Summary. Multitiered experiments are characterized by involving multiple randomizations, in a sense that we make explicit. We compare and contrast six types of multiple randomizations, using a wide range of examples, and discuss their use in designing experiments. We outline a system of describing the randomizations in terms of sets of objects, their associated tiers and the factor nesting, using randomization diagrams, which give a convenient and readily assimilated summary of an experiment's randomization. We also indicate how to formulate a randomization-based mixed model for the analysis of data from such experiments.
Standard factorial designs may sometimes be inadequate for experiments that aim to estimate a generalized linear model, for example, for describing a binary response in terms of several variables. A method is proposed for finding exact designs for such experiments which uses a criterion that allows for uncertainty in the link function, the linear predictor or the model parameters, together with a design search. Designs are assessed and compared by simulation of the distribution of efficiencies relative to locally optimal designs over a space of possible models. Exact designs are investigated for two applications and their advantages over factorial and central composite designs are demonstrated.
Aberrant glycosylation is a pathological alteration that is widespread in colon cancer, and usually accompanies the onset and progression of the disease. To date, the molecular mechanisms underlying aberrant glycosylation remain largely unknown. In this study, we identify somatic and germ-line mutations in the gene encoding for polypeptide N-acetylgalactosaminyltransferase 12 (GALNT12) in individuals with colon cancer. Biochemical analyses demonstrate that each of the 8 GALNT12 mutations identified inactivates the normal function of the GALNT enzyme in initiating mucin type O-linked protein glycosylation. Two of these inactivating GALNT12 mutations were identified as acquired somatic mutations in a set of 30 microsatellite stable colon tumors. Relative to background gene mutation rates, finding these somatic GALNT12 mutations was statistically significant at P < 0.001. Six additional inactivating GALNT12 mutations were detected as germ-line changes carried by patients with colon cancer; however, no inactivating variants were detected among cancer-free controls (P ؍ 0.005). Notably, in 3 of the 6 individuals harboring inactivating germ-line GALNT12 mutations, both a colon cancer and a second independent epithelial cancer had developed. These findings suggest that genetic defects in the O-glycosylation pathway in part underlie aberrant glycosylation in colon cancers, and they contribute to the development of a subset of these malignancies.cancer ͉ GALNT ͉ glycosylation
Colorectal cancer is the second most leading cause of cancer death among adult Americans. Two autosomal dominant hereditary forms of the disease, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, together account for perhaps 5% of all cases. However, in Ϸ20% of additional colon cancer cases, the affected individuals report a family history of colon cancer in a first-degree relative. Similar familial clusters of colon cancer and early-onset colon adenomas have also been reported. To determine whether such familial aggregations arise by chance or reflect a hereditary colon cancer susceptibility, we conducted a whole genome scan to test for genetic linkage in 53 kindreds in which two or more siblings were affected by age 65 or younger with colon cancer or with advanced colon adenomas that were >1 cm in size or that showed high-grade dysplasia. In this cohort we found genetic linkage of disease (P ؍ 0.00045) to chromosomal region 9q22.2-31.2 in a pattern consistent with autosomal dominant disease alleles. These data suggest that a single locus can contribute to disease susceptibility in a subset of patients with nonsyndromic forms of familial colorectal neoplasia.colorectal cancer ͉ colon adenomas ͉ genetic linkage ͉ familial cancers C olorectal cancer is the second most leading cause of cancer death among adult Americans (1). Strongly penetrant autosomal dominant hereditary forms of the disease, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), together account for perhaps 5% of all cases (2-4). However, in Ϸ20% of additional colon cancer cases the affected individuals report a family history of colon cancer in a first-degree relative, and a genetic basis for these familial disease clusters has also been hypothesized (5).Colorectal cancers themselves develop from precursor colon adenomas (3). Thus, the inherited FAP syndrome, which is caused by inactivating mutations in the adenomatous polyposis coli (APC) gene, is marked by development of a profusion of hundreds of colon adenomas that then confer a near 100% risk of colon cancer development by an average age of 40 (2, 3). A subtler adenoma and cancer phenotype is associated with an APC I1307K polymorphism present in the Ashkenazi Jewish population (2). The APC I1307K variant DNA sequence demonstrates enhanced vulnerability to development of inactivating somatic APC mutations, resulting in a slightly less than 2-fold increased risk of colon adenoma and cancer development (2). The existence of additional disease genes associated with increased risk of developing colon adenomas and cancers is suggested by observations of an Ϸ3-fold increased risk of colon cancer among first-degree relatives of individuals who develop colon adenomas before age 60 (6), and by one study that suggested that 19% of persons in the general population might carry autosomal dominant disease alleles conferring susceptibility for colon adenoma or cancer development (7). However, more recent endoscopic-based studies have sug...
