# Tests the pairwiseTTests function.
# library(scran); library(testthat); source("setup.R"); source("test-pairwise-t.R")

REFFUN <- function(y, grouping, direction="any", lfc=0) 
# A reference function using the t.test function.
{ 
    output <- pairwiseTTests(y, grouping, direction=direction, lfc=lfc)
    grouping <- factor(grouping)
    clust.vals <- levels(grouping)
    alt.hyp <- switch(direction, any="two.sided", up="greater", down="less")

    for (host in clust.vals) {
        host.y <- y[,grouping==host,drop=FALSE]
        for (target in setdiff(clust.vals, host)) {
            target.y <- y[,grouping==target,drop=FALSE]

            if (ncol(host.y)>1L && ncol(target.y)>1L) {
                effect <- rowMeans(host.y) - rowMeans(target.y)
                pval <- numeric(nrow(y))
                for (i in seq_along(pval)) {

                    if (lfc==0) {
                        cur.p <- t.test(host.y[i,], target.y[i,], alternative=alt.hyp)$p.value
                    } else {
                        if (direction=="any") {
                            left.p <- t.test(host.y[i,], target.y[i,], alternative="less", mu=-lfc)$p.value
                            right.p <- t.test(host.y[i,], target.y[i,], alternative="greater", mu=lfc)$p.value
                            cur.p <- pmin(left.p, right.p, 0.5) * 2
                        } else if (direction=="up") {
                            cur.p <- t.test(host.y[i,], target.y[i,], alternative=alt.hyp, mu=lfc)$p.value 
                        } else {
                            cur.p <- t.test(host.y[i,], target.y[i,], alternative=alt.hyp, mu=-lfc)$p.value 
                        }
                    }
                    pval[i] <- cur.p
                }
            } else {
                pval <- effect <- rep(NA_real_, nrow(y))
            }

			currow <- which(output$pairs[,1]==host & output$pairs[,2]==target)
            curres <- output$statistics[[currow]]
			expect_equal(unname(curres$logFC), unname(effect))
            expect_equal(pval, curres$p.value)
            expect_equal(p.adjust(pval, method="BH"), curres$FDR)
            expect_identical(rownames(y), rownames(curres))
        }
    }  
    return(TRUE)
}

set.seed(70000)
ncells <- 200
ngenes <- 250
means <- 2^runif(ngenes, -1, 5)
dummy <- matrix(rnbinom(ngenes*ncells, mu=means, size=5), ncol=ncells, nrow=ngenes)
X <- scuttle::normalizeCounts(dummy, colSums(dummy))
rownames(X) <- seq_len(nrow(X))

set.seed(7000001)
test_that("pairwiseTTests works as expected without blocking or design matrices", {
    clust <- kmeans(t(X), centers=3)
    clusters <- as.factor(clust$cluster)

    REFFUN(X, clusters)
    REFFUN(X, clusters, direction="up")
    REFFUN(X, clusters, direction="down")

    REFFUN(X, clusters, lfc=0.2)
    REFFUN(X, clusters, lfc=0.2, direction="up")
    REFFUN(X, clusters, lfc=0.2, direction="down")

    # Checking what happens if one of the groups has only one element.
    re.clust <- clust$cluster
    re.clust[1] <- 4
    re.clust <- factor(re.clust)
    expect_warning(REFFUN(X, re.clust), "no within-block")

    # Checking what happens if two of the groups have only one element.
    re.clust <- clust$cluster
    re.clust[1:2] <- 4:5
    re.clust <- factor(re.clust)
    expect_warning(REFFUN(X, re.clust), "no within-block")

    # Checking what happens if there is an empty level.
    re.clusters <- clusters
    levels(re.clusters) <- 1:4

    expect_warning(out <- pairwiseTTests(X, re.clusters), "no within-block")
    ref <- pairwiseTTests(X, clusters)
    subset <- match(paste0(ref$pairs$first, ".", ref$pairs$second), 
        paste0(out$pairs$first, ".", out$pairs$second))
    expect_false(any(is.na(subset)))
    expect_equal(out$statistics[subset], ref$statistics)
})

