Biomedical subjects

J E Connett

Publications and source records attributed to J E Connett.

At least 19 recordsLinked to original sources

PubMed2006

Tumour necrosis factor and lymphotoxin A polymorphisms and lung function in smokers.

Genetic variants in the tumour necrosis factor (TNF) gene have been investigated in chronic obstructive pulmonary disease (COPD). However, there are many instances of nonreplication of these associations due to insufficient power or other factors. In this study, a large number of subjects were examined to elucidate whether genetic variations of TNF and/or lymphotoxin A (LTA), which is clustered with TNF, are associated with variations in lung function among smokers. The present authors designed two nested case-control studies in the National Heart, Lung, and Blood Institute Lung Health Study (LHS), which enrolled 5,887 smokers. The first design included continuous smokers who had the fastest (n = 279) and the slowest (n = 304) decline of lung function during the 5-yr follow-up period, and the second included the subjects who had the lowest (n = 533) and the highest (n = 532) post-bronchodilator % predicted forced expiratory volume in one second at the start of the LHS. Within the TNF and LTA region, 10 tagging single-nucleotide polymorphisms were selected and genotyped. Unlike the previous associations between TNF-308 and COPD in Asians, the current study found no association between either of the two phenotypes and the LTA and TNF polymorphisms. In conclusion, these results support the findings of previous studies in late-onset chronic obstructive pulmonary disease in Caucasian populations.

Case-Control Studies↗

PubMed2006

C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease.

BACKGROUND: Although C-reactive protein (CRP) levels are increased in chronic obstructive pulmonary disease (COPD), it is not certain whether they are associated with adverse clinical outcomes. METHODS: Serum CRP levels were measured in 4803 participants in the Lung Health Study with mild to moderate COPD. The risk of all-cause and disease specific causes of mortality was determined as well as cardiovascular event rates, adjusting for important covariates such as age, sex, cigarette smoking, and lung function. Cardiovascular events were defined as death from coronary heart disease or stroke, or non-fatal myocardial infarction or stroke requiring admission to hospital. RESULTS: CRP levels were associated with all-cause, cardiovascular, and cancer specific causes of mortality. Individuals in the highest quintile of CRP had a relative risk (RR) for all-cause mortality of 1.79 (95% confidence interval (CI) 1.25 to 2.56) compared with those in the lowest quintile of CRP. For cardiovascular events and cancer deaths the corresponding RRs were 1.51 (95% CI 1.20 to 1.90) and 1.85 (95% CI 1.10 to 3.13), respectively. CRP levels were also associated with an accelerated decline in forced expiratory volume in 1 second (p < 0.001). The discriminative property of CRP was greatest during the first year of measurement and decayed over time. Comparing the highest and lowest CRP quintiles, the RR was 4.03 (95% CI 1.23 to 13.21) for 1 year mortality, 3.30 (95% CI 1.38 to 7.86) for 2 year mortality, and 1.82 (95% CI 1.22 to 2.68) for > or =5 year mortality. CONCLUSIONS: CRP measurements provide incremental prognostic information beyond that achieved by traditional markers of prognosis in patients with mild to moderate COPD, and may enable more accurate detection of patients at a high risk of mortality.

Adult↗

PubMed2005

Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease.

BACKGROUND: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown. METHODS: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality. RESULTS: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93). CONCLUSIONS: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2-3 years.

Administration, Inhalation↗

PubMed2005

Smoking reduction and the rate of decline in FEV(1): results from the Lung Health Study.

