Expansion of the modified Zelen's approach randomization and dynamic randomization with partial block supplies at the centers to unequal allocation.

Modified Zelen's approach is a randomization technique useful in multi-center trials where balance in treatment assignments within a center is desired. It has great balancing properties in a study with equal allocation to several treatment arms. This technique can also be used in studies with unequal allocation, where it would provide an allocation ratio close to the targeted one within centers as well as across centers. However, the implementation of the modified Zelen's approach for unequal allocation involves more than just imposing a constraint on within-center imbalance in treatment assignments, as is the case with equal allocation. Failure to account for this might provide a potential for accidental bias and (even in a double-blind study) selection and evaluation bias. The naive expansion of the modified Zelen's approach to unequal allocation can also lead to a shift in the re-randomization distribution of the between-group difference in treatment means. This paper will explain why and will offer an easy way to expand the modified Zelen's approach to unequal allocation that allows one to avoid these issues. The expansion to unequal allocation of another very useful in multi-center trials technique where partial blocks of supplies are sent to the centers will be offered.

Change in cartilage morphometry: a sample of the progression cohort of the Osteoarthritis Initiative.

OBJECTIVE: The performance characteristics of hyaline articular cartilage measurement on magnetic resonance imaging (MRI) need to be accurately delineated before widespread application of this technology. Our objective was to assess the rate of natural disease progression of cartilage morphometry measures from baseline to 1 year in knees with osteoarthritis (OA) from a subset of participants from the Osteoarthritis Initiative (OAI). METHODS: Subjects included for this exploratory analysis are a subset of the approximately 4700 participants in the OAI Study. Bilateral radiographs and 3T MRI (Siemans Trio) of the knees and clinical data were obtained at baseline and annually in all participants. 160 subjects from the OAI Progression subcohort all of whom had both frequent symptoms and, in the same knee, radiographic OA based on a screening reading done at the OAI clinics were eligible for this exploratory analysis. One knee from each subject was selected for analysis. 150 participants were included. Using sagittal 3D DESSwe (double echo, steady-state sequence with water excitation) MR images from the baseline and 12 follow-up month visit, a segmentation algorithm was applied to the cartilage plates of the index knee to compute the cartilage volume, normalised cartilage volume (volume normalised to bone surface interface area), and percentage denuded area (total cartilage bone interface area denuded of cartilage). RESULTS: Summary statistics of the changes (absolute and percentage) from baseline at 1 year and the standardised response mean (SRM), ie, mean change divided by the SD change were calculated. On average the subjects were 60.9 years of age and obese, with a mean body mass index of 30.3 kg/m2. The SRMs for cartilage volume of various locations are: central medial tibia -0.096; central medial femur -0.394; and patella -0.198. The SRMs for normalised cartilage volume of the various locations are central medial tibia -0.044, central medial femur -0.338 and patella -0.193. The majority of participants had a denuded area at baseline in the central medial femur (62%) and central medial tibia (60%). In general, the SRMs were small. CONCLUSIONS: These descriptive results of cartilage morphometry and its change at the 1-year time point from the first substantive MRI data release from the OAI Progression subcohort indicate that the annualised rates of change are small with the central medial femur showing the greatest consistent change.