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Article ; Online: Ghost QTL and hotspots in experimental crosses: novel approach for modeling polygenic effects.

Wallin, Jonas / Bogdan, Małgorzata / Szulc, Piotr A / Doerge, R W / Siegmund, David O

2021 Volume 217, Issue 3

Abstract: Ghost quantitative trait loci (QTL) are the false discoveries in QTL mapping, that arise due to the "accumulation" of the polygenic effects, uniformly distributed over the genome. The locations on the chromosome that are strongly correlated with the ... ...

Abstract	Ghost quantitative trait loci (QTL) are the false discoveries in QTL mapping, that arise due to the "accumulation" of the polygenic effects, uniformly distributed over the genome. The locations on the chromosome that are strongly correlated with the total of the polygenic effects depend on a specific sample correlation structure determined by the genotypes at all loci. The problem is particularly severe when the same genotypes are used to study multiple QTL, e.g. using recombinant inbred lines or studying the expression QTL. In this case, the ghost QTL phenomenon can lead to false hotspots, where multiple QTL show apparent linkage to the same locus. We illustrate the problem using the classic backcross design and suggest that it can be solved by the application of the extended mixed effect model, where the random effects are allowed to have a nonzero mean. We provide formulas for estimating the thresholds for the corresponding t-test statistics and use them in the stepwise selection strategy, which allows for a simultaneous detection of several QTL. Extensive simulation studies illustrate that our approach eliminates ghost QTL/false hotspots, while preserving a high power of true QTL detection.
MeSH term(s)	Animals ; Breeding/methods ; Crosses, Genetic ; Genome-Wide Association Study/methods ; Genome-Wide Association Study/standards ; Models, Genetic ; Multifactorial Inheritance ; Plants/genetics ; Quantitative Trait Loci
Language	English
Publishing date	2021-03-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2167-2
ISSN	1943-2631 ; 0016-6731
ISSN (online)	1943-2631
ISSN	0016-6731
DOI	10.1093/genetics/iyaa041
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Book: The statistics of gene mapping

Siegmund, David O / Yakir, Benjamin

(Statistics for biology and health)

2007

Author's details	David Siegmund; Benjamin Yakir
Series title	Statistics for biology and health
Keywords	Gene mapping/Statistical methods ; Genkartierung ; Statistik
Language	English
Size	XVII, 331 S., graph. Darst.
Publisher	Springer
Publishing place	New York, NY
Document type	Book
Note	Literaturverz. S. [323] - 327
ISBN	038749684X ; 0387496866 ; 9780387496849 ; 9780387496863
Database	Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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Article ; Online: Approximating the variance of the conditional probability of the state of a hidden Markov model.

Siegmund, David O / Yakir, Benjamin

Statistical applications in genetics and molecular biology

2007 Volume 6, Page(s) Article 18

Abstract: In a hidden Markov model, one "estimates" the state of the hidden Markov chain at t by computing via the forwards-backwards algorithm the conditional distribution of the state vector given the observed data. The covariance matrix of this conditional ... ...

Abstract	In a hidden Markov model, one "estimates" the state of the hidden Markov chain at t by computing via the forwards-backwards algorithm the conditional distribution of the state vector given the observed data. The covariance matrix of this conditional distribution measures the information lost by failure to observe directly the state of the hidden process. In the case where changes of state occur slowly relative to the speed at which information about the underlying state accumulates in the observed data, we compute approximately these covariances in terms of functionals of Brownian motion that arise in change-point analysis. Applications in gene mapping, where these covariances play a role in standardizing the score statistic and in evaluating the loss of noncentrality due to incomplete information, are discussed. Numerical examples illustrate the range of validity and limitations of our results.
MeSH term(s)	Markov Chains ; Models, Genetic ; Probability Theory
Language	English
Publishing date	2007
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ISSN	1544-6115
ISSN (online)	1544-6115
DOI	10.2202/1544-6115.1296
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Article: A modified Bayes information criterion with applications to the analysis of comparative genomic hybridization data.

