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Load packages

library(tidyverse)
library(ggridges)

library(coxme)
library(lme4)
library(nlme)
library(brms)
library(tidybayes)

library(kableExtra)
library(knitrhooks) # install with devtools::install_github("nathaneastwood/knitrhooks")

output_max_height() # a knitrhook option

options(stringsAsFactors = FALSE)

Load data

# load eclosion data
eclosion.dat <- read.csv("data/1.eclosion_times.csv")

# remove vials seeded with more than 100 larvae
unique(eclosion.dat[which(eclosion.dat$eclosing < 0), "ID"]) # 4 vials overseeded

eclosion.dat.trim <- eclosion.dat %>% 
  filter(ID %in% eclosion.dat[which(eclosion.dat$eclosing < 0), "ID"] == FALSE)

# expand data frame so each row is a single fly
ecl.dat <- reshape::untable(eclosion.dat.trim[ ,c(1:7, 9, 10)], 
                           num = eclosion.dat.trim[, 8])

# load wing length data
wing_length <- read.csv("data/1.wing_length.csv") %>% 
  # scale wing vein length to make effect size comparisons with other data sets?
  mutate(Length = as.numeric(scale(Length)))

# add replicate
wing_length$LINE <- paste0(wing_length$Treatment, substr(wing_length$Rep, 2, 2))

Inspecting the raw data

cols <- c("M females" = "pink", 
          "P females" = "red", 
          "M males" = "skyblue", 
          "P males" = "blue")

eplot <- ecl.dat %>% 
  filter(EVENT == 1) %>% 
  mutate(var = paste(TRT, SEX)) %>% 
  ggplot(aes(x = DAY, y = SEX, fill = var)) +
  geom_boxplot() +
  scale_fill_manual(values = c("pink", "skyblue", "red", "blue"), name = "") +
  theme_bw() +
  theme(legend.position = 'non') +
  NULL

lplot <- wing_length %>% 
  mutate(var = paste(Treatment, Sex)) %>% 
  ggplot(aes(x = Sex, y = Length)) +
  geom_violin(aes(fill = var), alpha = .5) + 
  geom_boxplot(aes(fill = var), width = .1, position = position_dodge(width = .9)) +
  scale_colour_manual(values = c("pink", "skyblue", "red", "blue"), name = "") +
  scale_fill_manual(values = c("pink", "skyblue", "red", "blue"), name = "") +
  theme_bw() +
  theme() +
  NULL

gridExtra::grid.arrange(eplot, lplot, ncol = 2)

Version Author Date
989e86f lukeholman 2020-12-18
96d1188 Martin Garlovsky 2020-12-13
df61dde Martin Garlovsky 2020-12-04

Figure 1: Time to eclosion in days for flies in each treatment split by sex. Wing vein IV length has been scaled (subtracted the mean and divided by the standard deviation). We see one Monogamy male with an unusually small value for wing length - possible error in data entry or measurement error?

Some information on survival analysis…

Here are some useful links for understanding survival analyis. For instance, this link provides an explanation of how to interpret hazard ratios.

The exponents of the coefficients from a Cox model give the hazard ratio, an estimate of the effect size of covariates. In short, hazard ratios give the probability of the event occurring compared to ‘control’ in our case compared to Monogamy females.

  • Hazard ratio = 1: no effect
  • Hazard ratio > 1: reduced hazard
  • Hazard ratio < 1: increased hazard

Fit the model for eclosion time in coxme

We will model time to eclosion (in days) using survival analysis. We measured the time in days from 1st instar until eclosion (EVENT = 1) upon which flies were stored in ethanol before counting. Of the initially seeded 100 flies per vial, the remaining flies not emerging after two consecutive days of no observed eclosions were right censored (EVENT = 0) on the last observation day. In total 14400 larvae were seeded (100 larvae x 2 Treatment x 4 LINE x 6 VIAL x 3 SEED). For P1 only three vials were seeded on day B so we seeded 3 additional vials on day C. Four vials were seeded with too many larvae and excluded from analysis. In total 10448 flies successfully emerged during the observation period leaving 3552 individuals to be right censored on day 9. Censored flies were assigned sex based on the observed sex ratio of eclosees. We calculated the number of flies of each sex that emerged from each vial, and assigned the remaining censored individuals (of unknown sex) sex based on the proportion of individuals of each sex that did emerge, so that overall an equal sex ratio of females:males was assigned to each vial.

