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Biomedical subjects

Vernon M Chinchilli

Publications and source records attributed to Vernon M Chinchilli.

At least 37 records · Page 2Linked to original sources
PubMed2005

Statistical issues in clinical trials that involve the double-blind, placebo-controlled food challenge.

The double-blind, placebo-controlled food challenge is a rigorous tool that has become popular for evaluating adverse reactions to foods. The standard use of the double-blind, placebo-controlled food challenge has been to document food allergies for individual patients, but it recently has been gaining acceptance as a procedure for investigating the effectiveness of therapies to prevent/minimize food-induced anaphylaxis. The purpose of this study was to describe the statistical design and analysis issues for clinical trials that use the double-blind, placebo-controlled food challenge in measuring sensitivity to food allergens. Nonparametric tests for within-group and between-group comparisons are described, as well as a discrete-time survival analysis. The statistical methods are applied to simulated data from a clinical trial that compares control therapy and experimental therapy groups. The results indicate that the experimental therapy is significantly better than control in improving the tolerance to peanut flour in patients with peanut allergy. Although simple nonparametric tests for within-group and between-group comparisons are easy to apply, a discrete-time survival analysis provides the best approach because of its flexibility in accounting for important independent variables (regressors) and longitudinal data. Statistical software packages can be adapted to perform such analyses.

Anaphylaxis↗
PubMed2005

Association of criteria pollutants with plasma hemostatic/inflammatory markers: a population-based study.

To elucidate the health effects of air pollution, the short-term association of criteria pollutants (particles <10 microm in diameter [PM(10)], O(3), CO, NO(2), and SO(2)) with hemostatic and inflammatory markers were examined using a population-based sample of 10,208 middle-age males and females of the biracial cohort of Atherosclerosis Risk in Communities (ARIC) study. For each participant, we calculated the following pollutant exposures 1-3 days prior to the randomly allocated cohort examination date: PM(10), CO, NO(2), and SO(2) as 24-h averages, and O(3) as an 8-h average of the hourly measures. The hemostatic/inflammatory factors included fibrinogen, factor VIII-C, von Willebrand factor (vWF), albumin, and white blood cell count (WBC). Linear regression models were used to adjust for cardiovascular disease (CVD) risk factors, demographic and socioeconomic variables, and relevant meteorological variables. One standard deviation (SD) increment of PM(10) (12.8 microg/m(3)) was significantly (P < 0.05) associated with 3.93% higher of vWF among diabetics and 0.006 g/dl lower of serum albumin among persons with a history of CVD. One SD increment of CO (0.60 p.p.m.) was significantly (P < 0.01) associated with 0.018 g/dl lower of serum albumin. Significant curvilinear associations, indicative of threshold effects, for PM(10) with factor VIII-C, O(3) with fibrinogen and vWF, and SO(2) with factor VIII-C, WBC, and serum albumin were found. This population-based study suggest that the hemostasis/inmflammation markers analyzed, which are linked to higher risk of CHD, are associated adversely with environmentally relevant ambient pollutants, with the strongest associations in the upper range of the pollutant distributions, and in persons with a positive history of diabetes and CHD.

Air Pollutants↗
PubMed2005

Alternatives for measuring endogenous adrenocortical activity in asthmatics treated with inhaled corticosteroids.

We compared a 12-hour, hourly integrated plasma cortisol profile in asthmatics treated with a corticosteroids with a variety of modified methods based on less frequent blood sampling. Excellent agreement with the reference was observed for sampling at 10 p.m. and 8 a.m. (correlation coefficient of 0.97; 95 % confidence interval 0.97, 0.98); at 9 p.m. and 7 a.m. (r = 0. 95; 0. 94, 0.96); at 11 p.m. and 7 a.m. (r = 0.94; 0.93, 0.95); every 2 hours (r = 0. 96; 0.96, 0.97); and every 3 hours (r = 0. 91, 0.91, 0.93). The two-sample alternatives (10 p.m/8 a.m. and 9 p.m/7 a.m.) are accurate, as well as more convenient, economical, and practical.

