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Biomedical subjects

J H Ware

Publications and source records attributed to J H Ware.

At least 55 records · Page 3Linked to original sources
PubMed1990

Early methodological developments for clinical trials at the National Heart, Lung and Blood Institute.

The National Heart Institute, now known as the National Heart, Lung and Blood Institute (NHLBI), initiated its first multicentre randomized clinical trials of rheumatic fever and rheumatic heart disease in 1951. The modern era of multicentre trials began, however, when the Coronary Drug Project was initiated in the 1960s. This trial and subsequent NHLBI trials stimulated a wide variety of research on clinical trial methodology. This paper reviews early methodologic developments in four areas. First, an organizational structure for multicentre clinical trials was developed and codified in the 'Greenberg Report' in 1967. Second, design considerations related to patient risk, non-compliance, a lag in treatment effect, and changing risk were explored. The 'intention-to-treat' principle was implicit in these investigations. Thirdly, the concept of periodic review of accumulating data, recommended in the Greenberg report, stimulated research on methods for sequential analysis. Three statistical approaches were developed and investigation of their statistical properties continues today. These approaches are usually described as group sequential, stochastic curtailment, and Bayesian methods. Finally, comparison of treatments in longitudinal studies has been an increasing part of NHLBI research and methods have been developed for design and analysis of longitudinal studies.

Blood↗
PubMed1990

Longitudinal and cross-sectional estimates of pulmonary function decline in never-smoking adults.

This paper describes methods for simultaneous cross-sectional and longitudinal analysis of repeated measurements obtained in cohort studies with regular examination schedules, then uses these methods to describe age-related changes in pulmonary function level among nonsmoking participants in the Six Cities Study, a longitudinal study of air pollution and respiratory health conducted between 1974 and 1983 in Watertown, Massachusetts; Kingston and Harriman, Tennessee; St. Louis, Missouri; Steubenville, Ohio; Portage, Wisconsin; and Topeka, Kansas. The subjects, initially aged 25-74, were examined on three occasions at 3-year intervals. Individual rates of loss increased more rapidly with age than predicted from the cross-sectional model. For example, for a male of height 1.75 m, the cross-sectional model predicted an increase in the annual rate of loss of FEV1 from 23.7 ml/yr at age 25 to 39.0 ml/yr at age 75, while the longitudinal model gave rates of loss increasing from 12.9 ml/yr at age 25 to 58.2 ml/yr at age 75. These results contrast with those of other studies comparing longitudinal and cross-sectional estimates of pulmonary function loss.

Adult↗
PubMed1989

Indoor air pollution and pulmonary performance: investigating errors in exposure assessment.

We use pulmonary function measurements on pre-adolescent children and indoor air pollution measurements in the homes of these children to illustrate estimation techniques for linear regression models containing independent variables measured with error. In our data set, replicate measures of indoor air pollutant concentrations provide one method of estimating measurement error variances. Surrogate information in the form of cigarettes smoked is also available for the pollutant of interest. Several estimation procedures are presented, and we combine two estimators, one based on surrogate information and one based on replication information, using generalized least squares.

Air Pollution↗
PubMed1989

Predictors of simple diarrhoea in children under 5 years--a study of a Sudanese rural community.

As a baseline to address the hypothesis that malnutrition increases the risk of childhood diarrhoea, 445 children under 5 years of age in a Sudanese rural community were categorized according to weight-for-age, and their history of diarrhoea during the previous 2 weeks was determined. Social, maternal and demographic characteristics were also recorded. A strong association between malnutrition and diarrhoea was observed with evidence for a dose-response relationship. Mildly-malnourished children had close to twice the risk of diarrhoea of well-nourished children (OR = 1.6; 95% CI: 1.0-2.6), and the moderately malnourished had more than twice that risk (OR = 2.4; 95% CI: 1.3-4.5). The association with malnutrition was independent of age, although age was a strong predictor of the risk of diarrhoea, particularly during the second year. The risk of diarrhoea was higher for females and diminished with the age of the mother and the mother's education. Age was a strong predictor of diarrhoea; the risk being particularly high during the second year of life. Although the results were suggestive of an association between nutritional status and risk of diarrhoea, prospective investigations to further elucidate the causal direction of the relationship is needed.

Adolescent↗
PubMed1989

An investigation of a reported cancer cluster in Randolph, Massachusetts.