Previous findings from the Lung Health Study have shown that smoking cessation and sustained abstinence substantially reduce the rate of decline in forced expiratory volume (FEV(1)) among smokers with early chronic obstructive pulmonary disease (COPD) when compared with continuing smoking. Intermittent quitters demonstrated rates of FEV(1) decline intermediate between those of sustained quitters and continuing smokers. In this study, data from 1,980 participants were analysed from 10 centres of the Lung Health Study in the USA and Canada. All participants were smokers with mild-to-moderate COPD who were unable to quit smoking at any time during the 1st yr of the study. No linear relationship was found between reduction in cigarettes per day and changes in FEV(1) during the 1st yr of the study. However, examination of the data revealed that this relationship was nonlinear. Further analysis found that smokers who reduced their cigarettes per day to very low amounts had smaller declines in FEV(1) than those who did not. Reduction in cigarettes per day was associated with only minimal changes in the presence of chronic respiratory symptoms. In conclusion, compensatory changes in smoking behaviour may account for the limited and unpredictable impact of smoking reduction on lung function decline and symptom prevalence when compared with smoking cessation.

Administration, Inhalation↗

PubMed2005

Bronchodilator response in the lung health study over 11 yrs.

Long-term changes in bronchodilator response in people with mild chronic obstructive pulmonary disease were assessed in this study. Changes in forced expiratory volume in one second (FEV1) in response to isoproterenol was measured in 4,194 participants in the Lung Health Study annually for 5 yrs, and again 11 yrs after study entry. Responses were quantitated in terms of mL (absolute), as per cent of the pre-bronchodilator value (relative), and as a per cent of the predicted normal value (% predicted). At baseline, the mean pre-bronchodilator FEV1 was 75.4% predicted, and responses were small. Relative and percentage predicted responses were similar in males and females; and correlated positively with methacholine reactivity, and negatively with smoking intensity and age. Baseline bronchodilator responses did not correlate with subsequent decline in FEV1. There was a substantial increase in response over the first year of the study, largely due to smoking cessation, with larger increases in those who stopped smoking. After the first year absolute responses changed little in those who maintained smoking cessation, but increased in those who did not. Mean relative and percentage predicted responses increased in all participants throughout the study. There was substantial annual variability of absolute response, and it was poorly reproducible in individual participants. In conclusion, smoking cessation increased bronchodilator response, and response did not predict the rate of decline of forced expiratory volume in one second.

Administration, Inhalation↗

PubMed2003

Polymorphisms in the beta2 adrenergic receptor and bronchodilator response, bronchial hyperresponsiveness, and rate of decline in lung function in smokers.

BACKGROUND: Non-specific bronchial hyperresponsiveness (NSBH) is a known predictor of accelerated rate of decline in lung function in smokers. Polymorphisms of the beta(2) adrenergic receptor (ADRB2) have previously been associated with NSBH and bronchodilator response (BDR) in asthmatics. Based on these associations, we hypothesised that ADRB2 polymorphisms would be associated with NSBH and BDR as well as an accelerated rate of decline in lung function among smokers. METHODS: The prevalence of two ADRB2 polymorphisms, Arg16-->Gly and Gln27-->Glu, was examined in 587 smokers chosen from the NHLBI Lung Health Study for having the fastest (n=282) and slowest (n=305) 5 year rate of decline in forced expiratory volume in 1 second (FEV(1); mean DeltaFEV(1) -4.14 and +1.08% predicted/year, respectively). RESULTS: Contrary to our hypothesis, no ADRB2 allele or haplotype was associated with NSBH, BDR, or rate of decline in lung function. However, there was a significant negative association between heterozygosity at position 27 and a fast decline in lung function (adjusted odds ratio 0.56, 95% CI 0.40 to 0.78, p=0.0007). CONCLUSIONS: Heterozygosity at position 27 may be protective against an accelerated rate of decline in lung function. The polymorphism at position 16 does not contribute to the rate of decline in lung function, measures of NSBH, or BDR in smokers.

Administration, Inhalation↗

PubMed2003

Lack of association of group specific component haplotypes with lung function in smokers.