Administration, Inhalation↗
PubMed2004

Bayesian inference for randomized clinical trials with treatment failures.

During the course of a clinical trial, subjects may experience treatment failure. For ethical reasons, it is necessary to administer emergency or rescue medications for such subjects. However, the rescue medications may bias the set of response measurements. This bias is of particular concern if a subject has been randomized to the control group, and the rescue medications improve the subject's condition. The standard approach to analysing data from a clinical trial is to perform an intent-to-treat (ITT) analysis, wherein the data are analysed according to treatment randomization. Supplementary analyses may be performed in addition to the ITT analysis to account for the effect of treatment failures and rescue medications. A Bayesian, counterfactual approach, which uses the data augmentation (DA) algorithm, is proposed for supplemental analysis. A simulation study is conducted to compare the operating characteristics of this procedure with a likelihood-based, counterfactual approach based on the EM algorithm. An example from the Asthma Clinical Research Network (ACRN) is used to illustrate the Bayesian procedure.

Algorithms↗
PubMed2004

Association of higher levels of ambient criteria pollutants with impaired cardiac autonomic control: a population-based study.

An association between air pollution and increased cardiovascular disease (CVD) mortality has been reported, but underlying mechanisms are unknown. The authors examined short-term associations between ambient pollutants (particulate matter less than 10 microm in aerodynamic diameter (PM10), ozone, carbon monoxide, nitrogen dioxide, and sulfur dioxide) and cardiac autonomic control using data from the fourth cohort examination (1996-1998) of the population-based Atherosclerosis Risk in Communities Study. For each participant, the authors calculated PM10 and gaseous pollutant exposures as 24-hour averages and ozone exposure as an 8-hour average 1 day prior to the randomly allocated examination date. They calculated 5-minute heart rate variability indices and used logarithmically transformed data on high-frequency (0.15-0.40 Hz) and low-frequency (0.04-0.15 Hz) power, standard deviation of normal R-R intervals, and mean heart rate. Linear regression was used to adjust for CVD risk factors and demographic, socioeconomic, and meteorologic variables. Regression coefficients for a one-standard-deviation increase in PM10 (11.5 microg/m3) were -0.06 ms2 (standard error (SE), 0.018), -1.03 ms (SE, 0.31), and 0.32 beats/minute (SE, 0.158) for log-transformed high-frequency power, standard deviation of normal R-R intervals, and heart rate, respectively. Similar results were found for gaseous pollutants. These cross-sectional findings suggest that higher ambient pollutant concentrations are associated with lower cardiac autonomic control, especially among persons with existing CVD, and highlight a putative mechanism through which air pollution is associated with CVD.

Air Pollutants↗
PubMed2004

The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network.

Pediatric asthma remains an important public health concern as its prevalence and cost to the health care system is rising. In order to promote innovative research in asthma therapies, the National Heart, Lung and Blood Institute created the Childhood Asthma Research and Education Network in 1999. As its first study, the steering committee of the Childhood Asthma Research and Education Network designed a randomized clinical trial to determine if persistent asthma could be prevented in children at a high risk to develop the disease. This communication presents the design of its first clinical trial, the Prevention of Asthma in Kids (PEAK) trial and the organization of the Childhood Asthma Research and Education Network that developed and implemented this trial. Studies of the natural history of asthma have shown that, in persistent asthma, the initial asthma-like symptoms and loss of lung function occur predominately during the first years of life. Therefore, in the Prevention of Asthma in Kids study, children 2 and 3 years old with a positive asthma predictive index were randomized to twice daily treatment with fluticasone 88 microg or placebo via metered-dose inhaler and Aerochamber for 2 years. The double blind treatment period was followed by a 1-year observational period. Lung function was measured by spirometry and oscillometry technique at 4-month intervals throughout the study. Bronchodilator reversibility and exhaled nitric oxide (ENO) studies were performed at the end of the treatment and observation periods. The primary outcome measure was the number of asthma-free days. Other secondary outcomes included number of exacerbations, use of asthma medications and lung function. These measures were chosen to reflect the progression of the disease from intermittent wheezing to persistent asthma and measurement of the extent of airflow limitation and airway reactivity.