Zhang, Nancy R / Siegmund, David O

Biometrics

2007 Volume 63, Issue 1, Page(s) 22–32

Abstract: In the analysis of data generated by change-point processes, one critical challenge is to determine the number of change-points. The classic Bayes information criterion (BIC) statistic does not work well here because of irregularities in the likelihood ... ...

Abstract	In the analysis of data generated by change-point processes, one critical challenge is to determine the number of change-points. The classic Bayes information criterion (BIC) statistic does not work well here because of irregularities in the likelihood function. By asymptotic approximation of the Bayes factor, we derive a modified BIC for the model of Brownian motion with changing drift. The modified BIC is similar to the classic BIC in the sense that the first term consists of the log likelihood, but it differs in the terms that penalize for model dimension. As an example of application, this new statistic is used to analyze array-based comparative genomic hybridization (array-CGH) data. Array-CGH measures the number of chromosome copies at each genome location of a cell sample, and is useful for finding the regions of genome deletion and amplification in tumor cells. The modified BIC performs well compared to existing methods in accurately choosing the number of regions of changed copy number. Unlike existing methods, it does not rely on tuning parameters or intensive computing. Thus it is impartial and easier to understand and to use.
MeSH term(s)	Bayes Theorem ; Biometry ; Cell Line ; Computer Simulation ; Genome ; Humans ; Models, Genetic ; Monte Carlo Method ; Nucleic Acid Hybridization ; Oligonucleotide Array Sequence Analysis/methods
Language	English
Publishing date	2007-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	213543-7
ISSN	0006-341X ; 0099-4987
ISSN	0006-341X ; 0099-4987
DOI	10.1111/j.1541-0420.2006.00662.x
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Article ; Online: Endpoints for extraintestinal manifestations in inflammatory bowel disease trials: the EXTRA consensus from the International Organization for the Study of Inflammatory Bowel Diseases.

Guillo, Lucas / Abreu, Maria / Panaccione, Remo / Sandborn, William J / Azevedo, Valderilio F / Gensler, Lianne / Moghaddam, Bahar / Ahuja, Vineet / Ali, Sabrina A / Allez, Matthieu / Ananthakrishnan, Ashwin N / Bhattacharya, Abhik / Dubinsky, Marla / Griffiths, Anne / Hart, Ailsa / Korelitz, Burton / Kotze, Paulo G / Koutroubakis, Ioannis E / Lakatos, Peter L /

The lancet. Gastroenterology & hepatology

2022 Volume 7, Issue 3, Page(s) 254–261

Abstract: Extraintestinal manifestations occur frequently in patients with inflammatory bowel disease (IBD) and remain a diagnostic and therapeutic challenge. The aim of the Endpoints for Extraintestinal Manifestations in Inflammatory Bowel Disease Trials (EXTRA) ... ...

Abstract	Extraintestinal manifestations occur frequently in patients with inflammatory bowel disease (IBD) and remain a diagnostic and therapeutic challenge. The aim of the Endpoints for Extraintestinal Manifestations in Inflammatory Bowel Disease Trials (EXTRA) initiative was to achieve international expert consensus on how to assess these manifestations in IBD trials. A systematic literature review was done to identify methods to diagnose extraintestinal manifestations in patients with IBD and measure treatment outcomes. A consensus meeting involving a panel of 41 attendees, including gastroenterologists and referral specialists, was held on March 31, 2021, as part of an International Organization for the Study of Inflammatory Bowel Diseases initiative. The panel agreed that a specialist's expertise is needed to confirm the diagnosis of extraintestinal manifestations before the inclusion of a patient in IBD trials, except for axial spondyloarthritis, for which typical symptoms and MRI can be sufficient. Easy-to-measure endpoints were identified to assess the response of extraintestinal manifestations to treatment without needing specialist involvement. For uveitis, peripheral spondyloarthritis, and arthralgia, endpoint measurements need specialist expertise. The timing of endpoint measurements was discussed for individual extraintestinal manifestations. The EXTRA consensus proposes guidelines on how to thoroughly evaluate extraintestinal manifestations within IBD trials, and recommends that these guidelines are implemented in future trials to enable prospective assessment of these manifestations and comparison between studies.
MeSH term(s)	Clinical Trials as Topic ; Eye Diseases/etiology ; Humans ; Inflammatory Bowel Diseases/complications ; Rheumatic Diseases/etiology ; Skin Diseases/etiology
Language	English
Publishing date	2022-01-17
Publishing country	Netherlands
Document type	Consensus Development Conference ; Journal Article ; Research Support, Non-U.S. Gov't ; Systematic Review
ISSN	2468-1253
ISSN (online)	2468-1253
DOI	10.1016/S2468-1253(21)00297-1
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Article ; Online: A genome-wide approach for detecting novel insertion-deletion variants of mid-range size.

