Path_Cutoff_052325

# =====================================================================
# Pathologist TIL (Stromal_invasviefront_TIL) Cutoff Analysis
# Adding to existing F_ratio cutoff analysis
# =====================================================================

# Required libraries
library(readxl)
library(dplyr)

## 
## Attaching package: 'dplyr'

## The following objects are masked from 'package:stats':
## 
##     filter, lag

## The following objects are masked from 'package:base':
## 
##     intersect, setdiff, setequal, union

library(survival)
library(survminer)

## Loading required package: ggplot2

## Loading required package: ggpubr

## 
## Attaching package: 'survminer'

## The following object is masked from 'package:survival':
## 
##     myeloma

library(pROC)

## Type 'citation("pROC")' for a citation.

## 
## Attaching package: 'pROC'

## The following objects are masked from 'package:stats':
## 
##     cov, smooth, var

library(ggplot2)
library(stringr)

# =====================================================================
# Required Functions (from F_ratio analysis)
# =====================================================================

# Log-rank cutoff function
find_optimal_cutoff <- function(data, variable, time_col, status_col) {
  # Get all possible cutpoints
  cutpoints <- unique(sort(data[[variable]]))
  # If too many cutpoints, use percentiles
  if(length(cutpoints) > 100) {
    percentiles <- seq(0.05, 0.95, by = 0.01)
    cutpoints <- quantile(data[[variable]], probs = percentiles, na.rm = TRUE)
  }
  # Need at least 2 cutpoints
  if (length(cutpoints) < 2) {
    stop("Not enough unique values in variable to find cutoff")
  }
  
  # Test each cutoff and store log-rank test p-value
  results <- data.frame(cutpoint = numeric(), p_value = numeric(), HR = numeric())
  
  for(cut in cutpoints) {
    # Check group sizes
    group_high <- sum(data[[variable]] >= cut, na.rm = TRUE)
    group_low <- sum(data[[variable]] < cut, na.rm = TRUE)
    
    # Skip if groups too small
    if (group_high < 5 || group_low < 5) {
      next
    }
    
    # Create groups based on cutoff
    data$group <- ifelse(data[[variable]] >= cut, "High", "Low")
    
    # Perform log-rank test
    tryCatch({
      # Log-rank test
      surv_diff <- survdiff(as.formula(paste("Surv(", time_col, ",", status_col, ") ~ group")), data = data)
      p_val <- 1 - pchisq(surv_diff$chisq, df = 1)
      
      # Cox model for HR
      cox_model <- coxph(as.formula(paste("Surv(", time_col, ",", status_col, ") ~ group")), data = data)
      hr <- exp(coef(cox_model))[1]
      
      # Store results
      results <- rbind(results, data.frame(cutpoint = cut, p_value = p_val, HR = hr))
    }, error = function(e) {
      # Skip this cutpoint on error
    })
  }
  
  # Check if any valid results
  if (nrow(results) == 0) {
    stop("No valid cutpoints found")
  }
  
  # Find cutoff with minimum p-value (best separation)
  best_result <- results[which.min(results$p_value), ]
  
  # Return results
  return(list(
    results = results,
    best_cutpoint = best_result$cutpoint,
    best_pvalue = best_result$p_value,
    best_HR = best_result$HR
  ))
}

# Modified Youden cutoff function that handles protective factors correctly
find_youden_cutoff_protective <- function(data, variable, time_col, status_col, time_point) {
  subset_data <- data %>% filter(!!sym(time_col) >= time_point | !!sym(status_col) == 1)
  subset_data$outcome <- ifelse(subset_data[[status_col]] == 1 &
                                subset_data[[time_col]] <= time_point, 1, 0)
  
  # For protective factors, we reverse the marker
  subset_data$marker_for_roc <- -subset_data[[variable]]
  
  roc_obj <- roc(subset_data$outcome, subset_data$marker_for_roc)
  coords <- coords(roc_obj, "best", best.method = "youden")
  
  # Convert back to original scale
  original_cutpoint <- -coords$threshold
  
  return(list(
    cutpoint = original_cutpoint,
    sensitivity = coords$sensitivity,
    specificity = coords$specificity,
    auc = as.numeric(auc(roc_obj))
  ))
}

# 5. Pathologist TIL Analysis
# 5.1. Load Data with Updated File Path
# =====================================================================

# OS 데이터 로드 (업데이트된 파일 경로)
dataset_os_til <- read_excel('/Volumes/SSD 1T/downloads_2024_iMAC/20241112_Tongue_AI.xlsx', sheet = 1)
print(str_c('OS dataset size for TIL analysis: ', nrow(dataset_os_til), ' rows'))

## [1] "OS dataset size for TIL analysis: 139 rows"

# 컬럼명 정리
colnames(dataset_os_til) <- str_c(dataset_os_til %>%
  colnames() %>% str_replace_all(' ', '') %>%
  str_replace_all(fixed('('), '_') %>%
  str_replace_all(fixed('%'), 'per') %>%
  str_replace_all(fixed(')'), '_') %>%
  str_replace_all(fixed('/'), '_') %>%
  str_squish())

# 데이터 전처리
dataset_os_til_select <- dataset_os_til %>%
  mutate(
    # 팩터 변수들
    RM5mm = as.factor(RM5mm),
    ENE = as.factor(ENE),
    Differentiation = as.factor(Differentiation),
    LVI = as.factor(LVI),
    PNI = as.factor(PNI),
    SEX = as.factor(SEX),
    
    # 연속 변수들
    DOIgrade = as.numeric(DOIgrade),
    Stromal_invasviefront_TIL = as.numeric(Stromal_invasviefront_TIL),
    F_ratio = as.numeric(F_ratio),
    LRratio = as.numeric(LRratio),
    status_modified = as.numeric(status_modified),
    Month = as.numeric(Month),
    
