Work pattern causes bias in self-reported activity duration: a randomised study of mechanisms and implications for exposure assessment and epidemiology.

BACKGROUND: Self-reported activity duration is used to estimate cumulative exposures in epidemiological research. OBJECTIVE: The effects of work pattern, self-reported task dullness (a measure of cognitive task demand), and heart rate ratio and perceived physical exertion (measures of physical task demands) on error in task duration estimation were investigated. METHODS: 24 participants (23-54 years old, 12 males) were randomly assigned to execute three tasks in either a continuous (three periods of 40 continuous minutes, one for each task) or a discontinuous work pattern (40 min tasks each divided into four periods of 4, 8, 12 and 16 min). Heart rate was measured during tasks. After completing the 2 h work session, subjects reported the perceived duration, dullness and physical exertion for each of the three tasks. Multivariate models were fitted to analyse errors and their absolute value to assess the accuracy in task duration estimation and the mediating role of task demands on the observed results. RESULTS: Participants overestimated the time spent shelving boxes (up to 38%) and filing journals (up to 9%), and underestimated the time typing articles (up to -22%). Over- and underestimates and absolute errors were greater in the discontinuous work pattern group. Only the self-reported task dullness mediated the differences in task duration estimation accuracy between work patterns. CONCLUSIONS: Task-related factors can affect self-reported activity duration. Exposure assessment strategies requiring workers to allocate work time to different tasks could result in biased measures of association depending on the demands of the tasks during which the exposure of interest occurs.

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.

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.

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)

Urinary excretion of Bowman-Birk inhibitor in humans after soy consumption as determined by a monoclonal antibody-based immunoassay.

The Bowman-Birk inhibitor (BBI) found in soybeans is a serine protease inhibitor with anticarcinogenic activity. In the present study, an ELISA for BBI was developed with the use of a monoclonal antibody against a reduced form of BBI. This newly developed ELISA method was used to measure the urinary levels of BBI metabolites in nine human subjects after consumption of 36-oz or 60-oz soymilk (containing 105 or 175 mg of BBI) at two time points 36 h apart. The results demonstrate that urinary BBI excretion rates peaked within 6 h and decreased to baseline levels within 12-24 h after soymilk ingestion. The changes in BBI:creatinine ratios in urine closely paralleled the changes in urinary BBI excretion rates after soymilk consumption. These data suggest that BBI ingested p.o. is absorbed and could be bioavailable for cancer chemoprevention in other organs in addition to those in the gastrointestinal tract.

Serum immunoglobulins: methods for the determination of normal values in international units.

This paper describes the proper statistical methods for the determination of the range of normal values of serum immunoglobulins in any population and for the conversion of those ranges, or any serum immunoglobulin value, from mg per ml to World Health Organization International Units. In determining the normal range, it is argued that the analysis should be based upon the logarithms of the serum immunoglobulin values and that the range of normal values about the mean should be determined by the application of tolerance limits, rather than the more familar but incorrect confidence limits. For converting normal ranges from mg per ml to International Units, methods of parallel line bioassay (for IgG and IgA) and non-linear bioassay (for IgM and IgD) are used. For both bioassay methods, graphical techniques are described.

The futility index. An approach to the cost-effective termination of randomized clinical trials.

Although the randomized clinical trial is recognized as the method of choice for evaluating therapeutic innovations, it is often enormously expensive--in some instances, as a result of the unnecessary continuation of a trial destined to conclude that an innovation is not superior to standard therapy. Although most large clinical trials in which results evolve over time are monitored for early evidence of efficacy or toxicity, trials are rarely terminated because the probability of a positive result regarding the value of the innovation has become low. This paper discusses the issues involved in the monitoring and early termination of long-term clinical trials and describes the futility index, a probabilistic basis for early termination of trials of innovative therapy when the accumulated data imply small probability of success. Utilization of the futility index in the management of clinical trials of innovations can be of value in reducing, at slight loss of power, the number of unproductive studies carried to completion, thereby creating new opportunities for more effective use of limited resources.

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).

Assessment of the health effects of atmospheric sulfur oxides and particulate matter: evidence from observational studies.