FACTORCHECK <- function(left, right) {
    expect_identical(names(left), names(right))

    oL <- order(left$pairs[,1], left$pairs[,2])
    oR <- order(right$pairs[,1], right$pairs[,2])
    expect_identical(left$pairs[oL,], right$pairs[oR,])

    expect_identical(names(left$statistics)[oL], names(right$statistics)[oR])
    for (x in seq_along(oL)) {
        curleft <- left$statistics[[oL[x]]]
        curright <- right$statistics[[oR[x]]]
        expect_identical(sort(colnames(curleft)), sort(colnames(curright)))
        expect_equal(curleft, curright[,colnames(curleft)])
    }
    return(TRUE)
}

set.seed(70000011)
test_that("pairwiseTTests responds to non-standard level ordering", {
    clusters <- sample(LETTERS[1:5], ncol(X), replace=TRUE)
    f1 <- factor(clusters)
    f2 <- factor(clusters, rev(levels(f1)))
    FACTORCHECK(pairwiseTTests(X, f1), pairwiseTTests(X, f2))
})

set.seed(70000012)
test_that("pairwiseTTests responds to restriction and exclusion", {
    clusters <- sample(LETTERS[1:5], ncol(X), replace=TRUE)

    restrict <- c("B", "C")
    keep <- clusters %in% restrict
    expect_identical(pairwiseTTests(X, clusters, restrict=restrict),
       pairwiseTTests(X[,keep], clusters[keep]))

    restrict <- c("A", "D", "E")
    keep <- clusters %in% restrict
    expect_identical(pairwiseTTests(X, clusters, restrict=restrict),
       pairwiseTTests(X[,keep], clusters[keep]))

    exclude <- c("A", "B", "C")
    keep <- !clusters %in% exclude
    expect_identical(pairwiseTTests(X, clusters, exclude=exclude),
       pairwiseTTests(X[,keep], clusters[keep]))
})

set.seed(70000012)
test_that("pairwiseTTests handles unused levels correctly", {
    clusters <- factor(sample(LETTERS[1:5], ncol(X), replace=TRUE))
    ref <- pairwiseTTests(X, clusters)

    # Correctly spawns a bunch of NA's.
    restrict <- c("A", "D", "E")
    keep <- clusters %in% restrict
    expect_warning(raw <- pairwiseTTests(X[,keep], clusters[keep]), "no within-block")

    both.present <- ref$pairs[,1] %in% restrict & ref$pairs[,2] %in% restrict
    expect_identical(raw$statistics[both.present], ref$statistics[both.present])

    for (other in which(!both.present)) {
        expect_true(all(is.na(raw$statistics[[other]][,"p.value"])))
    }

    # First attempting restriction.
    attempt <- pairwiseTTests(X, clusters, restrict=restrict)
    expect_identical(attempt, pairwiseTTests(X[,keep], as.character(clusters[keep])))

    clust2 <- clusters
    clust2[!clust2 %in% restrict] <- NA
    expect_identical(attempt, pairwiseTTests(X, as.character(clust2)))

    # Now attempting exclusion.
    exclude <- c("A", "B", "C")
    keep <- !clusters %in% exclude
    attempt <- pairwiseTTests(X, clusters, exclude=exclude)
    expect_identical(attempt, pairwiseTTests(X[,keep], as.character(clusters[keep])))

    clust2 <- clusters
    clust2[clust2 %in% exclude] <- NA
    expect_identical(attempt, pairwiseTTests(X, as.character(clust2)))

    # Handles empty spaces correctly.
    clust2 <- as.character(clusters)
    clust2[clust2 %in% exclude] <- ""
    expect_warning(attempt2 <- pairwiseTTests(X, clust2), "replacing")
    expect_identical(attempt, attempt2)
})

###################################################################

BLOCKFUN <- function(y, grouping, block, direction="any", ...) {
    out <- pairwiseTTests(y, grouping, block=block, direction=direction, ...)
    ngroups <- length(unique(grouping))
    expect_equal(nrow(out$pairs), ngroups^2L - ngroups)
    expect_identical(nrow(out$pairs), length(out$statistics))

    for (p in seq_len(nrow(out$pairs))) {
        curpair <- unlist(out$pairs[p,])
        ref.res <- out$statistics[[p]]