    # Z-점수 정규화
    DOIgrade_norm = scale(DOIgrade),
    LRratio_norm = scale(LRratio),
    F_ratio_norm = scale(F_ratio),
    Stromal_invasviefront_TIL_norm = scale(Stromal_invasviefront_TIL),
    
    # TIL 스케일링 (병리의사 10% 단위 측정을 반영하여 10배)
    TIL_scaled = Stromal_invasviefront_TIL * 10
  )

## Warning: There was 1 warning in `mutate()`.
## ℹ In argument: `LRratio = as.numeric(LRratio)`.
## Caused by warning:
## ! NAs introduced by coercion

# 불필요한 컬럼 제거
dataset_os_til_select <- dataset_os_til_select %>%
  select(-c(SurgicalN, OPDATE, LastFU, Recur_date, DATA_Chart))

# 결측값 확인
missing_values_os_til <- colSums(is.na(dataset_os_til_select))
print("Missing values in OS TIL data by variable:")

## [1] "Missing values in OS TIL data by variable:"

print(missing_values_os_til[missing_values_os_til > 0])

## LRratio         
##      10      10

# RFS 데이터 로드 (업데이트된 파일 경로)
dataset_rfs_til <- read_excel('/Volumes/SSD 1T/downloads_2024_iMAC/Recur_tongue_050325.xlsx', sheet = 1)
print(str_c('RFS dataset size for TIL analysis: ', nrow(dataset_rfs_til), ' rows'))

## [1] "RFS dataset size for TIL analysis: 96 rows"

# RFS 데이터 전처리 (OS와 동일한 방식)
colnames(dataset_rfs_til) <- str_c(dataset_rfs_til %>%
  colnames() %>% str_replace_all(' ', '') %>%
  str_replace_all(fixed('('), '_') %>%
  str_replace_all(fixed('%'), 'per') %>%
  str_replace_all(fixed(')'), '_') %>%
  str_replace_all(fixed('/'), '_') %>%
  str_squish())

dataset_rfs_til_select <- dataset_rfs_til %>%
  mutate(
    RM5mm = as.factor(RM5mm),
    ENE = as.factor(ENE),
    Differentiation = as.factor(Differentiation),
    LVI = as.factor(LVI),
    PNI = as.factor(PNI),
    SEX = as.factor(SEX),
    
    DOIgrade = as.numeric(DOIgrade),
    Stromal_invasviefront_TIL = as.numeric(Stromal_invasviefront_TIL),
    F_ratio = as.numeric(F_ratio),
    LRratio = as.numeric(LRratio),
    Time_to_Recur = as.numeric(Time_to_Recur),
    Recurrence = as.numeric(Recurrence),
    
    DOIgrade_norm = scale(DOIgrade),
    LRratio_norm = scale(LRratio),
    F_ratio_norm = scale(F_ratio),
    Stromal_invasviefront_TIL_norm = scale(Stromal_invasviefront_TIL),
    
    TIL_scaled = Stromal_invasviefront_TIL * 10
  )

## Warning: There was 1 warning in `mutate()`.
## ℹ In argument: `LRratio = as.numeric(LRratio)`.
## Caused by warning:
## ! NAs introduced by coercion

dataset_rfs_til_select <- dataset_rfs_til_select %>%
  select(-c(SurgicalN, OPDATE, LastFU, Recur_date, DATA_Chart))

missing_values_rfs_til <- colSums(is.na(dataset_rfs_til_select))
print("Missing values in RFS TIL data by variable:")

## [1] "Missing values in RFS TIL data by variable:"

print(missing_values_rfs_til[missing_values_rfs_til > 0])

## LRratio         
##       7       7

# =====================================================================
# 5.2. OS Pathologist TIL Log-rank Cutoff Analysis
# =====================================================================

# TIL cutoff 찾기 (OS) - 높은 TIL이 보호 효과가 있으므로 음수 처리 필요
set.seed(123)
til_cutoff_os <- find_optimal_cutoff(dataset_os_til_select, "TIL_scaled", "Month", "status_modified")

print(paste("OS TIL optimal cutoff:", round(til_cutoff_os$best_cutpoint, 2)))

## [1] "OS TIL optimal cutoff: 20"

print(paste("p-value:", format(til_cutoff_os$best_pvalue, scientific = FALSE, digits = 5)))

## [1] "p-value: 0.0011008"

print(paste("Hazard Ratio (HR):", round(til_cutoff_os$best_HR, 3)))

## [1] "Hazard Ratio (HR): 4.179"

# TIL 그룹 생성 (OS) - 높은 TIL = Low risk 그룹
dataset_os_til_select$TIL_group <- ifelse(dataset_os_til_select$TIL_scaled >= til_cutoff_os$best_cutpoint, "Low Risk (High TIL)", "High Risk (Low TIL)")

# Bootstrap analysis for OS TIL log-rank cutoff
set.seed(456)
n_boot <- 1000
boot_values_os_til <- numeric(n_boot)

for (i in 1:n_boot) {
  boot_indices <- sample(1:nrow(dataset_os_til_select), nrow(dataset_os_til_select), replace = TRUE)
  boot_data <- dataset_os_til_select[boot_indices, ]
  
  tryCatch({
    if (length(unique(boot_data$TIL_scaled)) < 5 || sum(boot_data$status_modified) < 5) {
      boot_values_os_til[i] <- NA_real_
    } else {
      boot_result <- find_optimal_cutoff(boot_data, "TIL_scaled", "Month", "status_modified")
      boot_values_os_til[i] <- boot_result$best_cutpoint
    }
  }, error = function(e) {
    boot_values_os_til[i] <- NA_real_
  })
}

## Warning in coxph.fit(X, Y, istrat, offset, init, control, weights = weights, :
## Loglik converged before variable 1 ; coefficient may be infinite.

