This is an analysis of significance for extra measurements in affected dogs

The characteristics of this dataset are: 1) small number of dogs (n=4) and small number of repeated measures: (N=4-7) at different timepoints.

The main goal is to perform a mixed model analysis to test the hypothesis of interaction of time and treatment while accounting for repeated measures. for that we use a random regression model with the fixed effects of treatment, time (days of measurement, with time=0 day of infection) and their interaction. We add a random intercept for the dog and we considered adding a random slope for the dog to account for correlation and heterogeneous variances between measuring times within each dog. No dog-specific slope was significant, and we decided to include only a dog-specific intercept.

Load all packages and data

## -- Attaching packages -------------------------------------------------------- tidyverse 1.3.0 --
## v ggplot2 3.3.0     v purrr   0.3.3
## v tibble  2.1.3     v dplyr   0.8.5
## v tidyr   1.0.2     v stringr 1.4.0
## v readr   1.3.1     v forcats 0.5.0
## -- Conflicts ----------------------------------------------------------- tidyverse_conflicts() --
## x dplyr::filter() masks stats::filter()
## x dplyr::lag()    masks stats::lag()
## Loading required package: Matrix
## 
## Attaching package: 'Matrix'
## The following objects are masked from 'package:tidyr':
## 
##     expand, pack, unpack
## Loading required package: emmeans
## The 'lsmeans' package is now basically a front end for 'emmeans'.
## Users are encouraged to switch the rest of the way.
## See help('transition') for more information, including how to
## convert old 'lsmeans' objects and scripts to work with 'emmeans'.
## Loading required package: mvtnorm
## Loading required package: survival
## Loading required package: TH.data
## Loading required package: MASS
## 
## Attaching package: 'MASS'
## The following object is masked from 'package:dplyr':
## 
##     select
## 
## Attaching package: 'TH.data'
## The following object is masked from 'package:MASS':
## 
##     geyser
## 
## Attaching package: 'lmerTest'
## The following object is masked from 'package:lme4':
## 
##     lmer
## The following object is masked from 'package:stats':
## 
##     step

perform first analysis to check models

## boundary (singular) fit: see ?isSingular
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## Warning in checkConv(attr(opt, "derivs"), opt$par, ctrl = control$checkConv, :
## Model failed to converge with max|grad| = 0.00848096 (tol = 0.002, component 1)
## boundary (singular) fit: see ?isSingular
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## boundary (singular) fit: see ?isSingular
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## Warning in checkConv(attr(opt, "derivs"), opt$par, ctrl = control$checkConv, :
## unable to evaluate scaled gradient
## Warning in checkConv(attr(opt, "derivs"), opt$par, ctrl = control$checkConv, :
## Model failed to converge: degenerate Hessian with 1 negative eigenvalues
## Warning: Model failed to converge with 1 negative eigenvalue: -4.0e-03
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## boundary (singular) fit: see ?isSingular
## boundary (singular) fit: see ?isSingular
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## boundary (singular) fit: see ?isSingular
## boundary (singular) fit: see ?isSingular
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)
## refitting model(s) with ML (instead of REML)

Results of mean comparisons

We tested for the interaction of time*treatment and we consider it significant at P < 0.15 (complete)

for (i in 1:11){

resu2<-lres[[i]]$resu
print("=======================================")
print(nms[i])
print("=======================================")

print(anova(resu2))


#compare trt (avg)
#ls<-lsmeans(resu2,~trt)
#print(pairs(ls))



#compare trt @ certain age
print(lsmeans(resu2,"trt",at=list(dpi=0))%>%pairs())
print("time 0")
print(lsmeans(resu2,"trt",at=list(dpi=120))%>%pairs())
print("time 120")
print(lsmeans(resu2,"trt",at=list(dpi=360))%>%pairs())
print("time 360")
print(lsmeans(resu2,"trt",at=list(dpi=720))%>%pairs())
print("time 720")



print(lsmeans(resu2,"trt",at=list(dpi=0)))
print("time 0")
print(lsmeans(resu2,"trt",at=list(dpi=120)))
print("time 120")
print(lsmeans(resu2,"trt",at=list(dpi=360)))
print("time 360")
print(lsmeans(resu2,"trt",at=list(dpi=720)))
print("time 720")
  
