tox.profile.nTTP: Generate nTTPs toxicity scores and the likelihhood-ratio (LR)...
In iAdapt: Two-Stage Adaptive Dose-Finding Clinical Trial Design

Description Usage Arguments Value Examples

The normalized total toxicity profiles (nTTP) are calculated by combining multiple toxicity grades and their weights. The nTTPs are considered a quasi-continuous toxicity measure that follows a normal distribution truncated to [0, 1]. The likelihood ratio per dose are based on nTTP toxicity.

1	tox.profile.nTTP(dose, p1, p2, K, coh.size, ntox, W, TOX, std.nTTP = 0.15)

`dose`	number of doses to be tested (scalar)
`p1`	toxicity under null (unsafe nTTP). Values range from 0 - 1.
`p2`	toxicity under alternative (safe nTTP). Values range from 0 - 1; p1 > p2
`K`	threshold for LR. Takes integer values: 1,2,...(recommended K=2)
`coh.size`	cohort size (number of patients) per dose (Stage 1)
`ntox`	number (integer) of different toxicity types (e.g, hematological, neurological, GI)
`W`	matrix defines burden weight of each grade level for all toxicity types. The dimensions are ntox rows by 5 columns (for grades 0-4). See Ezzalfani et al. (2013) for details.
`TOX`	matrix array of toxicity probabilities. There should be ntox matrices. Each matrix represents one toxicity type, where probabilities of each toxicity grade are specified across each dose. Each matrix has the same dimensions: n rows, representing number of doses, and 5 columns (for grades 0-4). Probabilities across each dose (rows) must sum to 1. See Ezzalfani et al. (2013) for details.
`std.nTTP`	the standard deviation of nTTP scores at each dose level (constant across doses)

mnTTP - 4-column matrix containing dose assignment, mean nTTP at each dose, cohort number, and likelihood ratio.
all_nttp - all observed nTTP values

# Number of pre-specified dose levels
dose <- 6  
    
# Acceptable (p2) and unacceptable nTTP values
p1 <- 0.35                                     
p2 <- 0.10    

# Likelihood-ratio (LR) threshold
K <- 2                                          

# Cohort size used in stage 1
coh.size <- 3 

# Number of toxicity types
ntox <- 3

# Standard deviation of nTTP values
std.nTTP = 0.15
 
# Toxicity burden weight matrix
W = matrix(c(0, 0.5, 0.75, 1.0, 1.5, # Burden weight for grades 0-4 for toxicity 1
             0, 0.5, 0.75, 1.0, 1.5, # Burden weight for grades 0-4 for toxicity 2
             0, 0.00, 0.00, 0.5, 1), # Burden weight for grades 0-4 for toxicity 3
             nrow = ntox, byrow = TRUE)
           

# Array of toxicity event probabilities
TOX = array(NA, c(dose, 5, ntox)) 

TOX[, , 1] = matrix(c(0.823, 0.152, 0.022, 0.002, 0.001,  #prob of tox for dose 1 and tox type 1
                      0.791, 0.172, 0.032, 0.004, 0.001,  #prob of tox for dose 2 and tox type 1
                      0.758, 0.180, 0.043, 0.010, 0.009,  #prob of tox for dose 3 and tox type 1
                      0.685, 0.190, 0.068, 0.044, 0.013,  #prob of tox for dose 4 and tox type 1
                      0.662, 0.200, 0.078, 0.046, 0.014,  #prob of tox for dose 5 and tox type 1
                      0.605, 0.223, 0.082, 0.070, 0.020), #prob of tox for dose 6 and tox type 1
                      nrow = 6, byrow = TRUE)
TOX[, , 2] = matrix(c(0.970, 0.027, 0.002, 0.001, 0.000,  #prob of tox for dose 1 and tox type 2
                      0.968, 0.029, 0.002, 0.001, 0.000,  #prob of tox for dose 2 and tox type 2
                      0.813, 0.172, 0.006, 0.009, 0.000,  #prob of tox for dose 3 and tox type 2
                      0.762, 0.183, 0.041, 0.010, 0.004,  #prob of tox for dose 4 and tox type 2
                      0.671, 0.205, 0.108, 0.011, 0.005,  #prob of tox for dose 5 and tox type 2
                      0.397, 0.258, 0.277, 0.060, 0.008), #prob of tox for dose 6 and tox type 2
                      nrow = 6, byrow = TRUE)
TOX[, , 3] = matrix(c(0.930, 0.060, 0.005, 0.001, 0.004,  #prob of tox for dose 1 and tox type 3
                      0.917, 0.070, 0.007, 0.001, 0.005,  #prob of tox for dose 2 and tox type 3
                      0.652, 0.280, 0.010, 0.021, 0.037,  #prob of tox for dose 3 and tox type 3
                      0.536, 0.209, 0.031, 0.090, 0.134,  #prob of tox for dose 4 and tox type 3
                      0.015, 0.134, 0.240, 0.335, 0.276,  #prob of tox for dose 5 and tox type 3
                      0.005, 0.052, 0.224, 0.372, 0.347), #prob of tox for dose 6 and tox type 3
                      nrow = 6, byrow = TRUE)

tox.profile.nTTP(dose = dose, 
p1 = p1, 
p2 = p2, 
K = K, 
coh.size = coh.size, 
ntox = ntox, 
W = W, 
TOX = TOX, 
std.nTTP = std.nTTP)