safe.dose.nTTP {iAdapt}

Identify safe/acceptable doses from stage 1 based on nTTP scores.

Description

Function safe.dose.nTTP() distinguishes acceptable from unacceptable doses

Usage

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

Arguments

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)

W

matrix defining burden weight of each grade level for all toxicity types. The dimensions are ntox rows by 4 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.

ntox

number (integer) of different toxicity types

std.nTTP

the standard deviation of nTTP scores at each dose level (constant across doses)

Value

List of the following objects:

• alloc.safe - matrix of assignments only for acceptable doses (to be used in stage 2) and their corresponding toxicities

• alloc.total - vector of all dose assignments from stage 1

• n1 - total number of subjects allocated in stage 1

• all_nttp - all observed nTTP values

Examples

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

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