Marcia Polansky

Crossover and self-controlled designs in clinical research.

Crossover studies (clinical trials in which each patient receives two or more treatments in sequence) and self-controlled studies (in which each patient serves as his or her own control) can produce results that are statistically and clinically valid with far fewer patients than would otherwise be required. We investigated the use of the crossover design in the 13 crossover studies that appeared in the Journal during 1978 and 1979. We considered the following important features of design and analysis as they applied to these studies: the method by which patients were assigned to initial treatment (only 7 of 13 studies used random assignment); the determination of when to switch treatments (10 of the 13 used a time-dependent rule, and 3 a less appropriate disease-state-dependent rule); blinding of the crossover point (in only 3 of the 13 studies was the crossover point concealed, but in 4 of the remaining 10 concealment was impossible); assessment of the effects of the order of treatments (included in only 1 of the 13 studies); and the use of at least minimally acceptable statistical analysis (11 of the 13 studies had such an analysis). We also report briefly on 28 additional studies of a single treatment each, in which each patient served as his or her own control before or after treatment or both. The scientific issues were much the same as in crossover studies except that self-controlled comparisons of treatments tended to be less precisely designed and conducted and to focus on clinical problems and patient groups that are especially difficult to study.

Patterns of Asthma Mortality in Philadelphia from 1969 to 1991

BACKGROUND The rate of mortality from asthma has increased substantially in the United States since 1978. We analyzed the patterns of the rates of death from asthma in Philadelphia between 1969 and 1991. METHODS The rates of death from asthma were analyzed and compared with trends in the concentrations of major air pollutants: ozone, carbon monoxide, nitrogen dioxide, particulate matter (particles < 10 microns in diameter), and sulfur dioxide. Univariate and multivariate analyses were used to study the rates of death from asthma from 1985 to 1991 and their association with race, poverty, sex, and other factors. RESULTS The rate of death from asthma decreased from 1.68 per 100,000 people in 1969 to 0.68 per 100,000 in 1977, but then increased to 0.92 per 100,000 in 1978 and 2.41 per 100,000 in 1991. Between 1965 and 1990, the concentrations of major air pollutants declined substantially. From 1985 to 1991, 258 people were identified for whom asthma was the primary cause of death. According to multivariate analysis, the rates of death from asthma from 1985 to 1991 were significantly higher in census tracts with higher percentages of blacks (P = 0.032), Hispanics (P = 0.013), female residents (P < 0.001), and people with incomes in the poverty range (P < 0.001). CONCLUSIONS The rates of death from asthma have increased in Philadelphia, whereas concentrations of major air pollutants have declined. The rates are highest in census tracts with the highest percentages of poor people and minority residents, particularly blacks. Public health efforts should target urban areas where the risk of death from asthma is highest.

Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects.

We have studied the effect of prolonged hyperinsulinemia and hyperglycemia on serum leptin levels in young nonobese males during 72-h euglycemic-hyperinsulinemic and hyperglycemic ( approximately 8.5 and 12.6 mM) clamps. Hyperinsulinemia increased serum leptin concentrations (by RIA) dose-dependently. An increase in serum insulin concentration of > 200 pM for > 24 h was needed to significantly increase serum leptin. An increase of approximately 800 pM increased serum leptin by approximately 70% over 72 h. Changes in plasma glucose concentrations (from approximately 5.0 to approximately 12.6 mM) or changes in plasma FFA concentrations (from < 100 to > 1,000 microM) had no effect on serum leptin. Serum leptin concentrations changed with circadian rhythmicity. The cycle length was approximately 24 h, and the cycle amplitude (peak to trough) was approximately 50%. The circadian leptin cycles and the circadian cycles of total body insulin sensitivity (i.e., GIR, the glucose infusion rates needed to maintain euglycemia during hyperinsulinemic clamping) changed in a mirror image fashion. Moreover, GIR decreased between Days 2 and 3 (from 11.4+/-0.2 to 9. 8+/-0.2 mg/kg min, P< 0.05) when mean 24-h leptin levels reached a peak. In summary, we found (a) that 72 h of hyperinsulinemia increased serum leptin levels dose-dependently; (b) that hyperglycemia or high plasma FFA levels did not affect leptin release; (c) that leptin was released with circadian rhythmicity, and (d) that 24-h leptin cycles correlated inversely with 24-h cycles of insulin sensitivity. We speculate that the close positive correlation between body fat and leptin is mediated, at least in part, by insulin.

Risk factors for gallbladder cancer. An international collaborative case–control study

Background. Gallbladder cancer has an unusual geographic and demographic distribution, suggesting many possible etiologies.

