One-Stage Design Evaluating Survival Distributions

Author(s):  
Jianrong Wu
Keyword(s):  
Author(s):  
Jaya M Satagopan ◽  
Saunak Sen ◽  
Gary A. Churchill

The etiology of complex diseases is heterogeneous. The presence of risk alleles in one or more genetic loci affects the function of a variety of intermediate biological pathways, resulting in the overt expression of disease. Hence, there is an increasing focus on identifying the genetic basis of disease by systematically studying phenotypic traits pertaining to the underlying biological functions. In this paper we focus on identifying genetic loci linked to quantitative phenotypic traits in experimental crosses. Such genetic mapping methods often use a one stage design by genotyping all the markers of interest on the available subjects. A genome scan based on single locus or multi-locus models is used to identify the putative loci. Since the number of quantitative trait loci (QTLs) is very likely to be small relative to the number of markers genotyped, a one-stage selective genotyping approach is commonly used to reduce the genotyping burden, whereby markers are genotyped solely on individuals with extreme trait values. This approach is powerful in the presence of a single quantitative trait locus (QTL) but may result in substantial loss of information in the presence of multiple QTLs. Here we investigate the efficiency of sequential two stage designs to identify QTLs in experimental populations. Our investigations for backcross and F2 crosses suggest that genotyping all the markers on 60% of the subjects in Stage 1 and genotyping the chromosomes significant at 20% level using additional subjects in Stage 2 and testing using all the subjects provides an efficient approach to identify the QTLs and utilizes only 70% of the genotyping burden relative to a one stage design, regardless of the heritability and genotyping density. Complex traits are a consequence of multiple QTLs conferring main effects as well as epistatic interactions. We propose a two-stage analytic approach where a single-locus genome scan is conducted in Stage 1 to identify promising chromosomes, and interactions are examined using the loci on these chromosomes in Stage 2. We examine settings under which the two-stage analytic approach provides sufficient power to detect the putative QTLs.


2008 ◽  
Vol 11 (2) ◽  
pp. 542-550 ◽  
Author(s):  
María Angeles Peláez-Fernández ◽  
Francisco Javier Labrador ◽  
Rosa María Raich

The aim of this research was to compare two different case-identification designs: (a) a one-stage anonymous design using the Eating Disorders Examination-Questionnaire (EDE-Q; Fairburn & Beglin, 1994) as diagnostic instrument and (b) a two-stage-non-anonymous design using the Eating Attitudes Test (EAT; Garner & Garfinkel, 1979) and the EDE-Q as screening instruments and the clinical interview Eating Disorders Examination (EDE; Fairburn & Cooper, 1993) as diagnostic instrument, in the estimation of eating disorders prevalence in community samples. Both epidemiological designs were compared in: eating disorders prevalence, population at risk, and weekly frequency of associated symptomatology (binge eating episodes, self-vomiting) within a sample of 559 scholars (14 to 18 year-old males and females) studying in the region of Madrid. Eating disorders prevalence estimation using single-stage design was 6.2%, and 3% using the two-stage design; however, these differences were not significant (p = .067). No significant differences between the two procedures were found either in population at risk or in weekly frequency of reported self-vomiting. Reported binge eating episodes were higher in the one-stage design. The use of a two-stage procedure with clinical interview (vs. questionnaire) leads to a better understanding of the items (specially the most ambiguous ones) and thus, to a more accurate prevalence estimation.


Genetics ◽  
2002 ◽  
Vol 162 (2) ◽  
pp. 875-892 ◽  
Author(s):  
Rongling Wu ◽  
Chang-Xing Ma ◽  
Maria Gallo-Meagher ◽  
Ramon C Littell ◽  
George Casella

AbstractThe endosperm, a result of double fertilization in flowering plants, is a triploid tissue whose genetic composition is more complex than diploid tissue. We present a new maximum-likelihood-based statistical method for mapping quantitative trait loci (QTL) underlying endosperm traits in an autogamous plant. Genetic mapping of quantitative endosperm traits is qualitatively different from traits for other plant organs because the endosperm displays complicated trisomic inheritance and represents a younger generation than its mother plant. Our endosperm mapping method is based on two different experimental designs: (1) a one-stage design in which marker information is derived from the maternal genome and (2) a two-stage hierarchical design in which marker information is derived from both the maternal and offspring genomes (embryos). Under the one-stage design, the position and additive effect of a putative QTL can be well estimated, but the estimates of the dominant and epistatic effects are upward biased and imprecise. The two-stage hierarchical design, which extracts more genetic information from the material, typically improves the accuracy and precision of the dominant and epistatic effects for an endosperm trait. We discuss the effects on the estimation of QTL parameters of different sampling strategies under the two-stage hierarchical design. Our method will be broadly useful in mapping endosperm traits for many agriculturally important crop plants and also make it possible to study the genetic significance of double fertilization in the evolution of higher plants.


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