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 3.3.3     v purrr   0.3.4
## v tibble  3.0.5     v dplyr   1.0.3
## v tidyr   1.1.2     v stringr 1.4.0
## v readr   1.4.0     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'.
## Warning: package 'multcompView' was built under R version 4.0.5
## Warning: package 'multcomp' was built under R version 4.0.5
## Loading required package: mvtnorm
## Loading required package: survival
## Loading required package: TH.data
## Warning: package 'TH.data' was built under R version 4.0.5
## 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
## 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)
## boundary (singular) fit: see ?isSingular
## boundary (singular) fit: see ?isSingular
## Warning: Model failed to converge with 1 negative eigenvalue: -4.4e-02
## 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
## Warning: Model failed to converge with 1 negative eigenvalue: -6.6e-01
## 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
## 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
## boundary (singular) fit: see ?isSingular
## Warning: Model failed to converge with 1 negative eigenvalue: -5.1e+00
## 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
## 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)

## [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     12017150 12017150     1 22.993  5.9365 0.02299 *
## dpi       113146   113146     1 23.360  0.0559 0.81517  
## trt:dpi  8149239  8149239     1 22.993  4.0258 0.05671 .
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated     2040 837 23 2.437   0.0230 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated     2479 680 23 3.648   0.0013 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated     3357 520 23 6.462   <.0001 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated     4674 836 23 5.587   <.0001 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean  SE   df lower.CL upper.CL
##  treated    10871 903 6.77     8720    13022
##  untreated   8830 903 6.77     6679    10982
## 
## 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    11117 833 5.03     8978    13255
##  untreated   8637 833 5.03     6499    10776
## 
## 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    11609 774 3.78     9409    13809
##  untreated   8252 774 3.78     6052    10452
## 
## 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    12346 909 6.85    10187    14506
##  untreated   7673 909 6.85     5513     9832
## 
## 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       1304    1304     1 23.012  0.7064 0.4092973    
## dpi      33526   33526     1 23.077 18.1642 0.0002913 ***
## trt:dpi  31332   31332     1 23.012 16.9755 0.0004169 ***
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated    -21.3 25.3 23 -0.840  0.4093 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated    -48.5 20.5 23 -2.362  0.0270 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     -103 15.7 23 -6.559  <.0001 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     -185 25.3 23 -7.306  <.0001 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated      174 56.2 3.55     10.4      339
##  untreated    196 56.2 3.55     31.6      360
## 
## 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      175 55.2 3.31     8.61      342
##  untreated    224 55.2 3.31    57.07      391
## 
## 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      177 54.4 3.13     7.74      346
##  untreated    280 54.4 3.13   110.63      449
## 
## 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 56.3 3.57     15.7      344
##  untreated    364 56.3 3.57    200.2      528
## 
## 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       2691    2691     1 23.037  0.1882    0.6684    
## dpi       3254    3254     1 23.225  0.2276    0.6378    
## trt:dpi 326630  326630     1 23.037 22.8403 8.041e-05 ***
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     30.5 70.4 23 0.434   0.6685 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated      118 57.1 23 2.073   0.0496 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated      294 43.7 23 6.736   <.0001 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated      558 70.3 23 7.933   <.0001 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated      495 97.5 4.76      241      750
##  untreated    465 97.5 4.76      210      719
## 
## 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      543 93 3.97      284      803
##  untreated    425 93 3.97      166      684
## 
## 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      640 89.3 3.38    373.4      907
##  untreated    346 89.3 3.38     79.3      613
## 
## 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      786 97.9 4.81    531.1     1040
##  untreated    228 97.9 4.81    -26.6      482
## 
## 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     0.19336 0.19336     1 12.782  0.1192 0.7356
## dpi     2.77477 2.77477     1 14.733  1.7099 0.2110
## trt:dpi 0.16267 0.16267     1 12.782  0.1002 0.7567
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.332 0.962 13 -0.345  0.7355 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.419 0.758 13 -0.552  0.5901 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.593 0.572 13 -1.036  0.3189 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated   -0.853 1.04 13 -0.819  0.4274 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     3.49 0.903 10.2     1.48     5.50