BACKGROUND: Airway inflammation may affect the decrease in lung function that occurs in response to cigarette smoke, and is an important pathological feature in chronic obstructive pulmonary disease (COPD). Group specific component (GC) can act as an inflammatory mediator and may therefore have important influences on the inflammatory reaction in the airway. Several reports have described associations between GC haplotypes and COPD but these remain controversial. In addition, most of these studies were based on a small number of subjects. METHODS: We have studied the contribution of GC haplotypes to the level of lung function in a large cohort of smokers with high or low lung function (mean FEV(1) % predicted 91.8 and 62.6, respectively). The frequency of the three major GC haplotypes (1S, 1F and 2) was investigated in 537 individuals with high lung function and 533 with low lung function. RESULTS: No significant difference was found in the frequency of any GC haplotype between the high and low lung function groups. There was also no significant difference between the groups in genotype frequency of the two single nucleotide polymorphisms that underlie the haplotypes. CONCLUSION: The GC haplotype does not contribute to reduced lung function in this cohort of smokers.

Adult↗

PubMed2002

The FEV1/FEV6 predicts lung function decline in adult smokers.

The use of FEV1/FEV6 in place of the traditional FEV1/FVC to detect airways obstruction during spirometry testing performed by primary care providers would reduce time and patient effort. We hypothesized that the FEV1/FEV6, would predict the subsequent decline in FEV1 in adult cigarette smokers who enrolled in the multicenter Lung Health Study. Ten clinical centers in the U.S. and Canada recruited 5887 male and female smokers, aged 35-60 years, with borderline to mild airways obstruction by spirometry. Those who successfully stopped smoking during the 5-yr study (usually as the result of the smoking cessation intervention) were excluded from this analysis. In those continuing to smoke, the relative strength of spirometric predictors of the change in FEV1 during 5 years of follow-up (DFEV1) was determined using a linear regression model. The following covariates were significant independent predictors of DFEV1: the baseline degree of airways obstruction, age, gender, cigarettes per day, years of education, and bronchial hyperresponsiveness. The FEV1/FEV6 was nearly as strong an independent predictor as was the FEV1/FVC (a traditional index of airways obstruction). The degree of airways obstruction, as determined by the FEV1/FEV6 from spirometry, is an independent predictor of subsequent decline in lung function; and therefore, may be used to detect smokers at higher risk of developing COPD.

Adult↗

PubMed2001

Graphical model checking with correlated response data.

Correlated response data arise often in biomedical studies. The generalized estimation equation (GEE) approach is widely used in regression analysis for such data. However, there are few methods available to check the adequacy of regression models in GEE. In this paper, a graphical method is proposed based on Cook and Weisberg's marginal model plot. A bootstrap method is applied to obtain the reference band to assess statistical uncertainties in comparing two marginal mean functions. We also propose using the generalized additive model (GAM) in a similar fashion. The proposed two methods are easy to implement by taking advantage of existing smoothing and GAM softwares for independent data. The usefulness of the methodology is demonstrated through application to a correlated binary data set drawn from a clinical trial, the Lung Health Study.

Adult↗

PubMed2001

Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study.

We analyzed Lung Health Study (LHS) data to assess the effect of self-reported lower respiratory illnesses resulting in physician visits (LRI) on lung function. Participants were 5,887 smokers aged 35-60 yr, FEV(1)/FVC < 0.70 and FEV(1) of 55-90% predicted. Two-thirds were randomized into an intensive smoking cessation program (SI); one-third were advised only to stop smoking (UC). For 5 yr participants had annual spirometry and questioning regarding LRI. SI had greater rates of smoking cessation than usual care (UC) with fewer LRI (p = 0.0008). Sustained quitters had fewer LRI than continuing smokers (p = 0.0003). In the year LRI occurred, FEV(1) did not change in sustained quitters, but decreased significantly in smokers (p = 0.0001) with some recovery the following year if no LRI occurred. Over 5 yr, LRI had a significant effect on rate of decline of FEV(1) only in smokers. In smokers averaging one LRI/yr over 5 yr there were additional declines in FEV(1) of 7 ml /yr (p = 0.001). Smokers with more than one LRI/yr had greater declines. Chronic bronchitis was associated with increased frequencies of LRI, but did not affect their influence on lung function. Smoking and LRI had an interactive effect on FEV(1) in people with mild COPD, and in smokers frequent LRI may influence the long-term course of the disease.

Adult↗

PubMed2001

A multiple imputation approach to linear regression with clustered censored data.

