RESUMO
BACKGROUND: Sample sizes for magnetic resonance imaging (MRI)-based clinical trials in multiple sclerosis (MS) generally assume that lesion counts are reasonably described by the negative binomial (NB) model. OBJECTIVE: This study aimed to assess the appropriateness of the NB model for lesion count data and to provide sample sizes for placebo-controlled, MRI-based clinical trials in relapsing-remitting MS using a more realistic model. METHODS: The fit of the NB model in each arm of five MS clinical trials was assessed using Pearson's chi-squared statistic. Required sample sizes associated with various tests of treatment effect were estimated by simulating data from a new, longitudinal model for repeated lesion count data on individual patients. RESULTS: Evidence (p < 0.05) against the NB model was found in at least one arm of four of the five trials. If a trial is designed using this model but the resulting clinical data do not follow its assumptions then this trial can be seriously under-powered for assessing differences in mean lesion counts. CONCLUSION: Sample sizes based on the longitudinal model are more realistic and often smaller than those previously reported using the NB model.
Assuntos
Encéfalo/patologia , Ensaios Clínicos Controlados como Assunto/estatística & dados numéricos , Imageamento por Ressonância Magnética , Modelos Estatísticos , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Tamanho da Amostra , Distribuição de Qui-Quadrado , Simulação por Computador , Ensaios Clínicos Controlados como Assunto/métodos , Determinação de Ponto Final , Humanos , Estudos Longitudinais , Esclerose Múltipla Recidivante-Remitente/patologia , Esclerose Múltipla Recidivante-Remitente/terapia , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The rate of new contrast-enhancing lesions (CELs) on monthly magnetic resonance imaging (MRI) scans has been shown to decrease over a 9-month period in placebo-treated patients with relapsing-remitting (RR) multiple sclerosis (RRMS). OBJECTIVE: We examined this phenomenon in placebo-treated secondary progressive MS (SPMS) patients. METHODS: Patients were chosen from two clinical trials. Monthly scans were taken at screening, baseline and months 1-9 for Cohort-1 and months 1-6 for Cohort-2. We examined the monthly new CEL rates according to initial CEL level: 0, 1-3, >3 CELs at screening, and presence and absence of pre-study relapses. RESULTS: Respectively, 59, 21 and 14 of the 94 Cohort-1 patients, and 36, 17 and 9 of the 62 Cohort-2 patients had 0, 1-3 and >3 initial CELs. For Cohort-1, the monthly new CEL rates did not change during follow-up, regardless of initial CEL level. For Cohort-2, the monthly rate was unchanged in the 0 initial CEL subgroup, but decreased 33% (95% confidence interval: 8%, 52%) from months 1-3 to months 4-6 in the other two subgroups. For the combined cohorts, a decreasing rate was observed in the 12 patients with >3 initial CELs and pre-study relapses. CONCLUSIONS: The short-term trend of new CEL activity in placebo-treated SPMS patients may vary across cohorts.
Assuntos
Encéfalo/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla Crônica Progressiva/diagnóstico , Adulto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Meios de Contraste , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Efeito Placebo , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de TempoRESUMO
Leukotriene D4 (2 c 10(-9) mole), injected into the left circumflex coronary artery of anesthetized sheep, produced profound coronary vasoconstriction and impaired regional ventricular wall motion. This cardiac effect was neither inhibited by prior treatment of the sheep with a cyclooxygenase inhibitor nor associated with thromboxane B2 release into the coronary sinus. Intravenous FPL 55712 completely abolished the coronary vasoconstriction of leukotriene D4, but a significant reduction of regional wall shortening persisted.