Xia, Li C / Sakshuwong, Sukolsak / Hopmans, Erik S / Bell, John M / Grimes, Susan M / Siegmund, David O / Ji, Hanlee P / Zhang, Nancy R

Nucleic acids research

2016 Volume 44, Issue 15, Page(s) e126

Abstract: We present SWAN, a statistical framework for robust detection of genomic structural variants in next-generation sequencing data and an analysis of mid-range size insertion and deletions (<10 Kb) for whole genome analysis and DNA mixtures. To identify ... ...

Abstract	We present SWAN, a statistical framework for robust detection of genomic structural variants in next-generation sequencing data and an analysis of mid-range size insertion and deletions (<10 Kb) for whole genome analysis and DNA mixtures. To identify these mid-range size events, SWAN collectively uses information from read-pair, read-depth and one end mapped reads through statistical likelihoods based on Poisson field models. SWAN also uses soft-clip/split read remapping to supplement the likelihood analysis and determine variant boundaries. The accuracy of SWAN is demonstrated by in silico spike-ins and by identification of known variants in the NA12878 genome. We used SWAN to identify a series of novel set of mid-range insertion/deletion detection that were confirmed by targeted deep re-sequencing. An R package implementation of SWAN is open source and freely available.
MeSH term(s)	Adenoviridae/genetics ; Algorithms ; Animals ; Benchmarking ; Computer Simulation ; DNA Mutational Analysis/methods ; Datasets as Topic ; Genome/genetics ; Genomics/methods ; INDEL Mutation/genetics ; Pan troglodytes/virology ; Poisson Distribution ; Reproducibility of Results
Language	English
Publishing date	2016-06-20
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkw481
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Article: Detecting simultaneous changepoints in multiple sequences.

Zhang, Nancy R / Siegmund, David O / Ji, Hanlee / Li, Jun Z

Biometrika

2010 Volume 97, Issue 3, Page(s) 631–645

Abstract: We discuss the detection of local signals that occur at the same location in multiple one-dimensional noisy sequences, with particular attention to relatively weak signals that may occur in only a fraction of the sequences. We propose simple scan and ... ...

Abstract	We discuss the detection of local signals that occur at the same location in multiple one-dimensional noisy sequences, with particular attention to relatively weak signals that may occur in only a fraction of the sequences. We propose simple scan and segmentation algorithms based on the sum of the chi-squared statistics for each individual sample, which is equivalent to the generalized likelihood ratio for a model where the errors in each sample are independent. The simple geometry of the statistic allows us to derive accurate analytic approximations to the significance level of such scans. The formulation of the model is motivated by the biological problem of detecting recurrent DNA copy number variants in multiple samples. We show using replicates and parent-child comparisons that pooling data across samples results in more accurate detection of copy number variants. We also apply the multisample segmentation algorithm to the analysis of a cohort of tumour samples containing complex nested and overlapping copy number aberrations, for which our method gives a sparse and intuitive cross-sample summary.
Language	English
Publishing date	2010-06-16
Publishing country	England
Document type	Journal Article
ZDB-ID	1119-8
ISSN	1464-3510 ; 0006-3444
ISSN (online)	1464-3510
ISSN	0006-3444
DOI	10.1093/biomet/asq025
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Article ; Online: A unified framework for linkage and association analysis of quantitative traits.

Dupuis, Josée / Siegmund, David O / Yakir, Benjamin

Proceedings of the National Academy of Sciences of the United States of America

2007 Volume 104, Issue 51, Page(s) 20210–20215

Abstract: We give a unified treatment of the statistical foundations of population based association mapping and of family based linkage mapping of quantitative traits in humans. A central ingredient in the unification involves the efficient score statistic. The ... ...