Purpose Return of individual research results from genomic studies is a hotly debated ethical issue in genomic research. However, the perspective of key stakeholders—Institutional Review Board (IRB) reviewers—has been missing from this dialogue. This study explores the positions and experiences of IRB members and staff regarding this issue. Methods In depth interviews with 31 IRB professionals at six sites across the United States. Results IRB professionals agreed that research results should be returned to research participants when results are medically actionable but only if the participants wanted to know the result. Many respondents expected researchers to address the issue of return of results (ROR) in the IRB application and informed-consent document. Many respondents were not comfortable with their expertise in genomics research, and only a few described actual experiences in addressing ROR. Although participants agreed that guidelines would be helpful, most were reticent to develop them in isolation. Even where IRB guidance exists (e.g., CLIA lab certification required for return), in practice, the guidance has been overruled to allow return (e.g., no CLIA lab performs the assay). Conclusion An IRB-researcher partnership is needed to help inform responsible and feasible institutional approaches to returning research results.
Purpose Genetic research involving human participants can pose challenging questions related to ethical and regulatory standards for research oversight. However, few empirical studies describe how genetic researchers and institutional review board (IRB) professionals conceptualize ethical issues in genetic research or where common ground might exist. Methods Parallel online surveys collected information from human genetic researchers (n = 351) and IRB professionals (n = 208) regarding their views about human participant oversight for genetic protocols. Results A range of opinions were observed within groups on most issues. In both groups, a minority thought it likely that people would be harmed by participation in genetic research or identified from coded genetic data. A majority of both groups agreed that reconsent should be required for four of the six scenarios presented. Statistically significant differences were observed between groups on some issues, with more genetic researcher respondents trusting the confidentiality of coded data, fewer expecting harms from reidentification, and fewer considering reconsent necessary in certain scenarios. Conclusions The range of views observed within and between IRB and genetic researcher groups highlights the complexity and unsettled nature of many ethical issues in genome research. Our findings also identify areas where researcher and IRB views diverge and areas of common ground.
Background: Researchers often relate personal experiences of difficulties and challenges with Institutional Review Board (IRB) review of their human genetic research protocols. However, there have been no studies that document the range and frequency of these concerns among researchers conducting human genetic/genomic studies. Methods: An online anonymous survey was used to collect information from human genetic researchers regarding views about IRB review of genetic protocols. Logistic regression was used to test specific hypotheses. Results from the national online survey of 351 human genomic researchers are summarized in this report. Results: Issues involving considerable discussion with IRBs included reconsent of subjects (51%), protection of participants’ personal information (39%) and return of results to participants (34%). Over half of the participants had experienced one or more negative consequences of the IRB review process and approximately 25% had experienced one or more positive consequences. Respondents who had served on an IRB were about 80% more likely to report positive consequences of IRB review than their colleagues who had never served on an IRB (p = 0.03). Survey responses were mixed on the need for reconsent before data sharing and risks related to participant reidentification from genomic data. Conclusion: The results from this study provide important perspectives of researchers regarding genetic research review and show lack of consensus on key research ethics issues in genomic research.
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