Administration, Inhalation↗
PubMed2004

Head injury and pulmonary embolism: a retrospective report based on the Pennsylvania Trauma Outcomes study.

OBJECTIVE: We retrospectively examined the database of the Pennsylvania Trauma Systems Foundation to determine the risk of pulmonary embolism in adult patients sustaining isolated head trauma or multiple injuries, including head trauma, to answer two questions: What is the incidence of symptomatic pulmonary embolism during hospitalization in a trauma center in patients who have sustained a head injury? Are patients with head injuries more at risk for pulmonary embolism than trauma patients without head injuries? METHODS: We determined the total number of adult submissions per year to the Pennsylvania Trauma Outcomes Study from 1992 to 1996. Age, sex, Glasgow Coma Scale score, Abbreviated Injury Score for head injury, Injury Severity Score, intensive care unit days, hospital days, and the presence or absence of head injury, spinal injury, pelvic fractures, and/or femur fractures were recorded. Statistical techniques to evaluate their correlation with the incidence of pulmonary embolism included chi(2) testing, linear regression analysis, Kendall analysis, and logistic regression analysis. RESULTS: The average incidence of symptomatic pulmonary embolism in head-injured patients occurring during their acute hospital stay was 0.38%. This rate was not significantly greater than the 0.27% incidence of pulmonary embolism in patients without head injury. Factors that significantly increased this incidence were age greater than 45 years, Injury Severity Score greater than 15, male sex, and the presence of pelvic or femur fractures or of spinal cord injury. CONCLUSION: We found no evidence that head injury is a significant independent risk factor for development of symptomatic pulmonary embolism during the acute hospitalization of the trauma patient.

Abbreviated Injury Scale↗
PubMed2004

Neutralizing antibody against interleukin-6 attenuates posthemorrhagic vasospasm in the rat femoral artery model.

OBJECTIVE: The degree to which inflammation contributes to the development of posthemorrhagic vasospasm is controversial. In the present study, we investigated the relationship between various inflammatory cytokines (tumor necrosis factor-alpha, interleukin [IL]-1alpha, IL-1beta, and IL-6) and the development of experimental vasospasm. METHODS: Posthemorrhagic vasospasm was produced in the rat femoral artery model. A latex pouch was placed around each femoral artery, and one pouch was injected with autologous blood and the other with saline as an internal control. Animals were killed at various time points (1 h to 16 d) after surgery (blood exposure), and the degree of vasospasm was assessed by image analysis of artery cross sectional area. Levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay, and the ability of a polyclonal antibody against rat IL-6 to inhibit vasospasm was tested. RESULTS: The rat femoral artery model produced a biphasic vasospasm response, with maximal chronic delayed vasospasm occurring at 8 days after hemorrhage. Enzyme-linked immunosorbent assay revealed a significant increase in IL-6 concentrations in blood-exposed arteries relative to saline-exposed arteries at multiple time points (6, 12, 24, and 48 h) after hemorrhage (P < 0.0001). A relative increase in IL-1alpha levels was noted at 24 hours (P < 0.01). IL-1beta levels were similarly elevated in both blood- and saline-exposed arteries, and tumor necrosis factor-alpha levels were not detectable. Administration of a neutralizing polyclonal antibody against rat IL-6 directly into the blood-exposed periarterial pouch at the time of initial surgery resulted in a dose-dependent reduction in the degree of vasospasm compared with vehicle-treated controls at 8 days after hemorrhage (P < 0.05). CONCLUSIONS: These results indicate that cytokine-mediated inflammation is active in the setting of posthemorrhagic vasospasm produced by the rat femoral artery model. In particular, the profound increase in IL-6 levels after exposure to hemorrhage and the ability of a polyclonal antibody against IL-6 to reduce vasospasm suggest that IL-6 may play a prominent role in the development of vasospasm in this model.