}
## [1] "======================================="
## [1] "ONH"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##          Sum Sq Mean Sq NumDF  DenDF F value Pr(>F)
## trt     2260366 2260366     1 15.032  0.9685 0.3406
## dpi       90778   90778     1 15.811  0.0389 0.8462
## trt:dpi 4972643 4972643     1 15.032  2.1307 0.1650
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     1597 1623 15 0.984   0.3407 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     2127 1298 15 1.638   0.1222 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated     3186 763 15 4.176   0.0008 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated     4775 950 15 5.027   0.0002 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated    10556 1335 15.7     7721    13391
##  untreated   8959 1335 15.7     6125    11794
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated    10858 1134 12.2     8392    13324
##  untreated   8732 1134 12.2     6266    11198
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean  SE   df lower.CL upper.CL
##  treated    11463 845 5.21     9315    13610
##  untreated   8277 845 5.21     6129    10424
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean  SE   df lower.CL upper.CL
##  treated    12369 954 7.53    10145    14594
##  untreated   7594 954 7.53     5369     9819
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"
## [1] "======================================="
## [1] "Cup_Vol"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##         Sum Sq Mean Sq NumDF  DenDF F value  Pr(>F)  
## trt     2112.6  2112.6     1 15.030  0.9077 0.35580  
## dpi     9392.6  9392.6     1 15.171  4.0356 0.06269 .
## trt:dpi 8241.2  8241.2     1 15.030  3.5409 0.07939 .
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated    -48.8 51.2 15 -0.953  0.3558 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate SE df t.ratio p.value
##  treated - untreated    -70.4 41 15 -1.717  0.1066 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     -114 24.1 15 -4.711  0.0003 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate SE df t.ratio p.value
##  treated - untreated     -178 30 15 -5.940  <.0001 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated      172 67.6 5.48     2.43      341
##  untreated    220 67.6 5.48    51.25      390
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated      173 63.8 4.44     2.57      343
##  untreated    243 63.8 4.44    72.95      414
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated      176 59.2 3.32    -2.67      354
##  untreated    289 59.2 3.32   110.84      468
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated      180 60.8 3.69     5.21      355
##  untreated    358 60.8 3.69   183.43      533
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"
## [1] "======================================="
## [1] "NRR"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##         Sum Sq Mean Sq NumDF  DenDF F value Pr(>F)  
## trt        524     524     1 15.087  0.0301 0.8646  
## dpi      10712   10712     1 15.480  0.6148 0.4448  
## trt:dpi 140790  140790     1 15.087  8.0799 0.0123 *
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated     24.3 140 15 0.173   0.8646 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated      113 112 15 1.011   0.3279 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated      292 65.9 15 4.425   0.0005 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated      559 82.1 15 6.812   <.0001 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean  SE   df lower.CL upper.CL
##  treated      452 133 10.6      158      746
##  untreated    428 133 10.6      134      722
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean  SE   df lower.CL upper.CL
##  treated      510 118 7.59      234      785
##  untreated    396 118 7.59      121      672
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE df lower.CL upper.CL
##  treated      625 98.7  4      351      899
##  untreated    333 98.7  4       59      607
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean  SE   df lower.CL upper.CL
##  treated      797 106 5.12      527     1067
##  untreated    238 106 5.12      -32      508
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"
## [1] "======================================="
## [1] "FaA"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##          Sum Sq Mean Sq NumDF  DenDF F value Pr(>F)
## trt     0.00518 0.00518     1 8.9930  0.0033 0.9551
## dpi     2.64808 2.64808     1 9.6857  1.7103 0.2211
## trt:dpi 0.24081 0.24081     1 8.9930  0.1555 0.7025
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated  -0.0828 1.43  9 -0.058  0.9551 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated   -0.227 1.11  9 -0.204  0.8431 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.515 0.652  9 -0.791  0.4494 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated   -0.948 1.1  9 -0.864  0.4099 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     3.84 1.17 11.9     1.29     6.40
##  untreated   3.93 1.17 11.9     1.37     6.48
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     3.52 0.964 10.4     1.38     5.65
##  untreated   3.75 0.964 10.4     1.61     5.88
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     2.87 0.696 4.92     1.07     4.67