First we plot Kaplan-Meier survival curves and the median time to eclosion without considering our full experimental design.

survminer::ggsurvplot(survfit(Surv(DAY, EVENT) ~ TRT + SEX, data = ecl.dat),
                      conf.int = TRUE,
                      risk.table = FALSE,
                      linetype = "SEX",
                      palette = c("pink", "red", "skyblue", "blue"),
                      fun = "event",
                      xlim = c(12, 21),
                      xlab = "Days",
                      ylab = "Cumulative proportion eclosed",
                      legend = 'right',
                      legend.title = "",
                      legend.labs = c("M \u2640","M \u2642",'P \u2640','P \u2642'),
                      break.time.by = 2,
                      ggtheme = theme_bw())

Version Author Date
989e86f lukeholman 2020-12-18
96d1188 Martin Garlovsky 2020-12-13
7d4b609 Martin Garlovsky 2020-12-05
df61dde Martin Garlovsky 2020-12-04

Figure X: Kaplan-Meier curve for eclosion time (in days) for flies in each treatment and sex. +’s indicate censored individuals (n = 3552).

# median eclosion times
survfit(Surv(DAY, EVENT) ~ TRT + SEX, data = ecl.dat)
Call: survfit(formula = Surv(DAY, EVENT) ~ TRT + SEX, data = ecl.dat)

                n events median 0.95LCL 0.95UCL
TRT=M, SEX=f 3637   3059     16      16      16
TRT=M, SEX=m 3363   2697     16      16      16
TRT=P, SEX=f 3568   2492     18      18      18
TRT=P, SEX=m 3432   2200     18      18      18

Next we need to check that the proportional hazards assumption is not violated before fitting the full model. Here we plot the log-log of the survival curves (take the natural logarithm of the cumulative hazard twice). Crossing hazards (lines) indicate violation of the proportional hazards assumption.

# assess proportional hazards assumption
par(mar = c(2, 2, 2, 2))
plot(survfit(Surv(DAY, EVENT) ~ TRT + SEX, data = ecl.dat), 
     lty = 1:2, lwd = 2,
     col = c("pink", "red", "skyblue", "blue"), 
     fun = "cloglog")

legend("bottomright", c("M \u2640","M \u2642",'P \u2640','P \u2642'), 
       col = c("pink", "skyblue", "red", "blue"), 
       lty = 1:2, 
       lwd = 2,
       bty = 'n'
)

Version Author Date
989e86f lukeholman 2020-12-18
96d1188 Martin Garlovsky 2020-12-13
7d4b609 Martin Garlovsky 2020-12-05
df61dde Martin Garlovsky 2020-12-04

Figure X: ln(-ln(survival))

Looks good so we continue to fit the model.

Fitting the coxme model

We fit a mixed effects Cox Proportional hazards model using the coxme package, with time (days) to event (eclosion) as the response and TRT (Monogamy or Polyandry), SEX (female or male) and their interaction as predictors. We also need to account for the experimental design by including the random effects of LINE, SEED day and vial ID. We calculated p-values using likelihood ratio tests comparing the full model to a model where the fixed effect of interest was removed.