# 결과 분석
boot_values_os_til <- boot_values_os_til[!is.na(boot_values_os_til)]
if(length(boot_values_os_til) < 10) {
  warning("Too few valid bootstrap samples for OS TIL log-rank cutoff.")
}

boot_ci_os_til <- quantile(boot_values_os_til, probs = c(0.025, 0.975), na.rm = TRUE)
names(boot_ci_os_til) <- c("2.5%", "97.5%")

print("OS - TIL scaled log-rank cutoff bootstrap analysis:")

## [1] "OS - TIL scaled log-rank cutoff bootstrap analysis:"

print(paste("Original cutoff:", round(til_cutoff_os$best_cutpoint, 2)))

## [1] "Original cutoff: 20"

print(paste("Bootstrap mean:", round(mean(boot_values_os_til, na.rm = TRUE), 2)))

## [1] "Bootstrap mean: 47.38"

print(paste("Bootstrap samples with valid results:", length(boot_values_os_til), "out of 1000"))

## [1] "Bootstrap samples with valid results: 1000 out of 1000"

print(paste("95% Confidence Interval:", round(boot_ci_os_til["2.5%"], 2), "-", round(boot_ci_os_til["97.5%"], 2)))

## [1] "95% Confidence Interval: 20 - 80"

# Bootstrap 분포 시각화
hist(boot_values_os_til, breaks = 30, main = "OS - TIL Log-rank Cutoff Bootstrap Distribution",
     xlab = "Cutoff Value", col = "lightcoral")
abline(v = til_cutoff_os$best_cutpoint, col = "red", lwd = 2)
abline(v = boot_ci_os_til["2.5%"], col = "blue", lty = 2, lwd = 2)
abline(v = boot_ci_os_til["97.5%"], col = "blue", lty = 2, lwd = 2)
legend("topright", legend = c("Original cutoff", "95% CI boundaries"),
       col = c("red", "blue"), lty = c(1, 2), lwd = 2)

# =====================================================================
# 5.3. OS Pathologist TIL Youden Cutoff Analysis
# =====================================================================

# TIL은 보호 효과가 있으므로 protective factor용 함수 사용
til_youden_cutoff_os <- find_youden_cutoff_protective(dataset_os_til_select, "TIL_scaled", "Month", "status_modified", 60)

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

print("OS - TIL Youden cutoff (5-year survival):")

## [1] "OS - TIL Youden cutoff (5-year survival):"

print(paste("Cutoff:", round(til_youden_cutoff_os$cutpoint, 2)))

## [1] "Cutoff: 65"

print(paste("Sensitivity:", round(til_youden_cutoff_os$sensitivity, 3)))

## [1] "Sensitivity: 0.754"

print(paste("Specificity:", round(til_youden_cutoff_os$specificity, 3)))

## [1] "Specificity: 0.474"

print(paste("AUC:", round(til_youden_cutoff_os$auc, 3)))

## [1] "AUC: 0.646"

# Bootstrap analysis for OS TIL Youden cutoff
set.seed(789)
boot_youden_values_os_til <- numeric(n_boot)

for (i in 1:n_boot) {
  boot_indices <- sample(1:nrow(dataset_os_til_select), nrow(dataset_os_til_select), replace = TRUE)
  boot_data <- dataset_os_til_select[boot_indices, ]
  
  tryCatch({
    if (length(unique(boot_data$TIL_scaled)) < 5 || sum(boot_data$status_modified) < 5) {
      boot_youden_values_os_til[i] <- NA_real_
    } else {
      boot_result <- find_youden_cutoff_protective(boot_data, "TIL_scaled", "Month", "status_modified", 60)
      boot_youden_values_os_til[i] <- boot_result$cutpoint
    }
  }, error = function(e) {
    boot_youden_values_os_til[i] <- NA_real_
  })
}

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## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_os_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_os_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_os_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls > cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_os_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls > cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_os_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls > cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_os_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_os_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls > cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

boot_youden_values_os_til <- boot_youden_values_os_til[!is.na(boot_youden_values_os_til)]
boot_youden_ci_os_til <- quantile(boot_youden_values_os_til, probs = c(0.025, 0.975), na.rm = TRUE)
names(boot_youden_ci_os_til) <- c("2.5%", "97.5%")

print("OS - TIL scaled Youden cutoff bootstrap analysis:")

## [1] "OS - TIL scaled Youden cutoff bootstrap analysis:"

print(paste("Original cutoff:", round(til_youden_cutoff_os$cutpoint, 2)))

## [1] "Original cutoff: 65"

print(paste("Bootstrap mean:", round(mean(boot_youden_values_os_til, na.rm = TRUE), 2)))

## [1] "Bootstrap mean: 54.39"

print(paste("Bootstrap samples with valid results:", length(boot_youden_values_os_til), "out of 1000"))

## [1] "Bootstrap samples with valid results: 1000 out of 1000"

print(paste("95% Confidence Interval:", round(boot_youden_ci_os_til["2.5%"], 2), "-", round(boot_youden_ci_os_til["97.5%"], 2)))

## [1] "95% Confidence Interval: 35 - 65"

# Youden 그룹 생성
dataset_os_til_select$TIL_youden_group <- ifelse(dataset_os_til_select$TIL_scaled >= til_youden_cutoff_os$cutpoint, "Low Risk (High TIL)", "High Risk (Low TIL)")