        # Extracting block-wise results.
        block.weights <- block.up <- block.down <- block.lfc <- list()
        for (b in unique(block)) { 
            B <- as.character(b)
            chosen <- block==b & grouping %in% curpair
            subgroup <- as.character(grouping[chosen])

            N1 <- sum(subgroup==curpair[1])
            N2 <- sum(subgroup==curpair[2])
            if (N1==0 || N2==0) {
                next
            }

            block.weights[[B]] <- 1/(1/N1 + 1/N2)

            if (direction=="any") { 
                up.res <- pairwiseTTests(y[,chosen], subgroup, direction="up", ...)
                to.use <- which(up.res$pairs$first==curpair[1] & up.res$pairs$second==curpair[2])
                block.up[[B]] <- up.res$statistics[[to.use]]$p.value

                down.res <- pairwiseTTests(y[,chosen], subgroup, direction="down", ...)
                to.use <- which(down.res$pairs$first==curpair[1] & down.res$pairs$second==curpair[2])
                block.down[[B]] <- down.res$statistics[[to.use]]$p.value

                block.lfc[[B]] <- down.res$statistics[[to.use]]$logFC
            } else {
                block.res <- pairwiseTTests(y[,chosen], subgroup, direction=direction, ...)
                to.use <- which(block.res$pairs$first==curpair[1] & block.res$pairs$second==curpair[2])
                block.up[[B]] <- block.down[[B]] <- block.res$statistics[[to.use]]$p.value
                block.lfc[[B]] <- block.res$statistics[[to.use]]$logFC
            }
        }

        block.weights <- unlist(block.weights)
        if (length(block.weights)==0) {
            expect_equal(ref.res$logFC, rep(NA_real_, nrow(ref.res)))
            expect_equal(ref.res$p.value, rep(NA_real_, nrow(ref.res)))
            next
        }

        # Taking a weighted average.
        all.lfc <- do.call(rbind, block.lfc)
        ave.lfc <- colSums(all.lfc * block.weights) / sum(block.weights)
        expect_equal(ave.lfc, ref.res$logFC)

        # Combining p-values in each direction.
        up.p <- metapod::parallelStouffer(block.up, weights=block.weights)$p.value
        down.p <- metapod::parallelStouffer(block.down, weights=block.weights)$p.value
        if (direction=="any") {
            expect_equal(pmin(up.p, down.p, 0.5) * 2, ref.res$p.value)
        } else if (direction=="up") {
            expect_equal(up.p, ref.res$p.value)
        } else if (direction=="down") {
            expect_equal(down.p, ref.res$p.value)
        }
    }

    return(TRUE)
}

set.seed(7000002)
test_that("pairwiseTTests works as expected with blocking", {
    clust <- kmeans(t(X), centers=3)
    clusters <- as.factor(clust$cluster)
    block <- sample(3, ncol(X), replace=TRUE)

    BLOCKFUN(X, clusters, block)
    BLOCKFUN(X, clusters, block, direction="up")
    BLOCKFUN(X, clusters, block, direction="down")

    BLOCKFUN(X, clusters, block, lfc=0.2)
    BLOCKFUN(X, clusters, block, lfc=0.2, direction="up")
    BLOCKFUN(X, clusters, block, lfc=0.2, direction="down")

    # Checking what happens to a block-specific group.
    re.clust <- clust$cluster
    re.clust[block!=1 & re.clust==1] <- 2
    re.clust <- factor(re.clust)
    expect_warning(BLOCKFUN(X, re.clust, block), NA)

    # Checking what happens to a group-specific block.
    re.clust <- clust$cluster
    re.clust[block==1] <- 1
    re.clust <- factor(re.clust)
    expect_warning(BLOCKFUN(X, re.clust, block), NA)