An increasingly common public health problem is the perception that disease incidence has increased or a cluster of disease has occurred in a community. In most cases, the disease of concern is cancer and a local hazardous waste site or other environmental problem is involved. These problems can be difficult to investigate and public health officials are frequently criticized for their inability to address community concerns. This paper reports a case study of such a situation occurring in the Barlett-Green Acres (BGA) neighborhood of Randolph, Massachusetts. Study data were obtained by interviews in households of persons belonging to a list of alleged cancer cases initially supplied by residents and supplemented using records available in town and state public health offices. One objective of the investigation was to develop methods that may be of value in similar situations arising in other communities. From a list of names compiled prior to and during the investigation, 45 incident cases of cancer were identified and found suitable for analysis. An additional four cases were added from the Massachusetts Cancer Registry. The analysis showed the existence of a cancer cluster, but overall cancer incidence and mortality in the BGA neighborhood were not elevated. Residence history, disease site, and other features of the cancer cases were investigated using methods less sensitive to incomplete reporting than total incidence. No unusual features of the cancer data other than the initiating cluster were identified and no environmental hazard likely to impact the BGA neighborhood was discovered, hence we conclude that the most likely cause of the cancer cluster was random variation in cancer rates.

Adolescent↗
PubMed1989

Short-term pulmonary function change in association with ozone levels.

As part of the ongoing Harvard Six Cities study of the respiratory effects of air pollution, repeated measurements of pulmonary function (FVC, FEV75, MMEF, and Vmax75) were taken at approximately weekly intervals in a population of 154 school children living in Kingston and Harriman, Tennessee. A series of as many as six measurements were obtained for each child over approximately a 2-month period beginning in February 1981. Concurrent measurements of ambient ozone, and fine particle and fine sulfate concentrations were obtained at a site near the study community. The maximal hourly ozone concentration observed during the study was 78 ppb. Child-specific linear regressions were fit that related short-term pulmonary function changes to air pollution or temperature. We found that decrements in FVC, FEV75, MMEF, and Vmax75 were associated with ozone, but not with particulate levels. Decrements in FVC, MMEF, and Vmax75 were also associated with temperature. Although slopes of pulmonary function on ozone varied across children, in general there was no evidence that this variation represented heterogeneity of response as opposed to random estimation errors. In addition, no evidence was found that individual response to ozone was related to sex, presence of asthma, respiratory illness before 2 yr of age, or the MMEF/FVC ratio, a rough surrogate for airway size. We conclude that ambient exposures to ozone at levels well below the National Ambient Air Quality Standard of 120 ppb are associated with transient decreases in lung function, the long-term significance of which is uncertain.

Air Pollutants↗
PubMed1989

Effects of inhalable particles on respiratory health of children.

Results are presented from a second cross-sectional assessment of the association of air pollution with chronic respiratory health of children participating in the Six Cities Study of Air Pollution and Health. Air pollution measurements collected at quality-controlled monitoring stations included total suspended particulates (TSP), particulate matter less than 15 microns (PM15) and 2.5 microns (PM2.5) aerodynamic diameter, fine fraction aerosol sulfate (FSO4), SO2, O3, and No2. Reported rates of chronic cough, bronchitis, and chest illness during the 1980-1981 school year were positively associated with all measures of particulate pollution (TSP, PM15, PM2.5, and FSO4) and positively but less strongly associated with concentrations of two of the gases (SO2 and NO2). Frequency of earache also tended to be associated with particulate concentrations, but no associations were found with asthma, persistent wheeze, hay fever, or nonrespiratory illness. No associations were found between pollutant concentrations and any of the pulmonary function measures considered (FVC, FEV1, FEV0.75, and MMEF). Children with a history of wheeze or asthma had a much higher prevalence of respiratory symptoms, and there was some evidence that the association between air pollutant concentrations and symptom rates was stronger among children with these markers for hyperreactive airways. These data provide further evidence that rates of respiratory illnesses and symptoms are elevated among children living in cities with high particulate pollution. They also suggest that children with hyperreactive airways may be particularly susceptible to other respiratory symptoms when exposed to these pollutants.(ABSTRACT TRUNCATED AT 250 WORDS)

Air Pollutants↗
PubMed1989

Home dampness and respiratory morbidity in children.