# Youden Bootstrap 분포 시각화
hist(boot_youden_values_os_til, breaks = 30, main = "OS - TIL Youden Cutoff Bootstrap Distribution",
     xlab = "Cutoff Value", col = "lightsalmon")
abline(v = til_youden_cutoff_os$cutpoint, col = "red", lwd = 2)
abline(v = boot_youden_ci_os_til["2.5%"], col = "blue", lty = 2, lwd = 2)
abline(v = boot_youden_ci_os_til["97.5%"], col = "blue", lty = 2, lwd = 2)
legend("topright", legend = c("Original cutoff", "95% CI boundaries"),
       col = c("red", "blue"), lty = c(1, 2), lwd = 2)

# =====================================================================
# 5.4. RFS Pathologist TIL Log-rank Cutoff Analysis
# =====================================================================

# TIL cutoff 찾기 (RFS)
set.seed(123)
til_cutoff_rfs <- find_optimal_cutoff(dataset_rfs_til_select, "TIL_scaled", "Time_to_Recur", "Recurrence")

print(paste("RFS TIL optimal cutoff:", round(til_cutoff_rfs$best_cutpoint, 2)))

## [1] "RFS TIL optimal cutoff: 40"

print(paste("p-value:", format(til_cutoff_rfs$best_pvalue, scientific = FALSE, digits = 5)))

## [1] "p-value: 0.012594"

print(paste("Hazard Ratio (HR):", round(til_cutoff_rfs$best_HR, 3)))

## [1] "Hazard Ratio (HR): 2.225"

# TIL 그룹 생성 (RFS)
dataset_rfs_til_select$TIL_group <- ifelse(dataset_rfs_til_select$TIL_scaled >= til_cutoff_rfs$best_cutpoint, "Low Risk (High TIL)", "High Risk (Low TIL)")

# Bootstrap analysis for RFS TIL log-rank cutoff
set.seed(456)
boot_values_rfs_til <- numeric(n_boot)

for (i in 1:n_boot) {
  boot_indices <- sample(1:nrow(dataset_rfs_til_select), nrow(dataset_rfs_til_select), replace = TRUE)
  boot_data <- dataset_rfs_til_select[boot_indices, ]
  
  tryCatch({
    if (length(unique(boot_data$TIL_scaled)) < 5 || sum(boot_data$Recurrence) < 5) {
      boot_values_rfs_til[i] <- NA_real_
    } else {
      boot_result <- find_optimal_cutoff(boot_data, "TIL_scaled", "Time_to_Recur", "Recurrence")
      boot_values_rfs_til[i] <- boot_result$best_cutpoint
    }
  }, error = function(e) {
    boot_values_rfs_til[i] <- NA_real_
  })
}

## Warning in coxph.fit(X, Y, istrat, offset, init, control, weights = weights, :
## Loglik converged before variable 1 ; coefficient may be infinite.
## Warning in coxph.fit(X, Y, istrat, offset, init, control, weights = weights, :
## Loglik converged before variable 1 ; coefficient may be infinite.
## Warning in coxph.fit(X, Y, istrat, offset, init, control, weights = weights, :
## Loglik converged before variable 1 ; coefficient may be infinite.

boot_values_rfs_til <- boot_values_rfs_til[!is.na(boot_values_rfs_til)]
boot_ci_rfs_til <- quantile(boot_values_rfs_til, probs = c(0.025, 0.975), na.rm = TRUE)
names(boot_ci_rfs_til) <- c("2.5%", "97.5%")

print("RFS - TIL scaled log-rank cutoff bootstrap analysis:")

## [1] "RFS - TIL scaled log-rank cutoff bootstrap analysis:"

print(paste("Original cutoff:", round(til_cutoff_rfs$best_cutpoint, 2)))

## [1] "Original cutoff: 40"

print(paste("Bootstrap mean:", round(mean(boot_values_rfs_til, na.rm = TRUE), 2)))

## [1] "Bootstrap mean: 49.92"

print(paste("Bootstrap samples with valid results:", length(boot_values_rfs_til), "out of 1000"))

## [1] "Bootstrap samples with valid results: 1000 out of 1000"

print(paste("95% Confidence Interval:", round(boot_ci_rfs_til["2.5%"], 2), "-", round(boot_ci_rfs_til["97.5%"], 2)))

## [1] "95% Confidence Interval: 30 - 80"

# =====================================================================
# 5.5. RFS Pathologist TIL Youden Cutoff Analysis
# =====================================================================

# RFS TIL Youden cutoff (protective factor)
til_youden_cutoff_rfs <- find_youden_cutoff_protective(dataset_rfs_til_select, "TIL_scaled", "Time_to_Recur", "Recurrence", 60)

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

print("RFS - TIL Youden cutoff (5-year recurrence-free survival):")

## [1] "RFS - TIL Youden cutoff (5-year recurrence-free survival):"

print(paste("Cutoff:", round(til_youden_cutoff_rfs$cutpoint, 2)))

## [1] "Cutoff: 65"

print(paste("Sensitivity:", round(til_youden_cutoff_rfs$sensitivity, 3)))

## [1] "Sensitivity: 0.732"

print(paste("Specificity:", round(til_youden_cutoff_rfs$specificity, 3)))

## [1] "Specificity: 0.491"

print(paste("AUC:", round(til_youden_cutoff_rfs$auc, 3)))

## [1] "AUC: 0.636"

# Bootstrap analysis for RFS TIL Youden cutoff
set.seed(789)
boot_youden_values_rfs_til <- numeric(n_boot)

for (i in 1:n_boot) {
  boot_indices <- sample(1:nrow(dataset_rfs_til_select), nrow(dataset_rfs_til_select), replace = TRUE)
  boot_data <- dataset_rfs_til_select[boot_indices, ]
  
  tryCatch({
    if (length(unique(boot_data$TIL_scaled)) < 5 || sum(boot_data$Recurrence) < 5) {
      boot_youden_values_rfs_til[i] <- NA_real_
    } else {
      boot_result <- find_youden_cutoff_protective(boot_data, "TIL_scaled", "Time_to_Recur", "Recurrence", 60)
      boot_youden_values_rfs_til[i] <- boot_result$cutpoint
    }
  }, error = function(e) {
    boot_youden_values_rfs_til[i] <- NA_real_
  })
}