##  untreated   3.39 0.696 4.92     1.59     5.18
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     1.90 0.953 10.3   -0.213     4.02
##  untreated   2.85 0.953 10.3    0.734     4.96
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"
## [1] "======================================="
## [1] "C_tono"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##            Sum Sq   Mean Sq NumDF  DenDF F value Pr(>F)
## trt     0.0031103 0.0031103     1 19.919  0.2723 0.6075
## dpi     0.0000272 0.0000272     1 12.265  0.0024 0.9619
## trt:dpi 0.0105133 0.0105133     1 19.919  0.9205 0.3488
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE   df t.ratio p.value
##  treated - untreated   0.0552 0.106 19.2 0.522   0.6077 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate     SE   df t.ratio p.value
##  treated - untreated   0.0818 0.0811 19.2 1.009   0.3255 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate     SE   df t.ratio p.value
##  treated - untreated    0.135 0.0442 19.2 3.057   0.0064 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE   df t.ratio p.value
##  treated - untreated    0.215 0.081 19.2 2.655   0.0156 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean     SE   df lower.CL upper.CL
##  treated    0.343 0.0973 14.1    0.134    0.551
##  untreated  0.288 0.0973 14.1    0.079    0.496
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean     SE   df lower.CL upper.CL
##  treated    0.355 0.0742 11.6    0.193    0.518
##  untreated  0.273 0.0742 11.6    0.111    0.436
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean     SE   df lower.CL upper.CL
##  treated    0.380 0.0425 4.54    0.267    0.493
##  untreated  0.245 0.0425 4.54    0.132    0.358
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean     SE   df lower.CL upper.CL
##  treated    0.417 0.0822 9.16   0.2317    0.603
##  untreated  0.202 0.0822 9.16   0.0168    0.388
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"
## [1] "======================================="
## [1] "b_wave"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##          Sum Sq Mean Sq NumDF  DenDF F value Pr(>F)
## trt      0.7986  0.7986     1 27.007  0.0380 0.8468
## dpi      5.5436  5.5436     1 27.394  0.2641 0.6114
## trt:dpi 15.2310 15.2310     1 27.007  0.7256 0.4018
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated   -0.659 3.38 27 -0.195  0.8468 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated   0.0553 2.66 27 0.021   0.9836 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     1.48 1.64 27 0.904   0.3742 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     3.63 2.58 27 1.408   0.1706 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     15.1 3.53 8.49     7.02     23.1
##  untreated   15.7 3.53 8.49     7.68     23.8
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     15.2 3.19 5.94     7.38       23
##  untreated   15.2 3.19 5.94     7.32       23
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     15.5 2.81 3.63     7.37     23.6
##  untreated   14.0 2.81 3.63     5.88     22.1
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     15.9 3.15 5.64     8.06     23.7
##  untreated   12.3 3.15 5.64     4.43     20.1
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"
## [1] "======================================="
## [1] "PhNR_wave"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##         Sum Sq Mean Sq NumDF  DenDF F value Pr(>F)
## trt     4.6425  4.6425     1 26.942  0.2326 0.6335
## dpi     9.2234  9.2234     1 27.886  0.4621 0.5023
## trt:dpi 0.3881  0.3881     1 26.942  0.0194 0.8901
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     1.59 3.29 27 0.482   0.6335 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated     1.47 2.6 27 0.568   0.5751 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated     1.25 1.6 27 0.779   0.4430 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated    0.904 2.51 27 0.360   0.7216 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     17.9 2.79 17.2     12.1     23.8
##  untreated   16.3 2.79 17.2     10.5     22.2
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     17.6 2.37 11.1     12.4     22.8
##  untreated   16.1 2.37 11.1     10.9     21.3
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     16.9 1.84 4.67     12.1     21.7
##  untreated   15.7 1.84 4.67     10.8     20.5
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     15.9 2.31 10.3    10.75     21.0
##  untreated   15.0 2.31 10.3     9.85     20.1
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"
## [1] "======================================="
## [1] "AXL"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##          Sum Sq Mean Sq NumDF  DenDF F value    Pr(>F)    
## trt     0.83919 0.83919     1 26.960   7.569 0.0104817 *  
## dpi     0.38239 0.38239     1 26.987   3.449 0.0742374 .  
## trt:dpi 1.80817 1.80817     1 26.960  16.309 0.0004007 ***
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated    0.676 0.246 27 2.751   0.0105 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated    0.426 0.193 27 2.206   0.0361 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated  -0.0748 0.118 27 -0.632  0.5329 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.825 0.192 27 -4.300  0.0002 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     21.5 0.345 4.95     20.6     22.4
