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1.  Regression Splines in the Time-Dependent Coefficient Rates Model for Recurrent Event Data 
Statistics in medicine  2008;27(28):5890-5906.
Many epidemiologic studies involve the occurrence of recurrent events and much attention has been given for the development of modelling techniques that take into account the dependence structure of multiple event data. This paper presents a time-dependent coefficient rates model that incorporates regression splines in its estimation procedure. Such method would be appropriate in situations where the effect of an exposure or covariates changes over time in recurrent event data settings. The finite sample properties of the estimators are studied via simulation. Using data from a randomized community trial that was designed to evaluate the effect of vitamin A supplementation on recurrent diarrheal episodes in small children, we model the functional form of the treatment effect on the time to the occurrence of diarrhea. The results describe how this effect varies over time. In summary, we observed a major impact of the vitamin A supplementation on diarrhea after 2 months of the dosage, with the effect diminishing after the third dosage. The proposed method can be viewed as a flexible alternative to the marginal rates model with constant effect in situations where the effect of interest may vary over time.
PMCID: PMC2804403  PMID: 18696748
2.  A Community Study of Factors Related to Poorly Controlled Asthma among Brazilian Urban Children 
PLoS ONE  2012;7(5):e37050.
Asthma constitutes a serious public health problem in many regions of the world, including the city of Salvador, State of Bahia – Brazil. The purpose of this study was to analyse the factors associated with poor asthma control.
Methodology/Principal Findings
Two definitions were used for asthma: 1) wheezing in the last 12 months; 2) wheezing in the last 12 months plus other asthma symptoms or asthma diagnosis ever. The definition of poorly controlled asthma was: at least one reported hospitalisation due to asthma and/or high frequency of symptoms, in the last year. Children with poorly controlled asthma (N = 187/374) were compared with wheezing children with controlled asthma regarding age, gender, atopy, parental asthma, rhinitis, eczema, exposure to second hand tobacco smoke, presence of moulds, pets and pests in the house, helminth infections and body mass index. Crude and logistic regression adjusted odds ratios were used as measures of association. There was a higher proportion of poorly controlled asthma among children with eczema (OR = 1.55; 95% CI 1.02; 2.37). The strength of the association was greater among children with eczema and rhinitis (42.6%, 53.4% and 57.7%, respectively, in children who had no rhinitis nor eczema, had only one of those, and had both (p = 0.02 for trend test). The presence of mould in the houses was inversely associated with poorly controlled asthma (OR = 0.54; 95% CI 0.34; 0.87).
Our results indicate an association between eczema and poor asthma control in this environment, but emphasize the role of various other individual and environmental factors as determinants of poor control.
PMCID: PMC3365022  PMID: 22693565
3.  Evidence for a modulatory effect of IL-10 on both Th1 and Th2 cytokine production: The role of the environment 
Clinical Immunology (Orlando, Fla.)  2011;139(1-3):57-64.
Allergic and other immune-mediated diseases are complex disease states determined by interplay between host genetics and environmental factors. Environmental changes such as fewer infections and reduced exposure to microbial products have been suggested to have led to insufficient regulation of Th1 and Th2 immune responses, causing an increased incidence of inflammatory diseases. The objective of the present study was to investigate the effect of poor living environmental conditions on mitogen-induced production of cytokines (Th1 and Th2) by peripheral blood leukocytes in children living in urban Brazil and investigate the role of IL-10 in modifying this effect. Our data showed that the proportion of children producing Th1 and Th2 cytokines was lower among those with poor living conditions and that this finding was stronger in children producing IL-10. These results provide a possible biologic explanation for the temporal trends of increasing risk of inflammatory diseases observed in populations living in affluent countries.
PMCID: PMC3070800  PMID: 21285005
BMI, Body mass index; CpG-DNA, bacterial DNA; DC, dendritic cell; IFN, Interferon; LB, B lymphocyte; LPS, lipopolysaccharide; MΦ, macrophage; MHC, major histocompatibility complex; Neu, neutrophil; NO, nitric oxide; OR, odds ratio; PBLs, peripheral blood leukocytes; SCAALA, Social Changes Asthma and Allergy in Latin America; TGF-β, transforming growth factor β; Th1, T helper 1; Th17, T helper 17; Th2, T helper 2; TLR, toll like receptors; Treg, T regulatory; WBC, whole blood cells culture; IL-10; Th1/Th2; Environment; Sewage system; Street paving; Immune regulation
4.  Poverty, dirt, infections and non-atopic wheezing in children from a Brazilian urban center 
Respiratory Research  2010;11(1):167.
The causation of asthma is poorly understood. Risk factors for atopic and non-atopic asthma may be different. This study aimed to analyze the associations between markers of poverty, dirt and infections and wheezing in atopic and non-atopic children.
1445 children were recruited from a population-based cohort in Salvador, Brazil. Wheezing was assessed using the ISAAC questionnaire and atopy defined as allergen-specific IgE ≥0.70 kU/L. Relevant social factors, environmental exposures and serological markers for childhood infections were investigated as risk factors using multivariate multinomial logistic regression.
Common risk factors for wheezing in atopic and non-atopic children, respectively, were parental asthma and respiratory infection in early childhood. No other factor was associated with wheezing in atopic children. Factors associated with wheezing in non-atopics were low maternal educational level (OR 1.49, 95% CI 0.98-2.38), low frequency of room cleaning (OR 2.49, 95% CI 1.27-4.90), presence of rodents in the house (OR 1.48, 95% CI 1.06-2.09), and day care attendance (OR 1.52, 95% CI 1.01-2.29).
