On the total expected study cost in two‐stage genome‐wide search designs for linkage analysis using the mean test for affected sib pairs

Ziegler, Andreas; Böddeker, Inke; Geller, Frank; Müller, Hans‐Helge; Guo, Xiuqing

doi:10.1002/gepi.9

Cited by 5 publications

(7 citation statements)

References 3 publications

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“…It is standard in this field to single out significant genomic regions from pilot analysis to follow up with increased sample sizes from independent cases (validation), more genetic markers (fine mapping), 16–19 or both in a second validation stage (Figure 1). We followed this strategy of independent validation and fine mapping of the “potentially interesting” regions identified by the pilot linkage-association analysis.…”

Section: Methodsmentioning

confidence: 99%

Germline Mutations in MSR1, ASCC1, and CTHRC1 in Patients With Barrett Esophagus and Esophageal Adenocarcinoma

Orloff¹,

Peterson²,

He³

et al. 2011

JAMA

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Context Barrett esophagus (BE) occurs in 1% to 10% of the general population and is believed to be the precursor of esophageal adenocarcinoma (EAC). The incidence of EAC has increased 350% in the last 3 decades without clear etiology. Finding predisposition genes may improve premorbid risk assessment, genetic counseling, and management. Genome-wide multiplatform approaches may lead to the identification of genes important in BE/EAC development. Objective To identify risk alleles or mutated genes associated with BE/EAC. Design, Setting, and Patients Model-free linkage analyses of 21 concordant-affected sibling pairs with BE/EAC and 11 discordant sibling pairs (2005–2006). Significant germline genomic regions in independent prospectively accrued series of 176 white patients with BE/EAC and 200 ancestry-matched controls (2007–2010) were validated and fine mapped. Integrating data from these significant genomic regions with somatic gene expression data from 19 BE/EAC tissues yielded 12 “priority” candidate genes for mutation analysis (2010). Genes that showed mutations in cases but not in controls were further screened in an independent prospectively accrued validation series of 58 cases (2010). Main Outcome Measures Identification of germline mutations in genes associated with BE/EAC cases. Functional interrogation of the most commonly mutated gene. Results Three major genes, MSR1, ASCC1, and CTHRC1 were associated with BE/EAC (all P<.001). In addition, 13 patients (11.2%) with BE/EAC carried germline mutations in MSR1, ASCC1, or CTHRC1. MSR1 was the most frequently mutated, with 8 of 116 (proportion, 0.069; 95% confidence interval [CI], 0.030–0.130; P<.001) cases with c.877C>T (p.R293X). An independent validation series confirmed germline MSR1 mutations in 2 of 58 cases (proportion, 0.035; 95% CI, 0.004–0.120; P=.09). MSR1 mutation resulted in CCND1 up-regulation in peripheral-protein lysate. Immunohistochemistry of BE tissues in MSR1-mutation carriers showed increased nuclear expression of CCND1. Conclusion MSR1 was significantly associated with the presence of BE/EAC in derivation and validation samples, although it was only present in a small percentage of the cases.

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Section: Methodsmentioning

confidence: 99%

Germline Mutations in MSR1, ASCC1, and CTHRC1 in Patients With Barrett Esophagus and Esophageal Adenocarcinoma

Orloff¹,

Peterson²,

He³

et al. 2011

JAMA

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“…The cost function used to be optimized, however, has been shown to be inadequate (Ziegler et al, 2001). It does not consider that genetic markers in small distance to the disease locus are correctly linked in addition to genetic markers that directly flank the disease locus.…”

Section: Theoretically Based Proceduresmentioning

confidence: 99%

Sequential Designs for Genetic Epidemiological Linkage or Association Studies A Review of the Literature

Böddeker

Ziegler

2001

Biom. J.

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Objectives. The cost of a genetic linkage or association study is largely determined by the number of individuals to be recruited, phenotyped, and genotyped. The efficiency can be increased by using a sequential procedure that reduces time and cost on average. Two strategies for sequential designs in genetic epidemiological studies can be distinguished: One approach is to increase the sample size sequentially and to conduct multiple significance tests on accumulating data. If significance or futility can be assumed with a certain probability, the study is stopped. Otherwise, it is carried on to the next stage. The second approach is to conduct early linkage analyses on a coarse marker grid, and to increase marker density in later stages. Interim analyses are performed to select interesting genomic areas for follow up. The aim of this article is to give a review on sequential procedures in the context of genetic linkage and association studies. Methods. A systematic literature search was performed in the Medline and the Linkage Bibliography databases. Articles were defined as relevant if a sequential design was proposed or applied in genetic linkage or association studies. Results. The majority of proposed study designs is developed to meet the demands of specific studies and lacks a theoretical foundation. A second group of procedures is based on simulation results and principally restricted to the specific simulated situations. Finally, some theoretically founded procedures have been proposed that are discussed in detail. Conclusions. Although interesting and promising procedures have been suggested, they still lack realizations for practical purposes. In addition, further developments are required to adapt sequential strategies for optimal use in genetic epidemiological studies.

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“…Therefore, it cannot be recommended for practical purposes. The other sequential procedure [Elston et al, 1996;Guo and Elston, 2000a,b;Ziegler et al, 2001] involved increasing the marker density in interesting genomic regions in the second of two stages. The other regions are excluded from further analysis at the same time, and the null hypothesis is accepted early.…”

Section: Introductionmentioning

confidence: 99%

Reducing sample sizes in genome scans: Group sequential study designs with futility stops

König

Schäfer

Ziegler

et al. 2003

Genetic Epidemiology

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Group sequential study designs can greatly facilitate analyses of genetic linkage in complex traits. We recently proposed designs allowing stopping investigations early if the result is significant (König et al. [2001] Am. J. Hum. Genet. 69:590-600), thereby decreasing average sample sizes under the alternative hypothesis. However, average sample sizes were slightly increased under the null hypothesis. We now present designs where the analysis of markers is additionally stopped in case of futility, i.e., if the probability for significant results is sufficiently low. These sequential designs are applied to linkage analyses of single loci. We calculated sample sizes, time points, and critical boundaries for all analyses for 2- and 3-stage designs at an overall significance level of 0.0001. To confirm the validity of asymptotic approximations, Monte Carlo simulations were performed. The utility is demonstrated analyzing genome scan data provided for the Genetic Analysis Workshop 12. Application of the novel sequential designs yields tremendous decreases in average sample sizes, regardless of the size of the underlying genetic effect at investigated loci. Depending on the applied design, almost half of the sample size is spared on average. These enormous savings are expected to have a special impact on costs and time of large-scale studies such as genome scans.

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On the total expected study cost in two‐stage genome‐wide search designs for linkage analysis using the mean test for affected sib pairs

Cited by 5 publications

References 3 publications

Germline Mutations in MSR1, ASCC1, and CTHRC1 in Patients With Barrett Esophagus and Esophageal Adenocarcinoma

Germline Mutations in MSR1, ASCC1, and CTHRC1 in Patients With Barrett Esophagus and Esophageal Adenocarcinoma

Sequential Designs for Genetic Epidemiological Linkage or Association Studies A Review of the Literature

Reducing sample sizes in genome scans: Group sequential study designs with futility stops

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