##  untreated   3.82 0.903 10.2     1.81     5.83
## 
## 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     3.25 0.773 6.98     1.42     5.07
##  untreated   3.66 0.773 6.98     1.84     5.49
## 
## 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     2.76 0.653 4.31    0.998     4.52
##  untreated   3.35 0.653 4.31    1.591     5.11
## 
## 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     2.03 0.918 11.3   0.0201     4.05
##  untreated   2.89 0.918 11.3   0.8732     4.90
## 
## 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     0.0045932 0.0045932     1 23.710  0.4092 0.5285
## dpi     0.0001359 0.0001359     1 10.758  0.0121 0.9144
## trt:dpi 0.0205916 0.0205916     1 23.710  1.8345 0.1884
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate     SE   df t.ratio p.value
##  treated - untreated   0.0477 0.0745 23.2 0.640   0.5286 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate     SE   df t.ratio p.value
##  treated - untreated   0.0761 0.0576 23.2 1.320   0.1996 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate     SE   df t.ratio p.value
##  treated - untreated    0.133 0.0387 23.2 3.437   0.0022 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate     SE   df t.ratio p.value
##  treated - untreated    0.218 0.0733 23.2 2.979   0.0067 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean     SE   df lower.CL upper.CL
##  treated    0.330 0.0703 10.8    0.175    0.486
##  untreated  0.283 0.0703 10.8    0.127    0.438
## 
## 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    0.346 0.0543 8.09    0.221    0.471
##  untreated  0.270 0.0543 8.09    0.145    0.395
## 
## 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    0.378 0.0373 4.24    0.276    0.479
##  untreated  0.245 0.0373 4.24    0.143    0.346
## 
## 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    0.425 0.0714 9.71    0.265    0.585
##  untreated  0.207 0.0714 9.71    0.047    0.366
## 
## 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      2.4527  2.4527     1 33.004  0.1362 0.7144
## dpi     25.5967 25.5967     1 33.167  1.4215 0.2416
## trt:dpi 26.4507 26.4507     1 33.004  1.4689 0.2341
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated   -0.857 2.32 33 -0.369  0.7144 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated  -0.0993 1.85 33 -0.054  0.9574 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     1.42 1.34 33 1.055   0.2991 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     3.69 2.29 33 1.611   0.1168 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     15.6 2.89 5.57     8.43     22.9
##  untreated   16.5 2.89 5.57     9.29     23.7
## 
## 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     15.6 2.71 4.35     8.34     22.9
##  untreated   15.7 2.71 4.35     8.44     23.0
## 
## 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     15.6 2.56 3.45     8.07     23.2
##  untreated   14.2 2.56 3.45     6.66     21.8
## 
## 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     15.6 2.88 5.48     8.43     22.9
##  untreated   12.0 2.88 5.48     4.74     19.2
## 
## 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     0.0831  0.0831     1 33.001  0.0047 0.9458
## dpi     8.4091  8.4091     1 33.428  0.4739 0.4959
## trt:dpi 3.3502  3.3502     1 33.001  0.1888 0.6667
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate  SE df t.ratio p.value
##  treated - untreated   -0.158 2.3 33 -0.068  0.9458 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated    0.112 1.83 33 0.061   0.9517 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated    0.651 1.33 33 0.489   0.6283 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated     1.46 2.27 33 0.642   0.5252 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean   SE   df lower.CL upper.CL
##  treated     16.7 2.12 10.8     12.0     21.4
##  untreated   16.9 2.12 10.8     12.2     21.6
## 
## 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     16.6 1.87 6.99     12.2     21.1
##  untreated   16.5 1.87 6.99     12.1     21.0
## 
## 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     16.5 1.64 4.26     12.0     20.9
##  untreated   15.8 1.64 4.26     11.4     20.3
## 
## 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     16.2 2.11 10.5     11.6     20.9
##  untreated   14.8 2.11 10.5     10.1     19.4
## 
## 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     0.03196 0.03196     1 34.943  0.1717 0.6812
## dpi     0.43333 0.43333     1 35.026  2.3280 0.1360
## trt:dpi 0.30412 0.30412     1 34.943  1.6338 0.2096
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated  -0.0913 0.22 35 -0.414  0.6811 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated    -0.17 0.175 35 -0.972  0.3377 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.328 0.134 35 -2.457  0.0191 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.565 0.236 35 -2.392  0.0223 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE  df lower.CL upper.CL