This study examined the relationship between measures of home dampness and respiratory illness and symptoms in a cohort of 4,625 eight- to 12-yr-old children living in six U.S. cities. Home dampness was characterized from questionnaire reports of mold or mildew inside the home, water damage to the home, and the occurrence of water on the basement floor. Symptoms of respiratory and other illness were collected by questionnaire. Pulmonary function was measured by spirometry. Signs of home dampness were reported in a large proportion of the homes. In five of the six cities, one or more of the dampness indicators were reported in more than 50% of the homes. The association between measures of home dampness and both respiratory symptoms and other non-chest illness was both strong and consistent. Odds ratios for molds varied from 1.27 to 2.12, and for dampness from 1.23 to 2.16 after adjustment for maternal smoking, age, gender, city of residence, and parental education. The relationship between home dampness and pulmonary function was weak, with an estimated mean reduction of 1.0% in FEF25-75 associated with dampness and 1.6% with molds. We conclude that dampness in the home is common in many areas of the United States and that home dampness is a strong predictor of symptoms of respiratory and other illness symptoms among 8- to 12-yr-old children.

Asthma↗
PubMed1989

Prognostic factors in small-cell carcinoma of the lung: an analysis of 1,521 patients.

Cancer and Leukemia Group B (CALGB) accrued 1,745 patients with limited (LD) or extensive (ED) small-cell lung cancer (SCCL) to five separate trials between 1972 and 1986. We reviewed these data to evaluate the impact of pretreatment prognostic factors on outcome. In multivariate analysis, female gender was predictive of improved response (LD, P = .01; ED, P = .04) and survival (LD, P = .01; ED, P = .02). A performance status of 0 or 1 was associated with improved response rates in both subsets, but was statistically significant (P = .04) only for overall objective response in LD patients. Performance status was a highly significant predictor of survival in both LD and ED groups (P less than .001). Supraclavicular lymph node involvement, while still LD, had a borderline unfavorable impact on survival (P = .06) compared with a lesser extent of LD involvement. In ED patients, a decrease in survival rates was associated with an increased number of metastatic sites (P = .01). Changes in the patient population were noted with time: the percentage of women increased from 21% to greater than 35%; an increased number of metastatic sites was identified among ED patients; mean performance status improved for both LD and ED subsets. These trends reflect the changing demographics of lung cancer, improved lung cancer staging, and probably lead-time bias. Response rates, overall survival, and long-term (greater than 2-year) survival varied significantly among the five protocols, both before and after multivariate correction for identified prognostic variables. However, the changing character of the study population limits the ability to determine retrospectively how much improvements in therapy contributed to the positive changes in failure-free survival, overall survival, and long-term survival observed in our sequentially studied population.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B.

The Cancer and Leukemia Group B (CALGB) conducted a prospective randomized trial to evaluate the role of warfarin and alternating chemotherapy in extensive small-cell lung cancer (SCCL). After stratification for sex and performance status, patients were randomly assigned to receive chemotherapy with methotrexate, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (CCNU) (MACC), or MACC plus warfarin (MACC + W), or mitomycin, etoposide, cisplatin, and hexamethylmelamine alternating with MACC (MEPH/MACC). Warfarin was given continuously to maintain a prothrombin time of one and one half to twice the control values. A total of 328 patients were enrolled, and 294 were evaluable. There was a statistically significant advantage in objective response rates (complete [CR] and partial responses [PR], respectively) for MACC + W (17% and 50%) as compared with MACC alone (8% and 43%) or MEPH/MACC (10% and 38%) (P = .012). Both failure-free survival (P = .054 Wilcoxon test) and overall survival (P = .098 Wilcoxon test) were higher on MACC + W (median, 6.6 months and 9.3 months, respectively), as compared with MACC (5.0 months and 7.9 months) and MEPH/MACC (5.0 months and 7.9 months). Toxicity was comparable among the three arms, except for increased hemorrhagic events on MACC + W, which were life-threatening in four patients (4%), and lethal in two others (2%). These data support the role of warfarin in the treatment of SCCL, but do not establish its mechanism of action. Warfarin deserves further studies in SCCL, particularly in patients with limited disease.

Altretamine↗
PubMed1989

Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: a prospective randomized study.

