From 1e88b61b2acc0718868bfdcea70e4a5739196c8f Mon Sep 17 00:00:00 2001
From: xuewei cao <36172337+xueweic@users.noreply.github.com>
Date: Tue, 12 May 2026 08:12:38 -0400
Subject: [PATCH 1/4] Update colocboost_plot.R

---
 R/colocboost_plot.R | 15 ++++++++++-----
 1 file changed, 10 insertions(+), 5 deletions(-)

diff --git a/R/colocboost_plot.R b/R/colocboost_plot.R
index 1f0f7c1..ebe1644 100644
--- a/R/colocboost_plot.R
+++ b/R/colocboost_plot.R
@@ -711,7 +711,10 @@ plot_initial <- function(cb_plot_input, y = "log10p",
   # - set data and x-lab and y-lab
   if (y == "log10p") {
     plot_data <- lapply(cb_plot_input$Zscores, function(z) {
-      -log10(2 * pnorm(-abs(z)))
+      y_val <- -log10(2 * pnorm(-abs(z)))
+      max_finite <- max(y_val[is.finite(y_val)], na.rm = TRUE)
+      y_val[!is.finite(y_val)] <- max_finite
+      return(y_val)
     })
     ylab <- "-log10(p)"
   } else if (y == "z_original") {
@@ -765,7 +768,11 @@ plot_initial <- function(cb_plot_input, y = "log10p",
     ymin <- rep(args$ylim[1], length(args$y))
   } else {
     ymax <- NULL
-    ymin <- rep(0, length(args$y))
+    if (y %in% c("z_original", "coef")) {
+      ymin <- sapply(plot_data, function(p) min(p[is.finite(p)], na.rm = TRUE) * 1.05)
+    } else {
+      ymin <- rep(0, length(args$y))
+    }
     
     # Check if ylim_each is FALSE but no ylim is provided
     if (!ylim_each) {
@@ -784,9 +791,7 @@ plot_initial <- function(cb_plot_input, y = "log10p",
       }
       return(ymax)
     })
-    if (y == "coef") {
-      ymin <- sapply(plot_data, function(p) min(p) * 1.05)
-    }
+      
   }
   args$ymax <- ymax
   args$ymin <- ymin

From 974279e3d30673e73493d703f7b7721b7a47a023 Mon Sep 17 00:00:00 2001
From: xuewei cao <36172337+xueweic@users.noreply.github.com>
Date: Wed, 20 May 2026 11:24:06 -0400
Subject: [PATCH 2/4] trim Xref before pre-calculating

Trim X_ref supersets before any expensive reference processing.
---
 R/colocboost.R             | 26 ++++++++++++++++++++++++++
 tests/testthat/test_Xref.R | 21 +++++++++++++++++++++
 2 files changed, 47 insertions(+)

diff --git a/R/colocboost.R b/R/colocboost.R
index 01693dc..542103c 100644
--- a/R/colocboost.R
+++ b/R/colocboost.R
@@ -734,6 +734,32 @@ colocboost_validate_input_data <- function(X = NULL, Y = NULL,
       } else {
         if (is.data.frame(X_ref)) X_ref <- as.matrix(X_ref)
         if (is.matrix(X_ref)) X_ref <- list(X_ref)
+
+        # Trim X_ref supersets before any expensive reference processing.
+        # ColocBoost later matches each sumstat by variant name, so columns
+        # absent from every mapped sumstat cannot affect the fit.
+        get_needed_sumstat_variants <- function(ref_idx) {
+          if (length(X_ref) == 1) {
+            ss_idx <- seq_along(sumstat)
+          } else if (length(X_ref) == length(sumstat)) {
+            ss_idx <- ref_idx
+          } else if (!is.null(dict_sumstatLD) && !is.null(dim(dict_sumstatLD))) {
+            ss_idx <- unique(dict_sumstatLD[dict_sumstatLD[, 2] == ref_idx, 1])
+          } else {
+            return(NULL)
+          }
+          unique(unlist(lapply(sumstat[ss_idx], function(ss) ss$variant), use.names = FALSE))
+        }
+        for (idx in seq_along(X_ref)) {
+          xref_variants <- colnames(X_ref[[idx]])
+          if (is.null(xref_variants)) next
+          needed_variants <- get_needed_sumstat_variants(idx)
+          if (is.null(needed_variants) || length(needed_variants) == 0) next
+          keep_variants <- intersect(xref_variants, needed_variants)
+          if (length(keep_variants) > 0 && length(keep_variants) < ncol(X_ref[[idx]])) {
+            X_ref[[idx]] <- X_ref[[idx]][, keep_variants, drop = FALSE]
+          }
+        }
         
