library("knitr") # opts_chunk$set(eval=FALSE) library(pander) panderOptions("digits", 3) set.seed(18090212) library(shiftR)

This package is designed for fast enrichment analysis of locally correlated statistics via circular permutations. Circular permutations are used to preserve local dependence of test statistics. This allows the permutation analysis to produce correct p-values when alternatives (like Fisher's exact test) would produce inflated test statistics (next chapter provides an example).

First, for the introduction, let us consider two data sets with binary measurements across the same set of conditions.

- Both data sets are binary (e.g. 0/1, success/failure outcomes).
- The values in one data set are matched to the values in the other, i.e. the values are available for the same location / time.

A practical example of such pair of data sets would be a set of daily weather measurements in two cities, with binary values 0/1 indicating if it was raining in the given city on a particular day. The values within each data set are clearly locally correlated, as the weather today depends on the weather yesterday.

Our goal is to test if the occurences of rain in the two cities are statistically dependent.

Note that Fisher's exact test should NOT be applied here because it requires independence of measurements within each data set.

With the following code we generate
a pair of **independent** data sets with high local dependence (`cor = 0.99`

)
and perform testing for dependence with `shiftR`

contrast it
with Fisher's exact test.
The local dependence causes Fisher's Exact test
to produce unreasonably small p-value < 10^-19^,
wrongly suggesting strong dependence between data sets,
while permutation testing by `shiftR`

does not detect any dependence (p-value > 0.1).

n = 1e6 sim = simulateBinary(n, corWithin = 0.99, corAcross = 0) offsets = getOffsetsUniform(n = n, npermute = 10e3) perm = shiftrPermBinary( sim$data1, sim$data2, offsets) message("Fisher exact test p-value: ", perm$fisherTest$p.value) message("Permutation p-value: ", perm$permPV)

(Permutation analysis on matched numeric data sets)

Consider the following scenario. We have performed two genome-wide (or methylome-wide) association studies. Our goal is to test whether the top genomic locations indicated by one study are enriched with top locations indicated by another study. For simplicity, we first assume the studies were testing the same set of genomic locations.

As in previous example, the p-values produced by each study are locally dependent (due to linkage disequilibrium).

Let `sim`

contain two simulated sets of p-values
from the aforementioned studies.

set.seed(18090212)

n = 1e6 sim = simulatePValues(n, corWithin = 0.99, corAcross = 0)

The dependence of p-values within each study causes Fisher's exact test to indicate strong dependence between top results (using 0.10 p-value threshold).

fisher.test(sim$data1 < 0.10, sim$data2 < 0.10)$p.value

The function `enrichmentAnalysis`

in our package
conducts enrichment testing on two sets of locally correlated
set of p-values (or other types of values, smaller being better).

The code below test for enrichment between the p-value data sets using 10,000 circular permutations. The first data set is thresholded at 0.01, 0.05, and 0.10 percentiles, as is the second.

enr = enrichmentAnalysis( sim$data1, sim$data2, percentiles1 = c(0.01, 0.05, 0.10), percentiles2 = c(0.01, 0.05, 0.10), npermute = 10e3, threads = 2) message('Enrichment p-value is: ', enr$overallPV[2])

Note that unlike Fisher's exact test, circular permutation analysis is robust to local correlation of the tests in each data set.

The enrichment testing is performed for each pair of percentile thresholds as descripbed in Section 2.

The overall testing (detailed below) tests across all thresholds and does not require additional correction for multiple testing. The overall testing is conducted as follows. For each permutation and each threshold, we calculate the overlap of top genomic sites and calculate the Cramer's V score for the overlap. Then, the maximim V score (maxV) across possible thresholds is calculated the permutation. The distribution of maxV under permutation is then compared to the maxV for the original data and the overall permutation p-value for enrichment is calculated. For overall test of depletion, minV equal to minimum V score is used. The overall two-sided test used maximum absolute value of V score.

In practice, the genomic locations at which the data in the data sets is available differs. This can happen, for example, it one data set has gene-wise information and the other has p-value for methylation sites.

Genomic data sets can be easily matched by location with the
`matchDatasets`

function.

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