    # Checking what happens to a doubly-specific group and block.
    re.clust <- clust$cluster
    re.clust[block==1] <- 1
    re.block <- block
    re.block[re.clust==1] <- 1
    expect_warning(BLOCKFUN(X, re.clust, re.block), "no within-block comparison")
})

set.seed(70000021)
test_that("pairwiseTTests with blocking works across multiple cores", {
    clust <- kmeans(t(X), centers=3)
    clusters <- as.factor(clust$cluster)
    block <- sample(3, ncol(X), replace=TRUE)
    ref <- pairwiseTTests(X, clusters, block=block)

    expect_equal(ref, pairwiseTTests(X, clusters, block=block, BPPARAM=safeBPParam(2)))

    expect_equal(ref, pairwiseTTests(X, clusters, block=block, BPPARAM=SnowParam(2)))
})

set.seed(70000022)
test_that("pairwiseTTests with blocking responds to non-standard level ordering", {
    clusters <- sample(LETTERS[1:5], ncol(X), replace=TRUE)
    f1 <- factor(clusters)
    f2 <- factor(clusters, rev(levels(f1)))

    b <- sample(1:3, ncol(X), replace=TRUE)
    FACTORCHECK(pairwiseTTests(X, f1, block=b), pairwiseTTests(X, f2, block=b))

    b1 <- factor(b, 1:3)
    b2 <- factor(b, 3:1)
    FACTORCHECK(pairwiseTTests(X, f1, block=b1), pairwiseTTests(X, f2, block=b2))
})

set.seed(70000023)
test_that("pairwiseTTests with blocking responds to restriction", {
    clusters <- sample(LETTERS[1:5], ncol(X), replace=TRUE)

    restrict <- c("B", "C")
    keep <- clusters %in% restrict
    b <- sample(1:3, ncol(X), replace=TRUE)
    expect_identical(pairwiseTTests(X, clusters, restrict=restrict, block=b),
       pairwiseTTests(X[,keep], clusters[keep], block=b[keep]))

    restrict <- c("A", "D", "E")
    keep <- clusters %in% restrict
    expect_identical(pairwiseTTests(X, clusters, restrict=restrict, block=b),
       pairwiseTTests(X[,keep], clusters[keep], block=b[keep]))

    # What happens if the block and cluster are correlated?
    b2 <- b
    b2[!clusters %in% restrict] <- 0
    expect_identical(pairwiseTTests(X, clusters, restrict=restrict, block=b2),
       pairwiseTTests(X[,keep], clusters[keep], block=b2[keep]))
})

###################################################################

LINEARFUN <- function(y, grouping, design, direction="any", lfc=0) {
    output <- pairwiseTTests(y, grouping, design=design, direction=direction, lfc=lfc)

    grouping <- factor(grouping)
    clust.vals <- levels(grouping)
    design2 <- model.matrix(~ 0 + grouping)
    colnames(design2) <- clust.vals
    design2 <- cbind(design2, design) # assume 'design' does not have an intercept.

    for (host in clust.vals) {
        design.custom <- design2
        design.custom[,host] <- 1
        fit <- limma::lmFit(y, design.custom)

        for (target in setdiff(clust.vals, host)) {
			currow <- which(output$pairs[,1]==host & output$pairs[,2]==target)
            curres <- output$statistics[[currow]]
            cur.lfc <- -fit$coefficients[,target] # Minus, as 'host' is currently the intercept.
			expect_equal(unname(curres$logFC), unname(cur.lfc))

            left <- pt((cur.lfc + lfc) / (fit$sigma * fit$stdev.unscaled[,target]), lower.tail=TRUE, df = fit$df.residual)
            right <- pt((cur.lfc - lfc) / (fit$sigma * fit$stdev.unscaled[,target]), lower.tail=FALSE, df = fit$df.residual)

            if (direction=="any") {
                pval <- pmin(left, right, 0.5) * 2
            } else if (direction=="up") {
                pval <- right
            } else {
                pval <- left
            }

            pval <- unname(pval)
            expect_equal(pval, curres$p.value)
            expect_equal(p.adjust(pval, method="BH"), curres$FDR)
            expect_identical(rownames(y), rownames(curres))
        }
    }  
    return(TRUE)
}

set.seed(7000003)
test_that("pairwiseTTests works as expected with a design matrix", {
    clust <- kmeans(t(X), centers=3)
    clusters <- as.factor(clust$cluster)

    covariate <- cbind(runif(ncol(X)))
    LINEARFUN(X, clusters, covariate)
    LINEARFUN(X, clusters, covariate, direction="up")
    LINEARFUN(X, clusters, covariate, direction="down")

    alternative <- cbind(runif(ncol(X)), sample(0:1, ncol(X), replace=TRUE))
    LINEARFUN(X, clusters, alternative, lfc=0.2)
    LINEARFUN(X, clusters, alternative, lfc=0.2, direction="up")
    LINEARFUN(X, clusters, alternative, lfc=0.2, direction="down")

