diff --git "a/data_all_eng_slimpj/shuffled/split2/finalzzbmtu" "b/data_all_eng_slimpj/shuffled/split2/finalzzbmtu" new file mode 100644--- /dev/null +++ "b/data_all_eng_slimpj/shuffled/split2/finalzzbmtu" @@ -0,0 +1,5 @@ +{"text":"\\section{Introduction}\\label{sec:intro}\n\nIn genome-wide association (GWA) studies the aim is to test for association between genetic markers and a phenotype. A large number of markers are tested, and it is important to control the overall Type I error rate. Our focus is on controlling the familywise error rate (FWER). Multiple testing correction methods may achieve this goal by estimating a local significance level for the individual tests. In this work we present a new method, {\\em the order $k$ FWER-approximation method}, for finding a local significance level in multiple hypothesis testing for correlated common variants, as is often observed in GWA studies.\n\nAssume that we have collected independent individual observations in a case--control, cohort or cross-sectional study. The phenotype of interest can be continuous or discrete. We consider biallelic genetic markers, giving three possible genotypes. For each genetic marker we specify a hypothesis situation, where the null hypothesis is of the type ``no association between the phenotype and genetic marker'' and we have a two sided alternative. We will model the data using a generalized linear regression model (GLM) with phenotype as response (outcome), genotype as the independent variable of interest (exposure), and possibly non-genetical, referred to as environmental, independent covariates (not of interest) in the model. In epidemiological studies, a confounder is a common factor which is associated with both the exposure and outcome. In GWA studies, population substructure may be associated with both the exposure (genotype) and outcome (phenotype) and therefore may be a confounding factor and need to be adjusted for in the analysis. Population stratification can be adjusted for by including principal components of the genotype covariance matrix of the individuals as covariates in the model \\citep{Price2006}. As test statistics for the multiple hypothesis problem we use the score test statistics to evaluate the genotype contribution to the model for each genetic marker separately. It is known that the vector of separate score test statistics asymptotically follows a multivariate normal distribution with a covariance matrix that can be estimated using key features of the fitted GLM model and the genetic markers \\citep{Schaid2002, SeamanMyhsok2005}. This has also been a key ingredient in the work of \\cite{ConneelyBoehnke2007}.\n\nFurther, we show that for the special case when no environmental covariates are present or when environmental and genetic covariates are observed to be independent, the estimated correlation matrix between score test statistics can be approximated by the estimated correlation matrix between the genetic markers.\n\nIn a multiple testing situation with $m$ tests the familywise error rate can be controlled at level $\\alpha$ by specifying a local $p$-value cut-off, $\\alpha_{\\text{loc}}$, to be used for all the $m$ hypothesis tests. Inspired from the work of \\cite{MoskvinaSchmidt2008} and \\cite{DickhausStange2013} we will use an approximation to the $m$-dimensional asymptotic simultaneous multivariate normal distribution of the score test statistics vector to estimate $\\alpha_{\\text{loc}}$. The $\\alpha_{\\text{loc}}$ estimate can be used to define an effective number of independent tests, and our FWER-approximation can be used to compute FWER-adjusted $p$-values.\n\nThe order $k$ FWER-approximation method is more powerful than the \\v Sid\\'ak method (which assumes that the score test statistics are independent across markers) and the Bonferroni method (which is valid for all dependence structures between the score test statistics). Further, it is more efficient and more widely applicable than the method of \\cite{ConneelyBoehnke2007}. In Section \\ref{sec:discuss} we will see that the method of \\cite{ConneelyBoehnke2007} is built on numerical integration in $m$ dimensions and is computationally intensive. \n\nThe Westfall--Young permutation procedure is known to have asymptotically optimal power for a broad class of problems, including block-dependent and sparse dependence structure \\citep{MeinshausenMaathuisBuhlman2011}. However, this method is computer intensive and to have a valid permutation test, the assumption of exchangeability needs to be satisfied \\citep{Commenges2003}. This assumption is in general not satisfied when environmental covariates are present in the model.