Correlation of volumetric magnetization transfer imaging with clinical data in MS

We examined the relations between quantitative volumetric estimates of cerebral lesion load based on magnetization transfer imaging (MTI), clinical data, and measures of neuropsychological function in 44 patients with clinically diagnosed MS. In this population we assessed the correlation between several volumetric MTI measures, measures of neurologic function (Kurtzke Expanded Disability Status Scale and Ambulation Index), and disease duration using Spearmans correlation coefficient. Patients were classified on the basis of neuropsychological test performance as severely impaired, moderately impaired, and normal. We assessed differences between these groups with respect to MTI results using the Kruskal-Wallis test. MTI measures corrected for brain volume were found to correlate with disease duration (p < 0.01) and showed suggestive correlations with measures of neurologic impairment (p < 0.05). Individual neuropsychological tests correlated with MTI measures corrected and not corrected for brain volume (p < 0.001). An MTI measure not corrected for brain volume differed (p < 0.05) between severely impaired, moderately impaired, and normal patients. These preliminary results suggest that volumetric MTI analysis provides new measures that reflect more accurately the global lesion load in the brain of MS patients, and they may serve as a method to study the natural course of the disease and as an outcome measure to evaluate the effect of drugs.

Effects of methylphenidate on attentional function after traumatic brain injury. A randomized, placebo-controlled trial.

Attention deficits after traumatic brain injury (TBI) are common and disabling. Many pharmacologic agents have been used to ameliorate attention deficits, and considerable interest has focused on methylphenidate (MP) because of its documented efficacy in attention deficit disorder. However, clinical studies of MP in subjects with TBI have yielded mixed results. We examined the effects of MP on attentional function in individuals with TBI referred specifically for attentional assessment and treatment. Subjects were studied in a double-blind, placebo-controlled, repeated crossover design, using five different tasks designed to measure various facets of attentional function. MP produced a significant improvement in the speed of mental processing. Orienting to distractions, most aspects of sustained attention, and measures of motor speed were unaffected. These results suggest that MP may be a useful treatment in TBI but is primarily useful for symptoms that can be attributed to slowed mental processing.

Thermic effect of food in lean and obese men.

A systemic reappraisal of the thermic effect of food was done in lean and obese males randomly fed mixed meals containing 0, 8, 16, 24, and 32 kcal/kg fat-free mass. Densitometric analysis was used to measure body composition. Preprandial and postprandial energy expenditures were measured by indirect calorimetry. The data show that the thermic effect of food was linearly correlated with caloric intake, and that the magnitude and duration of augmented postprandial thermogenesis increased linearly with caloric consumption. Postprandial energy expenditures over resting metabolic requirements were indistinguishable when comparing lean and obese men for a given caloric intake. Individuals, however, had distinct and consistent thermic responses to progressively greater caloric challenges. These unique thermic profiles to food ingestion were also independent of leanness or obesity. We conclude that the thermic effect of food increases linearly with caloric intake, and is independent of leanness and obesity.

Designs for experiments--parallel comparisons of treatment.

Clinical trials of medical treatments often compare two treated groups or a treated group with a separate but concurrent control group. We have examined a consecutive series of 47 such parallel studies reported in the Journal in 1978-1979, including 35 with random assignment to the treated or control group, to discover how this approach is actually used. A major strength of these studies as a group was the frequent use of randomized treatment assignment. Common problems included lack of sufficient detail about methods of randomization, failure to provide enough detail about patient sources, and insufficient use of multivariate statistical techniques and of statistical modeling. We emphasize the importance of avoiding bias by balancing prognostic factors when assigning patients to treatments, reducing bias by modeling the influence of prognostic factors on response, and increasing precision by modeling. We also advocate the careful consideration of the relevance of a treatment comparison within the study to the external world of clinical practice.

Participation in Home, Extracurricular, and Community Activities among Children and Young People with Cerebral Palsy.

Aim  Participation in home, extracurricular, and community activities is a desired outcome of rehabilitation services for children and young people with cerebral palsy (CP). The purpose of this study was to investigate the effect of age and gross motor function on participation among children and young people with CP.

Hydrogel/silver ion-coated urinary catheter reduces nosocomial urinary tract infection rates in intensive care unit patients: a multicenter study.

OBJECTIVES Indwelling urinary catheters are the leading source of nosocomial urinary tract infections (NUTIs). The Bardex I.C. catheter is a hydrogel latex Foley catheter with a monolayer of silver metal applied to the inner and outer surfaces of the catheter. We investigated the Bardex I.C. catheter for its ability to decrease the NUTI rate in critical care units. METHODS Five hospitals participated in a blind prospective study, exchanging the standard latex Foley catheter for the Bardex I.C. Foley catheter. The device use rate and NUTI rate were monitored. Data were collected and analyzed using Wilcoxon rank sum test and four-way analysis of variance. A cost analysis was also performed. RESULTS The baseline period, intervention period, and number of device days was similar for both periods. The unadjusted catheter-associated infection rate during the baseline and intervention periods was 7.1 and 4.5 infections per 1000 catheter days, respectively (P <0.01). The adjusted catheter-associated infection rate during the baseline and intervention periods was 8.1 and 4.9 infections per 1000 catheter days, respectively. This was not statistically significant (P = 0. 13). CONCLUSIONS A trend toward a reduction in NUTIs with the use of the hydrogel/silver-coated catheter was noted in all intensive care units at each institution as shown by the unadjusted and adjusted catheter-associated infection rates. One hospital demonstrated a statistically significant reduction in NUTIs. However, statistical significance was not met when the results were adjusted. The cost analysis at one institution demonstrated cost savings with the use of the silver-coated catheter. Future analysis may require a double-blind, prospective-controlled study of longer duration to reach statistical significance.