##  treated     21.1 0.311 4.7     20.3     21.9
##  untreated   21.2 0.311 4.7     20.4     22.0
## 
## 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     21.0 0.296 3.89     20.2     21.8
##  untreated   21.2 0.296 3.89     20.4     22.0
## 
## 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     20.8 0.285 3.36     20.0     21.7
##  untreated   21.2 0.285 3.36     20.3     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     20.6 0.318 5.12     19.8     21.4
##  untreated   21.1 0.318 5.12     20.3     22.0
## 
## 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     0.008563 0.008563     1    38  0.0631 0.8031
## dpi     0.128088 0.128088     1    38  0.9434 0.3375
## trt:dpi 0.251558 0.251558     1    38  1.8528 0.1815
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE   df t.ratio p.value
##  treated - untreated   0.0472 0.188 35.1 0.251   0.8032 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE   df t.ratio p.value
##  treated - untreated  -0.0245 0.15 35.1 -0.164  0.8706 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE   df t.ratio p.value
##  treated - untreated   -0.168 0.114 35.1 -1.474  0.1493 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE   df t.ratio p.value
##  treated - untreated   -0.383 0.202 35.1 -1.901  0.0655 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     4.26 0.133 32.8     3.99     4.53
##  untreated   4.21 0.133 32.8     3.94     4.48
## 
## 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     4.20 0.106 23.1     3.98     4.42
##  untreated   4.22 0.106 23.1     4.00     4.44
## 
## 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     4.08 0.0821 10.1     3.89     4.26
##  untreated   4.24 0.0821 10.1     4.06     4.43
## 
## 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     3.89 0.146 32.3     3.59     4.19
##  untreated   4.27 0.146 32.3     3.98     4.57
## 
## 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     0.10193 0.10193     1 34.557  1.9911 0.1671686    
## dpi     0.97444 0.97444     1 35.234 19.0340 0.0001068 ***
## trt:dpi 0.15272 0.15272     1 34.557  2.9830 0.0930713 .  
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated    0.163 0.115 35 1.411   0.1671 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate     SE df t.ratio p.value
##  treated - untreated    0.107 0.0918 35 1.166   0.2515 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate   SE df t.ratio p.value
##  treated - untreated  -0.0048 0.07 35 -0.069  0.9457 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.173 0.124 35 -1.393  0.1723 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     7.49 0.092 18.1     7.30     7.68
##  untreated   7.33 0.092 18.1     7.13     7.52
## 
## 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     7.39 0.0776 10.7     7.22     7.56
##  untreated   7.28 0.0776 10.7     7.11     7.45
## 
## 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     7.19 0.0657 5.73     7.03     7.35
##  untreated   7.20 0.0657 5.73     7.03     7.36
## 
## 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     6.89 0.0986 20.5     6.69     7.10
##  untreated   7.07 0.0986 20.5     6.86     7.27
## 
## 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     0.34886 0.34886     1 34.926  2.4789 0.12440  
## dpi     0.43664 0.43664     1 35.042  3.1027 0.08689 .
## trt:dpi 0.11613 0.11613     1 34.926  0.8252 0.36989  
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.301 0.191 35 -1.574  0.1244 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 0"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.253 0.152 35 -1.660  0.1058 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 120"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated   -0.155 0.116 35 -1.337  0.1899 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 360"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  contrast            estimate    SE df t.ratio p.value
##  treated - untreated -0.00889 0.205 35 -0.043  0.9657 
## 
## Degrees-of-freedom method: kenward-roger 
## [1] "time 720"
## [1] "======================================="
## NOTE: Results may be misleading due to involvement in interactions
##  trt       lsmean    SE   df lower.CL upper.CL
##  treated     9.35 0.238 5.45     8.75     9.95
##  untreated   9.65 0.238 5.45     9.06    10.25
## 
## 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     9.42 0.224 4.26     8.82     10.0
##  untreated   9.68 0.224 4.26     9.07     10.3
## 
## 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     9.57 0.213 3.5     8.94     10.2
##  untreated   9.72 0.213 3.5     9.10     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     9.78 0.245 6.05     9.19     10.4
##  untreated   9.79 0.245 6.05     9.19     10.4
## 
## Degrees-of-freedom method: kenward-roger 
## Confidence level used: 0.95 
## [1] "time 720"