\n\nWe will use two genetic data sets presented by \\cite{TOP1}, \\cite{TOP2}, \\cite{VO2max1} and \\cite{VO2max2} to illustrate our method applied to real data. \n\nThe paper is organized as follows. In Section \\ref{sec:background} we present statistical background on the score test, and derive expressions for the score test covariance matrix, which is of importance for the subsequent work. Our proposed method is outlined and presented in detail in Section \\ref{sec:multtest}, together with characteristics of our method. In Section \\ref{sec:invest} real data and an artificial correlation structure are used to evaluate our proposed model and compare to other methods. Finally, we discuss and conclude in Sections~\\ref{sec:discuss} and~6.\n\n\\section{Statistical background}\\label{sec:background}\n\nIn this section, we present notation and details on the score test in generalized linear models. \n\n\\subsection{Notation and data} \\label{sec:notation}\n\nWe assume that data -- phenotype, $m$ genetic covariates and $d$ environmental covariates -- from $n$ independent individuals are available in a case--control, cohort or cross-sectional study. Let $\\bm Y$ be an $n$-dimensional vector having the phenotype $Y_i$ of individual $i$ as its $i$th entry, $i=1$, \\ldots, $n$. Let $\\xe$ be an $n\\times d$ matrix having environmental covariates (the first one being 1 to allow for an intercept in the model presented below) for individual $i$ as its $i$th row, and let $\\xg$ be an $n\\times m$ matrix having genetic covariates, or genotypes, for individual~$i$ as its $i$th row, each column corresponding to a genetic marker.\n\nWe assume that the genetic data are from common variant biallelic genetic markers with alleles $a$ and $A$, where $A$ is the minor allele. We will use the additive coding 0, 1, 2 for the genotypes $aa$, $aA$, and $AA$, respectively, in the genetic covariate matrix $\\xg$, but other coding schemes are also possible. We denote the total design matrix $\\x=(\\xe\\ \\xg)$, which has the total covariate vector for individual $i$ as its $i$th row.\n\n\\subsection{Testing statistical hypotheses with the score test}\\label{sec:score}\n\nWe assume that the relationship between the phenotype $\\y$ and covariates $\\x$ can be modelled by a generalized linear model (GLM) \\citep{glm} with an $n$-dimensional vector $\\bm\\eta = \\xe\\be + \\xg\\bg = \\x\\bm\\beta$ of linear predictors, where $\\bm\\beta=(\\be^T\\ \\bg^T)^T$ is a $d+m$-dimensional parameter vector. Let $\\eta_i$ be the $i$th entry of $\\bm\\eta$, and let $\\bm\\mu$ be the $n$-dimensional vector having $\\mu_i=EY_i$ as its $i$th entry. We assume that the link function $g$ defined by $\\eta_i=g(\\mu_i)$ of the GLM is canonical, which implies that the log likelihood for individual~$i$ is $l_i=(Y_i\\eta_i-b(\\eta_i))\/\\phi_i+c(Y_i,\\phi_i)$, where $b$ and $c$ are functions defining the exponential family of the phenotypes and $\\phi_i$ the dispersion parameter. In our context $\\phi_i=\\phi$ will be equal for all observations. In general, $\\mu_i=b'(\\eta_i)$ and $\\var\\y[i]=\\sigma^2_i=\\phi b''(\\eta_i)$. For $Y_i$ normally distributed, this reduces to $\\sigma_i^2=\\sigma^2=\\phi$, and for $Y_i$ Bernoulli distributed, $\\sigma_i^2=\\mu_i(1-\\mu_i)$ with $\\phi=1$.\n\nThe full $d+m$-dimensional score vector $\\sum_{i=1}^n\\nabla_{\\!\\bm\\beta}l_i$ can then be calculated to be\n\\[\n \\bm U=\\frac1\\phi\\x^T(\\y-\\bm\\mu),\n\\]\nwhich is asymptotically normal with mean $\\bm0$ and covariance matrix \n\\[\n V=\\frac1{\\phi^2}\\x^T\\Lambda\\x,\n\\]\nwhere $\\Lambda$ is the diagonal matrix having $\\sigma_i^2$ as its $i$th entry.\n\nPartition $\\bm U$ into its environmental and genetic components, $\\bm U^T=(\\bm U_\\text e^T\\ \\bm U_\\text g^T)$. Since $\\be$ are nuisance parameters and unknown, they are estimated by their maximum likelihood estimates under the null hypothesis of $\\bg=\\bm0$. In effect, $\\bm\\mu$ is to be replaced by $\\hat{\\bm\\mu}_\\text e$, the fitted values in a model with only environmental covariates $\\xe$ present, giving the statistic\n\\begin{equation}\n \\bm U_{\\text g\\mid\\text e}=\\frac1\\phi\\xg^T(\\y-\\hat{\\bm\\mu}_\\text e).\\label{u}\n\\end{equation}\nThen $\\bm U_{\\text g\\mid\\text e}$ has the conditional distribution of $\\bm U_\\text g$ given $\\bm U_\\text e=\\bm 0$, which is asymptotically normal with mean $\\bm 0$ and covariance matrix\n\\begin{equation}\n V_{\\text g\\mid\\text e}^{\\vphantom1}=V_\\text{gg}^{\\vphantom1}-V_\\text{ge}^{\\vphantom1}V_\\text{ee}^{-1}V_\\text{eg}^{\\vphantom1}\n =\\frac{1}{\\phi^2}\\xg^T\\big(\\Lambda-\\Lambda \\xe(\\xe^T\\Lambda\\xe)^{-1}\\xe^T \\Lambda\\big)\\xg,\\label{var}\n\\end{equation}\nwhere $V_\\text{ee}$, $V_\\text{eg}$, $V_\\text{ge}$ and $V_\\text{gg}$ are the upper left $d\\times d$, upper right $d\\times m$, lower left $m\\times d$ and lower right $m\\times m$ submatrices of $V$, respectively \\citep[see][]{Smyth2003}.