# coxmod <- coxme(Surv(DAY, EVENT) ~ TRT * SEX + (1|LINE) + (1|SEED) + (1|ID), 
#                 data = ecl.dat)

# load in the model instead of running
coxmod <- readRDS('output/coxmod.rds')

# null models to generate P-values using likelihood ratio tests
# coxmod_dropTRT <- coxme(Surv(DAY, EVENT) ~ 1 + SEX + (1|LINE) + (1|SEED) + (1|ID), data = ecl.dat)
# coxmod_dropSEX <- coxme(Surv(DAY, EVENT) ~ TRT + 1 + (1|LINE) + (1|SEED) + (1|ID), data = ecl.dat)
# coxmod_dropINT <- coxme(Surv(DAY, EVENT) ~ TRT + SEX + (1|LINE) + (1|SEED) + (1|ID), data = ecl.dat)

coxmod_dropTRT <- readRDS('output/coxmod_dropTRT.rds')
coxmod_dropSEX <- readRDS('output/coxmod_dropSEX.rds')
coxmod_dropINT <- readRDS('output/coxmod_dropINT.rds')

# make a table of the results
bind_rows(
broom::tidy(anova(coxmod, coxmod_dropTRT)),
broom::tidy(anova(coxmod, coxmod_dropSEX)),
broom::tidy(anova(coxmod, coxmod_dropINT))) %>% 
  cbind(Parameter = rep(c('Treatment', 'Sex', 'Treatment x Sex'), each = 2)) %>% 
  na.omit() %>% 
  mutate(across(1:4, round, 3)) %>% 
  as_tibble %>% 
  relocate(Parameter, loglik, statistic, df, p.value) %>% 
  kable() %>% 
  kable_styling() %>% 
  kable_styling(full_width = FALSE)
Parameter loglik statistic df p.value
Treatment -92191.30 7.765 2 0.021
Sex -92235.26 95.679 2 0.000
Treatment x Sex -92187.43 0.011 1 0.916

We see there is an effect of treatment and sex but not their interaction. We can calculate estimates and confidence intervals for the hazard ratio by taking the exponent of the coefficients ± 1.96 * sqrt(vcov(???)). Polyandrous flies have a reduced hazard compared to Monogamy flies, i.e. take longer to eclose (hazard ratio = 0.377, CI = 0.227, 0.627). Males have a reduced hazard compared to females (hazard ratio = 0.823, CI = 0.782, 0.867).

Fit the model in brms

I found this link useful for fitting survival models in brms.

if(!file.exists("output/cox_brms.rds")){
  
  cox_brm <- brm(DAY | cens(1 - EVENT) ~ TRT * SEX + (1|LINE) + (1|SEED) + (1|ID),
               iter = 5000, chains = 4, cores = 4,
               control = list(max_treedepth = 20,
                              adapt_delta = 0.999),
               data = ecl.dat, family = cox())
  
  saveRDS(cox_brm, "output/cox_brms.rds")
} else {
  cox_brm <- readRDS('output/cox_brms.rds')
}

summary(cox_brm)
 Family: cox 
  Links: mu = log 
Formula: DAY | cens(1 - EVENT) ~ TRT * SEX + (1 | LINE) + (1 | SEED) + (1 | ID) 
   Data: ecl.dat (Number of observations: 14000) 
Samples: 4 chains, each with iter = 5000; warmup = 2500; thin = 1;
         total post-warmup samples = 10000

Group-Level Effects: 
~ID (Number of levels: 140) 
              Estimate Est.Error l-95% CI u-95% CI Rhat Bulk_ESS Tail_ESS
sd(Intercept)     0.44      0.03     0.38     0.50 1.00     1751     3037

~LINE (Number of levels: 8) 
              Estimate Est.Error l-95% CI u-95% CI Rhat Bulk_ESS Tail_ESS
sd(Intercept)     0.47      0.19     0.24     0.97 1.00     2189     3550

~SEED (Number of levels: 3) 
              Estimate Est.Error l-95% CI u-95% CI Rhat Bulk_ESS Tail_ESS
sd(Intercept)     0.51      0.61     0.08     2.25 1.00     1961     2566

Population-Level Effects: 
          Estimate Est.Error l-95% CI u-95% CI Rhat Bulk_ESS Tail_ESS
Intercept     0.89      0.49     0.00     1.98 1.00     2196     2184
TRTP         -0.89      0.36    -1.64    -0.16 1.00     2504     3307
SEXm         -0.18      0.03    -0.23    -0.12 1.00     7347     6755
TRTP:SEXm     0.01      0.04    -0.07     0.09 1.00     7296     7851