We extend Wei and Tanner's (1991) multiple imputation approach in semi-parametric linear regression for univariate censored data to clustered censored data. The main idea is to iterate the following two steps: 1) using the data augmentation to impute for censored failure times; 2) fitting a linear model with imputed complete data, which takes into consideration of clustering among failure times. In particular, we propose using the generalized estimating equations (GEE) or a linear mixed-effects model to implement the second step. Through simulation studies our proposal compares favorably to the independence approach (Lee et al., 1993), which ignores the within-cluster correlation in estimating the regression coefficient. Our proposal is easy to implement by using existing softwares.

Algorithms↗

PubMed2001

Experience of Black participants in the Lung Health Study smoking cessation intervention program.

This paper evaluates the hypothesis that Black smokers will respond differently than Whites to a smoking cessation intervention program where no adjustments are made in recognition of cultural differences. The responses of Black smokers who were recruited into the Lung Health Study (LHS) to the smoking cessation intervention are described. Black quit rates are compared with those of Whites. The LHS enrolled 5887 men and women smokers, aged 35-60 years, of whom 3923 were randomized to a group cessation intervention and 1964 to usual care. Blacks and Whites from six clinics who had complete covariate data (200 Blacks and 2868 Whites) were compared on baseline smoking characteristics and subsequent smoking cessation outcomes. Logistic models were constructed to adjust for baseline smoking variables and demographic characteristics to evaluate the effect of treatment group on smoking cessation among Blacks and Whites. At baseline, Blacks reported smoking fewer cigarettes than Whites, but had higher mean levels of salivary cotinine. The adjusted odds ratio of quitting at 1 year for the smoking intervention group vs. the usual care group was 1.48 for Blacks and 5.99 for Whites. This difference between Blacks and Whites was highly significant (p = 0.002). Across 5 years, the adjusted odds ratios of quitting were 1.87 for Blacks and 3.34 for Whites (p = 0.06). Although the treatment effect was stronger for Whites than for Blacks, over the 5 years of the study there was a significant treatment effect for Blacks. Indicators of physical dependence on nicotine at baseline were inconsistent in indicating whether Blacks were more dependent. We conclude that Blacks and Whites differed significantly in their response to the LHS group smoking intervention program.

Adult↗

PubMed2001

Association of IL-1beta and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers.

BACKGROUND: There is increasing evidence that the cytokine network is central to the immunopathology of inflammatory airway diseases. The interleukin 1 (IL-1) receptor antagonist (IL-1RN) is a naturally occurring anti-inflammatory agent that binds to the IL-1 receptor but does not possess agonist activity. Each of the genes of the IL-1 locus on chromosome 2q14 is polymorphic. The IL1RN gene contains an 86 bp tandem repeat and allele 2 of this polymorphism has been associated with various inflammatory diseases. The IL-1beta (IL1B) gene contains a promoter polymorphism (C-511T) that has been associated with inflammatory diseases and is in linkage disequilibrium with the IL1RN polymorphism. METHODS: We investigated whether polymorphisms in the IL1B and IL1RN genes were associated with rate of decline of lung function. Genotypes were determined in 284 smokers with a rapid decline in lung function and 306 smokers with no decline in lung function. RESULTS: None of the genotypes was associated with the rate of decline of lung function. However, the distribution of IL1B/IL1RN haplotypes was different between smokers with a rapid decline in lung function and those with no decline in lung function (p=0.0005). CONCLUSION: These results suggest that IL1B/IL1RN haplotypes play a role in the rate of decline in lung function in smokers.

Algorithms↗

PubMed2001

Susceptibility genes for rapid decline of lung function in the lung health study.

