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\begin{itemize}  \item VT \cite{Price_2010}:   \begin{itemize}  \item The variable threshold (VT) approach of \citeNP{Price_2010} \citeNP{Price_2010},  is based on the regression of phenotypes onto the counts of variants whose in the genomic region of interest which have  minor allele frequencies (MAFs)are  below some user-defined  threshold (e.g. $1 \%$ or $5\%$). \item The idea is that, that  variants with MAF below some threshold are more likely to be have a higher prior probability of being  functional than the variants with higher MAF. MAF, based on population-genetic arguments.  \item For each possible MAF threshold, VT computes a z-score score measuring the strength of association between the pheonotype and the genomic region,  and uses the maximum of z-score score  over all allele frequency thresholds. The statistical significance of the maximum score  is then assessed by a  permutation testing on phenotypes. test.    \item In their simulations, \citeNP{Price_2010} found that the VT approach had high power to detect the association between rare variants and disease traits when effects are in one direction.