Samples were drawn using sampling(NUTS). For each parameter, Bulk_ESS
and Tail_ESS are effective sample size measures, and Rhat is the potential
scale reduction factor on split chains (at convergence, Rhat = 1).
fixef(cox_brm) %>% 
  data.frame() %>% 
  rownames_to_column() %>% 
  rename(Parameter = rowname) %>% 
  kable() %>% 
  kable_styling() %>% 
  kable_styling(full_width = FALSE)
Parameter Estimate Est.Error Q2.5 Q97.5
Intercept 0.8907941 0.4862808 0.0025523 1.9775770
TRTP -0.8934343 0.3635685 -1.6424421 -0.1644978
SEXm -0.1750960 0.0264880 -0.2270423 -0.1228412
TRTP:SEXm 0.0103648 0.0397943 -0.0672883 0.0888395

Posterior means of hazard functions (\(\lambda\))

1 / exp(fixef(cox_brm)[, -2])
           Estimate      Q2.5     Q97.5
Intercept 0.4103298 0.9974509 0.1384042
TRTP      2.4435070 5.1677742 1.1788010
SEXm      1.1913606 1.2548830 1.1307049
TRTP:SEXm 0.9896887 1.0696037 0.9149924

Hypothesis testing - eclosion time

hyp_test <- bind_rows(
  hypothesis(cox_brm, 'TRTP = 0')$hypothesis,
  hypothesis(cox_brm, 'SEXm = 0')$hypothesis,
  hypothesis(cox_brm, 'TRTP:SEXm = 0')$hypothesis
) %>% 
  mutate(Parameter = c('Polandry', 'Male', 'Polyandry x Male'),
         across(2:5, round, 3)) %>% 
  #select(-Hypothesis) %>% 
  relocate(Parameter, Estimate, Est.Error, CI.Lower, CI.Upper, Star)

pvals <- bayestestR::p_direction(cox_brm) %>% 
  as.data.frame() %>%
  mutate(vars = map_chr(str_split(Parameter, "_"), ~ .x[2]),
         p_val = 1 - pd, 
         star = ifelse(p_val < 0.05, "\\*", "")) %>%
  select(vars, p_val, star)

hyp_test %>% 
  mutate(vars = c('TRTP', 'SEXm', 'TRTP:SEXm')) %>% 
  left_join(pvals %>% filter(vars != 'Intercept'), 
            by = c("vars")) %>% 
  select(Parameter, Estimate, Est.Error, CI.Lower, CI.Upper, `p` = p_val, star) %>% 
  rename(` ` = star) %>%
  kable() %>% 
  kable_styling(full_width = FALSE)
Parameter Estimate Est.Error CI.Lower CI.Upper p
Polandry -0.893 0.364 -1.642 -0.164 0.0125 *
Male -0.175 0.026 -0.227 -0.123 0.0000 *
Polyandry x Male 0.010 0.040 -0.067 0.089 NA NA

Plot posteriors.

# get posterior predictions
post_cox <- posterior_samples(cox_brm) %>% 
  as_tibble() %>%
  select(contains("b_"), -contains("Intercept")) %>% 
  mutate(draw = 1:n()) %>% 
  pivot_longer(-draw) %>% 
  mutate(key = str_remove_all(name, "b_"))

post_cox %>%
  ggplot(aes(value, key, fill = key)) + 
  geom_vline(xintercept = 0, linetype = 2) + 
  stat_halfeye(alpha = .8) +
  scale_fill_brewer(palette = "Spectral") +
  ylab("Model parameter") +
  xlab("Effect on Wing length") + 
  theme_ridges() +
  theme(legend.position = "none") +
  NULL

Version Author Date
989e86f lukeholman 2020-12-18
96d1188 Martin Garlovsky 2020-12-13
7d4b609 Martin Garlovsky 2020-12-05
df61dde Martin Garlovsky 2020-12-04
# wrangle
f <-
  fixef(cox_brm) %>% 
  data.frame() %>% 
  rownames_to_column() %>% 
  mutate(param = str_remove(rowname, "m|P")) %>% 
  tidyr::expand(nesting(Estimate, Q2.5, Q97.5, param),
         days = 0:24) %>% 
  mutate(m  = 1 - pexp(days, rate = 1 / exp(Estimate)),
         ll = 1 - pexp(days, rate = 1 / exp(Q2.5)),
         ul = 1 - pexp(days, rate = 1 / exp(Q97.5)))
  