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls > cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls > cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls > cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls > cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
## items to replace is not a multiple of replacement length

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

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## Warning in boot_youden_values_rfs_til[i] <- boot_result$cutpoint: number of
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boot_youden_values_rfs_til <- boot_youden_values_rfs_til[!is.na(boot_youden_values_rfs_til)]
boot_youden_ci_rfs_til <- quantile(boot_youden_values_rfs_til, probs = c(0.025, 0.975), na.rm = TRUE)
names(boot_youden_ci_rfs_til) <- c("2.5%", "97.5%")

print("RFS - TIL scaled Youden cutoff bootstrap analysis:")

## [1] "RFS - TIL scaled Youden cutoff bootstrap analysis:"

print(paste("Original cutoff:", round(til_youden_cutoff_rfs$cutpoint, 2)))

## [1] "Original cutoff: 65"

print(paste("Bootstrap mean:", round(mean(boot_youden_values_rfs_til, na.rm = TRUE), 2)))

## [1] "Bootstrap mean: 51.21"

print(paste("Bootstrap samples with valid results:", length(boot_youden_values_rfs_til), "out of 1000"))

## [1] "Bootstrap samples with valid results: 1000 out of 1000"

print(paste("95% Confidence Interval:", round(boot_youden_ci_rfs_til["2.5%"], 2), "-", round(boot_youden_ci_rfs_til["97.5%"], 2)))

## [1] "95% Confidence Interval: 35 - 65"

# RFS Youden 그룹 생성
dataset_rfs_til_select$TIL_youden_group <- ifelse(dataset_rfs_til_select$TIL_scaled >= til_youden_cutoff_rfs$cutpoint, "Low Risk (High TIL)", "High Risk (Low TIL)")

# =====================================================================
# 5.6. Pathologist TIL Kaplan-Meier Survival Curves
# =====================================================================

# OS Log-rank cutoff Kaplan-Meier
km_fit_os_til <- survfit(Surv(Month, status_modified) ~ TIL_group, data = dataset_os_til_select)
km_plot_os_til <- ggsurvplot(
  km_fit_os_til,
  data = dataset_os_til_select,
  risk.table = TRUE,
  pval = TRUE,
  conf.int = TRUE,
  palette = c("#2E9FDF", "#E7B800"),  # Low risk (blue), High risk (yellow)
  title = paste("Kaplan-Meier OS Curve by TIL (Log-rank Cutoff:", round(til_cutoff_os$best_cutpoint, 2), ")"),
  legend.title = "TIL Group",
  legend.labs = c("High Risk (Low TIL)", "Low Risk (High TIL)"),
  xlab = "Time (Months)",
  surv.median.line = "hv"
)

## Warning in geom_segment(aes(x = 0, y = max(y2), xend = max(x1), yend = max(y2)), : All aesthetics have length 1, but the data has 2 rows.
## ℹ Please consider using `annotate()` or provide this layer with data containing
##   a single row.

# OS Youden cutoff Kaplan-Meier
km_fit_os_til_youden <- survfit(Surv(Month, status_modified) ~ TIL_youden_group, data = dataset_os_til_select)
km_plot_os_til_youden <- ggsurvplot(
  km_fit_os_til_youden,
  data = dataset_os_til_select,
  risk.table = TRUE,
  pval = TRUE,
  conf.int = TRUE,
  palette = c("#2E9FDF", "#E7B800"),
  title = paste("Kaplan-Meier OS Curve by TIL (Youden Cutoff:", round(til_youden_cutoff_os$cutpoint, 2), ")"),
  legend.title = "TIL Group",
  legend.labs = c("High Risk (Low TIL)", "Low Risk (High TIL)"),
  xlab = "Time (Months)",
  surv.median.line = "hv"
)

## Warning in geom_segment(aes(x = 0, y = max(y2), xend = max(x1), yend = max(y2)), : All aesthetics have length 1, but the data has 2 rows.
## ℹ Please consider using `annotate()` or provide this layer with data containing
##   a single row.

# RFS Log-rank cutoff Kaplan-Meier
km_fit_rfs_til <- survfit(Surv(Time_to_Recur, Recurrence) ~ TIL_group, data = dataset_rfs_til_select)
km_plot_rfs_til <- ggsurvplot(
  km_fit_rfs_til,
  data = dataset_rfs_til_select,
  risk.table = TRUE,
  pval = TRUE,
  conf.int = TRUE,
  palette = c("#2E9FDF", "#E7B800"),
  title = paste("Kaplan-Meier RFS Curve by TIL (Log-rank Cutoff:", round(til_cutoff_rfs$best_cutpoint, 2), ")"),
  legend.title = "TIL Group",
  legend.labs = c("High Risk (Low TIL)", "Low Risk (High TIL)"),
  xlab = "Time (Months)",
  surv.median.line = "hv"
)

# RFS Youden cutoff Kaplan-Meier
km_fit_rfs_til_youden <- survfit(Surv(Time_to_Recur, Recurrence) ~ TIL_youden_group, data = dataset_rfs_til_select)
km_plot_rfs_til_youden <- ggsurvplot(
  km_fit_rfs_til_youden,
  data = dataset_rfs_til_select,
  risk.table = TRUE,
  pval = TRUE,
  conf.int = TRUE,
  palette = c("#2E9FDF", "#E7B800"),
  title = paste("Kaplan-Meier RFS Curve by TIL (Youden Cutoff:", round(til_youden_cutoff_rfs$cutpoint, 2), ")"),
  legend.title = "TIL Group",
  legend.labs = c("High Risk (Low TIL)", "Low Risk (High TIL)"),
  xlab = "Time (Months)",
  surv.median.line = "hv"
)