Assuntos
Vasos Coronários/efeitos dos fármacos , SRS-A/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Cromonas/farmacologia , Circulação Coronária/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase , Feminino , Ventrículos do Coração/efeitos dos fármacos , Ibuprofeno/farmacologia , Masculino , Contração Miocárdica/efeitos dos fármacos , Ovinos , Tromboxano B2/metabolismoRESUMO
Six patients with extensive polyostotic Paget's disease were treated for 3 months with dichloromethane diphosphonate (CL2MDP; 1600 mg/day, orally). Serum alkaline phosphatase and urinary hydroxyproline excretion decreased 60-80% in each patient. Blood ionized calcium (ca++) and immunoreactive PTH (iPTH) were measured weekly during the first month of therapy and monthly thereafter. As an index of parathyroid function, PTH secretory reserve was assessed by EDTA infusions before treatment, at the end of treatment, and 3 months after Cl2 MDP therapy was stopped. Before therapy, iPTH and Ca++ were normal in all patients. During treatment, Ca++ decreased and iPTH increased in all patients; mean iPTH approximately doubled (95% confidence limits, 1.5- to 2.7-fold increase). At the end of 3 months of treatment, EDTA infusion raised iPTH in each patient to a level higher than that in the control infusion, indicating augmented PTH secretory reserve. Ca++, iPTH, and the iPTH response to EDTA-induced hypocalcemia returned toward baseline by 3 months after the end of CL2MDP treatment. The results indicate that secondary hyperparathyroidism developed as a result of Cl2MDP therapy. The cause of the parathyroid-gland adaptation is not known; the hyperparathyroidism is, however, at least partly reversible. Cl2MDP inhibits bone resorption while allowing bone mineralization to continue; this differential effect could lead to the hypocalcemia and parathyroid hyperfunction.
Assuntos
Ácido Clodrônico/efeitos adversos , Difosfonatos/efeitos adversos , Hiperparatireoidismo Secundário/induzido quimicamente , Osteíte Deformante/tratamento farmacológico , Idoso , Fosfatase Alcalina/sangue , Cálcio/sangue , Ácido Clodrônico/uso terapêutico , Ácido Edético , Humanos , Hidroxiprolina/urina , Osteíte Deformante/sangue , Hormônio Paratireóideo/sangueRESUMO
OBJECTIVE: To determine the effect of treatment with interferon beta-1b (IFN-beta) on natural killer (NK) cell function and phenotype in relapsing-remitting MS (RRMS) patients, and their relationship to disease activity assessed both clinically and with serial MRI. BACKGROUND: NK cells may play a role in the immunopathogenesis of MS. Previously the authors reported a positive relationship between mean NK cell functional activity (FA) and total number of active lesions on MRI in a serial study of RRMS. Cycles in NK cell FA over time created a series of peaks and valleys, and a significant relationship has been identified between the valleys and the appearance of active lesions on MRI or onset of clinical attacks. The development of valleys in NK cell FA before the appearance of active lesions on MRI was statistically significant. METHODS: The authors studied the effect of alternate-day therapy with 8.0 mIU (high dose [HD]) or 1.6 mIU (low dose [LD]) IFN-beta on NK cell FA, assessed by an in vitro 51Cr release K-562 target cell assay, and phenotype determination in RRMS patients. RESULTS: Treatment with HD IFN-beta results in an inverse relationship between mean NK cell FA and total number of active lesions on MRI over 2 years. A stronger inverse relationship was found in those patients who did not develop neutralizing antibodies to IFN (HD-) compared with a positive relationship in those who did (HD +). Treatment with IFN-beta did not affect the cyclic nature of NK cell FA, mean NK cell FA, variability around the mean, mean length of the cycle, time spent in valleys and peaks, or the significant relationship between the appearance of active lesions on MRI/onset of clinical attacks and valleys in