# plot!
f %>% 
  ggplot(aes(x = days)) +
#  geom_hline(yintercept = .5, linetype = 3, aes(color = param)) +
  geom_ribbon(aes(ymin = ll, ymax = ul, fill = param),
              alpha = 1/2) +
 # geom_line(aes(y = m, aes(color = cols))) +
  # scale_fill_manual(values = wes_palette("Moonrise2")[c(4, 1)], breaks = NULL) +
  # scale_color_manual(values = wes_palette("Moonrise2")[c(4, 1)], breaks = NULL) +
  # scale_y_continuous("proportion remaining", , breaks = c(0, .5, 1), limits = c(0, 1)) +
  xlab("days to adoption") +
  NULL

Version Author Date
989e86f lukeholman 2020-12-18
96d1188 Martin Garlovsky 2020-12-13
7d4b609 Martin Garlovsky 2020-12-05
df61dde Martin Garlovsky 2020-12-04
f %>% 
  ggplot(aes(x = days, y = m, colour = param)) +
  geom_line() +
  geom_ribbon(aes(ymin = ll, ymax = ul, fill = param), alpha = 1/2) +
  scale_colour_manual(values = c("pink", "red", "skyblue", "blue")) +
  scale_fill_manual(values = c("pink", "red", "skyblue", "blue")) +
  theme_bw() +
  theme() +
  NULL

Version Author Date
989e86f lukeholman 2020-12-18
96d1188 Martin Garlovsky 2020-12-13

Body size differences between treatments and sexes

We measured the length of wing vein IV for a subset of flies as a correlate of body size, which may influence development time.

if(!file.exists("output/wing_brms.rds")){
  
  wing_brms <- brm(Length ~ Treatment * Sex + (1|LINE) + (1|Seed),
                 data = wing_length,
  iter = 5000, chains = 4, cores = 4,
  prior = c(set_prior("normal(0,1)", class = "b"),
            set_prior("cauchy(0,1)", class = "sd")),
  control = list(max_treedepth = 20,
                 adapt_delta = 0.999)
  )
  
  saveRDS(wing_brms, "output/wing_brms.rds")
} else {
  wing_brms <- readRDS('output/wing_brms.rds')
}

pp_check(wing_brms)

Version Author Date
989e86f lukeholman 2020-12-18
96d1188 Martin Garlovsky 2020-12-13

Plot posteriors.

# get posterior predictions
post_dat <- posterior_samples(wing_brms) %>% 
  as_tibble() %>%
  select(contains("b_"), -contains("Intercept")) %>% 
  mutate(draw = 1:n()) %>% 
  pivot_longer(-draw) %>% 
  mutate(key = str_remove_all(name, "b_"))

post_dat %>%
  ggplot(aes(value, key, fill = key)) + 
  geom_vline(xintercept = 0, linetype = 2) + 
  stat_halfeye(alpha = .8) +
  scale_fill_brewer(palette = "Spectral") +
  ylab("Model parameter") +
  xlab("Effect on Wing length") + 
  theme_ridges() +
  theme(legend.position = "none") +
  NULL

Version Author Date
989e86f lukeholman 2020-12-18
96d1188 Martin Garlovsky 2020-12-13
7d4b609 Martin Garlovsky 2020-12-05

