Family-based association tests for quantitative traits using pooled DNA

Bader, Joel S.; Sham, Pak C.

doi:10.1038/sj.ejhg.5200893

Cited by 8 publications

(8 citation statements)

References 35 publications

(9 reference statements)

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“…An alternative approach is to pool the most invasive and least invasive organoids, and then to perform genomic analysis of the pooled upper and lower tails. We have shown that power is optimized by selecting the upper and lower 27%, with efficiency equivalent to individual measurements of a population 80% as large; the selection threshold and efficiency are robust to sibship size, effect size, and allele frequency in the context of genetic studies [27].…”

Section: Pooled Designsmentioning

confidence: 99%

Between-tumor and within-tumor heterogeneity in invasive potential

et al. 2020

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For women with access to healthcare and early detection, breast cancer deaths are caused primarily by metastasis rather than growth of the primary tumor. Metastasis has been difficult to study because it happens deep in the body, occurs over years, and involves a small fraction of cells from the primary tumor. Furthermore, within-tumor heterogeneity relevant to metastasis can also lead to therapy failures and is obscured by studies of bulk tissue. Here we exploit heterogeneity to identify molecular mechanisms of metastasis. We use "organoids", groups of hundreds of tumor cells taken from a patient and grown in the lab, to probe tumor heterogeneity, with potentially thousands of organoids generated from a single tumor. We show that organoids have the character of biological replicates: within-tumor and between-tumor variation are of similar magnitude. We develop new methods based on population genetics and variance components models to build between-tumor and within-tumor statistical tests, using organoids analogously to large sibships and vastly amplifying the test power. We show great efficiency for tests based on the organoids with the most extreme phenotypes and potential cost savings from pooled tests of the extreme tails, with organoids generated from hundreds of tumors having power predicted to be similar to bulk tests of hundreds of thousands of tumors. We apply these methods to an association test for molecular correlates of invasion, using a novel quantitative invasion phenotype calculated as the spectral power of the organoid boundary. These new approaches combine to show a strong association between invasion and protein expression of Keratin 14, a known biomarker for poor prognosis, with p = 2 × 10 −45 for within-tumor tests of individual organoids and p < 10 −6 for pooled tests of extreme tails. Future studies using these methods could lead to discoveries of new classes of cancer targets and development of corresponding therapeutics. All data and methods are available under an open source license at https://github.com/ baderzone/invasion_2019.

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Section: Pooled Designsmentioning

confidence: 99%

Between-tumor and within-tumor heterogeneity in invasive potential

et al. 2020

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“…The optimal proportion of the distribution of individuals to include in such analysis was shown to be 27% under the circumstances where no measurement error was involved (Bader et al, 2002). In this study we investigated the comparative NCP that would be expected from selection proportions between 5% and 25% with measurement error of 0.0009.…”

Section: The Optimal Extreme Proportion Of the Distribution For Inclumentioning

confidence: 99%

“…One proposed strategy to reduce cost is the use of pooled DNA as a screening device, before following up interesting findings with individual genotyping and analysis (Downes et al, 2004;Norton et al, 2004;Sham et al, 2002). Although initially used for case-control designs, methods have also been derived for family based association studies (Bader and Sham, 2002;Risch and Teng, 1998). Recently it has been demonstrated that microarray technology can be used to accurately measure allele frequencies in pooled samples (Butcher et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Design and Analysis of Association Studies using Pooled DNA from Large Twin Samples

Knight

Sham

2006

Behav Genet

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Evidence is mounting that multiple genes are involved in complex traits and that these each account for very small proportions of the overall phenotypic variance. Association studies of many markers in 1000s of individuals will be required to identify such genes. A number of large twin cohorts have already been collected and provide a valuable resource for carrying out studies that are robust to the effect of population stratification. Technologies based on microarrays will soon allow 1.000,000 SNPs to be typed at one time, however financial considerations prevent most researchers from using these approaches to genotype all individuals. Recently, microarrays have been shown to give accurate allele frequency measurements in pooled DNA samples and provide a simple way to select the best markers for individual genotyping. This drastically reduces the cost and workload of large scale association studies. One limitation of this methodology relates to the analytical procedures which have only been developed to allow comparison of two pools e.g. case/control pools. In this paper we use meta-regression to analyze pooled DNA data allowing the allele frequency in each pool to be related to the average quantitative phenotypic measure of the individuals whose DNA were used to construct the pools. Alongside this we describe a technique that can be used to determine the power for such studies. We present results from some preliminary investigations of different pooling strategies that can be applied to large twin samples and demonstrate that the method retains a large proportion of the power available from individual genotyping.

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“…A case-parents design needs to genotype two controls (the biological parents) for each affected individual rather than the one control typical with case-control designs. To reduce the genotyping needed for family-based association studies while preserving robustness and statistical efficiency, several authors proposed comparing variant allele frequencies measured in pooled DNA specimens (Zou & Zhao, 2005, Risch & Teng, 1998, Bader & Sham, 2002, Lee, 2005, Beckman et al , 2006). Here we propose a method to analyze pooled DNA specimens based on probabilistically disaggregating the pooled genotypes into their component individual genotypes.…”

Section: Introductionmentioning

confidence: 99%

Disentangling Pooled Triad Genotypes for Association Studies

Shi

Umbach

Weinberg

2014

Annals of Human Genetics

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Association studies that genotype affected offspring and their parents (triads) offer robustness to genetic population structure while enabling assessments of maternal effects, parent-of-origin effects, and gene-by-environment interaction. We propose case-parents designs that use pooled DNA specimens to make economical use of limited available specimens. One can markedly reduce the number of genotyping assays required by randomly partitioning the case-parent triads into pooling sets of h triads each and creating three pools from every pooling set, one pool each for mothers, fathers, and offspring. Maximum-likelihood estimation of relative risk parameters proceeds via log-linear modeling using the expectation-maximization algorithm. The approach can assess offspring and maternal genetic effects and accommodate genotyping errors and missing genotypes. We compare the power of our proposed analysis for testing offspring and maternal genetic effects to that based on a difference approach considered by Lee and that of the gold-standard based on individual genotypes, under a range of allele frequencies, missing parent proportions and genotyping error rates. Power calculations show that the pooling strategies cause only modest reductions in power if genotyping errors are low, while reducing genotyping costs and conserving limited specimens.

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Family-based association tests for quantitative traits using pooled DNA

Cited by 8 publications

References 35 publications

Between-tumor and within-tumor heterogeneity in invasive potential

Between-tumor and within-tumor heterogeneity in invasive potential

Design and Analysis of Association Studies using Pooled DNA from Large Twin Samples

Disentangling Pooled Triad Genotypes for Association Studies

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