\n\nThe score test statistic $\\bm U_{\\text g\\mid\\text e}^TV_{\\text g\\mid\\text e}^{-1}\\bm U_{\\text g\\mid\\text e}$ with $\\bg=\\bm 0$ is asymptotically $\\chi^2$ distributed with $m$ degrees of freedom when the complete null hypothesis $\\bg=\\bm0$ is true \\citep[see][]{Smyth2003}. However, our interest lies not in the complete null hypothesis, but in the $m$ individual hypotheses $\\bg[j]=0$ for each component $\\bg[j]$ of $\\bg$, \\ $1\\leq j\\leq m$, against two-sided alternatives. We consider the standardized components of $\\bm U_{\\text g\\mid\\text e}$,\n\\begin{equation}\n T_j=\\frac{\\bm U_{\\text g\\mid\\text e\\,j}}{\\sqrt{V_{\\text g\\mid\\text e\\,jj}}}, \\label{eq:Tk}\n\\end{equation}\nwhere $\\bm U_{\\text g\\mid\\text e\\,j}$ denotes the $j$th entry of $\\bm U_{\\text g\\mid\\text e}$ and $V_{\\text g\\mid\\text e\\,jk}$ the $jk$ entry of $V_{\\text g\\mid\\text e}$. Under the null hypothesis $H_j\\colon \\bg[j]=0$, \\ $T_j$ is asymptotically standard normally distributed, and $H_j$ will be rejected for large values of $\\lvert T_j\\rvert$. Under the complete null hypothesis, $\\bg=\\bm0$, the vector $\\bm T=(T_1,T_2,\\ldots,T_m)$ is asymptotically multivariate standard normally distributed with covariance matrix $R$, having\n\\begin{equation}\n \\cov(T_j,T_k)=\\frac{V_{\\text g\\mid\\text e\\,jk}}{\\sqrt{V_{\\text g\\mid\\text e\\,jj}V_{\\text g\\mid\\text e\\,kk}}}, \\label{eq:R}\n\\end{equation}\nas its $jk$ entry, all evaluated at $\\bg=\\bm0$. Note that the dispersion parameter $\\phi$ is cancelled from $\\bm T$ and the covariances. However, the $\\sigma_i^2$ of $\\Lambda$ will have to be estimated.\n\n\\subsection{Special cases} \\label{sec:corr}\n\nWe will now look at $\\bm U_{\\text g\\mid\\text e}$ and $V_{\\text g\\mid\\text e}$ for some special cases.\n\n\\subsubsection{No environmental covariates}\\label{noenvcov}\n\nIf no evironmental covariates except the intercept are present in the GLM, then $\\xe=\\bm1$, the $n$-dimensional vector having all entries equal to 1, and $\\Lambda=\\sigma^2I$ under the null hypothesis, where $I$ is the $n\\times n$ identity matrix. Then\n\\[\n U_{\\text g\\mid\\text e}=\\frac1\\phi\\xg^T\\Big(I-\\frac{1}{n}\\bm1\\bm1^T\\Big)\\bm Y\\qquad\\text{and}\\qquad V_{\\text g\\mid\\text e}=\\frac{\\sigma^2}{\\phi^2}\\xg^T\\Big(I-\\frac{1}{n}\\bm1\\bm1^T\\Big)\\xg,\n\\]\nso that\n\\begin{equation}\nT_j=\\frac{\\bm x_j^T(I-\\frac{1}{n}\\bm1\\bm1^T)\\bm Y}{\\sigma\\sqrt{\\bm x_j^T(I-\\frac{1}{n}\\bm1\\bm1^T)\\bm x_j}},\\quad\\cov(T_j,T_k)=\\frac{\\bm x_j^T(I-\\frac{1}{n}\\bm1\\bm1^T)\\bm x_k}{\\sqrt{\\bm x_j^T(I-\\frac{1}{n}\\bm1\\bm1^T)\\bm x_j}\\sqrt{\\bm x_k^T(I-\\frac{1}{n}\\bm1\\bm1^T)\\bm x_k}},\\label{Tk-noenv}\n\\end{equation}\nwhere $\\bm x_j$ is the $j$th column of $\\xg$, \\ $1\\leq j\\leq m$, \\ $1\\leq k\\leq m$. So $T_j$, the score test statistic for testing $\\bg[j]=0$, is $\\sqrt n$ times the Pearson correlation between $\\bm x_j$ and $\\bm Y$ when $\\sigma^2=\\var Y_i$ is replaced by the estimate $\\bm Y^T(I-\\frac{1}{n}\\bm1\\bm1^T)\\bm Y\/n$, and $\\cov(T_j,T_k)$ is the sample correlation between $\\bm x_j$ and $\\bm x_k$. Thus, for a GLM without adjustment for environmental covariates, the correlation between the score test statistics can be estimated by estimating the genotype correlation. The genotype correlation estimates twice the composite linkage disequilibrium if the genotypes are coded 0, 1,~2 \\citep{Weir2008}.\n\n\\subsubsection{Uncorrelated environmental and genetic covariates}\\label{uncorrenvgen}\n\nTwo $n$-dimensional vectors $\\bm X_1$ and $\\bm X_2$ of observations have zero Pearson correlation if their centered observations are orthogonal,\n\\[\n 0=(\\bm X_1-\\bar X_1\\bm1)^T(\\bm X_2-\\bar X_2\\bm1)=\\bm X_1^T\\Big(I-\\frac1n\\bm1\\bm1^T\\Big)\\bm X_2.\n\\]\nIf $X_1$ and $X_2$ are two matrices, then near zero Pearson correlation of each combination of a column of $X_1$ and a column of $X_2$ can be written compactly as\n\\begin{equation}\n X_1^T\\Big(I-\\frac1n\\bm1\\bm1^T\\Big)X_2\\approx\\bm0,\\qquad\\text{or}\\qquad\n X_1^TX_2\\approx\\frac1nX_1^T\\bm1\\bm1^TX_2.\\label{centeredorth}\n\\end{equation}\n\nIf we consider genetic and environmental covariates to be random variables, and all pairs of an environmental and a genetic covariate to be independent, we would expect~\\eqref{centeredorth} to hold for all $X_1$ having columns that are functions of genetic covariates and $X_2$ having columns that are functions of environmental covariates. In particular, we consider $X_1=\\xg$ and $X_2=\\Lambda\\xe$. Since $\\Lambda$ is a function of environmental covariates only under the null hypothesis, so is $X_2$. By~\\eqref{centeredorth}, $\\xg^T\\Lambda\\xe\\approx\\frac1n\\xg^T\\bm1\\bm1^T\\Lambda\\xe$, Then, from~\\eqref{var},\n\\begin{align*}\n \\phi^2V_{\\text g\\mid\\text e}\n &\\approx\\xg^T\\Lambda\\xg\n -\\frac1{n^2}\\xg^T\\bm1\\bm1^T\\Lambda\\xe(\\xe^T\\Lambda\\xe)^{-1}\\xe^T \\Lambda\\bm1\\bm1^T\\xg\\\\\n &=\\xg^T\\Lambda\\xg\n -\\frac1{n^2}\\xg^T\\bm1\\bm1^T\\Lambda^{1\/2}H\\Lambda^{1\/2}\\bm1\\bm1^T\\xg,\n\\end{align*}\nwhere $H=\\Lambda^{1\/2}\\xe(\\xe^T\\Lambda\\xe)^{-1}\\xe^T\\Lambda^{1\/2}$ will project onto the column space of $\\Lambda^{1\/2}\\xe$. Since $\\bm1$ is a column (the intercept) of $\\xe$, \\ $\\Lambda^{1\/2}\\bm1$ is in the column space of $\\Lambda^{1\/2}\\xe$, so that $H\\Lambda^{1\/2}\\bm1=\\Lambda^{1\/2}\\bm1$, and\n\\[\n \\phi^2V_{\\text g\\mid\\text e}\n \\approx\\xg^T\\Lambda\\xg\n -\\frac1{n^2}(\\tr\\Lambda)\\xg^T\\bm1\\bm1^T\\xg.