Reintroduce interface to saemix

Also after the upgrade from buster to bullseye of my local system, some
test results for saemix have changed.

4 files changed, 240 insertions, 1 deletions

diff --git a/tests/testthat/setup_script.R b/tests/testthat/setup_script.R
index 547b2d6c..9229c198 100644
--- a/tests/testthat/setup_script.R
+++ b/tests/testthat/setup_script.R
@@ -178,6 +178,10 @@ ds_biphasic <- lapply(ds_biphasic_mean, function(ds) {
 })
 
 # Mixed model fits
+saemix_available <- FALSE
+if (requireNamespace("saemix", quietly = TRUE)) {
+  if(packageVersion("saemix") >= "3.1.9000") saemix_available <- TRUE
+}
 mmkin_sfo_1 <- mmkin("SFO", ds_sfo, quiet = TRUE, error_model = "tc", cores = n_cores)
 mmkin_dfop_1 <- mmkin("DFOP", ds_dfop, quiet = TRUE, cores = n_cores)
 mmkin_biphasic <- mmkin(list("DFOP-SFO" = DFOP_SFO), ds_biphasic, quiet = TRUE, cores = n_cores)
@@ -186,6 +190,16 @@ mmkin_biphasic_mixed <- mixed(mmkin_biphasic)
 dfop_nlme_1 <- nlme(mmkin_dfop_1)
 nlme_biphasic <- nlme(mmkin_biphasic)
 
+if (saemix_available) {
+  sfo_saem_1 <- saem(mmkin_sfo_1, quiet = TRUE, transformations = "saemix")
+
+  dfop_saemix_1 <- saem(mmkin_dfop_1, quiet = TRUE, transformations = "mkin")
+  dfop_saemix_2 <- saem(mmkin_dfop_1, quiet = TRUE, transformations = "saemix")
+
+  saem_biphasic_m <- saem(mmkin_biphasic, transformations = "mkin", quiet = TRUE)
+  saem_biphasic_s <- saem(mmkin_biphasic, transformations = "saemix", quiet = TRUE)
+}
+
 ds_uba <- lapply(experimental_data_for_UBA_2019[6:10],
   function(x) subset(x$data[c("name", "time", "value")]))
 names(ds_uba) <- paste("Dataset", 6:10)
@@ -197,3 +211,7 @@ f_uba_mmkin <- mmkin(list("SFO-SFO" = sfo_sfo_uba, "DFOP-SFO" = dfop_sfo_uba),
   ds_uba, quiet = TRUE, cores = n_cores)
 f_uba_dfop_sfo_mixed <- mixed(f_uba_mmkin[2, ])
 
