Causal inference in genetic trio studies.
Causal inference in genetic trio studies.
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DOI：
10.1073/pnas.2007743117
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发表时间：
2020-09-29
影响因子：
11.1
通讯作者：
Candès E
中科院分区：
文献类型：
--
作者：
Bates S;Sesia M;Sabatti C;Candès E
全基因组关联研究的目标是确定基因型和感兴趣的结果之间有意义的关系。遗传数据分析的一个挑战是，并非所有真正的统计关联都代表相关的生物活动;环境条件或其他因素的混杂效应可能会产生不相关但真实的关联。我们提出了一种方法来分析这样的数据，是免疫这个问题，因为它使用遗传的变化作为一个随机实验。该方法可以利用任何机器学习算法以及其他研究的结果。我们介绍了一种方法，以得出因果关系的推断免疫所有可能的混淆从遗传数据，包括父母和后代。因果关系的结论是可能的，因为在减数分裂的自然随机性可以被看作是一个高维随机实验。我们通过开发一种条件独立性测试来确定基因组中包含不同因果变异的区域，从而使这一观察结果具有可操作性。拟议的数字孪生测试将观察到的后代与来自相同父母的精心构建的合成后代进行比较，以确定统计学显著性，并且它可以利用任何黑盒多变量模型和额外的非三重遗传数据来增加功效。最重要的是，我们的推论仅基于一个完善的重组数学模型，并没有对基因型和表型之间的关系做出任何假设。我们比较我们的方法，广泛使用的传输不平衡测试，并证明增强的功率和本地化。
The goal of genome-wide association studies is to identify meaningful relationships between genotypes and outcomes of interest. One challenge in the analysis of genetic data is that not all true statistical associations represent relevant biological activity; irrelevant but true associations can arise from the confounding effect of environmental conditions or other factors. We propose a method to analyze such data that is immune to this problem because it uses the variation in inheritance as a randomized experiment. The method can leverage any machine-learning algorithm as well as findings from other studies. We introduce a method to draw causal inferences—inferences immune to all possible confounding—from genetic data that include parents and offspring. Causal conclusions are possible with these data because the natural randomness in meiosis can be viewed as a high-dimensional randomized experiment. We make this observation actionable by developing a conditional independence test that identifies regions of the genome containing distinct causal variants. The proposed digital twin test compares an observed offspring to carefully constructed synthetic offspring from the same parents to determine statistical significance, and it can leverage any black-box multivariate model and additional nontrio genetic data to increase power. Crucially, our inferences are based only on a well-established mathematical model of recombination and make no assumptions about the relationship between the genotypes and phenotypes. We compare our method to the widely used transmission disequilibrium test and demonstrate enhanced power and localization.
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影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
12.3
作者：
Acuna-Hidalgo R;Veltman JA;Hoischen A
通讯作者：
Hoischen A
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
3.5
作者：
Anney R;Klei L;Pinto D;Almeida J;Bacchelli E;Baird G;Bolshakova N;Bölte S;Bolton PF;Bourgeron T;Brennan S;Brian J;Casey J;Conroy J;Correia C;Corsello C;Crawford EL;de Jonge M;Delorme R;Duketis E;Duque F;Estes A;Farrar P;Fernandez BA;Folstein SE;Fombonne E;Gilbert J;Gillberg C;Glessner JT;Green A;Green J;Guter SJ;Heron EA;Holt R;Howe JL;Hughes G;Hus V;Igliozzi R;Jacob S;Kenny GP;Kim C;Kolevzon A;Kustanovich V;Lajonchere CM;Lamb JA;Law-Smith M;Leboyer M;Le Couteur A;Leventhal BL;Liu XQ;Lombard F;Lord C;Lotspeich L;Lund SC;Magalhaes TR;Mantoulan C;McDougle CJ;Melhem NM;Merikangas A;Minshew NJ;Mirza GK;Munson J;Noakes C;Nygren G;Papanikolaou K;Pagnamenta AT;Parrini B;Paton T;Pickles A;Posey DJ;Poustka F;Ragoussis J;Regan R;Roberts W;Roeder K;Roge B;Rutter ML;Schlitt S;Shah N;Sheffield VC;Soorya L;Sousa I;Stoppioni V;Sykes N;Tancredi R;Thompson AP;Thomson S;Tryfon A;Tsiantis J;Van Engeland H;Vincent JB;Volkmar F;Vorstman JA;Wallace S;Wing K;Wittemeyer K;Wood S;Zurawiecki D;Zwaigenbaum L;Bailey AJ;Battaglia A;Cantor RM;Coon H;Cuccaro ML;Dawson G;Ennis S;Freitag CM;Geschwind DH;Haines JL;Klauck SM;McMahon WM;Maestrini E;Miller J;Monaco AP;Nelson SF;Nurnberger JI Jr;Oliveira G;Parr JR;Pericak-Vance MA;Piven J;Schellenberg GD;Scherer SW;Vicente AM;Wassink TH;Wijsman EM;Betancur C;Buxbaum JD;Cook EH;Gallagher L;Gill M;Hallmayer J;Paterson AD;Sutcliffe JS;Szatmari P;Vieland VJ;Hakonarson H;Devlin B
通讯作者：
Devlin B
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y