Hypothesis testing - body size

wing_test <- bind_rows(
  hypothesis(wing_brms, 'TreatmentP = 0')$hypothesis,
  hypothesis(wing_brms, 'SexM = 0')$hypothesis,
  hypothesis(wing_brms, 'TreatmentP:SexM = 0')$hypothesis
) %>% 
  mutate(Parameter = c('Polandry', 'Male', 'Polyandry x Male'),
         across(2:5, round, 3)) %>% 
  #select(-Hypothesis) %>% 
  relocate(Parameter, Estimate, Est.Error, CI.Lower, CI.Upper, Star)

pvals <- bayestestR::p_direction(wing_brms) %>% 
  as.data.frame() %>%
  mutate(vars = map_chr(str_split(Parameter, "_"), ~ .x[2]),
         p_val = 1 - pd, 
         star = ifelse(p_val < 0.05, "\\*", "")) %>%
  select(vars, p_val, star)

wing_test %>% mutate(vars = c('TreatmentP', 'SexM', 'TreatmentP.SexM')) %>% 
  left_join(pvals %>% filter(vars != 'Intercept'), 
              by = c("vars")) %>% 
    select(Parameter, Estimate, Est.Error, CI.Lower, CI.Upper, `p` = p_val, star) %>% 
  mutate(p = ifelse(p > 0.001, round(p, 3), '< 0.001')) %>% 
  rename(` ` = star) %>%
  kable() %>% 
  kable_styling(full_width = FALSE)
Parameter Estimate Est.Error CI.Lower CI.Upper p
Polandry 0.125 0.289 -0.457 0.701 0.316
Male -1.764 0.042 -1.847 -1.681 < 0.001 *
Polyandry x Male 0.040 0.060 -0.077 0.159 0.256

Extract posterior estimates and plot

fitbrms <- wing_length %>%
  modelr::data_grid(Treatment, Sex, LINE, Seed) %>%
  add_fitted_draws(wing_brms) %>%
  sample_frac(size = .5)

fitbrms %>%
  mutate(Treatment = ifelse(Treatment == "M", "Monogamy", "Polyandry"),
         Sex = ifelse(Sex == "F", "Female", "Male"),
         var = paste(Treatment, Sex)) %>%
  ggplot(aes(x = Sex, y = .value, colour = var)) + 
  geom_hline(yintercept = 0, linetype = 2) + 
  stat_pointinterval(position = position_dodge(0.4), 
                     fill = NA, .width = c(0.5, 0.95), alpha = 0.7) +
  scale_colour_manual(values = c("pink", "skyblue", "red", "blue"), name = "") +
  labs(y = 'Wing vein IV') +
  theme_bw() +
  theme(legend.position = 'top',
        axis.title.x = element_blank()) +
  NULL

Version Author Date
989e86f lukeholman 2020-12-18
96d1188 Martin Garlovsky 2020-12-13

Males are smaller than females and there is no effect of selection treatment on wing length.


sessionInfo()
R version 4.0.3 (2020-10-10)
Platform: x86_64-apple-darwin17.0 (64-bit)
Running under: macOS Catalina 10.15.4

Matrix products: default
BLAS:   /Library/Frameworks/R.framework/Versions/4.0/Resources/lib/libRblas.dylib
LAPACK: /Library/Frameworks/R.framework/Versions/4.0/Resources/lib/libRlapack.dylib

locale:
[1] en_AU.UTF-8/en_AU.UTF-8/en_AU.UTF-8/C/en_AU.UTF-8/en_AU.UTF-8

attached base packages:
[1] stats     graphics  grDevices utils     datasets  methods   base     

other attached packages:
 [1] knitrhooks_0.0.4 knitr_1.30       kableExtra_1.1.0 tidybayes_2.0.3 
 [5] brms_2.14.4      Rcpp_1.0.4.6     nlme_3.1-149     lme4_1.1-23     
 [9] Matrix_1.2-18    coxme_2.2-16     bdsmatrix_1.3-4  survival_3.2-7  
[13] ggridges_0.5.2   forcats_0.5.0    stringr_1.4.0    dplyr_1.0.0     
[17] purrr_0.3.4      readr_1.3.1      tidyr_1.1.0      tibble_3.0.1    
[21] ggplot2_3.3.2    tidyverse_1.3.0  workflowr_1.6.2 

