David G. Weiss

Some adaptive strategies for inadequate sample acquisition in veterans administration cooperative clinical trials.

A major concern of any clinical trial is being able to recruit sufficient patients of the proper type so that reliable answers can be obtained for the hypotheses being tested. This article considers patient recruitment in seven VA cooperative studies and the adaptive strategies used for inadequate sample acquisition. These strategies are: (1) the re-evaluation of the required sample size; (2) the addition of new hospitals; (3) the replacement of poor recruiting hospitals; (4) the extension of the patient intake period; and (5) the modification of the patient exclusion-inclusion criteria. When there is no expectation of achieving the required sample size in a reasonable time, the study is terminated. Although each of the five strategies will increase the likelihood of successfully completing a study should a recruitment problem occur, preventing these problems from occurring should be a major concern during the planning of a study.

Modest Evidence for Linkage and Possible Confirmation of Association Between NOTCH4 and Schizophrenia in a Large Veterans Affairs Cooperative Study Sample

Wei and Hemmings [2000: Nat Genet 25:376–377], using 80 British parent–offspring trios, identified a number of NOTCH4 variants and haplotypes that showed statistically significant evidence of association to schizophrenia. Specifically, the 10 repeat allele of a (CTG)n marker and the 8 repeat allele of a (TAA)n marker demonstrated excess transmission to affected individuals; SNP2 1 and haplotypes SNP2‐(CTG)n and SNP1 2 ‐SNP2‐(CTG)n also showed significant associations. In an attempt to replicate these findings, we tested for linkage and association between the same five markers used by Wei and Hemmings in 166 families collected from a multi‐center study conducted by the Department of Veterans Affairs (DVA) Cooperative Study Program (CSP). The families include 392 affected subjects (schizophrenia or schizoaffective disorder, depressed) and 216 affected sibling pairs. The families represent a mix of European Americans (n = 62, 37%), African Americans (n = 60, 36%), and racially mixed or other races (n = 44, 27%). We identified moderate evidence for linkage in the pooled race sample (LOD = 1.25) and found excess transmission of the 8 (P = 0.06) and 13 (P = 0.04) repeat alleles of the (TAA)n marker to African American schizophrenic subjects. The 8 and 13 repeat alleles were previously identified to be positively associated with schizophrenia by Wei and Hemmings [2000: Nat Genet 25:376–377] and Sklar et al. [2001: Nat Genet 28:126–128], respectively.

The “constant intake rate” assumption in interim recruitment goal methodology for multicenter clinical trials

A primary concern of any multihospital clinical trial is the recruitment of a predetermined number of patients during a prespecified interval of time. In several recent papers a Poisson based model was used to estimate the time needed to recruit a predetermined number of patients and the probabilities of recruiting specified fractions of the sample during subintervals. The Poisson model requires the assumption that patients be recruited at a constant rate over the entire length of the interval. In this paper we test the adequacy of this model and assumption using patient intake data from nine multihospital VA clinical trials and propose an alternative Bayesian model.

Department of Veterans Affairs Cooperative Studies Program genetic linkage study of schizophrenia: Ascertainment methods and sample description

To help clarify the genetics of schizophrenia, the Department of Veterans Affairs Cooperative Studies Program has completed data collection for a genetic linkage study of schizophrenia. This article describes the methodological details of the data collection. Subsequent articles will describe the results of our genome scan, which is now in progress. The data collection protocol included the Diagnostic Interview for Genetic Studies, the Family Interview for Genetic Studies, a review of medical records, and the collection of blood for transformation into lymphoblast cell lines. Among relatives of schizophrenic probands, we assessed auditory attention and verbal memory with neuropsychological tests. Among the 166 families ascertained for the study, 143 had a single affected sib-pair, 17 had three affected siblings, one had five affected siblings and five had two sets of affected siblings. There was a total of 216 affected sib-pairs in these families. Using the n-1 rule, these families contain 188 independent affected sib-pairs.

Planning multicenter clinical trials: A biostatistician's perspective

Abstract In the planning and management of multicenter clinical trials, the role of the biostatistician has been expanded beyond that of a passive statistical consultant to medical researchers. The biostatistician is a full member of the planning committee from the outset and assumes active participation and direction in protocol development and general study management. This article provides a discussion of this role from the perspective of the coordinating center biostatistician.

The Multicenter Clinical Trials Coordinating Center Statistician: “More than a Consultant”

Abstract Over the past several decades the employment of statisticians in the area of medical clinical trials in private industry, academic centers, and the federal government has increased significantly. This trend does not appear to be slowing, particularly in those organizations that have come to be termed coordinating centers. In this article we will describe the expanded role that statisticians employed in these centers are expected to be able to fill.