library(survival) aeq <- function(x,y) all.equal(as.vector(x), as.vector(y)) test1 <- data.frame(time= c(9, 3,1,1,6,6,8), status=c(1,NA,1,0,1,1,0), x= c(0, 2,1,1,1,0,0)) # Verify that cox.zph computes a score test # First for the Breslow estimate r <- (3 + sqrt(33))/2 # actual MLE for log(beta) U <- c(1/(r+1), 3/(r+3), -r/(r+3), 0) # score statistic imat <- c(r/(r+1)^2, 3*r/(r+3)^2, 3*r/(r+3)^2, 0) # information matrix g = c(1, 6, 6, 9) # death times u2 <- c(sum(U), sum(g*U)) # first derivative i2 <- matrix(c(sum(imat), sum(g*imat), sum(g*imat), sum(g^2*imat)), 2,2) # second derivative sctest <- solve(i2, u2) %*% u2 # Verify that centering makes no difference for the test (though i2 changes) g2 <- g - mean(g) u2b <- c(sum(U), sum(g2*U)) i2b <- matrix(c(sum(imat), sum(g2*imat), sum(g2*imat), sum(g2^2*imat)), 2,2) sctest2 <- solve(i2b, u2b) %*% u2b all.equal(sctest, sctest2) # Now check the program fit1 <- coxph(Surv(time, status) ~ x, test1, ties='breslow') aeq(fit1$coef, log(r)) zp1 <- cox.zph(fit1, transform='identity', global=FALSE) aeq(zp1$table[,1], sctest) aeq(zp1$y, resid(fit1, type="scaledsch")) dummy <- rep(0, nrow(test1)) fit1b <- coxph(Surv(dummy, time, status) ~ x, test1, ties='breslow') aeq(fit1b$coef, log(r)) zp1b <- cox.zph(fit1b, transform='identity', global=FALSE) aeq(zp1b$table[,1], sctest) # the pair of tied times gets reversed in the zph result # but since the 'y' values are only used to plot it doesn't matter aeq(zp1b$y[c(1,3,2,4)], resid(fit1b, type="scaledsch")) # log time check g3 <- log(g) - mean(log(g)) u3 <- c(sum(U), sum(g3*U)) # first derivative i3 <- matrix(c(sum(imat), sum(g3*imat), sum(g3*imat), sum(g3^2*imat)), 2,2) # second derivative sctest3 <- solve(i3, u3) %*% u3 zp3 <- cox.zph(fit1, transform='log', global=FALSE) aeq(zp3$table[,1], sctest3) # Efron approximation phi <- acos((45/23)*sqrt(3/23)) r <- 2*sqrt(23/3)* cos(phi/3) # actual MLE for log(beta) U <- c(1/(r+1), 3/(r+3), -r/(r+5), 0) # score statistic imat <- c(r/(r+1)^2, 3*r/(r+3)^2, 5*r/(r+5)^2, 0) # information matrix u4 <- c(sum(U), sum(g3*U)) # first derivative i4 <- matrix(c(sum(imat), sum(g3*imat), sum(g3*imat), sum(g3^2*imat)), 2,2) # second derivative sctest4 <- solve(i4, u4) %*% u4 fit4 <- coxph(Surv(time, status) ~ x, test1, ties='efron') aeq(fit4$coef, log(r)) zp4 <- cox.zph(fit4, transform='log', global=FALSE) aeq(zp4$table[,1], sctest4) aeq(zp4$y, resid(fit4, type="scaledsch")) fit5 <- coxph(Surv(dummy, time, status) ~ x, test1, ties="efron") aeq(fit5$coef, log(r)) zp5 <- cox.zph(fit5, transform="log", global=FALSE) aeq(zp5$table[,1], sctest4) # Artificial stratification test2 <- rbind(test1, test1) test2$group <- rep(letters[1:2], each=nrow(test1)) # U, imat, and sctest will all double dummy <- c(dummy, dummy) fit6 <- coxph(Surv(dummy, time, status) ~ x + strata(group), test2) aeq(fit6$coef, log(r)) zp6 <- cox.zph(fit6, transform="log", globa=FALSE) aeq(zp6$table[,1], 2*sctest4) # A multi-state check, 2 covariates # Verify that the multi-state result = the single state Cox models etime <- with(mgus2, ifelse(pstat==0, futime, ptime)) event <- with(mgus2, ifelse(pstat==0, 2*death, 1)) event <- factor(event, 0:2, labels=c("censor", "pcm", "death")) table(event) ct1 <- coxph(Surv(etime, event) ~ sex + age, mgus2, id=id, ties='efron') ct2 <- coxph(Surv(etime, event=='pcm') ~ sex + age, mgus2) ct3 <- coxph(Surv(etime, event=='death') ~ sex + age, mgus2) zp1 <- cox.zph(ct1, transform='identity') zp2 <- cox.zph(ct2, transform='identity') zp3 <- cox.zph(ct3, transform='identity') aeq(zp1$table[1:2,], zp2$table[1:2,]) aeq(zp1$table[3:4,], zp3$table[1:2,]) # Now add a starting time of zero dummy <- rep(0, nrow(mgus2)) ct4 <- coxph(Surv(dummy, etime, event) ~ sex + age, mgus2, id=id, ties='efron') ct5 <- coxph(Surv(dummy, etime, event=='pcm') ~ sex + age, mgus2) ct6 <- coxph(Surv(dummy, etime, event=='death') ~ sex + age, mgus2) zp4 <- cox.zph(ct4, transform='identity') zp5 <- cox.zph(ct5, transform='identity') zp6 <- cox.zph(ct6, transform='identity') aeq(zp4$table[1:2,], zp5$table[1:2,]) aeq(zp4$table[3:4,], zp6$table[1:2,]) # Direct check of a multivariate model with start, stop data p1 <- pbcseq[!duplicated(pbcseq$id), 1:6] pdata <- tmerge(p1[, c("id", "trt", "age", "sex")], p1, id=id, death = event(futime, status==2)) pdata <- tmerge(pdata, pbcseq, id=id, bili=tdc(day, bili), edema = tdc(day, edema), albumin=tdc(day, albumin), protime = tdc(day, protime)) pfit <- coxph(Surv(tstart, tstop, death) ~ log(bili) + albumin + edema + age + log(protime), data = pdata, ties='efron') zp7 <- cox.zph(pfit, transform='log', global=FALSE) direct <- function(fit) { nvar <- length(fit$coef) dt <- coxph.detail(fit) gtime <- log(dt$time) - mean(log(dt$time)) # key idea: at any event time I have a first deriviative vector # c(dt$score[i,], gtime[i]* dt$score[i,]) # and second derivative matrix # dt$imat[,,i] gtime[i] * dt$imat[,,i] # gtime[i]*dt$imat[,,i] gtime[i]^2 * dt$imat[,,i] # for the expanded model, where imat[,,i] is symmetric, # and colSums(dt$score) =0 (since the model converged) # # Create score tests for adding one time-dependent variable # gtime * x[,j] at a time: first derivative of this test is # c(dt$score[i,], gtime[i]* dt$score[i,j]) # and etc. unew <- colSums(gtime * dt$score) temp1 <- apply(dt$imat, 1:2, sum) temp2 <- apply(dt$imat, 1:2, function(x) sum(x*gtime)) temp3 <- apply(dt$imat, 1:2, function(x) sum(x * gtime^2)) score <- double(nvar) smat <- matrix(0., nvar+1, nvar+1) # second deriv matrix for the test smat[1:nvar, 1:nvar] <- temp1 for (i in 1:nvar) { smat[nvar+1,] <- c(temp2[i,], temp3[i,i]) smat[,nvar+1] <- c(temp2[,i], temp3[i,i]) utemp <- c(rep(0,nvar), unew[i]) score[i] <- solve(smat, utemp) %*% utemp } list(sctest = score, u= c(colSums(dt$score), unew), imat=cbind(rbind(temp1, temp2), rbind(temp2, temp3))) } aeq(zp7$table[,1], direct(pfit)$sctest) # Last, make sure that NA coefficients are ignored d1 <- survSplit(Surv(time, status) ~ ., veteran, cut=150, episode="epoch") fit <- coxph(Surv(tstart, time, status) ~ celltype:strata(epoch) + age, d1) zz <- cox.zph(fit) fit2 <- coxph(Surv(tstart, time, status) ~ celltype:strata(epoch) + age, d1, x=TRUE) zz2 <- cox.zph(fit2) x2 <- fit2$x[, !is.na(fit$coefficients)][,-1] fit3 <- coxph(Surv(tstart, time, status) ~ age + x2, d1) all.equal(fit3$loglik, fit2$loglik) zz3 <- cox.zph(fit3) all.equal(unclass(zz)[1:7], unclass(zz2)[1:7]) #ignore the call component all.equal(as.vector(zz$table), as.vector(zz3$table)) # variable names change