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A robust and efficient statistical method for genetic association studies using case and control samples from multiple cohorts.

ABSTRACT: The theoretical basis of genome-wide association studies (GWAS) is statistical inference of linkage disequilibrium (LD) between any polymorphic marker and a putative disease locus. Most methods widely implemented for such analyses are vulnerable to several key demographic factors and deliver a poor statistical power for detecting genuine associations and also a high false positive rate. Here, we present a likelihood-based statistical approach that accounts properly for non-random nature of case-control samples in regard of genotypic distribution at the loci in populations under study and confers flexibility to test for genetic association in presence of different confounding factors such as population structure, non-randomness of samples etc.We implemented this novel method together with several popular methods in the literature of GWAS, to re-analyze recently published Parkinson's disease (PD) case-control samples. The real data analysis and computer simulation show that the new method confers not only significantly improved statistical power for detecting the associations but also robustness to the difficulties stemmed from non-randomly sampling and genetic structures when compared to its rivals. In particular, the new method detected 44 significant SNPs within 25 chromosomal regions of size?

SUBMITTER: Wang M

PROVIDER: S-EPMC3626840 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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A robust and efficient statistical method for genetic association studies using case and control samples from multiple cohorts.

Wang Minghui M Wang Lin L Jiang Ning N Jia Tianye T Luo Zewei Z

BMC genomics 20130208

<h4>Background</h4>The theoretical basis of genome-wide association studies (GWAS) is statistical inference of linkage disequilibrium (LD) between any polymorphic marker and a putative disease locus. Most methods widely implemented for such analyses are vulnerable to several key demographic factors and deliver a poor statistical power for detecting genuine associations and also a high false positive rate. Here, we present a likelihood-based statistical approach that accounts properly for non-ran ...[more]

PMID: 23394771

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Project description:Pooling biomarker data across multiple studies allows for examination of a wider exposure range than generally possible in individual studies, evaluation of population subgroups and disease subtypes with more statistical power, and more precise estimation of biomarker-disease associations. However, circulating biomarker measurements often require calibration to a single reference assay prior to pooling due to assay and laboratory variability across studies. We propose several methods for calibrating and combining biomarker data from nested case-control studies when reference assay data are obtained from a subset of controls in each contributing study. Specifically, we describe a two-stage calibration method and two aggregated calibration methods, named the internalized and full calibration methods, to evaluate the main effect of the biomarker exposure on disease risk and whether that association is modified by a potential covariate. The internalized method uses the reference laboratory measurement in the analysis when available and otherwise uses the estimated value derived from calibration models. The full calibration method uses calibrated biomarker measurements for all subjects, including those with reference laboratory measurements. Under the two-stage method, investigators complete study-specific analyses in the first stage followed by meta-analysis in the second stage. Our results demonstrate that the full calibration method is the preferred aggregated approach to minimize bias in point estimates. We also observe that the two-stage and full calibration methods provide similar effect and variance estimates but that their variance estimates are slightly larger than those from the internalized approach. As an illustrative example, we apply the three methods in a pooling project of nested case-control studies to evaluate (i) the association between circulating vitamin D levels and risk of stroke and (ii) how body mass index modifies the association between circulating vitamin D levels and risk of cardiovascular disease.

Dataset Information

A robust and efficient statistical method for genetic association studies using case and control samples from multiple cohorts.

Publications

A robust and efficient statistical method for genetic association studies using case and control samples from multiple cohorts.

Similar Datasets

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