Thirty-nine newborn infants with severe persistent pulmonary hypertension and respiratory failure who met criteria for 85% likelihood of dying were enrolled in a randomized trial in which extracorporeal membrane oxygenation (ECMO) therapy was compared with conventional medical therapy (CMT). In phase I, 4 of 10 babies in the CMT group died and 9 of 9 babies in the ECMO group survived. Randomization was halted after the fourth CMT death, as planned before initiating the study, and the next 20 babies were treated with ECMO (phase II). Of the 20, 19 survived. All three treatment groups (CMT and ECMO in phase I and ECMO, phase II) were comparable in severity of illness and mechanical ventilator support. The overall survival of ECMO-treated infants was 97% (28 of 29) compared with 60% (6 of 10) in the CMT group (P less than .05).

Extracorporeal Membrane Oxygenation↗
PubMed1988

The efficacy of the addition of nifedipine in patients with mixed angina compared to patients with classic exertional angina: a multicenter, randomized, double-blind, placebo-controlled clinical trial.

Episodes of myocardial ischemia in patients with coronary artery disease may be due to transient increases in coronary vasomotor tone superimposed on a fixed atherosclerotic obstruction. The purpose of this study was to determine whether identification of the clinical pattern of angina could predict the therapeutic response to the addition of nifedipine to a regimen of beta blockers and/or long-acting nitrates. Seventy-two patients with stable exertional angina were divided into two groups: "classic exertional angina" (17 patients), defined as exertional angina with a stable threshold; and "mixed angina" (55 patients), defined as exertional angina provoked by a variable threshold and/or at least two episodes of rest angina within the 3 months prior to screening. Patients were studied with nifedipine and placebo in a 6-week, double-blind, crossover design that used serial anginal diaries, exercise treadmill tests, and 24-hour ambulatory ECG monitoring. In patients with mixed angina, nifedipine reduced the frequency of angina compared to that during placebo treatment (13.1 vs 9.9 episodes/3 weeks, p less than 0.01) and reduced nitroglycerin consumption (11.7 vs 7.5 tablets/3 weeks, p less than 0.05); while in patients with classic exertional angina, nifedipine had no symptomatic effect (7.9 vs 6.8 anginal episodes/3 weeks, NS; 6.4 vs 5.8 nitroglycerin tablets/3 weeks, NS). Patients in both groups experienced a significant decrease in the manifestations of ischemia during exercise testing. Patients with mixed angina experienced a reduction in the daily frequency of painful episodes of ST segment depression during nifedipine treatment compared to placebo (0.6 vs 0.2 episodes, p less than 0.05), but there was no effect on the frequency of episodes of silent ischemia (4.2 vs 3.4 episodes, NS). In patients with classic exertional angina, the addition of nifedipine had no effect on any measure of ambulatory ischemia. We conclude that patients with mixed angina are more likely to benefit symptomatically from the addition of nifedipine therapy than patients with classic exertional angina. The lack of a consistently preferential response to nifedipine in patients with mixed angina, however, suggests that episodic coronary vasoconstriction may not be the only mechanism responsible for ischemia in these patients, and/or that nifedipine may not necessarily provide additional therapeutic benefit beyond that conferred by a regimen of beta blockers and/or nitrates.

Adrenergic beta-Antagonists↗
PubMed1988

Association of malnutrition and diarrhea in children aged under five years. A prospective follow-up study in a rural Sudanese community.

Results are reported from a one-year follow-up study conducted in 1983 and 1984 of 445 Sudanese children aged under five years that was designed to address the hypothesis that malnutrition increases the incidence of diarrheal disease. Children were weighed and measured at two-month intervals ("child intervals") and diarrhea incidence was ascertained during biweekly house visits. During child intervals that followed a prior episode of diarrhea, underweight (weight-for-age less than 90% of expected) was associated with a higher incidence of diarrhea after adjusting for the potential confounding effects of age and socioeconomic factors (odds ratio (OR) = 1.7, 95% confidence interval (CI) = 1.1-2.8). During child intervals with no history of diarrhea in the preceding interval, the association with underweight was less (OR = 1.2, 95% CI = 0.9-1.6); among these children, stunting (height-for-age less than 95% of expected) was significantly associated with diarrhea (OR = 1.4, 95% CI = 1.0-1.8). Moderate malnutrition (weight-for-age less than 75% of expected) was associated with a twofold increased risk of multiple episodes of diarrhea during a follow-up interval whether or not diarrhea had occurred in the preceding interval (OR = 2.0, 95% CI = 1.2-3.5) after adjusting for age, socioeconomic factors, and diarrhea in preceding interval. Age, rainy season, and history of diarrhea in preceding interval were found to be strongly associated with incidence of diarrhea. These data are consistent with the hypothesis that malnutrition increases the risk of childhood diarrhea.

