge. However, the absolute numbers of leukocytes and PMNs recruited to the airways were significantly lower in AA patients compared with those seen in HVs with inhaled LPS challenge. Sputum levels of IL-6 and TNF-α were significantly increased in both cohorts, but levels of IL-1β and IL-18 were only significantly increased in the HV group. Cell-surface expression of Toll-like receptors 4 and 2 were significantly enhanced only in the HV group.
The airway inflammatory response to inhaled LPS challenge is blunted in AA patients compared with that seen in HVs and accompanied by reductions in airway neutrophilia and inflammasome-dependent cytokine production. These factors might contribute to increased susceptibility to airway microbial infection or colonization in AA patients.
PMCID: PMC3652253  PMID: 22770265
Asthma; LPS; induced sputum; inflammasome; innate immunity
16.  Mixed effect regression analysis for a cluster-based two-stage outcome-auxiliary-dependent sampling design with a continuous outcome 
Biostatistics (Oxford, England)  2012;13(4):650-664.
Two-stage design is a well-known cost-effective way for conducting biomedical studies when the exposure variable is expensive or difficult to measure. Recent research development further allowed one or both stages of the two-stage design to be outcome dependent on a continuous outcome variable. This outcome-dependent sampling feature enables further efficiency gain in parameter estimation and overall cost reduction of the study (e.g. Wang, X. and Zhou, H., 2010. Design and inference for cancer biomarker study with an outcome and auxiliary-dependent subsampling. Biometrics 66, 502–511; Zhou, H., Song, R., Wu, Y. and Qin, J., 2011. Statistical inference for a two-stage outcome-dependent sampling design with a continuous outcome. Biometrics 67, 194–202). In this paper, we develop a semiparametric mixed effect regression model for data from a two-stage design where the second-stage data are sampled with an outcome-auxiliary-dependent sample (OADS) scheme. Our method allows the cluster- or center-effects of the study subjects to be accounted for. We propose an estimated likelihood function to estimate the regression parameters. Simulation study indicates that greater study efficiency gains can be achieved under the proposed two-stage OADS design with center-effects when compared with other alternative sampling schemes. We illustrate the proposed method by analyzing a dataset from the Collaborative Perinatal Project.
PMCID: PMC3440236  PMID: 22723503
Center effect; Mixed model; Outcome-auxiliary-dependent sampling; Validation sample
17.  An efficient sampling and inference procedure for studies with a continuous outcome 
Epidemiology (Cambridge, Mass.)  2007;18(4):461-468.
To characterize the relation between an exposure and a continuous outcome, the sampling of subjects can be done much as it is in a case-control study, such that the sample is enriched with subjects who are especially informative. In an outcome dependent sampling (ODS) design, observations made on a judiciously chosen subset of the base population can provide nearly the same statistical efficiency as observing the entire base population. Reaping the benefits of such sampling, however, requires use of an analysis that accounts for the ODS design. In this report, the authors examined the statistical efficiency of a plain random sample analyzed with standard methods, compared with that of data collected with an ODS design and analyzed by either of two appropriate methods. In addition, three real datasets were analyzed using an ODS approach. The results demonstrate the improved statistical efficiency obtained by using an ODS approach and its applicability in a wide range of settings. An ODS design, coupled with an appropriate analysis, can offer a cost-efficient approach to studying the determinants of a continuous outcome.
PMCID: PMC3664946  PMID: 17568219
biased sampling; continuous outcome; empirical likelihood; epidemiologic methods; epidemiologic research design; semiparametric
18.  Bronchoscopy-Derived Correlates of Lung Injury following Inhalational Injuries: A Prospective Observational Study 
PLoS ONE  2013;8(5):e64250.
Acute lung injury (ALI) is a major factor determining morbidity following burns and inhalational injury. In experimental models, factors potentially contributing to ALI risk include inhalation of toxins directly causing cell damage; inflammation; and infection. However, few studies have been done in humans.
We carried out a prospective observational study of patients admitted to the NC Jaycees Burn Center who were intubated and on mechanical ventilation for burns and suspected inhalational injury. Subjects were enrolled over an 8-month period and followed till discharge or death. Serial bronchial washings from clinically-indicated bronchoscopies were collected and analyzed for markers of cell injury and inflammation. These markers were compared with clinical markers of ALI.
Forty-three consecutive patients were studied, with a spectrum of burn and inhalation injury severity. Visible soot at initial bronchoscopy and gram negative bacteria in the lower respiratory tract were associated with ALI in univariate analyses. Subsequent multivariate analysis also controlled for % body surface area burns, infection, and inhalation severity. Elevated IL-10 and reduced IL-12p70 in bronchial washings were statistically significantly associated with ALI.