Steadily rising energy costs have increased the need for reliable information on the health effects of atmospheric sulfur oxides and particulate matter. Because ethical and practical considerations limit studies of this question under controlled conditions, observational studies provide an important part of the relevant information. This paper examines the currently available epidemiologic evidence from population studies of the health effects of these pollutants. Nonexperimental studies also have important limitations, including the inability to measure accurately the exposure burden of free living individuals, and the potential for serious confounding by other factors affecting health. We begin with a discussion of some of these methodologic issues. The evidence is then reviewed, first in association with fluctuations in 24 hr mean concentration of sulfur oxides and particulate matter, and then in association with differences in mean annual concentration. In the last section, this evidence is summarized and used to approximate the exposure-response relationship linking pollutant concentrations with mortality and morbidity levels.

The Six-City Study: examples of problems in analysis of the data.

This paper presents some of the results from cross-sectional analyses and studies during air pollution alerts obtained as a part of the Six-City Study, a longitudinal study of the respiratory effects of air pollution. These analyses illustrate some of the limitations and uncertainties of epidemiologic studies. For example, an earlier report noted increased respiratory illness rates for children living in homes where gas was used for cooking. A later analysis did not confirm this. Reasons for this are explored by using different criteria and variables to be controlled for. The results illustrate that the strength of the association between cooking fuel and illness was sensitive to the definitions of the variables and the number of subjects and city cohorts. Similar examples are presented for illness rates for four respiratory diseases: asthma, bronchitis, illness before age 2 and illness last winter. These examples of cross-sectional analyses emphasize the ambiguities of studies of possible health effects of air pollution exposures close to the present ambient air quality standards.

Sensitive subgroups and normal variation in pulmonary function response to air pollution episodes.

The Clean Air Act requires that sensitive subgroups of exposed populations be protected from adverse health effects of air pollution exposure. Hence, data suggesting the existence of sensitive subgroups can have an important impact on regulatory decisions. Some investigators have interpreted differences among individuals in observed pulmonary function response to air pollution episodes as evidence that individuals differ in their sensitivity. An alternative explanation is that the differences are due entirely to normal variation in repeated pulmonary function measurements. This paper investigates this question by reanalyzing data from three studies of children exposed to air pollution episodes to determine whether the observed variability in pulmonary function response indicates differences in sensitivity or natural interoccasion variability. One study investigated exposures to total suspended particulates (TSP), the other two investigated exposure to ozone. In all studies, each child's response to air pollution exposures was summarized by regressing that child's set of pulmonary function measurements on the air pollution concentrations on the day or days before measurement. The within-child and between-child variances of these slopes were used to test the hypothesis of variable sensitivity. Regression slopes did not vary significantly among children exposed to episodes of high TSP concentration, but there was evidence of heterogeneity in both studies of ozone exposures. The finding of heterogeneous response to ozone exposure is consistent with the epidemiologic and chamber studies of ozone exposures, but the lack of evidence for heterogeneous response to TSP exposures implies that observed variation in response can be explained by sampling variability rather than the presence of sensitive subgroup.

Health effects of acid aerosols on North American children: respiratory symptoms.

We examined the respiratory health effects of exposure to acidic air pollution among 13,369 white children 8 to 12 years old from 24 communities in the United States and Canada between 1988 and 1991. Each child's parent or guardian completed a questionnaire. Air quality and meteorology were measured in each community for a 1-year period. We used a two-stage logistic regression model to analyze the data, adjusting for the potential confounding effects of sex, history of allergies, parental asthma, parental education, and current smoking in the home. Children living in the community with the highest levels of particle strong acidity were significantly more likely [odds ratio (OR) = 1.66; 95% confidence interval (CI) 1.11-2.48] to report at least one episode of bronchitis in the past year compared to children living in the least-polluted community. Fine particulate sulfate was also associated with higher reporting of bronchitis (OR = 1.65; 95% CI 1.12-2.42). No other respiratory symptoms were significantly higher in association with any of the air pollutants of interest. No sensitive subgroups were identified. Reported bronchitis, but neither asthma, wheeze, cough, nor phlegm, were associated with levels of particle strong acidity for these children living in a nonurban environment.

Health effects of acid aerosols on North American children: pulmonary function.