Animals↗
PubMed2003

Titrating and evaluating multi-drug regimens within subjects.

The dosing of combination therapies is commonly undertaken empirically by practising physicians, and a coherent algorithm to approach the problem of combination dosing is currently lacking. Current methods of evaluating multiple drug combinations in clinical trials fail to provide information regarding the location of more effective doses when the combination is not found to differ from the standard, even though the absence of a difference does not necessarily mean the new combination is ineffective. Moreover, in studies where the new combination is found more effective, often a large proportion of the study participants obtain no benefit from the trial. Even with early stopping rules, the time these subjects spend on inferior treatments can have lasting detrimental effects, leading to problems with patient enrolment and adherence to study protocol. This paper describes an evolutionary operation (EVOP) direct-search procedure to titrate combination doses within individual patients. The Nelder-Mead simplex direct-search algorithm is used to titrate combinations of drugs within individual subjects. Desirability functions are utilized to define the main response of interest and additional responses or constraints. Statistical methodology for determining whether the titrated treatment combination has resulted in an improvement in subject response and for evaluating for therapeutic synergism is developed. Inferences can then be made about the efficacy of the combination or about the individual drugs that comprise the combination. The advantages of this approach include affording every patient the potential to benefit from the combination under study and permitting the consideration of multiple endpoints simultaneously.

Algorithms↗
PubMed2003

Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children.

BACKGROUND: Exhaled nitric oxide (eNO) is a noninvasive test that measures airway inflammation. Insufficient information is available concerning correlations between eNO and biologic, physiologic, and clinical characteristics of asthma in children currently not taking controller medications. OBJECTIVE: The aim of this study was to find correlations between eNO and other characteristics of children with mild to moderate asthma currently not taking medications. METHODS: Children aged 6 to 17 years with mild to moderate persistent asthma, taking only albuterol as needed, were characterized during 2 visits 1 week apart before being randomly assigned into a clinical trial. At the screening visit, online measurements of eNO, spirometry before and after bronchodilator, and biomarkers of peripheral blood eosinophils, serum eosinophil cationic protein, total serum IgE, and urinary leukotriene E4 were obtained. During a week characterization period before randomization, symptoms were recorded on a diary and peak expiratory flows were measured twice daily using an electronic device. At the randomization visit, eNO was repeated followed by a methacholine challenge and aeroallergen skin testing. Correlations and rank regression analyses between eNO and clinical characteristics, pulmonary function, and biomarkers were evaluated. RESULTS: eNO was significantly correlated with peripheral blood eosinophils (r =.51, P <.0001), IgE (r =.48, P <.0001), and serum eosinophil cationic protein (r =.31, P =.0003) but not with urinary leukotriene E4 (r =.16, P =.08). A moderate correlation was found between eNO and the number of positive aeroallergen skin tests (r =.45, P <.0001). eNO did not correlate with FEV1% predicted but was weakly correlated with FEV1/forced vital capacity (r = -.19, P =.032), bronchodilator response (r =.20, P =.023), and FEV1 PC20 methacholine (r = -.31, P =.0005). No significant correlations were found between eNO and clinical characteristics or morning or evening peak expiratory flow measurements. The rank regression analysis demonstrated that 5 variables accounted for an R square of.52 (eosinophils [P <.0001], IgE [P =.0023], age [P <.0001], months of inhaled corticosteroid use in the year before study entry [P =.01], and FEV1 PC20 [P =.0061]). CONCLUSIONS: These findings suggest that eNO provides information about the asthmatic state consistent with information from other markers of inflammation. It is a noninvasive technique that could be used in decisional management of children with asthma.

Adolescent↗
PubMed2003

A likelihood-based, counterfactual approach to accounting for treatment failures in clinical trials.