NK cell FA. In contrast, treatment with HD but not LD IFN-beta did result in a significant reduction in CD57+ (a cell surface marker for subsets of NK cells) peripheral blood lymphocytes (PBL) compared with placebo. This effect, which originated largely from the HD- group of patients, developed shortly after treatment was initiated and was maintained throughout the study. CONCLUSIONS: RRMS patients with higher mean NK cell FA may be not only at greater risk for the development of active lesions but also may be more likely to respond to IFN-beta. Development of neutralizing antibodies to IFN-beta could interfere with this effect. This effect may be mediated through an action on a CD57+ subset of PBL.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Indução de Remissão/métodos , Adulto , Método Duplo-Cego , Feminino , Citometria de Fluxo , Humanos , Interferon beta-1a , Interferon beta-1b , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/imunologia , Fenótipo , Proteínas Recombinantes/uso terapêutico , RecidivaRESUMO
A randomized, double-blind, placebo-controlled, noncrossover trial determined the efficacy of lymphoblastoid interferon (IFN) in chronic progressive multiple sclerosis (CP MS). Fifty patients received 5 X 10(6) IU IFN subcutaneously daily for 6 months while 50 received placebo. After 2 years, there were no significant differences between the 2 groups based on clinical evaluations and quantitative MRI analysis of the brain, although a trend was observed in the IFN group. Clinically, the IFN group was worse at 1 and 3 months and improved at 6 to 18 months, when compared with the placebo group. Results of MRI evaluations of the brain at 6 months support this trend. This trend likely resulted from a subpopulation of 10 IFN-treated patients, characterized by a higher women:men ratio and a lower EDSS score at entry into the trial. We cannot recommend lymphoblastoid IFN as treatment for CP MS at this time.
Assuntos
Interferon Tipo I/uso terapêutico , Esclerose Múltipla/terapia , Adulto , Encéfalo/patologia , Método Duplo-Cego , Estudos de Avaliação como Assunto , Feminino , Humanos , Interferon Tipo I/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estatística como AssuntoRESUMO
Seventeen relapsing-remitting (R/R) multiple sclerosis (MS) patients and age/sex matched controls were studied every 6 weeks for 2 years. Disease activity, determined both clinically and by serial MRI, was correlated with natural killer (NK) cell functional activity (FA) and phenotype. Mean NK cell FA is significantly lower in MS patients, compared to controls (P < 0.001), while variability around the means is significantly greater (P < 0.01). The spectrum of mean NK cell FA, observed in the patient cohort, along with cyclical nature of the FA and phenotype over time, observed in both patients and controls, may begin to explain the discrepant results reported in previous studies. In R/R MS, there is a significant correlation between reductions (valleys) in NK cell FA and the development of active lesions on MRI, new (P < 0.001) or enlarging (P = 0.05). More importantly, a significant number of active lesions, new (P = 0.01) and enlarging (P = 0.02), are preceded by a reduction in NK cell FA. The correlation between the onset of clinical attacks and valleys of NK cell FA is also significant (P = 0.002). When taken together, the results suggest that reductions (valleys) in NK cell FA represent periods of susceptibility for the development of active lesions on MRI and clinical attacks. A significant positive correlation is also identified between mean NK cell FA for each R/R MS patient and total number of active MRI lesions developed by that patient over the 2 years (P = 0.001). The results would suggest that R/R MS patients with a higher mean NK cell FA are at greater risk for the development of active lesions. These results support the proposal that NK cells may play a role in the immunopathogenesis of R/R MS.
