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\item Pooled-variant method  \begin{itemize}  \item VT \cite{Price_2010}: Variants with MAF below some threshold are more likely to be functional than the variants with higher MAF.   \begin{itemize}  \item For each possible MAF threshold, a genotype score is computed based on given collapsing theme. The chosen MAF threshold maximizes the association signal and permutation testing is used to adjust for the multiple thresholds. \begin{itemize} \item Based on collapsing variants into a two categories: variants with MAF below the threshold, and above the threshold. \item Suitable for effects in one direction. \item \citeNP{Price_2010} found the VT approach had high power to detect the association between rare variants and disease trait in their simulations. \end{itemize}  \item We used VTWOD function in RVtests R package.  \end{itemize}  \item We used VTWOD function in RVtests R package.   \item C-alpha \cite{Neale_2011}: Test the variance of the effect size for variants in a specific genomic window (No effect, increase or decrease risk).  \begin{itemize}  \item Sensitive to risk and protective variants in the same gene.