\n\\]\n\nWe now turn to the term $\\xg^T\\Lambda\\xg$. Its $(j,k)$ entry is $\\bm X_1^T\\Lambda\\bm1$, where $\\bm X_1$ is the vector consisting of the entry-wise products of the $j$th and the $k$th column of $\\xg$. Letting $\\bm X_2=\\Lambda\\bm1$, by~\\eqref{centeredorth}, independence of environmental and genetic covariates yields $\\bm X_1^T\\Lambda\\bm1\\approx\\frac1n\\bm X_1^T\\bm1\\bm1^T\\Lambda\\bm1=\\frac1n(\\tr\\Lambda)\\bm X_1^T\\bm1$, which is the $(j,k)$ entry of $\\frac1n(\\tr\\Lambda)\\xg^T\\xg$. Thus $\\xg^T\\Lambda\\xg\\approx\\frac1n(\\tr\\Lambda)\\xg^T\\xg$, and we have\n\\[\n V_{\\text g\\mid\\text e} \\approx\\frac{\\tr\\Lambda}{n\\phi^2}\\xg^T\\Big(I-\\frac1n\\bm1\\bm1^T\\Big)\\xg,\n\\]\nwhich is the same expression as in the case of no environmental covariates with the exception that the common variance $\\sigma^2$ of the responses is replaced by their average variance $\\tr\\Lambda\/n=\\frac1n\\sum_{i=1}^n\\sigma_i^2$, where the $\\sigma_i^2$ are defined by the environmental covariates. The conclusion is that, if environmental and genetic covariates are uncorrelated, correlations of the score vector under the null hypothesis can be estimated more easily by estimating only correlations between genetic covariates instead \n\n\\subsubsection{The normal model}\n\nFor $Y_i$ normally distributed, $\\Lambda=\\sigma^2I$, where $I$ is the $n\\times n$ identity matrix. The score vector can then be written\n\\[\n \\bm U_{\\text g \\mid\\text e}=\\frac1{\\sigma^2} \\xg^T (I-H)\\y,\n\\]\nand \\eqref{var} reduces to\n\\[\n V_{\\text g\\mid\\text e}=\\frac{1}{\\sigma^2}\\xg^T(I-H)\\xg,\n\\]\nwhere $H=\\xe(\\xe^T\\xe)^{-1}\\xe^T$ is the idempotent matrix projecting onto the column space of $\\xe$. Then $I-H$ is the idempotent matrix projecting onto the orthogonal complement of the column space of $\\xe$, and $(I-H)\\bm Y$ are the residuals when fitting the multiple linear model with only the environmental covariates present. Note that $\\sigma^2$ enters into the test statistics $T_j$~\\eqref{eq:Tk}, and needs to be replaced by an estimate; we have used the residual sum of squares of a fitted model with only environmental covariates present (the null hypothesis), divided by $n-d$.\n\n\\subsubsection{The logistic model}\n\nFor $Y_i$ Bernoulli distributed, $\\phi=1$ and the $\\sigma_i^2$ of $\\Lambda$ are estimated by $\\hat \\mu_{\\text ei}(1-\\hat \\mu_{\\text ei})$, where $\\hat \\mu_{\\text ei}$ are the fitted values under the null hypothesis with only environmental covariates. Inference about $\\bg$ is valid also if data are collected in a case--control study since the canonical (logit) link is used \\citep[pp. 170--171]{agresti2002categorical}.\n\nIn the special case of no environmental covariates, that is, $\\xe=\\bm1$, each score test statistic, $T_j$ \\eqref{Tk-noenv}, is equal to the Cochran--Armitage trend test \\citep{Armitage1955,Cochran1954} statistic,\n\\[\n \\frac{\\sum_{i=0}^2s_i(n_2x_i-n_1y_i)}\n {\\sqrt{n_1n_2\\big(\\sum_{i=0}^2s_i^2m_i-\\frac1n(\\sum_{i=0}^2s_im_i)^2\\big)}},\n\\]\nwhere $s_i$ are the possible values of the genetic covariates, $n_1$ and $n_2$ the number of 0 and 1 phenotypes $Y_i$, respectively, $x_i$ the number of observations having phenotype 1 and genotype $s_i$ at marker $k$, \\ $y_i$ the number of observations having phenotype 0 and genotype $s_i$, and $m_i=x_i+y_i$. The Cochran--Armitage test is used in disease--genotype association testing with scores $(s_0,s_1,s_2)=(0,s,1)$ \\citep{sasieni1997genotypes,slager2001case}, for example with $s=\\frac12$ for an additive genetic model.\n\n\\section{Familywise error rate control and approximations}\\label{sec:multtest}\n\nWe now turn to the topic of how to control the familywise error rate (FWER) by intersection approximations, and then apply this to our situation.\n\n\\subsection{Multiple hypothesis familywise error rate control}\\label{sec:fwer}\n\nWe have a collection of $m$ null hypotheses, $H_k\\colon \\bg[k]=0$ (no association between phenotype and genotype at marker $k$), $1\\leq k\\leq m$, against two-sided alternatives. We will present a method for multiple testing correction that controls the FWER -- the probability of making at least one type~I error. We adopt the notation of \\cite{MoskvinaSchmidt2008}, and denote by $O_k$ the event that the null hypothesis $H_k$ is not rejected, and by $\\bar O_k$ its complement, $1\\leq k\\leq m$. Then, if all $m$ null hypotheses are true,\n\\begin{equation}\n \\text{FWER} = P(\\bar O_1 \\cup \\cdots \\cup \\bar O_m) = 1-P(O_1 \\cap \\cdots \\cap O_m). \\label{eq:FWER}\n\\end{equation}\nIn our case, $O_k$ is an event of the form $|T_k| < c$, where $T_k$ is the test statistic of \\eqref{eq:Tk}. We will consider single-step multiple testing