+if (saemix_available) {
+  f_uba_sfo_sfo_saem <- saem(f_uba_mmkin["SFO-SFO", ], quiet = TRUE, transformations = "saemix")
+  f_uba_dfop_sfo_saem <- saem(f_uba_mmkin["DFOP-SFO", ], quiet = TRUE, transformations = "saemix")
+}
diff --git a/tests/testthat/summary_saem_biphasic_s.txt b/tests/testthat/summary_saem_biphasic_s.txt
new file mode 100644
index 00000000..1e0f1ccc
--- /dev/null
+++ b/tests/testthat/summary_saem_biphasic_s.txt
@@ -0,0 +1,77 @@
+saemix version used for fitting:      Dummy 0.0 for testing 
+mkin version used for pre-fitting:  Dummy 0.0 for testing 
+R version used for fitting:         Dummy R version for testing 
+Date of fit:     Dummy date for testing 
+Date of summary: Dummy date for testing 
+
+Equations:
+d_parent/dt = - ((k1 * g * exp(-k1 * time) + k2 * (1 - g) * exp(-k2 *
+           time)) / (g * exp(-k1 * time) + (1 - g) * exp(-k2 * time)))
+           * parent
+d_m1/dt = + f_parent_to_m1 * ((k1 * g * exp(-k1 * time) + k2 * (1 - g)
+           * exp(-k2 * time)) / (g * exp(-k1 * time) + (1 - g) *
+           exp(-k2 * time))) * parent - k_m1 * m1
+
+Data:
+509 observations of 2 variable(s) grouped in 15 datasets
+
+Model predictions using solution type analytical 
+
+Fitted in test time 0 s using 300, 100 iterations
+
+Variance model: Constant variance 
+
+Mean of starting values for individual parameters:
+      parent_0           k_m1 f_parent_to_m1             k1             k2 
+       1.0e+02        4.8e-03        4.8e-01        6.8e-02        1.3e-02 
+             g 
+       4.2e-01 
+
+Fixed degradation parameter values:
+None
+
+Results:
+
+Likelihood computed by importance sampling
+   AIC  BIC logLik
+  2645 2654  -1310
+
+Optimised parameters:
+                  est.   lower   upper
+parent_0       1.0e+02  99.627 1.0e+02
+k_m1           4.8e-03   0.004 5.6e-03
+f_parent_to_m1 4.8e-01   0.437 5.2e-01
+k1             6.5e-02   0.051 8.0e-02
+k2             1.2e-02   0.010 1.4e-02
+g              4.3e-01   0.362 5.0e-01
+
+Correlation: 
+               prnt_0 k_m1   f_p__1 k1     k2    
+k_m1           -0.156                            
+f_parent_to_m1 -0.157  0.372                     
+k1              0.159  0.000 -0.029              
+k2              0.074  0.145  0.032  0.332       
+g              -0.072 -0.142 -0.044 -0.422 -0.570
+
+Random effects:
+                  est.  lower upper
+SD.parent_0       1.14  0.251  2.03
+SD.k_m1           0.14 -0.073  0.35
+SD.f_parent_to_m1 0.29  0.176  0.41
+SD.k1             0.36  0.211  0.52
+SD.k2             0.18  0.089  0.27
+SD.g              0.32  0.098  0.53
+
+Variance model:
+    est. lower upper
+a.1  2.7   2.5   2.9
+
+Resulting formation fractions:
+              ff
+parent_m1   0.48
+parent_sink 0.52
+
+Estimated disappearance times:
+       DT50 DT90 DT50back DT50_k1 DT50_k2
+parent   25  145       44      11      58
+m1      145  481       NA      NA      NA
diff --git a/tests/testthat/test_mixed.R b/tests/testthat/test_mixed.R
index 6f28d0c3..0eb1f0d5 100644
--- a/tests/testthat/test_mixed.R
+++ b/tests/testthat/test_mixed.R
@@ -1,9 +1,98 @@
 context("Nonlinear mixed-effects models")
 