Assuntos
Células Matadoras Naturais/imunologia , Esclerose Múltipla/etiologia , Esclerose Múltipla/imunologia , Adulto , Radioisótopos de Cromo , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/diagnóstico , RecidivaRESUMO
Arachidonic acid is metabolized to prostaglandins and thromboxane via the cyclooxygenase pathway and to leukotrienes B4, C4, D4, and E4 via the lipooxygenase pathway. A possible role played by leukotrienes in cardiogenic shock resulting from anaphylaxis prompted us to investigate the action of these compounds on coronary vessels and myocardial contractility. In this study leukotriene B4 (LTB4) and C4 (LTC4) were injected directly into the left circumflex (LCx) coronary artery of nine anesthetized Suffolk sheep. LTB4 had no effect on coronary artery blood flow or myocardial contractility, but 3 X 10(-9) mole induced profound transient circulating neutropenia, reflecting the potent chemotactic and chemokinetic properties of this compound. Injecting as little as 1.6 X 10(-11) mole of LTC4 caused a 14.5 +/- 4.3% (mean +/- SE) reduction of LCx coronary artery flow while 1.6 X 10(-10) mole caused a 26.5 +/- 3.7% decrease of LCx coronary artery flow and an 18.1 +/- 3.2% decrease in systolic shortening of the myocardial region supplied by the LCx coronary artery. Since the decrease in systolic shortening was far greater than that expected on the basis of the reduction in coronary artery flow, we postulate that LTC4 has a direct negative inotropic effect. FPL 55712, a receptor antagonist of leukotrienes C4, D4, and E4, blocked the vasoconstriction induced by LTC4 but only partially blocked the negative inotropic effects of LTC4. LTC4 is a potent vasoconstrictor and negative inotropic agent and may play an important role in anaphylactic shock.
Assuntos
Circulação Coronária/efeitos dos fármacos , Leucotrieno B4/farmacologia , Contração Miocárdica/efeitos dos fármacos , SRS-A/farmacologia , Animais , Cateterismo Cardíaco , Cromonas/farmacologia , Relação Dose-Resposta a Droga , Feminino , Técnicas In Vitro , Leucotrieno B4/administração & dosagem , Masculino , Neutropenia/induzido quimicamente , SRS-A/administração & dosagem , SRS-A/antagonistas & inibidores , OvinosRESUMO
The application of rigorous statistical criteria to the design and analysis of in-vitro assay techniques can lead to more reliable assessments of their utility. The authors demonstrate that an objective criterion for in-vitro drug sensitivity would yield less pronounced false-negative error rates than a fixed-cutoff rule, and would therefore be more suitable for screening of putative chemotherapeutic agents.
Assuntos
Ensaio de Unidades Formadoras de Colônias , Modelos Estatísticos , Ensaio Tumoral de Célula-Tronco , Teoria da Decisão , Relação Dose-Resposta a Droga , Reações Falso-Negativas , Humanos , Valor Preditivo dos Testes , ProbabilidadeRESUMO
To examine hypotheses regarding air pollution health effects, we conducted an exploratory study to evaluate relationships between personal and ambient concentrations of particles with measures of cardiopulmonary health in a sample of patients with chronic obstructive pulmonary disease (COPD). Sixteen currently non-smoking COPD patients (mean age=74) residing in Vancouver were equipped with a particle (PM(2.5)) monitor for seven 24-h periods. Subjects underwent ambulatory heart monitoring, had their lung function and blood pressure (BP) measured, and recorded symptoms and medication use. Ambient PM(2.5), PM(10), sulfate, and gaseous pollutant concentrations were monitored at five sites within the study area. Although no associations between air pollution and lung function were statistically significant, an estimated effect of 3% and 1% declines in daily FEV(1) change (DeltaFEV(1)) for each 10 microg/m(3) increase in ambient PM(10) and PM(2.5), respectively, was observed. Increases of 1 microg/m(3) in personal or ambient sulfate were associated with 1.0% and 0.3% declines in DeltaFEV(1), respectively. Weak associations were observed between particle concentrations and increased supraventricular ectopic heartbeats and with decreased systolic BP. No consistent associations were observed between any particle metric and diastolic BP, heart rate, or heart rate variability (r-MSSD or SDNN), symptom severity, or bronchodilator use. Of the pollutants measured, ambient PM(10) was most consistently associated with health parameters; the use of personal exposures did not improve the strength of any associations or lead to increased effect estimates.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Doenças Cardiovasculares/etiologia , Exposição Ambiental , Pneumopatias/etiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Idoso , Pressão Sanguínea , Estudos Epidemiológicos , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Testes de Função Respiratória , Sulfatos/efeitos adversosRESUMO