methods, and choose the same cut-off $c$ for each $k$. We denote by $\\alpha_{\\text{loc}}=2\\Phi(-c)=P(\\bar O_k)$, the asymptotic probability of false rejection of $H_k$, where $\\Phi$ is the univariate standard normal cumulative distribution function. When the joint distribution of the test statistics is known under the complete null hypothesis, or can be estimated, FWER control at the $\\alpha$ significance level can be achieved by solving the inequality $\\text{FWER} \\leq \\alpha$ for $\\alpha_{\\text{loc}}$, based on either the union or intersection formulation of~\\eqref{eq:FWER}. When $m$ is large, this involves evaluating high dimensional integrals over the acceptance or rejection regions, which is suggested by \\cite{ConneelyBoehnke2007}.\n\nTo avoid evalulating these costly integrals, we may instead control FWER by considering bounds based on~\\eqref{eq:FWER}. For example, the Bonferroni method is based on the Boole inequality applied to the union formulation of~\\eqref{eq:FWER},\n\\[\n \\text{FWER} = P(\\bar O_1 \\cup \\cdots \\cup \\bar O_m) \\leq \\sum_{k=1}^m P(\\bar O_k)=\\sum_{k=1}^m \\alpha_{\\text{loc}}=m\\alpha_{\\text{loc}},\n\\]\nfrom which it is seen that a local significance level of $\\alpha_{\\text{loc}}=\\alpha\/m$ guarantees $\\text{FWER}\\leq\\alpha$.\n\nWhen the FWER is calculated under the complete null hypothesis, so-called weak FWER control is achieved. However, in our situation, subset pivotality is satisfied, meaning that the distribution of any subvector $(T_k)_{k\\in K}$ is identical under $\\bigcap_{k\\in K}H_k$ and under the complete null hypothesis $\\bigcap_{k=1}^mH_k$, for all subsets $K\\subseteq\\{1,2,\\ldots, m\\}$. In particular, a subvector of $\\bm U_{\\text g\\mid\\text{e}}$~\\eqref{u} and a submatrix of $V_{\\text g\\mid\\text{e}}$~\\eqref{var} corresponding to $K$ only involves genetic covariates corresponding to~$K$. Then strong FWER control is achieved, meaning that $\\text{FWER}\\leq\\alpha$ regardless of which null hypotheses are true \\citep{WestfallYoung1993,westfall2008multiple}. \n\nThe focus in this work will be on the intersection formulation of~\\eqref{eq:FWER}. Background theory will be given next and new application in \\ref{sec:FWERkapprox}.\n\n\\subsection{Intersection approximations}\\label{sec:fwerk}\n\nFollowing \\cite{glazjohnson}, we define $k$th order product-type approximations to $P(O_1\\cap\\nobreak\\cdots\\cap O_m)$ by\n\\begin{equation}\n \\gamma_k=P(O_1\\cap\\cdots\\cap O_k)\\prod_{j=k+1}^mP(O_j\\mid O_{j-k+1}\\cap\\cdots\\cap O_{j-1})\n =\\frac{\\prod_{j=k}^{m}P(O_{j-k+1}\\cap\\cdots\\cap O_j)}{\\prod_{j=k+1}^{m}P(O_{j-k+1}\\cap\\cdots\\cap O_{j-1})},\n\\label{gammak}\n\\end{equation}\n$1\\leq k\\leq m$, where probabilities are evaluated under the complete null hypothesis. This is similar to the usual multiplicative rule for the probability of intersection of events applied to $\\gamma_m=P(O_1\\cap\\nobreak\\cdots\\cap O_m)$, but with dimension of distributions limited to $k$. The idea is that the $\\gamma_k$ should constitute increasingly better approximations of $\\gamma_m$ as $k$ increases, and that calculation of $\\gamma_k$ is less costly than calculation of $\\gamma_m$ when $k1$) helps to understand the bulk properties of\nQGP phase which also affect the in-medium properties\nof the quarkonium states. So we wish to \nto see how the potential in anisotropic medium behaves in these\n(short, intermediate and long) limiting cases.\nIn the short-distance limit, the vacuum contribution \ndominates over the medium contribution and this is exactly happens \nhere \n\\begin{eqnarray}\nV(r,\\theta_n,T)\\stackrel{\\hat{r}\\ll 1}{\\simeq} \\sigma r - \\frac{\\alpha}{r}\n\\label{vprime}\n\\end{eqnarray} \nfor $\\xi=0$. On the other hand, in the long-distance limit ($\\hat{r}\\gg 1 $), the \npotential is reduced to a long-range Coulombic interaction after\nidentifying the factor $2\\sigma\/m_D^2$ with the coupling ($g_s^2$)\nof the interaction\n\\begin{eqnarray}\n\\label{largp}\nV(r,\\theta_n,T) &\\stackrel{\\hat{r}\\gg1}{\\simeq}& -\\frac{2\\sigma}{m^2_{{}_D}r}-\\alpha m_{{}_D}\n-\\frac{5\\xi}{12}~\\frac{2\\sigma}{m^2_{{}_D}r} \\left(1+\\frac{3}{5}\\cos 2\\theta_n \\right)\\nonumber\\\\\n&\\equiv & V_{\\rm{iso}} (\\hat{r} \\gg 1,T)+ V_{\\rm{tensor}} (\\hat{r} \\gg 1~.\n\\theta_n,T)~.\n\\end{eqnarray}\nSince the resulting potential is Coulombic plus a\nsubleading anisotropic contribution, it then has to satisfy\nthe condition: $a_0 m_D\\gg 1$, where $a_0$ is the Bohr radius and $m_D$ is\nthe Debye mass. Since the Bohr radius $a_0$ is proportional to \n$m_D^2\/(m_Q \\sigma)$,\nthe above condition for the long-distance limit implies that \n$m_D^3\/(m_Q \\sigma)$ \nshould be greater than 1. Thus this inequality results in a condition on the\nDebye mass and hence on the temperature. It is seen that the above condition \nis satisfied for the temperatures above the critical temperature ($>T_c$)\nfor the charmonium states and above 1.6$T_c$ \nfor the bottomonium states. The temperature ranges ($T_c$ and \n1.6$T_c$) for $c \\bar c$ and $b\\bar b$ states above which \nthe effective potential looks Coulombic are\nsmaller than their respective dissociation temperatures and thus seems \njustified to approximate the potential in the long-distance limit. In the intermediate distance ($rm_D \\simeq 1$) scale, the \ninteraction becomes complicated and thus the potential\ndoes not look simpler in contrast to the asymptotic limits, so\nthis limit needs to be dealt numerically with the full potential in\na Schr\\\"odinger equation.