Independently of several factors including initial inhalational injury severity, infection, and extent of surface burns, high early levels of IL-10 and low levels of IL-12p70 in the central airways are associated with ALI in patients intubated after acute burn/inhalation injury. Lower airway secretions can be collected serially in critically ill burn/inhalation injury patients and may yield important clues to specific pathophysiologic pathways.
PMCID: PMC3656836  PMID: 23691180
19.  Adjusted Exponentially Tilted Likelihood with Applications to Brain Morphology 
Biometrics  2008;65(3):919-927.
In this paper, we develop a nonparametric method, called adjusted exponentially tilted likelihood, and apply it to the analysis of morphometric measures. The adjusted exponential tilting estimator is shown to have the same first order asymptotic properties as that of the original exponentially tilted likelihood. The adjusted exponentially tilted likelihood ratio statistic is applied to test linear hypotheses of unknown parameters, such as the associations of brain measures (e.g., cortical and subcortical surfaces) with covariates of interest, such as age, gender, and gene. Simulation studies show that the adjusted exponential tilted likelihood ratio statistic performs as well as the t-test when the imaging data are symmetrically distributed, while it is superior when the imaging data have skewed distribution. We demonstrate the application of our new statistical methods to the detection of statistically significant differences in the morphology of the hippocampus between two schizophrenia groups and healthy subjects.
PMCID: PMC3572721  PMID: 18945269
Adjusted exponential tilted likelihood; Hypothesis testing; M-rep; Morphometric measure
20.  Estimation of AUC or Partial AUC under Test-Result-Dependent Sampling 
The area under the ROC curve (AUC) and partial area under the ROC curve (pAUC) are summary measures used to assess the accuracy of a biomarker in discriminating true disease status. The standard sampling approach used in biomarker validation studies is often inefficient and costly, especially when ascertaining the true disease status is costly and invasive. To improve efficiency and reduce the cost of biomarker validation studies, we consider a test-result-dependent sampling (TDS) scheme, in which subject selection for determining the disease state is dependent on the result of a biomarker assay. We first estimate the test-result distribution using data arising from the TDS design. With the estimated empirical test-result distribution, we propose consistent nonparametric estimators for AUC and pAUC and establish the asymptotic properties of the proposed estimators. Simulation studies show that the proposed estimators have good finite sample properties and that the TDS design yields more efficient AUC and pAUC estimates than a simple random sampling (SRS) design. A data example based on an ongoing cancer clinical trial is provided to illustrate the TDS design and the proposed estimators. This work can find broad applications in design and analysis of biomarker validation studies.
PMCID: PMC3564679  PMID: 23393612
Area under ROC curve (AUC); Empirical likelihood; Nonparametric; Partial area under ROC curve (pAUC); Simple random sampling; Test-result-dependent sampling
The purpose of this review is to highlight recent data regarding the impact of exposure to tobacco smoke on influenza virus infection. This is timely because of the continuing pattern for influenza to cause epidemics and pandemics.
Recent findings
Experimental animal studies suggest that tobacco smoke severity of respiratory disease with influenza. The interaction is complex and dependent on dose and chronicity of both virus and smoke exposure. Smoke-induced oxidant stress and suppression of innate immunity are mechanistic factors leading to worse disease. Experiments using human respiratory cells show that tobacco smoke increases viral replication through mechanisms including suppression of antiviral pathways and altered cytokine patterns in cell types with central roles in mucosal innate immunity, such as epithelium, dendritic cells and natural killer cells. Studies also suggest a role for antioxidant strategies in reducing risk. Human volunteer studies using live attenuated influenza virus as a model appear to corroborate many of these findings.
Exposure to tobacco smoke remains extremely prevalent worldwide. While avoidance of exposure is a primary goal, it is important to understand the mechanisms underlying increased infection risk with tobacco smoke and other pollutant exposures, so that novel preventive or treatment strategies can be developed.
PMCID: PMC3305994  PMID: 22157158
Influenza; tobacco smoke; interferon
22.  Diesel Exhaust Exposure and Nasal Response to Attenuated Influenza in Normal and Allergic Volunteers 
Rationale: Diesel exhaust enhances allergic inflammation, and pollutants are associated with heightened susceptibility to viral respiratory infections. The effects of combined diesel and virus exposure in humans are unknown.
Objectives: Test whether acute exposure to diesel modifies inflammatory responses to influenza virus in normal humans and those with allergies.
Methods: We conducted a double-blind, randomized, placebo-controlled study of nasal responses to live attenuated influenza virus in normal volunteers and those with allergic rhinitis exposed to diesel (100 μg/m3) or clean air for 2 hours, followed by standard dose of virus and serial nasal lavages. Endpoints were inflammatory mediators (ELISA) and virus quantity (quantitative reverse-transcriptase polymerase chain reaction). To test for exposure effect, we used multiple regression with exposure group (diesel vs. air) as the main explanatory variable and allergic status as an additional factor.