The genes that contribute to the genetic susceptibility to chronic obstructive pulmonary disease (COPD) remain largely unknown. We hypothesized that widely divergent rates of decline in lung function in smokers would be a robust phenotype for detection of genes that contribute to COPD severity. We selected 283 rapid decliners (deltaFEV1 = -154 +/- 3 ml/yr) and 308 nondecliners (deltaFEV1 = +15 +/- 2 ml/yr) from among smokers followed for 5 yr in the NHLBI Lung Health Study. Rapid decline of FEV1 was associated with the MZ genotype of the alpha1-antitrypsin gene (odds ratio [OR] = 2.8, p = 0.03). This association was stronger for a combination of a family history of COPD with MZ (OR = 9.7, p = 0.03). These data suggest that the MZ genotype results in an increased rate of decline in lung function and interacts with other familial factors. Haplotype frequencies of the microsomal epoxide hydrolase (mEH) gene were significantly different between rapid decliners and nondecliners (p = 0.03). A combination of a family history of COPD with homozygosity for the His113/His139 mEH haplotype was also associated with rapid decline of lung function (OR = 4.9, p = 0.04). The alpha1-antitrypsin S and 3' polymorphisms, vitamin D-binding protein isoforms, and tumor necrosis factor (TNF-alpha G-308A and TNF-beta A252G) polymorphisms were not associated with rate of decline of lung function.

Adult↗

PubMed2000

Neurodevelopmental follow-up at 36 months' corrected age of preterm infants treated with prophylactic indomethacin.

BACKGROUND: Previous reports have suggested that prophylactic indomethacin decreases cerebral blood flow and may play a role in the development of ischemic brain injury and developmental handicaps. OBJECTIVE: To assess the neurodevelopmental outcome of subjects at 36 months' corrected age (CA) who, as low-birth-weight infants, received prophylactic low-dose indomethacin within the first 24 hours of life to prevent patent ductus arteriosus. SETTING: Newborn intensive care nursery and outpatient follow-up clinic at Children's Hospitals and Clinics of Minneapolis, Minneapolis, Minn. DESIGN: Ninety infants with birth weights of 600 to 1250 g were entered into a prospective, randomized, controlled trial to receive either prophylactic indomethacin, 0.1 mg/kg, or placebo in the first 24 hours and again every 24 hours for 6 doses to prevent patent ductus arteriosus. Nonresponders were treated with standard therapeutic indomethacin or ligation. Neurodevelopmental assessment at approximately 36 months' CA included medical and developmental histories, physical examinations, and developmental testing using the Bayley II Scales of Infant Development on subjects up to 42 months' CA. Subjects were classified as (1) normal, (2) mildly to moderately abnormal, or (3) severely impaired. RESULTS: Forty-two (98%) of 43 subjects who received prophylactic indomethacin survived compared with 46 (98%) of 47 who received placebo. Sixty-six (75%) of 88 survivors were seen for neurodevelopmental assessment at 36 months' CA. This group included 29 (69%) of 42 who received prophylactic indomethacin and 37 (80%) of 46 who received placebo. Twenty-three (79%) of 29 infants in the prophylactic indomethacin group had normal neurodevelopmental assessments at 36 months' CA compared with 26 (70%) of 37 placebo-treated subjects (P = .68). Of 4 significantly impaired subjects treated with prophylactic indomethacin, 1 had spastic diplegia; 1, spastic quadriplegia; 1, cognitive delay; and 1, significant motor delay. Of 8 significantly impaired placebo-treated subjects, 7 had spastic diplegia; 1, microcephaly. CONCLUSION: The use of prophylactic low-dose indomethacin when initiated in the first 24 hours of life in low-birth-weight infants to prevent patent ductus arteriosus is not associated with adverse neurodevelopmental outcome at 36 months' CA.

Cardiovascular Agents↗

PubMed2000

Randomized controlled trial of volume-targeted synchronized ventilation and conventional intermittent mandatory ventilation following initial exogenous surfactant therapy.