    # Automatically removes the intercept.
    b <- sample(LETTERS[1:3], ncol(X), replace=TRUE)
    block <- model.matrix(~b)
    expect_warning(out <- pairwiseTTests(X, clusters, design=block), "intercept")
    expect_identical(out, pairwiseTTests(X, clusters, design=block[,-1,drop=FALSE]))
})

set.seed(70000031)
test_that("pairwiseTTests with linear models works across multiple cores", {
    clust <- kmeans(t(X), centers=3)
    clusters <- as.factor(clust$cluster)
    covariate <- cbind(runif(ncol(X)))
    ref <- pairwiseTTests(X, clusters, design=covariate)

    expect_equal(ref, pairwiseTTests(X, clusters, design=covariate, BPPARAM=safeBPParam(2)))

    expect_equal(ref, pairwiseTTests(X, clusters, design=covariate, BPPARAM=SnowParam(2)))
})

set.seed(70000032)
test_that("pairwiseTTests with linear models responds to non-standard level ordering", {
    clusters <- sample(LETTERS[1:5], ncol(X), replace=TRUE)

    # Releveled factors.
    f1 <- factor(clusters)
    f2 <- factor(clusters, rev(levels(f1)))

    covariate <- cbind(runif(ncol(X)))
    FACTORCHECK(pairwiseTTests(X, f1, design=covariate), pairwiseTTests(X, f2, design=covariate))

    # Linearly equivalent design matrices.
    d1 <- cbind(sample(0:1, ncol(X), replace=TRUE), sample(0:1, ncol(X), replace=TRUE))
    d2 <- d1
    d2[,1] <- d2[,1] + d2[,2]
    FACTORCHECK(pairwiseTTests(X, f1, design=d1), pairwiseTTests(X, f2, design=d2))

    # Checking that the two tests above are non-trivial,
    # i.e., involve some differences in the pivoting.
    CHECK_PIVOTING <- function(X1, X2) {
        expect_false(identical(qr(X1, LAPACK=TRUE)$pivot, qr(X2, LAPACK=TRUE)$pivot))
        QR <- qr(cbind(X1, X2)) # making sure X1 and X2 are equivalent.
        expect_identical(QR$rank, ncol(X1))
        expect_identical(QR$pivot[seq_len(QR$rank)], seq_len(QR$rank))
    }
    CHECK_PIVOTING(cbind(model.matrix(~f1), covariate), cbind(model.matrix(~f2), covariate))
    CHECK_PIVOTING(cbind(model.matrix(~f1), d1), cbind(model.matrix(~f2), d2))
})

set.seed(70000023)
test_that("pairwiseTTests with design matrices responds to restriction", {
    clusters <- sample(LETTERS[1:5], ncol(X), replace=TRUE)
    cov <- cbind(runif(ncol(X)))

    restrict <- c("B", "C")
    keep <- clusters %in% restrict
    expect_identical(pairwiseTTests(X, clusters, restrict=restrict, design=cov),
       pairwiseTTests(X[,keep], clusters[keep], design=cov[keep,,drop=FALSE]))

    restrict <- c("A", "D", "E")
    keep <- clusters %in% restrict
    expect_identical(pairwiseTTests(X, clusters, restrict=restrict, design=cov),
       pairwiseTTests(X[,keep], clusters[keep], design=cov[keep,,drop=FALSE]))
})

###################################################################

set.seed(7000004)
test_that("pairwiseTTests behaves as expected with subsetting", {
    y <- matrix(rnorm(12000), ncol=12)
    rownames(y) <- seq_len(nrow(y))
    g <- gl(4,3)
    X <- cbind(runif(ncol(y)))

