{ "cells": [ { "cell_type": "markdown", "id": "46e329ab", "metadata": {}, "source": [ "# Multiple testing inflates the chances of false positives" ] }, { "cell_type": "markdown", "id": "12c2f106", "metadata": {}, "source": [ "In neuroimaging, it is very common to test many variables simultaneously (e.g. the brain activity in different voxels), which results in a multiple testing problem.\n", "\n", "Let's say that we have one variable, \"var1\", whose mean we know is not significantly different from zero because we are simulating it as such. Assuming $\\alpha=0.05$, we would expect to observe, on average, 5% false positives if we tested its mean multiple times:" ] }, { "cell_type": "code", "execution_count": 1, "id": "8357e495", "metadata": {}, "outputs": [ { "data": { "text/html": [ "0.04" ], "text/latex": [ "0.04" ], "text/markdown": [ "0.04" ], "text/plain": [ "[1] 0.04" ] }, "metadata": {}, "output_type": "display_data" } ], "source": [ "set.seed(1234)\n", "\n", "n.trials<-100\n", "alpha<-0.05\n", "\n", "is.sig<-c()\n", "for(itrial in c(1:n.trials)){\n", " var1<-rnorm(20)\n", " pv<-t.test(var1)$p.value\n", " is.sig<-c(is.sig, pvalpha)/m.sig\n", "cat(\"Type II error = \", type.II.error)" ] }, { "cell_type": "markdown", "id": "338d4129", "metadata": {}, "source": [ "Let's correct for Bonferroni by taking $\\alpha' = 0.05/1000$, instead of $\\alpha$=0.05." ] }, { "cell_type": "code", "execution_count": 11, "id": "3e64068c", "metadata": {}, "outputs": [ { "name": "stdout", "output_type": "stream", "text": [ "number of tests claimed significant using bonferroni = 16 \n", "Number of true tests claimed significant = 16 \n", "Number of false positives = 0 \n", "Type I error = 0 \n", "Type II error = 0.84" ] } ], "source": [ "alphap <- alpha/m\n", "\n", "cat(\"number of tests claimed significant using bonferroni = \", sum(pvsalphap)/m.sig\n", "cat(\"Type II error = \", type.II.error.bonf)" ] }, { "cell_type": "markdown", "id": "599be408", "metadata": {}, "source": [ "By controlling for the false positives using Bonferroni, we have reduced our the number of true effects being claimed significant!!! This means that our statistical power is reduced (or our Type II error rate increased)." ] }, { "cell_type": "markdown", "id": "dd2a2119", "metadata": {}, "source": [ "# Controlling the FDR: BH Correction" ] }, { "cell_type": "code", "execution_count": 12, "id": "463a9aa0", "metadata": {}, "outputs": [], "source": [ "q<-0.05\n", "\n", "# Sort p-values in decreasing order\n", "o <- order(pvs, decreasing = TRUE)\n", "# reverse order\n", "ro <- order(o)\n", "# Adjust p-values multiplying with the number of tests and dividing by each test rank\n", "p.adj.sorted<-m/c(m:1) * pvs[o]\n", "# Fine tune p-values \n", "p.adj<-pmin(1, cummin(p.adj.sorted))[ro]" ] }, { "cell_type": "code", "execution_count": 13, "id": "0eccae17", "metadata": {}, "outputs": [ { "data": { "image/png": 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yF9+vRJRxKgYxSjAAAAAO12+umnt2t9QUHBSSedlKYwQAcoRgEAAADa7Ygjjrjo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\ndfd+XPzpwbu5QhbSbdSoAa3CvF20ipSbf/741aa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Gjw8ssvGzW+9NJLLVu2fLZ6AQAAUFYQjAIAAKAsys7OfvjwYd4WjUaz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\ntLDevXv37t1bv2161MPDY8yYMYbdcvbrSjFotVqdTsfXAfZGoVCU4N8RgTJ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"text/plain": [ "plot without title" ] }, "metadata": { "image/png": { "height": 600, "width": 900 } }, "output_type": "display_data" } ], "source": [ "library(tidyverse)\n", "\n", "p.adjust.df<-data.frame(p.adj=sort(p.adj), ix=c(1:m))\n", "\n", "ggplot(p.adjust.df, mapping = aes(x=ix, y=p.adj)) + geom_point() + \n", "geom_hline(yintercept=0.05, color='red') + scale_x_log10() + theme_bw(20)" ] }, { "cell_type": "code", "execution_count": 14, "id": "c8ade0dd", "metadata": {}, "outputs": [ { "name": "stdout", "output_type": "stream", "text": [ "number of tests claimed significant using FDR = 48 \n", "Number of true tests claimed significant = 45 \n", "Number of false positives = 3 \n", "Type I error = 0.003333333 \n", "Type II error = 0.55" ] } ], "source": [ "q<-0.05\n", "cat(\"number of tests claimed significant using FDR = \", sum(p.adjq)/m.sig\n", "cat(\"Type II error = \", type.II.error.bonf)" ] }, { "cell_type": "markdown", "id": "01ebbb95", "metadata": {}, "source": [ "As we can see, correcting for FDR can increases the number of true positive effects that are detected, which can increase the statistical power and potentially reduce the Type II error rate.\n", "\n", "It's important to keep in mind that this also comes at the cost of potentially increasing the number of false positives, since FDR control is a trade-off between the proportion of true positives and false positives among all rejected null hypotheses. Choosing an appropriate FDR threshold is important to balance the trade-off between statistical power and Type I error rate (false positives)." ] }, { "cell_type": "markdown", "id": "f3b3e951", "metadata": {}, "source": [ "# Multiple testing correction in R" ] }, { "cell_type": "markdown", "id": "df574072", "metadata": {}, "source": [ "We can use the `p.adjust` R built-in function to adjust p-values for multiple testing. It takes as input a vector of p-values, and a method argument that specifies the method to use for adjusting the p-values.\n", "\n", "The available methods are:\n", "\n", "- *bonferroni*: The Bonferroni correction, which is a simple method that controls the FWER at a strict level by multiplying each p-value by the number of tests.\n", "\n", "- *holm*: Holm's step-down procedure, which is a more powerful version of the Bonferroni correction that controls the FWER.\n", "\n", "- *hochberg*: Hochberg's step-up procedure, which controls the FWER at a slightly weaker level than Holm's method.\n", "\n", "- *BH*: The Benjamini-Hochberg procedure, which is a widely used method for controlling the FDR.\n", "\n", "- *BY*: The Benjamini-Yekutieli procedure, which is a modified version of the Benjamini-Hochberg procedure that controls the FDR under weaker assumptions.\n", "\n", "- *fdr*: the same as *BH*." ] }, { "cell_type": "markdown", "id": "07b8c356", "metadata": {}, "source": [ "Let's see how tow apply this function to correct our generated p-values for bonferroni and FDR:" ] }, { "cell_type": "code", "execution_count": 15, "id": "c67922b7", "metadata": {}, "outputs": [ { "name": "stdout", "output_type": "stream", "text": [ "number of tests claimed significant using bonferroni = 16 \n", "number of tests claimed significant using FDR = 48 \n" ] } ], "source": [ "cat(\"number of tests claimed significant using bonferroni = \", sum(p.adjust(pvs, method = \"bonferroni\")< 0.05), \"\\n\")\n", "cat(\"number of tests claimed significant using FDR = \", sum(p.adjust(pvs, method = \"BH\")< 0.05), \"\\n\")" ] } ], "metadata": { "kernelspec": { "display_name": "R", "language": "R", "name": "ir" }, "language_info": { "codemirror_mode": "r", "file_extension": ".r", "mimetype": "text/x-r-source", "name": "R", "pygments_lexer": "r", "version": "4.2.2" } }, "nbformat": 4, "nbformat_minor": 5 }