Mot time-series studies of particulate air pollution and acute health outcomes assess exposure of the study population using fixed-site outdoor measurements. To address the issue of exposure misclassification, we evaluate the relationship between ambient particle concentrations and personal exposures of a population expected to be at risk of particle health effects. Sampling was conducted within the Vancouver metropolitan area during April-September 1998. Sixteen subjects (non-smoking, ages 54-86) with physician-diagnosed chronic obstructive pulmonary disease (COPD) wore personal PM2.5 monitors for seven 24-hr periods, randomly spaced approximately 1.5 weeks apart. Time-activity logs and dwelling characteristics data were also obtained for each subject. Daily 24-hr ambient PM10 and PM2.5 concentrations were measured at five fixed sites spaced throughout the study region. SO4(2-), which is found almost exclusively in the fine particle fraction and which does not have major indoor sources, was measured in all PM2.5 samples as an indicator of accumulation mode particulate matter of ambient origin. The mean personal and ambient PM2.5 concentrations were 18 micrograms/m3 and 11 micrograms/m3, respectively. In analyses relating personal and ambient measurements, ambient concentrations were expressed either as an average of the values obtained from five ambient monitoring sites for each day of personal sampling, or as the concentration obtained at the ambient site closest to each subject's home. The mean personal to ambient concentration ratio of all samples was 1.75 (range = 0.24 to 10.60) for PM2.5, and 0.75 (range = 0.09 to 1.42) for SO4(2-). Regression analyses were conducted for each subject separately and on pooled data. The median correlation (Pearson's r) between personal and average ambient PM2.5 concentrations was 0.48 (range = -0.68 to 0.83). Using SO4(2-) as the exposure metric, the median r between personal and average ambient concentrations was 0.96 (range = 0.66 to 1.0). Use of the closest ambient site did not improve the median correlation of the group for either PM2.5 or SO4(2-). All pooled analyses resulted in lower correlation coefficients than the median correlation coefficient of individual regressions. Personal SO4(2-) was more highly correlated with all ambient measures than PM2.5. Inclusion of time-activity and dwelling characteristics data did not result in a useful predictive regression model for PM2.5 personal exposure, but improved the model fit from simply regressing against ambient concentration (R2 = 0.27). The model for SO4(2-) was predictive (R2 = 0.82), as personal exposures were largely explained by ambient levels. These results indicate a relatively low correlation between personal exposure and ambient PM2.5 that is not improved by assigning exposure to the closest ambient monitor. The correlation between personal exposure and ambient concentration is high, however, when using SO4(2-), an indicator of accumulation mode particulate matter of ambient origin.
Assuntos
Poluição do Ar/efeitos adversos , Pneumopatias Obstrutivas/etiologia , Idoso , Idoso de 80 Anos ou mais , Exposição Ambiental/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
OBJECTIVE: We evaluate variants of a commonly used data safety monitoring guideline in clinical trials in multiple sclerosis (MS) that flags patients who, at a follow-up visit, have 5 or more contrast-enhancing lesions (CELs) above their baseline count. METHODS: We apply the guideline to a relapsing cohort and a secondary progressive cohort. We assess the number of patients that meet the guideline and describe the characteristics of these patients; we also examine the value of the guideline in predicting relapse occurrence in the 28 days following that MRI. These analyses were repeated for thresholds varying from 1 to 10 CELs above baseline. RESULTS: Between 4% and 6% of patients met the threshold of 5 in both cohorts; patients with higher baseline counts and higher T2 lesion burden were more apt to meet the threshold. After adjustment for other covariates, the odds ratio (OR) of relapse associated with meeting the threshold is significant (p < 0.05) or near significant (0.05 ≤ p < 0.10) for thresholds between 5 and 8 for the relapsing cohort, but not for the secondary progressive cohort. Across thresholds, the adjusted OR is consistently greater than 1, and there is an increasing trend as the threshold increases from 1 to 7. CONCLUSIONS: A guideline based on crossing a threshold CEL count above baseline may be valuable in monitoring patient safety. Further study should be conducted using different datasets to assess the generalizability of these results.