\n\n\\par We have thus noticed overall that in the short \ndistance limit, the potential have not been affected in the isotropic limit.\nOn the contrary, in the long-distance limit, the momentum anisotropy \ntranspires an angular dependence in the potential \nand gives rise a characteristic angular ($\\theta_n$) dependence \nbetween the relative \nseparation ($\\mathbf{r}$) and the direction of anisotropy ($\\mathbf{n}$). \nAs a corollary, the quark pairs aligned \nalong the direction of anisotropy feel more attraction than the transverse \nalignment because the inter-quark potential along\nthe direction of anisotropy is screened less than the transverse alignment.\nHowever, the potential in the anisotropic medium is always stronger than in \nisotropic medium. \n\n\nTo see the effects of anisotropy, we have shown the potentials \nfor $Q \\bar Q$ pairs in an anisotropic medium in Figures 1 and 2,\nfor $\\theta_n=0$ (parallel) and $\\theta_n=\\pi\/2$\n(perpendicular), respectively. The immediate observation\ncommon to all figures is that the inter-quark potential in anisotropic\nmedium is always more attractive than in isotropic medium. \nThis can be understood physically: In the small \nanisotropic limit, the anisotropic distribution function may be \nobtained from an isotropic distribution $f_{iso} (|\\mathbf{k}|)$\nby removing particles with a large momentum component along\n$\\mathbf{n}$ {\\it i.e.}\n$f_{iso}(\\sqrt{\\mathbf{k}^{2} + \\xi(\\mathbf{k}.\\mathbf{n})^{2}}$.\nThis transpires in the reduction of the number of partons (around\na static test heavy quark) than in isotropic medium {\\it i.e.} $n_{\\rm{aniso}} (\\xi)= \nn_{\\rm{iso}}\/\\sqrt{1+\\xi}$. Therefore, the (effective) Debye mass \nalways becomes smaller and results in less screening of the potential than \nin isotropic medium.\n\\begin{figure}\n\\begin{subfigure}{\n\\includegraphics[width=7.9cm,height=8.5cm]{para.eps}\n\\label{para_plot_a}}\n\\end{subfigure}\n \\hspace{-5mm}\n\\begin{subfigure}{\n \\includegraphics[width=7.9cm,height=8.5cm]{paraz1.eps}\n\\label{para_plot_b}}\n\\end{subfigure}\n\\caption{\\footnotesize The left panel represents the potential \ndivided by $(g^2 C_F m_{{}_D})$ and the right panel represents the \ncontribution of Coulomb, string and both together as a function of \n$\\hat{r}$ (= $rm_{{}_D} $) for quark pairs parallel to the \ndirection of anisotropy, $\\mathbf{n}$.} \n\\end{figure}\n\n\n\\begin{figure}\n\\vspace{0mm}\n\\begin{subfigure}{\n\\includegraphics[width=7.9cm,height=8.5cm]{perp.eps}\n\\label{perp_plot_a}}\n\\end{subfigure}\n\\hspace{-5mm}\n\\begin{subfigure}{\n\\includegraphics[width=7.9cm,height=8.5cm]{perpz1.eps}\n\\label{perp_plot_b}}\n\\end{subfigure}\n\\caption{\\footnotesize The notations are same as in Figure 1\nbut for quark pairs perpendicular to the \ndirection of anisotropy, $\\mathbf{n}$.} \n\\vspace{0mm}\n\\end{figure}\nThe second observation is that the quark pairs aligned along ($\\theta_n=0$) the\ndirection of anisotropy are stronger than aligned perpendicular \n($\\theta_n=\\pi\/2$) to the direction of anisotropy because for the parallel alignment, the component of momentum to be removed is higher\nthan the transverse alignment so the distribution function \nfor the parallel alignment case contributing to the Debye mass is\nsmaller than the transverse alignment.\nHence the potential for parallel case will be screened less compared to \nthe transverse case. However the difference between the two scenario \nwill be not much different\nbecause the contributions to the Debye mass from the partons having higher \nmomenta are very small.\n \nTo understand the effect of linear term on the medium modified \npotential quantitatively, in addition to the Coulomb term, we have \nplotted separately the medium modifications to the linear term, \nthe Coulomb term and their sum in the right panels of \nFigure 1 and 2, for parallel and transverse case, respectively.\nMedium modification to the Cornell potential contains two parts: one is due to\nthe medium modifications of linear term ($\\sigma r$) and the other one is due \nto the medium modifications of\nCoulomb term. As usually done in the literature, medium \nmodification to the linear term does not arise because\nthe string tension was assumed to be \nzero~\\cite{mocsyprd,Satz,shro,Alb05} \nat or beyond deconfinement temperature~\\cite{Lusch}.