loaded via a namespace (and not attached):
  [1] readxl_1.3.1         backports_1.1.7      plyr_1.8.6          
  [4] igraph_1.2.5         svUnit_1.0.3         splines_4.0.3       
  [7] crosstalk_1.1.0.1    TH.data_1.0-10       rstantools_2.1.1    
 [10] inline_0.3.15        digest_0.6.25        htmltools_0.5.0     
 [13] rsconnect_0.8.16     fansi_0.4.1          magrittr_2.0.1      
 [16] openxlsx_4.1.5       modelr_0.1.8         RcppParallel_5.0.1  
 [19] matrixStats_0.56.0   xts_0.12-0           sandwich_2.5-1      
 [22] prettyunits_1.1.1    colorspace_1.4-1     blob_1.2.1          
 [25] rvest_0.3.5          haven_2.3.1          xfun_0.19           
 [28] callr_3.4.3          crayon_1.3.4         jsonlite_1.7.0      
 [31] zoo_1.8-8            glue_1.4.2           survminer_0.4.8     
 [34] gtable_0.3.0         emmeans_1.4.7        webshot_0.5.2       
 [37] V8_3.4.0             car_3.0-8            pkgbuild_1.0.8      
 [40] rstan_2.21.2         abind_1.4-5          scales_1.1.1        
 [43] mvtnorm_1.1-0        DBI_1.1.0            rstatix_0.5.0       
 [46] miniUI_0.1.1.1       viridisLite_0.3.0    xtable_1.8-4        
 [49] foreign_0.8-80       km.ci_0.5-2          stats4_4.0.3        
 [52] StanHeaders_2.21.0-3 DT_0.13              htmlwidgets_1.5.1   
 [55] httr_1.4.1           threejs_0.3.3        arrayhelpers_1.1-0  
 [58] ellipsis_0.3.1       farver_2.0.3         reshape_0.8.8       
 [61] pkgconfig_2.0.3      loo_2.3.1            dbplyr_1.4.4        
 [64] labeling_0.3         tidyselect_1.1.0     rlang_0.4.6         
 [67] reshape2_1.4.4       later_1.0.0          munsell_0.5.0       
 [70] cellranger_1.1.0     tools_4.0.3          cli_2.0.2           
 [73] generics_0.0.2       broom_0.5.6          evaluate_0.14       
 [76] fastmap_1.0.1        yaml_2.2.1           processx_3.4.2      
 [79] fs_1.4.1             zip_2.0.4            survMisc_0.5.5      
 [82] whisker_0.4          mime_0.9             projpred_2.0.2      
 [85] xml2_1.3.2           compiler_4.0.3       bayesplot_1.7.2     
 [88] shinythemes_1.1.2    rstudioapi_0.11      gamm4_0.2-6         
 [91] curl_4.3             ggsignif_0.6.0       reprex_0.3.0        
 [94] statmod_1.4.34       stringi_1.5.3        highr_0.8           
 [97] ps_1.3.3             Brobdingnag_1.2-6    lattice_0.20-41     
[100] nloptr_1.2.2.1       markdown_1.1         KMsurv_0.1-5        
[103] shinyjs_1.1          vctrs_0.3.0          pillar_1.4.4        
[106] lifecycle_0.2.0      bridgesampling_1.0-0 estimability_1.3    
[109] insight_0.8.4        data.table_1.12.8    httpuv_1.5.3.1      
[112] R6_2.4.1             promises_1.1.0       rio_0.5.16          
[115] gridExtra_2.3        codetools_0.2-16     boot_1.3-25         
[118] colourpicker_1.0     MASS_7.3-53          gtools_3.8.2        
[121] assertthat_0.2.1     rprojroot_1.3-2      withr_2.2.0         
[124] shinystan_2.5.0      multcomp_1.4-13      bayestestR_0.6.0    
[127] mgcv_1.8-33          parallel_4.0.3       hms_0.5.3           
[130] grid_4.0.3           coda_0.19-3          minqa_1.2.4         
[133] rmarkdown_2.5        carData_3.0-4        ggpubr_0.3.0        
[136] git2r_0.27.1         shiny_1.4.0.2        lubridate_1.7.8     
[139] base64enc_0.1-3      dygraphs_1.1.1.6