Abstract	We give a unified treatment of the statistical foundations of population based association mapping and of family based linkage mapping of quantitative traits in humans. A central ingredient in the unification involves the efficient score statistic. The discussion focuses on generalized linear models with an additional illustration of the Cox (proportional hazards) model for age of onset data. We give analytic expressions for noncentrality parameters and show how they give qualitative insight into the loss of power that occurs if the scientist's assumed genetic model differs from nature's "true" genetic model. Issues to be studied in detail in the future development of this approach are discussed.
MeSH term(s)	Chromosome Mapping ; Data Interpretation, Statistical ; Humans ; Models, Genetic ; Pedigree ; Quantitative Trait Loci
Language	English
Publishing date	2007-12-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0707138105
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Article ; Online: Statistical corrections of linkage data suggest predominantly cis regulations of gene expression.

Shi, Jianxin / Siegmund, David O / Levinson, Douglas F

BMC proceedings

2007 Volume 1 Suppl 1, Page(s) S145

Abstract: Morley et al. (Nature 2004, 430:743-747) detected significant linkages to the expression levels of 142 genes (of 3554) at a reported threshold of genome-wide p = 0.001 (LOD asymptotically equal to 5.3), using 14 three-generation Centre d'Etude du ... ...

Abstract	Morley et al. (Nature 2004, 430:743-747) detected significant linkages to the expression levels of 142 genes (of 3554) at a reported threshold of genome-wide p = 0.001 (LOD asymptotically equal to 5.3), using 14 three-generation Centre d'Etude du Polymorphisme Humain pedigrees. Most of the linkages (77%) were trans, i.e., more than 5 Mb from the expressed gene. However, the analysis did not account for the expected anti-conservative effect of the skewed distribution of score- or regression-based statistics in large sibships, or for the possible variance distortion due to correlations among tests. Therefore, we re-analyzed their data, using a robust score statistic for the entire pedigrees and correcting the p-values for skewness. We found that a LOD of 5.3 had a skewness-corrected genome-wide p-value of 0.016 instead of 0.001 (a result that we confirmed using simulation), with around 50 expected false positives. We then further corrected for correlation among the (skew-corrected) p-values by using Efron's method for obtaining the empirical null distribution. Setting a threshold of FDR = 10% (Z = 6.4, LOD = 8.9), we detected linkage for the expression levels of 22 genes, 19 of which are cis. Limiting the analysis to cis regions, linkage was detected to the expression levels of 46 genes with 4.6 expected false positives (FDR = 10%).
Language	English
Publishing date	2007-12-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2411867-9
ISSN	1753-6561 ; 1753-6561
ISSN (online)	1753-6561
ISSN	1753-6561
DOI	10.1186/1753-6561-1-s1-s145
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Article: On the power for linkage detection using a test based on scan statistics.

Hernández, Sonia / Siegmund, David O / de Gunst, Mathisca

Biostatistics (Oxford, England)

2005 Volume 6, Issue 2, Page(s) 259–269

Abstract: We analyze some aspects of scan statistics, which have been proposed to help for the detection of weak signals in genetic linkage analysis. We derive approximate expressions for the power of a test based on moving averages of the identity by descent ... ...

Abstract	We analyze some aspects of scan statistics, which have been proposed to help for the detection of weak signals in genetic linkage analysis. We derive approximate expressions for the power of a test based on moving averages of the identity by descent allele sharing proportions for pairs of relatives at several contiguous markers. We confirm these approximate formulae by simulation. The results show that when there is a single trait-locus on a chromosome, the test based on the scan statistic is slightly less powerful than that based on the customary allele sharing statistic. On the other hand, if two genes having a moderate effect on a trait lie close to each other on the same chromosome, scan statistics improve power to detect linkage.
MeSH term(s)	Chromosome Mapping/methods ; Computer Simulation ; Data Interpretation, Statistical ; Genetic Linkage ; Humans ; Models, Genetic
Language	English
Publishing date	2005-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2031500-4
ISSN	1465-4644
ISSN	1465-4644
DOI	10.1093/biostatistics/kxi007
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