    # Integer subsetting.
    expect_identical(
        pairwiseTTests(y, g, subset.row=1:10),
        pairwiseTTests(y[1:10,], g)
    )
    expect_identical(
        pairwiseTTests(y, g, design=X, subset.row=1:10),
        pairwiseTTests(y[1:10,], g, design=X)
    )

    # Logical subsetting.
    keep <- rbinom(nrow(y), 1, 0.5)==1
    expect_identical(
        pairwiseTTests(y, g, subset.row=keep),
        pairwiseTTests(y[keep,], g) 
    )
    expect_identical(
        pairwiseTTests(y, g, design=X, subset.row=keep),
        pairwiseTTests(y[keep,], g, design=X)
    )

    # Character subsetting.
    rownames(y) <- paste0("GENE_", seq_len(nrow(y)))
    chosen <- sample(rownames(y), 100)
    expect_identical(
        pairwiseTTests(y, g, subset.row=chosen),
        pairwiseTTests(y[chosen,], g)
    )
    expect_identical(
        pairwiseTTests(y, g, design=X, subset.row=chosen),
        pairwiseTTests(y[chosen,], g, design=X)
    )

    # Auto-generates names for the subset.
    y <- y0 <- matrix(rnorm(1200), ncol=12)
    rownames(y) <- seq_len(nrow(y))
    chosen <- 10:1
    expect_identical(
        pairwiseTTests(y, g, subset.row=chosen),
        pairwiseTTests(y[chosen,], g)
    )
    expect_identical(
        pairwiseTTests(y, g, design=X, subset.row=chosen),
        pairwiseTTests(y[chosen,], g, design=X)
    )
})

set.seed(7000005)
test_that("pairwiseTTests behaves as expected with log-transformation", {
    y <- matrix(rnorm(12000), ncol=20)
    g <- gl(5,4)
    X <- cbind(rnorm(ncol(y)))

    # For Welch:
    ref <- pairwiseTTests(y, g)
    out <- pairwiseTTests(y, g, log.p=TRUE)
    expect_identical(ref$pairs, out$pairs)

    for (i in seq_along(ref$statistics)) {
        expect_equal(ref$statistics[[i]]$logFC, out$statistics[[i]]$logFC)
        expect_equal(log(ref$statistics[[i]]$p.value), out$statistics[[i]]$log.p.value)
        expect_equal(log(ref$statistics[[i]]$FDR), out$statistics[[i]]$log.FDR)
    }

    # For linear modelling:
    ref <- pairwiseTTests(y, g, design=X)
    out <- pairwiseTTests(y, g, design=X, log.p=TRUE)
    expect_identical(ref$pairs, out$pairs)

    for (i in seq_along(ref$statistics)) {
        expect_equal(ref$statistics[[i]]$logFC, out$statistics[[i]]$logFC)
        expect_equal(log(ref$statistics[[i]]$p.value), out$statistics[[i]]$log.p.value)
        expect_equal(log(ref$statistics[[i]]$FDR), out$statistics[[i]]$log.FDR)
    }
})

set.seed(70000051)
test_that("pairwiseTTests behaves with standardization of the log-fold changes", {
    y <- matrix(rnorm(12000), ncol=20)
    g <- rep(LETTERS[1:5], c(6,5,4,3,2))
    X <- cbind(rnorm(ncol(y)))

    ref <- pairwiseTTests(y, g)
    std <- pairwiseTTests(y, g, std.lfc=TRUE)
    expect_identical(ref[[1]][[1]]$PValue, std[[1]][[1]]$PValue)

    in.1 <- g=="A"
    s1 <- apply(y[,in.1], 1, var)
    in.2 <- g=="B"
    s2 <- apply(y[,in.2], 1, var)
    s.pool <- sqrt((s1 * (sum(in.1) - 1) + s2 * (sum(in.2) - 1))/(sum(in.1|in.2) -2))
    expect_equal(ref[[1]][[1]]$logFC / s.pool, std[[1]][[1]]$logFC)