We set out to evaluate the impact of volume-targeted synchronized ventilation and conventional intermittent mandatory ventilation (IMV) on the early physiologic response to surfactant replacement therapy in neonates with respiratory distress syndrome (RDS). We hypothesized that volume-targeted, patient-triggered synchronized ventilation would stabilize minute ventilation at a lower respiratory rate than that seen during volume-targeted IMV, and that synchronization would improve oxygenation and decrease variation in measured tidal volume (V(t)). This was a prospective, randomized study of 30 hospitalized neonates with RDS. Infants were randomly assigned to volume-targeted ventilation using IMV (n = 10), synchronized IMV (SIMV; n = 10), or assist/control ventilation (A/C; n = 10) after meeting eligibility requirements and before initial surfactant treatment. Following measurements of arterial blood gases and cardiovascular and respiratory parameters, infants received surfactant. Infants were studied for 6 hr following surfactant treatment. Infants assigned to each mode of ventilation had similar birth weight, gestational age, and Apgar scores at birth, and similar oxygenation indices at randomization. Three patients were eliminated from final data analysis because of exclusionary conditions unknown at randomization. Oxygenation improved significantly following surfactant therapy in all groups by 1 hr after surfactant treatment (P < 0.05). No further improvements occurred with time. Total respiratory rate was lowest (P < 0.05) and variation in tidal volume (V(t)) was least in the A/C group (P < 0. 05). Minute ventilation (V(')(E)), delivered airway pressures, respiratory system mechanics, and hemodynamic parameters were similar in all groups. We conclude that volume-targeted A/C ventilation resulted in more consistent tidal volumes at lower total respiratory rates than IMV or SIMV. Oxygenation and lung mechanics were not altered by synchronization, possibly due to the volume-targeting strategy. Of the modes studied, A/C, a fully-synchronized mode, may be the most efficient method of mechanical ventilator support in neonates receiving surfactant for treatment of RDS.

Blood Gas Analysis↗

PubMed2000

Characteristics of participants who stop smoking and sustain abstinence for 1 and 5 years in the Lung Health Study.

BACKGROUND: This study describes baseline and Year 1 predictors of abstinence from smoking for the 3,523 intervention participants who had complete annual 5-year follow-up data in the Lung Health Study (LHS). METHODS: The LHS enrolled 5,887 smokers, aged 35 to 60 years, of whom 3,923 were offered a cessation intervention. Of these, 22% achieved biochemically verified abstinence for 5 years. Logistic regressions were performed. The first outcome variable was abstinence from smoking at 1 year. Then for those who were quit at 1 year, the outcome variable was 5 years of sustained abstinence. RESULTS: All participants who were not using nicotine gum after 1 year in the study were more likely to sustain cessation over 5 years than were gum users at year 1 (OR ranged from 0.31 to 0.44 for four age- and sex-specific groups). Baseline number of previous quit attempts was negatively associated with 5-year quitting success among younger and older men (OR = 0.82 and 0.83). Older participants who were less likely to associate smoking with emotional coping had higher abstinence rates at 5 years of follow-up (OR = 0.89 and 0.84). CONCLUSIONS: Different mechanisms may be responsible for achieving cessation in age/gender groups. These results have implications for planning successful interventions.

Adult↗

PubMed2000

Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease. The Lung Health Study.

Previous studies of lung function in relation to smoking cessation have not adequately quantified the long-term benefit of smoking cessation, nor established the predictive value of characteristics such as airway hyperresponsiveness. In a prospective randomized clinical trial at 10 North American medical centers, we studied 3, 926 smokers with mild-to-moderate airway obstruction (3,818 with analyzable results; mean age at entry, 48.5 yr; 36% women) randomized to one of two smoking cessation groups or to a nonintervention group. We measured lung function annually for 5 yr. Participants who stopped smoking experienced an improvement in FEV(1) in the year after quitting (an average of 47 ml or 2%). The subsequent rate of decline in FEV(1) among sustained quitters was half the rate among continuing smokers, 31 +/- 48 versus 62 +/- 55 ml (mean +/- SD), comparable to that of never-smokers. Predictors of change in lung function included responsiveness to beta-agonist, baseline FEV(1), methacholine reactivity, age, sex, race, and baseline smoking rate. Respiratory symptoms were not predictive of changes in lung function. Smokers with airflow obstruction benefit from quitting despite previous heavy smoking, advanced age, poor baseline lung function, or airway hyperresponsiveness.

Adult↗