##  untreated   20.8 0.345 4.95     20.0     21.7
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     21.3 0.328 4.06     20.4     22.2
##  untreated   20.9 0.328 4.06     20.0     21.8
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     21.0 0.31 3.24     20.0     21.9
##  untreated   21.1 0.31 3.24     20.1     22.0
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     20.4 0.328 4.08     19.5     21.3
##  untreated   21.3 0.328 4.08     20.3     22.2
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"
## [1] "======================================="
## [1] "ACD"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##          Sum Sq Mean Sq NumDF DenDF F value  Pr(>F)  
## trt     0.48721 0.48721     1    30  3.8583 0.05883 .
## dpi     0.12032 0.12032     1    30  0.9528 0.33681  
## trt:dpi 0.89685 0.89685     1    30  7.1022 0.01227 *
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE   df t.ratio p.value
##  treated - untreated    0.515 0.262 27.1 1.964   0.0598 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE   df t.ratio p.value
##  treated - untreated    0.339 0.206 27.1 1.645   0.1115 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE   df t.ratio p.value
##  treated - untreated  -0.0137 0.126 27.1 -0.109  0.9143 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE   df t.ratio p.value
##  treated - untreated   -0.542 0.205 27.1 -2.648  0.0133 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     4.52 0.186 29.9     4.15     4.90
##  untreated   4.01 0.186 29.9     3.63     4.39
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE df lower.CL upper.CL
##  treated     4.40 0.146 28     4.10     4.70
##  untreated   4.06 0.146 28     3.77     4.36
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE df lower.CL upper.CL
##  treated     4.16 0.091 11     3.96     4.36
##  untreated   4.18 0.091 11     3.98     4.38
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     3.80 0.149 26.2     3.50     4.11
##  untreated   4.34 0.149 26.2     4.04     4.65
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"
## [1] "======================================="
## [1] "LT"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##          Sum Sq Mean Sq NumDF  DenDF F value    Pr(>F)    
## trt     0.11483 0.11483     1 26.706  2.2428 0.1459642    
## dpi     0.75252 0.75252     1 26.958 14.6975 0.0006873 ***
## trt:dpi 0.16400 0.16400     1 26.706  3.2032 0.0848425 .  
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated     0.25 0.167 27 1.498   0.1458 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated    0.175 0.131 27 1.332   0.1940 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate     SE df t.ratio p.value
##  treated - untreated   0.0239 0.0805 27 0.297   0.7688 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated   -0.202 0.13 27 -1.550  0.1329 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     7.58 0.133 20.4     7.30     7.85
##  untreated   7.33 0.133 20.4     7.05     7.60
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     7.46 0.112 13.3     7.22     7.70
##  untreated   7.28 0.112 13.3     7.04     7.52
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean     SE   df lower.CL upper.CL
##  treated     7.22 0.0848 5.09     7.00     7.44
##  untreated   7.19 0.0848 5.09     6.98     7.41
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     6.86 0.113 13.2     6.62     7.10
##  untreated   7.06 0.113 13.2     6.82     7.31
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"
## [1] "======================================="
## [1] "VCD"
## [1] "======================================="
## Type III Analysis of Variance Table with Satterthwaite's method
##          Sum Sq Mean Sq NumDF  DenDF F value Pr(>F)
## trt     0.01462 0.01462     1 26.891  0.1040 0.7496
## dpi     0.36587 0.36587     1 26.964  2.6028 0.1183
## trt:dpi 0.00005 0.00005     1 26.891  0.0004 0.9846
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated  -0.0892 0.277 27 -0.323  0.7496 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated  -0.0878 0.217 27 -0.404  0.6892 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated  -0.0851 0.133 27 -0.638  0.5289 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.081 0.216 27 -0.375  0.7106 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     9.42 0.283 8.54     8.77     10.1
##  untreated   9.51 0.283 8.54     8.86     10.2
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 0"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     9.47 0.255 5.93     8.85     10.1
##  untreated   9.56 0.255 5.93     8.94     10.2
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 120"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     9.59 0.225 3.64     8.94     10.2
##  untreated   9.67 0.225 3.64     9.02     10.3
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 360"
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     9.76 0.256 5.97     9.13     10.4
##  untreated   9.84 0.256 5.97     9.22     10.5
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"