Measurements and Main Results: Baseline levels of mediators did not differ among groups. For most postvirus nasal cytokine responses, there was no significant diesel effect, and no significant interaction with allergy. However, diesel was associated with significantly increased IFN-γ responses (P = 0.02), with no interaction with allergy in the regression model. Eotaxin-1 (P = 0.01), eosinophil cationic protein (P < 0.01), and influenza RNA sequences in nasal cells (P = 0.03) were significantly increased with diesel exposure, linked to allergy.
Conclusions: Short-term exposure to diesel exhaust leads to increased eosinophil activation and increased virus quantity after virus inoculation in those with allergic rhinitis. This is consistent with previous literature suggesting a diesel “adjuvant” effect promoting allergic inflammation, and our data further suggest this change may be associated with reduced virus clearance.
Clinical trial registered with (NCT00617110).
PMCID: PMC3297091  PMID: 22071326
diesel; influenza; eosinophil cationic protein; eotaxin-1; interferon-γ
23.  Airway cells from atopic asthmatics exposed to ozone display an enhanced innate immune gene profile 
Capsule Summary
This study identifies transcriptional phenotypes of sputum samples from normal volunteers and atopic asthmatics exposed to ozone. Network analyses suggest that asthmatics elevate immune signaling following oxidative stress, while nonasthmatics attempt to mitigate the ozone-induced response.
PMCID: PMC3254026  PMID: 22196529
Asthma; Ozone; Induced Sputum; Profiling; Oxidative Stress
24.  Marginal Hazard Regression for Correlated Failure Time Data with Auxiliary Covariates 
Lifetime Data Analysis  2011;18(1):116-138.
In many biomedical studies, it is common that due to budget constraints, the primary covariate is only collected in a randomly selected subset from the full study cohort. Often, there is an inexpensive auxiliary covariate for the primary exposure variable that is readily available for all the cohort subjects. Valid statistical methods that make use of the auxiliary information to improve study efficiency need to be developed. To this end, we develop an estimated partial likelihood approach for correlated failure time data with auxiliary information. We assume a marginal hazard model with common baseline hazard function. The asymptotic properties for the proposed estimators are developed. The proof of the asymptotic results for the proposed estimators is nontrivial since the moments used in estimating equation are not martingale-based and the classical martingale theory is not sufficient. Instead, our proofs rely on modern empirical theory. The proposed estimator is evaluated through simulation studies and is shown to have increased efficiency compared to existing methods. The proposed methods are illustrated with a data set from the Framingham study.
PMCID: PMC3259288  PMID: 22094533
Marginal hazard model; Correlated failure time; Validation set; Auxiliary covariate
25.  Individuals with increased inflammatory response to ozone demonstrate muted signaling of immune cell trafficking pathways 
Respiratory Research  2012;13(1):89.
Exposure to ozone activates innate immune function and causes neutrophilic (PMN) airway inflammation that in some individuals is robustly elevated. The interplay between immuno-inflammatory function and genomic signaling in those with heightened inflammatory responsiveness to ozone is not well understood.
Determine baseline predictors and post exposure discriminators for the immuno-inflammatory response to ozone in inflammatory responsive adult volunteers.
Sputum induction was performed on 27 individuals before and after a two hour chamber exposure to 0.4 ppm ozone. Subjects were classified as inflammatory responders or non-responders to ozone based on their PMN response. Innate immune function, inflammatory cell and cytokine modulation and transcriptional signaling pathways were measured in sputum.
Post exposure, responders showed activated innate immune function (CD16: 31,004 MFI vs 8988 MFI; CD11b: 44,986 MFI vs 24,770 MFI; CD80: 2236 MFI vs 1506 MFI; IL-8: 37,603 pg/ml vs 2828 pg/ml; and IL-1β: 1380 pg/ml vs 318 pg/ml) with muted signaling of immune cell trafficking pathways. In contrast, non-responders displayed decreased innate immune activity (CD16, CD80; phagocytosis: 2 particles/PMN vs 4 particles/PMN) post exposure that was accompanied by a heightened signaling of immune cell trafficking pathways.
Inflammatory responsive and non responsive individuals to ozone show an inverse relationship between immune cell trafficking and immuno-inflammatory functional responses to ozone. These distinct genomic signatures may further our understanding about ozone-induced morbidity in individuals with different levels of inflammatory responsiveness.
PMCID: PMC3607990  PMID: 23033980
Air pollution; Environment; Ozone; Gene expression; Human sputum; Immune response; Innate immunity; Systems biology

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