\nSince string tension is found to be nonzero at $T_c$ rather it \napproaches zero much beyond $T_c$~\\cite{string1,string2,string3} and hence\nthe medium modification to the linear term may be\nnon-zero contribution to the potential even at temperatures beyond $T_c$, although it is very small. \nIn isotropic medium, medium modification to the linear term\nremains positive up to 2-3 $T_c$, making the potential less attractive \ncompared to $T=0$. On contrast, in anisotropic case medium \nmodification to the linear term becomes negative\nand the overall full potential becomes more attractive.\n\nAs mentioned earlier we used the same screening scale for both the linear\nand Coulombic terms in our calculation which does not look plausible.\nIt would thus be interesting to see the effects of different scales for the \nCoulomb and linear pieces of the T=0 potential~\\cite{megiasind,megiasprd}.\nTo illustrate it graphically, we have compared our results with their results\n(in Figure 3) for the isotropic case. The difference in the large\ndistance limit arises due to the difference in the potential\nat infinity (-$\\sigma\/m_D$) so the \npotential in Ref.\\cite{megiasprd} is more attractive than our potential.\n\\begin{figure}\n\\vspace{0mm}\n\\includegraphics[width=7.9cm,height=8.5cm]{pot_emegias_our.eps} \n\\caption{\\footnotesize The dotted-circle represents the results from \nMegias et al. \\cite{megiasprd} where\ndifferent scales was used for linear and Coulomb terms separately whereas\nthe solid line represents our work.}\n\\vspace{0mm}\n\\end{figure}\n\n\\section{Properties of Quarkonium in an Anisotropic Medium}\\label{prop_q}\n\\subsection{Binding energy}\nTo understand the in-medium properties of the quarkonium states,\nwe need to model the heavy quark potential as a function of\ntemperature and solve the resulting Schr\\\"{o}dinger equation.\nThe potential thus obtained in anisotropic medium (\\ref{fullp}), \nin contrast to the (spherically symmetric) potential in isotropic medium,\nis non-spherical and so one cannot simply obtain the energy eigen values \nby solving the radial part of the Schr\\\"{o}dinger equation only because \nthe radial part is no longer sufficient due to \nthe angular dependence in the potential. Other way to understand\nis that because of the anisotropic\nscreening scale, the wave functions are no longer radially symmetric for\n$\\xi \\ne 0$. So one has to solve the potential in anisotropic medium\nthrough the Schr\\\"odinger equation in three dimension. \nHowever, we have seen in the potential (55) that in the small $\\xi$-limit, \nthe spherically non-symmetric component\n$V_{\\rm{tensor}}(r,\\theta_n,T)$ is much smaller in comparison to spherically \nsymmetric (isotropic) component $V(r,T)$ and thus\ncan be treated as perturbation. This can be understood physically:\nThe tensorial (non-sphericity) nature\nof the potential in the co-ordinate space is arisen due to anisotropy \nin the momentum space. However, we are restricted to a plasma which\nis very much close to equilibrium because\nby the time quarkonium states are formed in the plasma\naround (1-2)$T_c$, the plasma becomes almost \nisotropized. Thus this weak (momentum) anisotropy\n($\\xi \\ll 1$) transpires feeble angular dependence in the potential\nso the potential will be spherically abundant\nwith a tiny non-spherical component. So we could \ntreat the anisotropic component through the perturbation theory in quantum \nmechanics and the isotropic part should be\nhandled numerically by the one-dimensional radial\nSchr\\\"{o}dinger equation.\n\nThere are some numerical methods to solve the Schr\\\"odinger equation\neither in partial differential form (time-dependent) or eigen value form\n(time-independent\/stationary) by the\nfinite difference time domain method (FDTD) or matrix method, respectively.\nHowever, we choose the matrix method to solve the\nstationary Schr\\\"odinger equation with the isotropic part of the potential\n(55) in anisotropic medium. In this method, the Schr\\\"odinger equation\ncan be cast in a matrix form through a discrete basis, instead\nof the continuous real-space position basis spanned by the states\n$|\\overrightarrow{x}\\rangle$. Here the confining potential V is subdivided\ninto N discrete wells with potentials $V_{1},V_{2},...,V_{N+2}$ such that\nfor $i^{\\rm{th}}$ boundary potential, $V=V_{i}$ for $x_{i-1} < x < x_{i};~i=2, 3,..\n.,(N+1)$. Therefore for the existence of a bound state, there\nmust be exponentially decaying wave function\nin the region $x > x_{N+1}$ as $x \\rightarrow \\infty $ and\nhas the form:\n\\begin{equation}\n\\Psi_{N+2}(x)=P_{{}_E} \\exp[-\\gamma_{{}_{N+2}}(x-x_{N+1})]+ \nQ_{{}_E} \\exp [\\gamma_{{}_{N+2}}(x-x_{N+1})] , \n\\end{equation}\nwhere, $P_{{}_E}= \\frac{1}{2}(A_{N+2}- B_{N+2})$,\n$Q_{{}_E}= \\frac{1}{2}(A_{N+2}+ B_{N+2}) $ and,\n$ \\gamma_{{}_{N+2}} = \\sqrt{2 \\mu(V_{N+2}-E)}$. The eigenvalues\ncan be obtained by identifying the zeros of $Q_{E} $.