Sample size re-estimation for clinical trials with longitudinal negative binomial counts including time trends

In some diseases, such as multiple sclerosis, lesion counts obtained from magnetic resonance imaging (MRI) are used as markers of disease progression. This leads to longitudinal, and typically overdispersed, count data outcomes in clinical trials. Models for such data invariably include a number of nuisance parameters, which can be difficult to specify at the planning stage, leading to considerable uncertainty in sample size specification. Consequently, blinded sample size re-estimation procedures are used, allowing for an adjustment of the sample size within an ongoing trial by estimating relevant nuisance parameters at an interim point, without compromising trial integrity. To date, the methods available for re-estimation have required an assumption that the mean count is time-constant within patients. We propose a new modeling approach that maintains the advantages of established procedures but allows for general underlying and treatment-specific time trends in the mean response. A simulation study is conducted to assess the effectiveness of blinded sample size re-estimation methods over fixed designs. Sample sizes attained through blinded sample size re-estimation procedures are shown to maintain the desired study power without inflating the Type I error rate and the procedure is demonstrated on MRI data from a recent study in multiple sclerosis.     

The Multimedia activity recall for children and adolescents (MARCA): development and evaluation

Background  

Self-report recall questionnaires are commonly used to measure physical activity, energy expenditure and time use in children and adolescents. However, self-report questionnaires show low to moderate validity, mainly due to inaccuracies in recalling activity in terms of duration and intensity. Aside from recall errors, inaccuracies in estimating energy expenditure from self-report questionnaires are compounded by a lack of data on the energy cost of everyday activities in children and adolescents. This article describes the development of the Multimedia Activity Recall for Children and Adolescents (MARCA), a computer-delivered use-of-time instrument designed to address both the limitations of self-report recall questionnaires in children, and the lack of energy cost data in children.     

Kappa-opioid-receptor agonists modulate the renal excretion of water and electrolytes in anaesthetized rats.

1. Subcutaneous injection of the kappa-opioid agonists U50,488 (10 mg kg-1) and tifluadom (3.5 mg kg-1) into Inactin-anaesthetized, saline-infused rats was associated with a diuresis, antinatriuresis and antikaliuresis which lasted for up to 2 h. A high (5 mg kg-1), but not low (0.1 mg kg-1), dose of naloxone blocked the renal effects of U50,488. 2. U50,488 administration in anaesthetized, vasopressin-deficient Brattleboro DI rats was associated with an attenuated diuresis, though the antinatriuretic response remained intact. 3. The diuretic action of U50,488 was associated with an increase in glomerular filtration rate while fractional fluid reabsorption remained steady. In contrast, fractional sodium and potassium reabsorption were increased. 4. These data suggest that kappa-opioid agonists alter renal handling of both water and electrolytes. This appears to be mediated by two separate mechanisms: increased fluid loss largely reflects altered glomerular events while the fall in electrolyte excretion results from altered tubular handling.     

Population screening and referral for hypercholesterolemia

To determine the potential effect of screening on referral patterns, an adult population sample (4,404 men, 5,164 women, 20-69 years of age) was systematically recruited and screened for hypercholesterolemia and then analyzed by different cholesterol referral recommendations. Using levels suggested by the Lipid Research Clinics Coronary Primary Prevention Trial (greater than or equal to 265 mg/dL), 7.3% of men and 5.8% of women would be referred for follow-up. With the suggested recommendations of the National Cholesterol Education Program (NCEP), (greater than or equal to 200 mg/dL), 49.2% of men and 40.2% of women would be referred. The use of age-related definitions of the NIH Consensus Conference on Lipid Lowering results in 28.0% referrals in men and 21.8% in women. From this population, hypercholesterolemia subjects (greater than or equal to 265 mg/dL at screening; n = 624) were invited for a second cholesterol determination (58% returned), which found 36% below the 265 mg/dL level. Population screening for cholesterol is likely to produce large numbers of patients for follow-up, with the actual numbers strongly dependent on cutoff levels and age-sex distributions. Referral and follow-up of these patients may place a significant load on an unprepared health care community.