Assuntos
Encéfalo/patologia , Esclerose Múltipla/patologia , Segurança do Paciente , Adulto , Progressão da Doença , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
Clinical observations suggested that children long recovered from burn injury required larger doses of thiopental for a smooth anesthetic induction. A prospective randomized study examined children 6-16 yr old, with greater than 15% burn, and more than 1 year after injury, for loss of lid reflex (LR), corneal reflex (CR), and acceptance of the anesthesia mask (AM) 60 sec after administration of thiopental. Children were unpremedicated, received the thiopental (2.5%) through a rapidly running peripheral intravenous line, and received either 2, 3, 4, 5, 6, 7, or 8 mg/kg. LR, CR, and AM were examined at 30, 60, and 90 sec. Blood pressure and heart rate were recorded for those patients receiving 7 or 8 mg/kg thiopental. The mean age was 12.0 +/- 0.5 yr, weight 43.9 +/- 2.9 kg, % burn 44.7 +/- 2.9, time since burn 68.4 +/- 7.7 months, and time since previous thiopental 25.1 +/- 6.6 months. The estimated ED50 (95% confidence limits) for loss of LR was 4.78 (3.95-5.78) mg/kg; for loss of CR was 7.04 (4.87-10.10) mg/kg; and for AM was 6.74 (4.68-9.71) mg/kg. These doses of thiopental were significantly greater for LR and AM (P less than 0.001) but not CR (P = 0.15) compared to non-thermally injured children. There were no clinically important or statistically significant decreases in blood pressure while heart rate did increase 11 beats/min (P less than 0.05) in children who received 7 or 8 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anestesia , Queimaduras/fisiopatologia , Tiopental/administração & dosagem , Adolescente , Piscadela/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Criança , Relação Dose-Resposta a Droga , Pálpebras/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Estudos Prospectivos , Distribuição Aleatória , Reflexo/efeitos dos fármacos , Fatores de TempoRESUMO
Health authorities are often alerted to suspected cancer clusters near the vicinity of potential point sources by members of the public. A surveillance system, where administrative regions around the potential point sources are regularly monitored for high disease rates, would allow for responses which are easier to obtain, timelier, and less expensive than individual thorough investigations. The monitoring could be done by using the so-called 'focused' tests for detecting disease clustering. However, these tests, generally designed to detect clusters of a fixed size around the foci, are not particularly effective when dealing with administrative regions with substantial differences in populations. In this work, an approach which overcomes the problem to a certain extent is described. Here the selected cluster sizes are based on the populations of the administrative regions under examination. The approach is used to investigate whether cancer clustering appears in the vicinity of the pulp and paper mills in British Columbia for the years 1983-1989. The results indicate that the approach performs reasonably well in identifying cancer sites for which elevated risks have also been suggested in the epidemiologic literature. Consequently, this methodology could be utilized to provide guidance for further investigation even in the absence of local reports. Similarly, it could be readily utilized to provide timely responses to local reports.