+test_that("Parent fits using saemix are correctly implemented", {
+  skip_if(!saemix_available)
+
+  expect_error(saem(fits), "Only row objects")
+  # Some fits were done in the setup script
+  mmkin_sfo_2 <- update(mmkin_sfo_1, fixed_initials = c(parent = 100))
+  expect_error(update(mmkin_sfo_1, models = c("SFOOO")), "Please supply models.*")
+
+  sfo_saem_2 <- saem(mmkin_sfo_1, quiet = TRUE, transformations = "mkin")
+  sfo_saem_3 <- expect_error(saem(mmkin_sfo_2, quiet = TRUE), "at least two parameters")
+  s_sfo_s1 <- summary(sfo_saem_1)
+  s_sfo_s2 <- summary(sfo_saem_2)
+
+  sfo_nlme_1 <- expect_warning(nlme(mmkin_sfo_1), "not converge")
+  s_sfo_n <- summary(sfo_nlme_1)
+
+  # Compare with input
+  expect_equal(round(s_sfo_s2$confint_ranef["SD.log_k_parent", "est."], 1), 0.3)
+  # k_parent is a bit different from input 0.03 here
+  expect_equal(round(s_sfo_s1$confint_back["k_parent", "est."], 3), 0.035)
+  expect_equal(round(s_sfo_s2$confint_back["k_parent", "est."], 3), 0.035)
+
+  # But the result is pretty unanimous between methods
+  expect_equal(round(s_sfo_s1$confint_back["k_parent", "est."], 3),
+    round(s_sfo_s2$confint_back["k_parent", "est."], 3))
+  expect_equal(round(s_sfo_s1$confint_back["k_parent", "est."], 3),
+    round(s_sfo_n$confint_back["k_parent", "est."], 3))
+
+  mmkin_fomc_1 <- mmkin("FOMC", ds_fomc, quiet = TRUE, error_model = "tc", cores = n_cores)
+  fomc_saem_1 <- saem(mmkin_fomc_1, quiet = TRUE)
+  ci_fomc_s1 <- summary(fomc_saem_1)$confint_back
+
+  fomc_pop <- as.numeric(fomc_pop)
+  expect_true(all(ci_fomc_s1[, "lower"] < fomc_pop))
+  expect_true(all(ci_fomc_s1[, "upper"] > fomc_pop))
+
+  mmkin_fomc_2 <- update(mmkin_fomc_1, state.ini = 100, fixed_initials = "parent")
+  fomc_saem_2 <- saem(mmkin_fomc_2, quiet = TRUE, transformations = "mkin")
+  ci_fomc_s2 <- summary(fomc_saem_2)$confint_back
+
+  expect_true(all(ci_fomc_s2[, "lower"] < fomc_pop[2:3]))
+  expect_true(all(ci_fomc_s2[, "upper"] > fomc_pop[2:3]))
+
+  s_dfop_s1 <- summary(dfop_saemix_1)
+  s_dfop_s2 <- summary(dfop_saemix_2)
+  s_dfop_n <- summary(dfop_nlme_1)
+
+  dfop_pop <- as.numeric(dfop_pop)
+  expect_true(all(s_dfop_s1$confint_back[, "lower"] < dfop_pop))
+  expect_true(all(s_dfop_s1$confint_back[, "upper"] > dfop_pop))
+  expect_true(all(s_dfop_s2$confint_back[, "lower"] < dfop_pop))
+  expect_true(all(s_dfop_s2$confint_back[, "upper"] > dfop_pop))
+
+  dfop_mmkin_means_trans <- apply(parms(mmkin_dfop_1, transformed = TRUE), 1, mean)
+  dfop_mmkin_means <- backtransform_odeparms(dfop_mmkin_means_trans, mmkin_dfop_1$mkinmod)
+
+  # We get < 22% deviations by averaging the transformed parameters
+  rel_diff_mmkin <- (dfop_mmkin_means - dfop_pop) / dfop_pop
+  expect_true(all(rel_diff_mmkin < 0.22))
+
+  # We get < 50% deviations with transformations made in mkin
+  rel_diff_1 <- (s_dfop_s1$confint_back[, "est."] - dfop_pop) / dfop_pop
+  expect_true(all(rel_diff_1 < 0.5))
+
+  # We get < 12% deviations with transformations made in saemix
+  rel_diff_2 <- (s_dfop_s2$confint_back[, "est."] - dfop_pop) / dfop_pop
+  expect_true(all(rel_diff_2 < 0.12))
+
+  mmkin_hs_1 <- mmkin("HS", ds_hs, quiet = TRUE, error_model = "const", cores = n_cores)
+  hs_saem_1 <- saem(mmkin_hs_1, quiet = TRUE)
+  ci_hs_s1 <- summary(hs_saem_1)$confint_back
+
+  hs_pop <- as.numeric(hs_pop)
+  # expect_true(all(ci_hs_s1[, "lower"] < hs_pop)) # k1 is overestimated
+  expect_true(all(ci_hs_s1[, "upper"] > hs_pop))
+
+  mmkin_hs_2 <- update(mmkin_hs_1, state.ini = 100, fixed_initials = "parent")
+  hs_saem_2 <- saem(mmkin_hs_2, quiet = TRUE)
+  ci_hs_s2 <- summary(hs_saem_2)$confint_back
+
+  #expect_true(all(ci_hs_s2[, "lower"] < hs_pop[2:4])) # k1 again overestimated
+  expect_true(all(ci_hs_s2[, "upper"] > hs_pop[2:4]))
+
+  # HS would likely benefit from implemenation of transformations = "saemix"
+})
+
 test_that("Print methods work", {
   expect_known_output(print(fits[, 2:3], digits = 2), "print_mmkin_parent.txt")
   expect_known_output(print(mmkin_biphasic_mixed, digits = 2), "print_mmkin_biphasic_mixed.txt")
   expect_known_output(print(nlme_biphasic, digits = 1), "print_nlme_biphasic.txt")
+
+  skip_if(!saemix_available)
+  expect_known_output(print(sfo_saem_1, digits = 1), "print_sfo_saem_1.txt")
 })
 
 test_that("nlme results are reproducible to some degree", {
@@ -20,6 +109,50 @@ test_that("nlme results are reproducible to some degree", {
 