\n\n\nTherefore, the corrected energy eigen value comes\nfrom the solution of Schr\\\"odinger equation\nof the isotropic component $V_{\\rm{iso}}(r,T)$, using the \nabovementioned matrix method\nplus the first-order perturbation due to the anisotropic \ncomponent $V_{\\rm{aniso}}(r,\\theta;\\xi,T)$ (55) through\nthe quantum mechanical perturbation theory.\nThe variations of the binding energies with the \ntemperature are shown in figure~(\\ref{bind_jsi})\nfor $J\/\\psi$ and $\\Upsilon$ \nfor different values of anisotropy parameter $\\xi$,\nto see the effect of anisotropy on the binding energies compared to\nthe isotropic case. \n\n\\begin{figure*}\n\\begin{subfigure}{\n\\includegraphics[trim = 1mm 1mm 1mm 1mm, clip,height=7cm,width=7cm]{charm.eps}\n}\n\\end{subfigure}\n\\hspace{5mm}\n\\begin{subfigure}{\n\\includegraphics[trim = 1mm 1mm 1mm 1mm, clip,height=7cm,width=7cm]{bot.eps}\n}\n\\end{subfigure}\n\\vspace{0mm}\n\\caption{\\footnotesize Variation of $J\/\\psi$ and $\\Upsilon$ binding \nenergy (in $GeV$) with the temperature in an anisotropic hot QCD medium.}\n\\label{bind_jsi}\n\\end{figure*}\n\nThere are mainly two observations: First, as the anisotropy increases, the binding of \n$Q \\bar Q$ pairs get\nstronger with respect to their isotropic counterpart because \nthe potential becomes deeper with the increase of anisotropy due to\nweaker screening. It seems \nthat the (effective) Debye mass $m_D(\\xi,T)$ in an anisotropic\nmedium is always smaller than in an isotropic medium. As a result\nthe screening of the Coulomb and string contribution are \nless accentuated and hence the quarkonium states \nbecome more stronger than in an isotropic medium.\nHowever, the effects of anisotropy on the \nexcited states are not \nso pronounced compared to the ground states\nbecause they are generically weakly bound.\nSecondly, there is\na strong decreasing trend with the temperature.\nThis is due to the fact that the screening becomes always stronger with the increase of\ntemperature, so the potential becomes weaker compared to $T=0$ and\nresults in early dissolution of quarkonia in the medium.\nOur results on the temperature dependence of the binding energies show\nan agreement with the similar variations in other\ncalculations~\\cite{Dumitru09}.\n\nIn our calculation, we use the Debye mass \n($m_{{}_D}^{\\rm L}=1.4 m^{\\rm LO}_{{}_D}$) obtained by fitting\nthe (color-singlet) free energy in lattice QCD~\\cite{mocsyprl} \nwhere both one and two-loop expression \n~\\cite{shro,shaung,ijmp} for coupling have been used to explore the\neffects of running coupling on the dissociation process.\n\nThus the study of the temperature dependence of the binding \nenergies are poised\nto provide a wealth of information about the dissociation\npattern of quarkonium states in an anisotropic thermal medium that can be\nused to determine the dissociation temperatures of different states\nin the next Section.\n\n\\subsection{Dissociation temperatures for heavy quarkonia}\\label{diss}\nDissociation of a two-body bound state in an thermal medium can be \nunderstood qualitatively: When the binding energy of a resonance state\ndrops below the mean thermal energy of a parton, \nthe state becomes feebly bound. The thermal\nfluctuation then can easily dissociate by exciting\nthem into the continuum.\nThe spectral function technique in potential models defines the dissociation\ntemperature as the temperature above which the quarkonium spectral\nfunction shows no resonance-like structures but the widths shown \nin spectral functions from current potential model calculations\nare not physical. The broadening of states with the increase in \ntemperature is not included in any of these models. \nIn Ref.\\cite{mocsyprl}, the authors\nargued that one need not to reach the binding energy ($E_{\\rm{bin}}$) to\nbe zero for the dissociation rather a weaker condition $E_{\\rm{bin}}0$) {\\em viz.} $J\/\\psi$ \nis dissociated at $1.38~T_c$ in an isotropic medium while in an \nanisotropic medium with the anisotropies $\\xi$=0.3 and 0.6, they will \nsurvive higher \ntemperatures, $1.41~T_c$ and $1.43~T_c$, respectively. Similarly \nthe dissociation temperatures of \n$\\Upsilon$ for $\\xi$=0.3 and 0.6 are $1.71~T_c$\nand $1.72~T_c$, respectively, corresponding to the value \n($1.70~T_c$) in an isotropic medium. \n\n\\begin{table}\n\\centering\n\\begin{tabular}{|c|c|c|c|}\n\\hline\nState &$\\xi=0.0$ & $\\xi=0.3$ & $\\xi=0.6$\\\\\n\\hline\\hline\n$J \/ \\psi$ & 1.38& 1.41& 1.43 \\\\\n\\hline\n$\\Upsilon$ & 1.70 & 1.71 & 1.72 \\\\\n\\hline\n\\end{tabular} \n\\caption{\\footnotesize Dissociation temperatures ($T_D$)\nfor the quarkonium states with one-loop QCD coupling}\n\\label{tdpara1l}\n\\end{table}\n\\par Finally we wish to explore the effects of perturbative as well as\nnon-perturbative contributions on the dissociation of quarkonia states\nqualitatively in terms of the debye mass.\nInstead of lattice Debye mass ($m_D^L$), if we use the leading-order\nDebye mass ($m_D^{\\rm{LO}}