Assuntos
Exposição Ambiental , Indústrias , Neoplasias/epidemiologia , Neoplasias/etiologia , Papel , Características de Residência , Adolescente , Colúmbia Britânica/epidemiologia , Criança , Pré-Escolar , Análise por Conglomerados , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Método de Monte Carlo , Vigilância da População/métodos , Sistema de Registros , Fatores de Risco , Instituições AcadêmicasRESUMO
Linear, no-threshold relationships are typically reported for time series studies of air pollution and mortality. Since regulatory standards and economic valuations typically assume some threshold level, we evaluated the fundamental question of the impact of exposure misclassification on the persistence of underlying personal-level thresholds when personal data are aggregated to the population level in the assessment of exposure-response relationships. As an example, we measured personal exposures to two particle metrics, PM2.5 and sulfate (SO4(2-)), for a sample of lung disease patients and compared these with exposures estimated from ambient measurements Previous work has shown that ambient:personal correlations for PM2.5 are much lower than for SO4(2-), suggesting that ambient PM2.5 measurements misclassify exposures to PM2.5. We then developed a method by which the measured:estimated exposure relationships for these patients were used to simulate personal exposures for a larger population and then to estimate individual-level mortality risks under different threshold assumptions. These individual risks were combined to obtain the population risk of death, thereby exhibiting the prominence (and the value) of the threshold in the relationship between risk and estimated exposure. Our results indicated that for poorly classified exposures (PM2.5 in this example) population-level thresholds were apparent at lower ambient concentrations than specified common personal thresholds, while for well-classified exposures (e.g., SO4(2-)), the apparent thresholds were similar to these underlying personal thresholds. These results demonstrate that surrogate metrics that are not highly correlated with personal exposures obscure the presence of thresholds in epidemiological studies of larger populations, while exposure indicators that are highly correlated with personal exposures can accurately reflect underlying personal thresholds.
Assuntos
Poluição do Ar/efeitos adversos , Exposição Ambiental , Monitoramento Ambiental , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Modelos Biológicos , Doença Pulmonar Obstrutiva Crônica/mortalidade , Medição de Risco , Fatores de TempoRESUMO
Sequential procedures based on the Mantel-Haenszel statistic (Muenz, Green and Byar, 1977, Biometrics 33, 617-626), the Wilcoxon statistic (Davis, 1978, Communications in Statistics, Series A 7, 389-398) and the Savage statistic (Koziol and Petkau, 1978, Biometrika 65, 615-623) have been proposed for testing the equality of two survival distributions when observations are singly censored. These procedures, and their fixed sample-size counterparts, are numerically compared with respect to power against Lehmann alternatives and expected proportions sampled. Of the sequential procedures, those based on the Wilcoxon and the Savage statistics seem preferable to that based on the Mantel-Haenszel statistic. Early decision rules are introduced and shown to be of value if used in conjunction with either the sequential or the fixed-sample procedures. Small-sample corrections to the asymptotic critical values of the sequential Savage procedure are presented.
Assuntos
Modelos Biológicos , Mortalidade , Humanos , Prognóstico , Projetos de Pesquisa , Estudos de Amostragem , Estatística como AssuntoRESUMO
Compression of gases (Boyle's law) and circuit compliance are major determinants of anesthesia circuit function. The materials of which circuits are constructed and the use of heated humidifiers may result in clinically important variations in delivered minute ventilation (VE) secondary to variations in compression volume. We examined eight anesthetic circuits both with and without a heated humidifier in an in vitro setting. Compression volume was determined with a large calibrated syringe. Circuit efficiency was determined by measuring VE at multiple peak inflation pressures (PIP) while using a pediatric ventilator with fixed VE, respiratory rate, fresh gas flow, and I/E ratio. As expected, both compression volume and delivered VE highly correlated with the type of circuit and the pressure at which it was examined (P less than 0.001). Mapleson D circuits had the lowest compression volume and were the most efficient circuits (P less than 0.0001). Pediatric circle systems were intermediate and adult circle systems had the largest compression volume and were the least efficient. Humidifiers uniformly increased compression volume. The following conclusions were drawn: 1) the anesthetic circuit, its material, and the pressure at which it operates are important determinants of circuit function; 2) humidifiers increase compression volume; 3) Mapleson D circuits had the lowest compression volume and therefore were the most efficient; 4) highly compliant adult circuits may result in compression volume losses that exceed the tidal volume of a pediatric ventilator; 5) humidifiers with low volume and rigid tubing should have the least effect on minute ventilation; and 6) highly compliant adult circuits when used in the care of infants and small children must be used with caution.