Consider a two-armed, placebo-controlled trial in which subjects may experience treatment failure. For ethical reasons, it is necessary to administer emergency or rescue medications for such subjects. However, the emergency medications may bias the set of response measurements. When analyzing the data from clinical trials, the standard approach is to perform an intent-to-treat (ITT) analysis, wherein the data are analyzed according to treatment assignment. Secondary statistical analyses that supplement the ITT analysis can be performed to account for the impact of treatment failures and emergency medications. A likelihood-based, counterfactual approach to supplemental analyses uses the expectation maximization (EM) algorithm for parameter estimation and a likelihood ratio test to test the equality of the placebo and experimental treatment means for subjects who would not fail under either treatment assignment. A simulation study is performed to assess the operating characteristics of the likelihood ratio test. An example from the Asthma Clinical Research Network (ACRN) is used to draw comparisons between the standard ITT procedure and the developed supplemental analysis.

Clinical Trials as Topic↗
PubMed2003

A case-control study of menstrual factors in relation to breast cancer risk in African-American women.

Menstrual characteristics may serve as surrogate measures of endogenous estrogen and may be related to breast cancer risk. No previous studies have systematically investigated menstrual factors in relation to the disease in African-American women. This case-control study is aimed to assess the relationship between menstrual factors and breast cancer in African-American women. Cases were 304 African-American women, aged 20-64 living in three Tennessee counties, diagnosed with breast cancer between 1995 and 1998. Controls were selected through random-digit dialing and frequency matched to cases (n=305). Phone interviews were conducted on menstrual factors--age at menarche, time to regularity, cycle length, flow length, age at menopause--and other risk factors. Logistic regression showed that compared to women with short cycle length (<28 days), women with average cycle length > or =28 had decreased risk of breast cancer (odds ratio (OR)=0.60, 95% confidence interval (CI), 0.38-0.94). Dose-response analyses showed decreasing risk with longer cycle length. Results by menopausal status revealed an inverse relationship was shown only in postmenopausal women. No significant associations were observed for other menstrual factors. Findings suggest that cycle length has an inverse association with breast cancer in African-American women that may primarily exist for post-menopausal tumors.

Adult↗
PubMed2002

Systemic effect comparisons of six inhaled corticosteroid preparations.

The goal of this study was to establish a reliable method to evaluate systemic bioavailability and to determine equisystemic effects (microgram dose producing equal systemic cortisol suppression) of inhaled corticosteroids (ICS). Steroid naive asthma subjects (n = 156) were enrolled at six centers. A 1-week doubling dose design was used for each of six ICS and matched placebos for a total of four doses. Systemic effect was evaluated by hourly plasma cortisol concentrations (8 P.M. to 8 A.M.), 12- and 24-hour urine cortisol concentrations, and a morning blood osteocalcin. The area under the concentration-time curve for hourly cortisol concentrations was the best outcome variable to assess systemic effect. For the six ICS and matching placebos (beclomethasone-chlorofluorocarbon [CFC], budesonide dry powder inhaler [DPI], fluticasone DPI, fluticasone-CFC metered dose inhaler [MDI], flunisolide-CFC, and triamcinolone-CFC), only the placebo group and fluticasone DPI did not demonstrate a significant dose-response effect. Thus microgram comparison of all ICS could only be performed at a 10% cortisol suppression: flunisolide-CFC - 936; triamcinolone-CFC - 787; beclomethasone-CFC - 548; fluticasone DPI - 445; budesonide DPI - 268; fluticasone-CFC MDI - 111. This study represents the first step in evaluation of ICS efficacy based on equisystemic (cortisol suppression) effects of a given ICS, rather than doses judged arbitrarily to be comparable on a microgram basis.

Administration, Inhalation↗
PubMed2002

Significant variability in response to inhaled corticosteroids for persistent asthma.