# 모든 그래프 출력
print(km_plot_os_til)

## Warning in geom_segment(aes(x = 0, y = max(y2), xend = max(x1), yend = max(y2)), : All aesthetics have length 1, but the data has 2 rows.
## ℹ Please consider using `annotate()` or provide this layer with data containing
##   a single row.
## All aesthetics have length 1, but the data has 2 rows.
## ℹ Please consider using `annotate()` or provide this layer with data containing
##   a single row.
## All aesthetics have length 1, but the data has 2 rows.
## ℹ Please consider using `annotate()` or provide this layer with data containing
##   a single row.

print(km_plot_os_til_youden)

## Warning in geom_segment(aes(x = 0, y = max(y2), xend = max(x1), yend = max(y2)), : All aesthetics have length 1, but the data has 2 rows.
## ℹ Please consider using `annotate()` or provide this layer with data containing
##   a single row.
## All aesthetics have length 1, but the data has 2 rows.
## ℹ Please consider using `annotate()` or provide this layer with data containing
##   a single row.
## All aesthetics have length 1, but the data has 2 rows.
## ℹ Please consider using `annotate()` or provide this layer with data containing
##   a single row.

print(km_plot_rfs_til)

print(km_plot_rfs_til_youden)

# =====================================================================
# 5.7. Summary Comparison of TIL Cutoffs
# =====================================================================

cat("Overall Comparison of Pathologist TIL Cutoff Methods:\n\n")

## Overall Comparison of Pathologist TIL Cutoff Methods:

cat("OS Log-rank cutoff:", round(til_cutoff_os$best_cutpoint, 2),
    "95% CI:", round(boot_ci_os_til["2.5%"], 2), "-", round(boot_ci_os_til["97.5%"], 2), "\n")

## OS Log-rank cutoff: 20 95% CI: 20 - 80

cat("OS Youden cutoff:", round(til_youden_cutoff_os$cutpoint, 2),
    "95% CI:", round(boot_youden_ci_os_til["2.5%"], 2), "-", round(boot_youden_ci_os_til["97.5%"], 2), "\n")

## OS Youden cutoff: 65 95% CI: 35 - 65

cat("RFS Log-rank cutoff:", round(til_cutoff_rfs$best_cutpoint, 2),
    "95% CI:", round(boot_ci_rfs_til["2.5%"], 2), "-", round(boot_ci_rfs_til["97.5%"], 2), "\n")

## RFS Log-rank cutoff: 40 95% CI: 30 - 80

cat("RFS Youden cutoff:", round(til_youden_cutoff_rfs$cutpoint, 2),
    "95% CI:", round(boot_youden_ci_rfs_til["2.5%"], 2), "-", round(boot_youden_ci_rfs_til["97.5%"], 2), "\n\n")

## RFS Youden cutoff: 65 95% CI: 35 - 65

# TIL cutoff 비교 시각화
til_cutoffs <- c(
  til_cutoff_os$best_cutpoint,
  til_youden_cutoff_os$cutpoint,
  til_cutoff_rfs$best_cutpoint,
  til_youden_cutoff_rfs$cutpoint
)

names(til_cutoffs) <- c("OS Log-rank", "OS Youden", "RFS Log-rank", "RFS Youden")

barplot(til_cutoffs,
        col = c("lightcoral", "lightsalmon", "lightcoral", "lightsalmon"),
        main = "Comparison of Pathologist TIL Cutoff Methods",
        ylab = "TIL Cutoff Value (scaled × 10)",
        las = 2)

# 결과 요약 테이블
til_summary <- data.frame(
  Method = c("OS Log-rank", "OS Youden", "RFS Log-rank", "RFS Youden"),
  Cutoff = c(til_cutoff_os$best_cutpoint, til_youden_cutoff_os$cutpoint, 
             til_cutoff_rfs$best_cutpoint, til_youden_cutoff_rfs$cutpoint),
  Bootstrap_Mean = c(mean(boot_values_os_til, na.rm = TRUE), 
                     mean(boot_youden_values_os_til, na.rm = TRUE),
                     mean(boot_values_rfs_til, na.rm = TRUE), 
                     mean(boot_youden_values_rfs_til, na.rm = TRUE)),
  CI_Lower = c(boot_ci_os_til["2.5%"], boot_youden_ci_os_til["2.5%"],
               boot_ci_rfs_til["2.5%"], boot_youden_ci_rfs_til["2.5%"]),
  CI_Upper = c(boot_ci_os_til["97.5%"], boot_youden_ci_os_til["97.5%"],
               boot_ci_rfs_til["97.5%"], boot_youden_ci_rfs_til["97.5%"])
)

print("Pathologist TIL Cutoff Summary:")

## [1] "Pathologist TIL Cutoff Summary:"

print(til_summary)

##         Method Cutoff Bootstrap_Mean CI_Lower CI_Upper
## 1  OS Log-rank     20          47.38       20       80
## 2    OS Youden     65          54.39       35       65
## 3 RFS Log-rank     40          49.92       30       80
## 4   RFS Youden     65          51.21       35       65

cat("\n===== Pathologist TIL Analysis Complete =====\n")

## 
## ===== Pathologist TIL Analysis Complete =====

cat("Note: TIL values are scaled × 10 for analysis convenience (pathologist measured in 10% units)\n")

## Note: TIL values are scaled × 10 for analysis convenience (pathologist measured in 10% units)

cat("Higher TIL values indicate better prognosis (protective factor)\n")

## Higher TIL values indicate better prognosis (protective factor)

cat("Groups are labeled as 'Low Risk (High TIL)' vs 'High Risk (Low TIL)'\n")