    # Handles zero-variance cases properly.
    ref <- pairwiseTTests(rbind(rep(0, 20)), g, std.lfc=TRUE)
    expect_identical(unname(ref[[1]][[1]]$logFC), 0)

    ref <- pairwiseTTests(rbind(c(0,0,1,1)), c(1,1,2,2), std.lfc=TRUE)
    expect_identical(unname(ref[[1]][[1]]$logFC), -Inf)

    # With linear models.
    ref <- pairwiseTTests(y, g, design=X) 
    std <- pairwiseTTests(y, g, design=X, std.lfc=TRUE)
    expect_identical(ref[[1]][[1]]$PValue, std[[1]][[1]]$PValue)

    fit <- lm.fit(x=cbind(model.matrix(~g), X), y=t(y))
    s2 <- colMeans(fit$effects[-seq_len(fit$rank),]^2)
    expect_equal(ref[[1]][[1]]$logFC / sqrt(s2), std[[1]][[1]]$logFC)
})

set.seed(70000051)
test_that("pairwiseTTests works with SEs and SCEs", {
    y <- matrix(rnorm(1200), ncol=12)
    g <- gl(4,3)

    out <- pairwiseTTests(y, g)
    out2 <- pairwiseTTests(SummarizedExperiment(list(logcounts=y)), g)
    expect_identical(out, out2)

    X2 <- SingleCellExperiment(list(logcounts=y))
    colLabels(X2) <- g
    out3 <- pairwiseTTests(X2)
    expect_identical(out, out3)
})

set.seed(70000052)
test_that("pairwiseTTests works with sparse matrices", {
    X_ <- matrix(rpois(100000, lambda=1), ncol=100)
    X <- as(X_, "dgCMatrix")

    groups <- sample(2, ncol(X), replace=TRUE)
    expect_equal(
        pairwiseTTests(X_, groups),
        pairwiseTTests(X, groups),
    )

    block <- sample(2, ncol(X), replace=TRUE)
    expect_equal(
        pairwiseTTests(X_, groups, block=block),
        pairwiseTTests(X, groups, block=block),
    )
})
set.seed(7000006)
test_that("pairwiseTTests fails gracefully with silly inputs", {
    y <- matrix(rnorm(12000), ncol=20)
    g <- gl(5,4)
    X <- cbind(rnorm(ncol(y)))

    # Errors on incorrect inputs.
    expect_error(pairwiseTTests(y[,0], g), "does not equal")
    expect_error(pairwiseTTests(y, rep(1, ncol(y))), "need at least two")
    expect_error(pairwiseTTests(y, g, design=X[0,,drop=FALSE]), "is not equal")
    expect_error(pairwiseTTests(y, g, design=cbind(rep(1, ncol(y)))), "not of full rank")

    # No genes.
    empty <- pairwiseTTests(y[0,], g)
    expect_identical(length(empty$statistics), nrow(empty$pairs))
    expect_true(all(sapply(empty$statistics, nrow)==0L))

    empty <- pairwiseTTests(y[0,], g, design=X)
    expect_identical(length(empty$statistics), nrow(empty$pairs))
    expect_true(all(sapply(empty$statistics, nrow)==0L))

    # Avoid NA p-values when variance is zero.
    clusters <- rep(1:2, each=ncol(y)/2)
    stuff <- matrix(clusters, ngenes, ncol(y), byrow=TRUE)
    out <- pairwiseTTests(stuff, clusters)
    expect_true(all(out$statistics[[1]]$FDR < 1e-8))
    expect_true(all(out$statistics[[2]]$FDR < 1e-8))
    expect_equal(out$statistics[[1]]$logFC, rep(-1, ngenes))
    expect_equal(out$statistics[[2]]$logFC, rep(1, ngenes))

    out <- pairwiseTTests(stuff, clusters, design=X)
    expect_true(all(out$statistics[[1]]$FDR < 1e-8))
    expect_true(all(out$statistics[[2]]$FDR < 1e-8))
    expect_equal(out$statistics[[1]]$logFC, rep(-1, ngenes))
    expect_equal(out$statistics[[2]]$logFC, rep(1, ngenes))
})