BACKGROUND: A clinical model is needed to compare inhaled corticosteroids (ICSs) with respect to efficacy. OBJECTIVE: The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs. METHODS: A 24-week, parallel, open-label, multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma. Benefit was assessed by improvements in FEV(1) and PC(20); risk was assessed by overnight plasma cortisol suppression. Thirty subjects were randomized to either beclomethasone dipropionate (BDP) 168, 672, and 1344 microg/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 microg/day (n = 15), both administered by means of a metered dose inhaler (MDI) with chlorofluorocarbon propellant via a spacer, in 3 consecutive 6-week intervals; this was followed by 3 weeks of FP dry powder inhaler (DPI) 2000 microg/day. RESULTS: Maximum FEV(1) response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI. Near-maximum methacholine PC(20) improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI. Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression. Responsiveness to ICS treatment was found to vary markedly among subjects. Good (>15%) FEV(1) response, in contrast to poor (<5%) response, was found to be associated with high exhaled nitric oxide (median, 17.6 vs 11.1 ppb), high bronchodilator reversibility (25.2% vs 8.8%), and a low FEV(1)/forced vital capacity ratio (0.63 vs 0.73) before treatment. Excellent (>3 doubling dilutions) improvement in PC(20), in contrast to poor (<1 doubling dilution) improvement, was found to be associated with high sputum eosinophil levels (3.4% vs 0.1%) and older age at onset of asthma (age, 20-29 years vs <10 years). CONCLUSIONS: Near-maximal FEV(1) and PC(20) effects occurred with low-medium dose for both ICSs in the subjects studied. High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated, but it did increase the systemic effect measure, overnight cortisol secretion. Significant intersubject variability in response occurred with both ICSs. It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study, such as prevention of asthma exacerbations.

Administration, Inhalation↗
PubMed2002

The effects of sex steroids on spatial performance: a review and an experimental clinical investigation.

Males typically surpass females in spatial performance, an outcome that may be linked to testosterone and estrogen. The authors (a) review physiological mechanisms, developmental periods, and past empirical work relevant to sex steroids' effects on human spatial performance and (b) report an experimental study of the role of actively circulating sex steroids in adolescents being treated for delayed puberty (N = 55; mean age = 13.70 years). Sex steroids (simulating early, middle, and late puberty) and placebos were given alternately over 21 months and spatial tests were given every 3 months. Spatial performance showed traditional sex differences but did not vary with levels of actively circulating sex steroids.

Adolescent↗
PubMed2002

Relationship of serum HER-2/neu and serum CA 15-3 in patients with metastatic breast cancer.

BACKGROUND: Serum HER-2/neu antigen concentrations have been reported to correlate with increased tumor volume in patients with breast cancer. We measured serum CA 15-3, a surrogate marker of disease burden, and correlated serum CA 15-3 with serum HER-2/neu and analyzed the association of both markers with clinical outcomes. METHODS: Pretreatment serum samples from 566 patients were retrospectively analyzed from 2 phase III clinical trials of estrogen receptor-positive (ER(+)), ER(-)/progesterone receptor-positive, or ER status unknown metastatic breast cancer patients randomized in two similar studies to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole). The extracellular domain of the HER-2/neu (c-erbB-2) oncogene and serum CA 15-3 were measured by ELISA on the Bayer Immuno 1. RESULTS: Serum HER-2/neu protein was increased in 168 patients (30%), and CA 15-3 was increased in 337 (60%) patients. Serum CA 15-3 and HER-2/neu were weakly correlated (r = 0.39; P <0.0001). The clinical benefit (complete responses plus partial responses plus stable disease) of endocrine therapy was significantly lower in patients with increased serum HER-2/neu. When adjusted for serum HER-2/neu, serum CA 15-3 was not predictive of response rates. The median time to progression was shorter in patients with increased serum HER-2/neu (89 days) compared with patients with normal serum HER-2/neu (176 days). Survival was significantly shorter in patients with increased serum HER-2/neu (513 vs 869 days; P <0.0001) or increased serum CA 15-3 (689 vs 939 days; P <0.0001). This observation was confirmed by multivariate analysis. CONCLUSIONS: Serum HER-2/neu is a significant independent predictive and prognostic factor in hormone receptor-positive metastatic breast cancer, even when adjusted for tumor burden as measured by CA 15-3. The combination of increased serum HER-2/neu and increased serum CA 15-3 predicts a worse prognosis than does increased CA 15-3 alone.

Adult↗