Non-atopic wheezing was associated with risk factors indicative of poverty, dirt and infections. Further research is required to more precisely define the mediating exposures and the mechanisms by which they may cause non-atopic wheeze.
PMCID: PMC3002921  PMID: 21122116
5.  Chronic Intestinal Helminth Infections Are Associated with Immune Hyporesponsiveness and Induction of a Regulatory Network▿ † ‡  
Infection and Immunity  2010;78(7):3160-3167.
Helminth infections have been associated with protection against allergy and autoimmune diseases. We investigated the effects of chronic infections with Ascaris lumbricoides and Trichuris trichiura (measured twice over a 5-year period) on cytokine and antibody responses. We collected blood from 1,060 children aged 4 to 11 years living in a poor urban area of Brazil and measured Th1 (gamma interferon [IFN-γ]) and Th2 (interleukin-5 [IL-5] and IL-13) cytokines and the regulatory cytokine IL-10 in unstimulated and stimulated (with mitogen or A. lumbricoides antigens) cultures of peripheral blood leukocytes and levels of total IgE and anti-A. lumbricoides IgG4 and IgE in serum. Intestinal helminth infections were associated with an increased proportion of children producing IL-5 in response to A. lumbricoides and producing IL-10 spontaneously, especially among coinfected and chronically infected children. Helminth infections were associated with a generalized suppression of cytokine responses to mitogen. Levels of total IgE and anti-A. lumbricoides IgG4 and IgE were especially elevated in chronically infected children. In conclusion, intestinal helminth infections were associated with a typical Th2 immune response profile and with the induction of immune hyporesponsiveness that was associated with greater frequencies of the production of spontaneous IL-10.
PMCID: PMC2897394  PMID: 20404082
6.  Spontaneous Cytokine Production in Children According to Biological Characteristics and Environmental Exposures 
Environmental Health Perspectives  2009;117(5):845-849.
Environmental factors are likely to have profound effects on the development of host immune responses, with serious implications for infectious diseases and inflammatory disorders such as asthma.
This study was designed to investigate the effects of environmental exposures on the cytokine profile of children.
The study involved measurement of T helper (Th) 1 (interferon-gamma), 2 [interleukin (IL)-5 and IL-13], and the regulatory cytokine IL-10 in unstimulated peripheral blood leukocytes from 1,376 children 4–11 years of age living in a poor urban area of the tropics. We also assessed the impact of environmental exposures in addition to biological characteristics recorded at the time of blood collection and earlier in childhood (0–3 years before blood collection).
The proportion of children producing IL-10 was greater among those without access to drinking water [p < 0.05, chi-square test, odds ratio (OR) = 1.67]. The proportion of children producing IL-5 and IL-10 (OR = 10.76) was significantly greater in households that had never had a sewage system (p < 0.05, trend test).
These data provide evidence for the profound effects of environmental exposures in early life as well as immune homeostasis in later childhood. Decreased hygiene (lack of access to clean drinking water and sanitation) in the first 3 years of life is associated with higher spontaneous IL-10 production up to 8 years later in life.
PMCID: PMC2685851  PMID: 19478971
age; breast-feeding; cytokine profile; IL-10; SCAALA; sewage; sex; tap water
7.  Estimating adjusted prevalence ratio in clustered cross-sectional epidemiological data 
Many epidemiologic studies report the odds ratio as a measure of association for cross-sectional studies with common outcomes. In such cases, the prevalence ratios may not be inferred from the estimated odds ratios. This paper overviews the most commonly used procedures to obtain adjusted prevalence ratios and extends the discussion to the analysis of clustered cross-sectional studies.
Prevalence ratios(PR) were estimated using logistic models with random effects. Their 95% confidence intervals were obtained using delta method and clustered bootstrap. The performance of these approaches was evaluated through simulation studies. Using data from two studies with health-related outcomes in children, we discuss the interpretation of the measures of association and their implications.
The results from data analysis highlighted major differences between estimated OR and PR. Results from simulation studies indicate an improved performance of delta method compared to bootstrap when there are small number of clusters.
We recommend the use of logistic model with random effects for analysis of clustered data. The choice of method to estimate confidence intervals for PR (delta or bootstrap method) should be based on study design.
PMCID: PMC2625349  PMID: 19087281
8.  Adolescents with metabolic syndrome have a history of low aerobic fitness and physical activity levels 
Metabolic syndrome (MS) is a clustering of cardiovascular disease risk factors that identifies individuals with the highest risk for heart disease. Two factors that may influence the MS are physical activity and aerobic fitness. This study determined if adolescent with the MS had low levels of aerobic fitness and physical activity as children.
This longitudinal, exploratory study had 389 participants: 51% girls, 84% Caucasian, 12% African American, 1% Hispanic, and 3% other races, from the State of North Carolina. Habitual physical activity (PA survey), aerobic fitness (VO2max), body mass index (BMI), blood pressure, and lipids obtained at 7–10 y of age were compared to their results obtained 7 y later at ages 14–17 y.
Eighteen adolescents (4.6%) developed 3 or more characteristics of the MS. Logistic regression, adjusting for BMI percentile, blood pressure, and cholesterol levels, found that adolescents with the MS were 6.08 (95%CI = 1.18–60.08) times more likely to have low aerobic fitness as children and 5.16 (95%CI = 1.06–49.66) times more likely to have low PA levels.
Low levels of childhood physical activity and aerobic fitness are associated with the presence of the metabolic syndrome in adolescents. Thus, efforts need to begin early in childhood to increase exercise.
PMCID: PMC2358885  PMID: 18394155

Results 1-8 (8)