Child, Preschool↗
PubMed1988

Cumulative and reversible effects of lifetime smoking on simple tests of lung function in adults.

Data from a random sample of 8,191 men and women from 6 U.S. cities are used to fit a model describing the effects of cumulative and current cigarette smoking on pulmonary function. The data show that smokers suffer an irreversible loss of FVC and FEV1, which is described by a linear function of their cumulative cigarette smoking as measured in pack-years. For a typical male 173 cm tall, the estimated loss of FEV1 is 7.4 ml for each pack-year smoked. For a typical woman, 161 cm tall, the estimated effect is 4.4 ml per pack-year. Current cigarette smoking adds an acute deficit over and above the cumulative effect of lifetime smoking. For any lifetime pack-years, exsmokers have higher levels of FEV1, 123 ml for a typical man, 107 ml for a typical woman, than do current smokers of a pack per day (p less than 0.001). A man who starts smoking one pack of cigarettes per day at 25 yr of age would at age 60, after 35 pack-years of exposure, have an expected FEV1 equal to that of a man 69.4 yr of age who had never smoked. If he stopped smoking at 60 yr of age, his expected level would increase to that of a 66.5-yr-old never-smoker. This model therefore estimates how much lung function is irreversibly lost by smoking, estimates how much could be regained with cessation of smoking, and predicts the future loss of lung function in both cases.

Adult↗
PubMed1987

Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung.

We conducted a prospective, randomized study to clarify the role of radiotherapy of the primary tumor in limited small-cell cancer of the lung. After stratification for sex and for performance score based on the ability to ambulate, patients were randomly assigned to receive initial radiotherapy plus chemotherapy, delayed radiotherapy plus chemotherapy, or chemotherapy alone. The chemotherapy consisted of cyclophosphamide, etoposide (VP-16-213), and vincristine, with doxorubicin subsequently replacing etoposide in alternate cycles 7 through 18. Chemotherapy was given every three weeks for 18 months. The radiotherapy comprised 4000 rad in four weeks, followed by a 1000-rad "boost" directed against residual disease. All patients received prophylactic whole-brain radiation. The patients enrolled totaled 426, and 399 were evaluable. There was a statistically significant difference in the frequency of complete responses in favor of the two radiotherapy regimens (P = 0.0013). Failure-free survival was also longer with these two regimens (P less than 0.001), as was the interval before treatment failure in the chest (P less than 0.001) and overall survival (P = 0.0099). As expected, toxic effects--chiefly neutropenia--were also increased. The addition of radiotherapy of the primary tumor to combination chemotherapy improved both complete-response rates and survival, with increased but acceptable toxicity.

Aged↗
PubMed1987

Effect of age, sex, and body surface area on echocardiographic left ventricular wall mass in normal subjects.

M-mode echocardiography was used to estimate left ventricular wall mass in 136 older normal subjects (Group I: 78 men and 58 women, ages 20 to 97 years) and 105 younger normal subjects (Group II: 52 male and 53 female subjects, ages 1 day to 23 years). Echocardiographic left ventricular mass (in grams) was estimated from the following formula: left ventricular mass = 1.05 ([ left ventricular internal diastolic dimension + ventricular septal thickness (diastole) + posterior wall thickness (diastole)] - [left ventricular internal diastolic dimension]). In both groups, female subjects had a slightly smaller left ventricular mass than male subjects (mean difference 7.2% in Group I, p less than 0.05, and 3.6% in Group II, p = 0.05) for any given age and body surface area. Left ventricular mass varied linearly with body surface area and increased as a function of age. In group I subjects, echocardiographic left ventricular mass (in grams) could be estimated by the general formula: left ventricular mass = 124 (body surface area) + A +/- C, where A is the age-dependent intercept; +/- C encompasses a 95% prediction interval for normal values, which is assumed to be nearly constant (+/- 58 g); and body surface area is expressed in square meters. In the Group II (younger) subjects, with age not considered, left ventricular mass (in grams) could be estimated from the following formula: left ventricular mass = 115 (body surface area) -11 +/- C, where +/- C = +/- 32% and this 95% prediction interval varies as a percentage of the mean.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