We examined the health effects of exposure to acidic air pollution among children living in 24 communities in the United States and Canada. Parents of children between the ages of 8 and 12 completed a self-administered questionnaire and provided consent for their child to perform a standardized forced expiratory maneuver at school in 22 of these communities. Air quality and meteorology were measured in each community for the year preceding the pulmonary function tests. Forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1.0) measurements of 10,251 white children were examined in a two-stage regression analysis that adjusted for age, sex, height, weight, and sex-height interaction. In this study, a 52 nmol/m3 difference in annual mean particle strong acidity was associated with a 3.5% (95% CI, 2.0-4.9) decrement in adjusted FVC and a 3.1% (95% CI, 1.6-4.6) decrement in adjusted FEV1.0. The FVC decrement was larger, although not significantly different, for children who were lifelong residents of their communities (4.1%, 95% CI, 2.5-5.8). The relative odds for low lung function (that is, measured FVC less than or equal to 85% of predicted), was 2.5 (95% CI, 1.8-3.6) across the range of particle strong acidity exposures. These data suggest that long-term exposure to ambient particle strong acidity may have a deleterious effect on lung growth, development, and function.

Effects of passive smoking on health of children.

Analysis of data on the effects of passive smoking obtained in preadolescent children from the Harvard Six-Cities Study demonstrates an exposure-response relationship between the number of smokers in the household and the reporting rates for doctor-diagnosed respiratory illness before age 2, history of bronchitis, wheeze most days and nights apart from colds, and a composite of symptoms defined as the lower respiratory index. Similarly, when only the amount currently smoked by the mother was used, the data indicated a relatively uniform increase in each of the reported diseases and symptoms. FEV1 was lower in children with smoking mothers compared to children of nonsmoking mothers. Rate of increases in FEV1 after adjusting for normal growth was significantly smaller in children of smoking mothers and was related also to amount smoked. Notably the effect on level of FVC was not seen and this finding, consistent in several studies, remains unexplained. Although children of smoking mothers were shorter on the average than children of nonsmoking mothers, no on-going passive smoking effect on height growth can be ascertained. All these differences are small and their medical significance remains to be defined.

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.

Passive smoking and height growth of preadolescent children.

The attained height and height growth rate of 9273 children participating in a longitudinal study of the health effects of air pollutants were analysed to assess the association between passive exposure to cigarette smoke and physical growth between 6 and 11 years of age. Children were measured annually for 2 to 6 years. Each height measurement was adjusted for sex and age by the NCHS anthropometric standards. Each child's adjusted heights were then re-expressed as level of attained height and growth rate. Attained height exhibited a dose-response relationship with amount of current maternal cigarette smoking (p less than 0.001). Children whose mothers smoked ten or more cigarettes daily were approximately 0.65 cm shorter than children of non-smokers, while children whose mothers smoked between 1 and 9 cigarettes per day were 0.45 cm shorter. However, passive smoking was not correlated with the child's growth rate. Exposure to paternal smoking was not significantly associated with height, either in terms of attained level or growth rate. These results indicate that passive smoking in the 6- to 11-year-old child does not continue to affect the growth rate of height and that the observed association between attained height and maternal smoking behaviour is due to exposures in utero and/or during infancy and the preschool years.

Localization of tissue plasminogen activator mRNA in adult rat brain.

The distribution of tissue plasminogen activator (tPA) messenger RNA in rat brain was studied using in situ hybridization with 35S UTP-labeled RNA probes derived from a full-length tPA cDNA. Sense strand controls produced low, even backgrounds, with small elevations in the hippocampus. Full-length antisense probes produced strong signals over cerebral ventricular ependyma (including ependyma of the subcommissural organ), meninges, blood vessels, and Purkinje cell layer of the cerebellum, as well as strong signals over scattered cells throughout the brain. Some of these scattered labeled cells were large with lightly stained nuclei, while others were small with darkly stained nuclei. The large labeled cells, which were probably neurons, constituted 6% and 8% of cells in the brain stem and neocortex, respectively, and 100% of Purkinje cells. The small cells, which were present in all areas of the brain, constituted 3-11% of cells in individual brain areas.

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.

Longitudinal studies with continuous responses.

The analysis of serial measurements obtained in longitudinal studies plays an increasingly prominent role in applied research. The last few years have seen the development of many new techniques for carrying out analyses, including computer software. These methods can be used in a variety of standard problems, including repeated measures and cross-over designs, as well as growth curve analyses. We review these new methods, their application, and available computer packages. Data from a longitudinal study of lung function is used to illustrate the methods.