   dfop_sfo_pop <- as.numeric(dfop_sfo_pop)
   ci_dfop_sfo_n <- summary(nlme_biphasic)$confint_back
-  # expect_true(all(ci_dfop_sfo_n[, "lower"] < dfop_sfo_pop)) # k2 is overestimated
+  expect_true(all(ci_dfop_sfo_n[, "lower"] < dfop_sfo_pop))
   expect_true(all(ci_dfop_sfo_n[, "upper"] > dfop_sfo_pop))
 })
+
+test_that("saem results are reproducible for biphasic fits", {
+
+  skip_if(!saemix_available)
+  test_summary <- summary(saem_biphasic_s)
+  test_summary$saemixversion <- "Dummy 0.0 for testing"
+  test_summary$mkinversion <- "Dummy 0.0 for testing"
+  test_summary$Rversion <- "Dummy R version for testing"
+  test_summary$date.fit <- "Dummy date for testing"
+  test_summary$date.summary <- "Dummy date for testing"
+  test_summary$time <- c(elapsed = "test time 0")
+
+  expect_known_output(print(test_summary, digits = 2), "summary_saem_biphasic_s.txt")
+
+  dfop_sfo_pop <- as.numeric(dfop_sfo_pop)
+  no_k1 <- c(1, 2, 3, 5, 6)
+  no_k2 <- c(1, 2, 3, 4, 6)
+  no_k1_k2 <- c(1, 2, 3, 6)
+
+  ci_dfop_sfo_s_s <- summary(saem_biphasic_s)$confint_back
+  # k1 and k2 are overestimated
+  expect_true(all(ci_dfop_sfo_s_s[no_k1_k2, "lower"] < dfop_sfo_pop[no_k1_k2]))
+  expect_true(all(ci_dfop_sfo_s_s[, "upper"] > dfop_sfo_pop))
+
+  # k1 and k2 are not fitted well
+  ci_dfop_sfo_s_m <- summary(saem_biphasic_m)$confint_back
+  expect_true(all(ci_dfop_sfo_s_m[no_k2, "lower"] < dfop_sfo_pop[no_k2]))
+  expect_true(all(ci_dfop_sfo_s_m[no_k1, "upper"] > dfop_sfo_pop[no_k1]))
+
+  # I tried to only do few iterations in routine tests as this is so slow
+  # but then deSolve fails at some point (presumably at the switch between
+  # the two types of iterations)
+  #saem_biphasic_2 <- saem(mmkin_biphasic, solution_type = "deSolve",
+  # control = list(nbiter.saemix = c(10, 5), nbiter.burn = 5), quiet = TRUE)
+
+  skip("Fitting with saemix takes around 10 minutes when using deSolve")
+  saem_biphasic_2 <- saem(mmkin_biphasic, solution_type = "deSolve", quiet = TRUE)
+
+  # As with the analytical solution, k1 and k2 are not fitted well
+  ci_dfop_sfo_s_d <- summary(saem_biphasic_2)$confint_back
+  expect_true(all(ci_dfop_sfo_s_d[no_k2, "lower"] < dfop_sfo_pop[no_k2]))
+  expect_true(all(ci_dfop_sfo_s_d[no_k1, "upper"] > dfop_sfo_pop[no_k1]))
+})
+
diff --git a/tests/testthat/test_plot.R b/tests/testthat/test_plot.R
index 0bf3ee66..1c95d069 100644
--- a/tests/testthat/test_plot.R
+++ b/tests/testthat/test_plot.R
@@ -35,6 +35,11 @@ test_that("Plotting mkinfit, mmkin and mixed model objects is reproducible", {
   plot_biphasic_mmkin <- function() plot(f_uba_dfop_sfo_mixed)
   vdiffr::expect_doppelganger("mixed model fit for mmkin object", plot_biphasic_mmkin)
 
+  if (saemix_available) {
+    plot_biphasic_saem_s <- function() plot(f_uba_dfop_sfo_saem)
+    vdiffr::expect_doppelganger("mixed model fit for saem object with saemix transformations", plot_biphasic_saem_s)
+  }
+
   skip_on_travis()
 
   plot_biphasic_nlme <- function() plot(dfop_nlme_1)
@@ -43,6 +48,12 @@ test_that("Plotting mkinfit, mmkin and mixed model objects is reproducible", {
   #plot_biphasic_mmkin <- function() plot(mixed(mmkin_biphasic))
   # Biphasic fits with lots of data and fits have lots of potential for differences
   plot_biphasic_nlme <- function() plot(nlme_biphasic)
+  if (saemix_available) {
+    #plot_biphasic_saem_s <- function() plot(saem_biphasic_s)
+    plot_biphasic_saem_m <- function() plot(saem_biphasic_m)
+
+    vdiffr::expect_doppelganger("mixed model fit for saem object with mkin transformations", plot_biphasic_saem_m)
+  }
 
   # different results when working with eigenvalues
   plot_errmod_fit_D_obs_eigen <- function() plot_err(fit_D_obs_eigen, sep_obs = FALSE)