## Groups are labeled as 'Low Risk (High TIL)' vs 'High Risk (Low TIL)'

# =====================================================================
# 5.8. 5-Fold Cross-Validation for TIL Youden Cutoffs
# =====================================================================

# TIL을 위한 5-fold CV 함수 (보호 인자용)
perform_5fold_cv_youden_til <- function(data, variable, time_col, status_col, time_point = 60) {
  # 5개 fold로 분할
  set.seed(123)
  fold_indices <- sample(1:5, nrow(data), replace = TRUE)
  
  # 결과 저장용 데이터프레임
  fold_results <- data.frame(
    Fold = 1:5,
    Cutoff = NA,
    AUC = NA,
    Sensitivity = NA,
    Specificity = NA
  )
  
  # 각 fold에 대해 분석
  for(i in 1:5) {
    # 훈련 및 테스트 데이터 분할
    train_data <- data[fold_indices != i, ]
    test_data <- data[fold_indices == i, ]
    
    # Youden cutoff 찾기 (보호 인자용)
    tryCatch({
      cutoff_result <- find_youden_cutoff_protective(train_data, variable, time_col, status_col, time_point)
      
      # 결과 저장
      fold_results$Cutoff[i] <- cutoff_result$cutpoint
      fold_results$AUC[i] <- cutoff_result$auc
      fold_results$Sensitivity[i] <- cutoff_result$sensitivity
      fold_results$Specificity[i] <- cutoff_result$specificity
      
      # 테스트 데이터에서 성능 평가
      test_data$group <- ifelse(test_data[[variable]] >= cutoff_result$cutpoint, "High", "Low")
      
      # 이벤트 데이터 필터링
      test_event_data <- test_data %>%
        filter(!!sym(time_col) >= time_point | !!sym(status_col) == 1)
      test_event_data$outcome <- ifelse(test_event_data[[status_col]] == 1 &
                                        test_event_data[[time_col]] <= time_point, 1, 0)
      
      # 테스트 데이터에서 AUC 계산 (충분한 데이터가 있을 때만)
      if(nrow(test_event_data) >= 10 &&
         sum(test_event_data$outcome) >= 3 &&
         sum(1-test_event_data$outcome) >= 3) {
        # TIL은 보호 인자이므로 High TIL = Low risk
        test_roc <- roc(test_event_data$outcome,
                        as.numeric(test_event_data$group == "Low"))  # High TIL = Low risk
        fold_results$AUC[i] <- as.numeric(auc(test_roc))
      }
      
    }, error = function(e) {
      cat("Error in fold", i, ":", e$message, "\n")
      # 에러 시 NA로 유지
    })
  }
  
  # 스케일링된 cutoff 계산
  fold_results$Cutoff_scaled <- fold_results$Cutoff
  if(variable == "TIL_scaled") {
    # 이미 10배 스케일링되어 있음
    fold_results$Cutoff_scaled <- fold_results$Cutoff
  }
  
  # 평균 결과 계산
  mean_results <- list(
    cutoff = mean(fold_results$Cutoff, na.rm = TRUE),
    cutoff_scaled = mean(fold_results$Cutoff_scaled, na.rm = TRUE),
    cutoff_sd = sd(fold_results$Cutoff, na.rm = TRUE),
    cutoff_scaled_sd = sd(fold_results$Cutoff_scaled, na.rm = TRUE),
    auc = mean(fold_results$AUC, na.rm = TRUE),
    auc_sd = sd(fold_results$AUC, na.rm = TRUE),
    sensitivity = mean(fold_results$Sensitivity, na.rm = TRUE),
    specificity = mean(fold_results$Specificity, na.rm = TRUE),
    fold_results = fold_results
  )
  
  return(mean_results)
}

# OS TIL 5-fold CV 수행
cat("Performing 5-fold CV for OS TIL Youden cutoffs...\n")

## Performing 5-fold CV for OS TIL Youden cutoffs...

os_til_youden_cv <- perform_5fold_cv_youden_til(dataset_os_til_select, "TIL_scaled", "Month", "status_modified")

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

# RFS TIL 5-fold CV 수행
cat("Performing 5-fold CV for RFS TIL Youden cutoffs...\n")

## Performing 5-fold CV for RFS TIL Youden cutoffs...

rfs_til_youden_cv <- perform_5fold_cv_youden_til(dataset_rfs_til_select, "TIL_scaled", "Time_to_Recur", "Recurrence")

## Setting levels: control = 0, case = 1
## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

## Setting levels: control = 0, case = 1

## Setting direction: controls < cases

# CV 결과 정리
til_cv_results <- data.frame(
  Method = c("OS TIL Youden", "RFS TIL Youden"),
  Original_Cutoff = c(
    til_youden_cutoff_os$cutpoint,
    til_youden_cutoff_rfs$cutpoint
  ),
  CV_Cutoff = c(
    os_til_youden_cv$cutoff_scaled,
    rfs_til_youden_cv$cutoff_scaled
  ),
  CV_Cutoff_SD = c(
    os_til_youden_cv$cutoff_scaled_sd,
    rfs_til_youden_cv$cutoff_scaled_sd
  ),
  CV_AUC = c(
    os_til_youden_cv$auc,
    rfs_til_youden_cv$auc
  ),
  CV_AUC_SD = c(
    os_til_youden_cv$auc_sd,
    rfs_til_youden_cv$auc_sd
  ),
  CV_Sensitivity = c(
    os_til_youden_cv$sensitivity,
    rfs_til_youden_cv$sensitivity
  ),
  CV_Specificity = c(
    os_til_youden_cv$specificity,
    rfs_til_youden_cv$specificity
  )
)

# 결과 출력
cat("\n5-fold Cross-Validation Results for TIL Youden Cutoffs:\n")

## 
## 5-fold Cross-Validation Results for TIL Youden Cutoffs:

print(til_cv_results)

##           Method Original_Cutoff CV_Cutoff CV_Cutoff_SD    CV_AUC  CV_AUC_SD
## 1  OS TIL Youden              65        55     10.00000 0.5624106 0.05121034
## 2 RFS TIL Youden              65        49     15.16575 0.5284421 0.13308541
##   CV_Sensitivity CV_Specificity
## 1      0.6013276      0.6382399
## 2      0.5297913      0.7089567

# CV 결과 시각화
par(mfrow = c(1, 2))

boxplot(os_til_youden_cv$fold_results$Cutoff_scaled,
        main = "OS TIL Youden Cutoffs (5-fold CV)",
        ylab = "TIL Cutoff Value (×10)")
abline(h = til_youden_cutoff_os$cutpoint, col = "red", lwd = 2)
legend("topright", legend = "Original cutoff", col = "red", lwd = 2)

boxplot(rfs_til_youden_cv$fold_results$Cutoff_scaled,
        main = "RFS TIL Youden Cutoffs (5-fold CV)",
        ylab = "TIL Cutoff Value (×10)")
abline(h = til_youden_cutoff_rfs$cutpoint, col = "red", lwd = 2)
legend("topright", legend = "Original cutoff", col = "red", lwd = 2)

par(mfrow = c(1, 1))

# 5-fold CV 안정성 분석
cat("\n===== 5-fold Cross-Validation Analysis for TIL =====\n")

## 
## ===== 5-fold Cross-Validation Analysis for TIL =====

# OS TIL Youden
cat("OS TIL Youden Cutoff:\n")

## OS TIL Youden Cutoff:

cat(" - Original cutoff:", round(til_youden_cutoff_os$cutpoint, 1), "\n")

##  - Original cutoff: 65

cat(" - 5-fold CV mean cutoff:", round(os_til_youden_cv$cutoff_scaled, 1),
    "±", round(os_til_youden_cv$cutoff_scaled_sd, 1), "(SD)\n")

##  - 5-fold CV mean cutoff: 55 ± 10 (SD)

cat(" - 5-fold CV relative difference:",
    round(100 * abs(os_til_youden_cv$cutoff_scaled - til_youden_cutoff_os$cutpoint) /
          til_youden_cutoff_os$cutpoint, 1), "%\n")

##  - 5-fold CV relative difference: 15.4 %

# RFS TIL Youden
cat("\nRFS TIL Youden Cutoff:\n")

## 
## RFS TIL Youden Cutoff:

cat(" - Original cutoff:", round(til_youden_cutoff_rfs$cutpoint, 1), "\n")

##  - Original cutoff: 65

cat(" - 5-fold CV mean cutoff:", round(rfs_til_youden_cv$cutoff_scaled, 1),
    "±", round(rfs_til_youden_cv$cutoff_scaled_sd, 1), "(SD)\n")

##  - 5-fold CV mean cutoff: 49 ± 15.2 (SD)

cat(" - 5-fold CV relative difference:",
    round(100 * abs(rfs_til_youden_cv$cutoff_scaled - til_youden_cutoff_rfs$cutpoint) /
          til_youden_cutoff_rfs$cutpoint, 1), "%\n")

##  - 5-fold CV relative difference: 24.6 %

# 안정성 평가
cat("\nConclusion on TIL Youden Cutoff Stability:\n")

## 
## Conclusion on TIL Youden Cutoff Stability:

os_til_stable <- os_til_youden_cv$cutoff_scaled_sd < 0.2 * os_til_youden_cv$cutoff_scaled
rfs_til_stable <- rfs_til_youden_cv$cutoff_scaled_sd < 0.2 * rfs_til_youden_cv$cutoff_scaled

if(os_til_stable && rfs_til_stable) {
  cat("Both OS and RFS TIL Youden cutoffs show good stability across cross-validation folds,\n")
  cat("suggesting that these cutoff values are robust and generalizable.\n")
} else if(os_til_stable) {
  cat("OS TIL Youden cutoff shows good stability across cross-validation folds, but\n")
  cat("RFS TIL Youden cutoff shows higher variability, suggesting caution in its interpretation.\n")
} else if(rfs_til_stable) {
  cat("RFS TIL Youden cutoff shows good stability across cross-validation folds, but\n")
  cat("OS TIL Youden cutoff shows higher variability, suggesting caution in its interpretation.\n")
} else {
  cat("Both OS and RFS TIL Youden cutoffs show substantial variability across cross-validation folds.\n")
  cat("This suggests caution in the interpretation and application of these cutoffs.\n")
}

## OS TIL Youden cutoff shows good stability across cross-validation folds, but
## RFS TIL Youden cutoff shows higher variability, suggesting caution in its interpretation.

cat("===================================================\n")

## ===================================================

# 최종 TIL 분석 요약
cat("\n===== Final TIL Analysis Summary =====\n")

## 
## ===== Final TIL Analysis Summary =====

cat("Pathologist TIL (Stromal_invasviefront_TIL) Analysis Complete\n")

## Pathologist TIL (Stromal_invasviefront_TIL) Analysis Complete

cat("- Measured in 10% units by pathologist, scaled ×10 for analysis\n")

## - Measured in 10% units by pathologist, scaled ×10 for analysis

cat("- Higher TIL = Better prognosis (protective factor)\n")

## - Higher TIL = Better prognosis (protective factor)

cat("- Used protective factor-specific Youden Index calculation\n")

## - Used protective factor-specific Youden Index calculation

cat("- Bootstrap and 5-fold CV performed for validation\n")

## - Bootstrap and 5-fold CV performed for validation

cat("==============================================\n")

## ==============================================