         # When N_ref >= P, precompute LD (avoids repeated O(N_ref*P) in boosting loop)
         # When N_ref < P, keep X_ref for on-the-fly computation (avoids P*P memory)
diff --git a/tests/testthat/test_Xref.R b/tests/testthat/test_Xref.R
index 5d30abc..b5cb8a6 100644
--- a/tests/testthat/test_Xref.R
+++ b/tests/testthat/test_Xref.R
@@ -113,6 +113,27 @@ test_that("X_ref with N_ref >= P precomputes LD and produces valid results", {
   expect_equal(length(result_xref$data_info$variables), 30)
 })
 
+test_that("X_ref superset is trimmed before LD precomputation", {
+  test_data <- generate_xref_test_data(n_ref = 80, p = 20)
+  extra_ref <- matrix(rnorm(nrow(test_data$X_ref) * 35), nrow(test_data$X_ref), 35)
+  colnames(extra_ref) <- paste0("EXTRA", seq_len(ncol(extra_ref)))
+  X_ref_superset <- cbind(test_data$X_ref, extra_ref)
+
+  validated <- suppressMessages(
+    colocboost_validate_input_data(
+      sumstat = test_data$sumstat,
+      X_ref = X_ref_superset
+    )
+  )
+
+  expected_variants <- unique(unlist(lapply(test_data$sumstat, function(ss) ss$variant)))
+  expect_equal(validated$ref_label, "LD")
+  expect_null(validated$X_ref)
+  expect_equal(ncol(validated$LD[[1]]), length(expected_variants))
+  expect_setequal(colnames(validated$LD[[1]]), expected_variants)
+  expect_false(any(grepl("^EXTRA", colnames(validated$LD[[1]]))))
+})
+
 
 # ============================================================================
 # Test 3: X_ref with N_ref < P keeps X_ref for on-the-fly computation

From 821e5b98ad2391cf09e3f1f9ec94a31f613dcdd4 Mon Sep 17 00:00:00 2001
From: xuewei cao <36172337+xueweic@users.noreply.github.com>
Date: Wed, 20 May 2026 14:12:09 -0400
Subject: [PATCH 3/4] Update colocboost_inference.R

simple profiling computational improvement
---
 R/colocboost_inference.R | 2 +-
 1 file changed, 1 insertion(+), 1 deletion(-)

diff --git a/R/colocboost_inference.R b/R/colocboost_inference.R
index a837d11..bb5edd7 100644
--- a/R/colocboost_inference.R
+++ b/R/colocboost_inference.R
@@ -474,7 +474,7 @@ get_between_purity <- function(pos1, pos2, X = NULL, Xcorr = NULL, miss_idx = NU
     X_sub2 <- scale(X[, pos2, drop = FALSE], center = T, scale = F)
     value <- abs(get_matrix_mult(X_sub1, X_sub2))
   } else {
-    if (identical(ref_label, "No_ref") || sum(Xcorr) == 1) {
+    if (identical(ref_label, "No_ref") || (length(Xcorr) == 1 && Xcorr == 1)) {
       value <- 0
     } else {
       if (length(miss_idx) != 0) {

From b7dd40628f97c61b748fec053e7507195b4eea41 Mon Sep 17 00:00:00 2001
From: xuewei cao <36172337+xueweic@users.noreply.github.com>
Date: Wed, 20 May 2026 14:48:56 -0400
Subject: [PATCH 4/4] improve of computational

---
 R/colocboost_init.R   | 19 ++++++++++++++-----
 R/colocboost_update.R | 24 ++++++++++++++++++------
 2 files changed, 32 insertions(+), 11 deletions(-)

diff --git a/R/colocboost_init.R b/R/colocboost_init.R
index 077a217..403e114 100644
--- a/R/colocboost_init.R
+++ b/R/colocboost_init.R
@@ -163,11 +163,16 @@ colocboost_init_model <- function(cb_data,
       "ld_jk" = c(),
       "jk" = c(),
       "scaling_factor" = if (!is.null(cb_data$data[[i]]$N)) (cb_data$data[[i]]$N - 1) else 1,
-      "beta_scaling" = if (!is.null(cb_data$data[[i]]$N)) 1 else 100
+      "beta_scaling" = if (!is.null(cb_data$data[[i]]$N)) 1 else 100,
+      "XtX_beta_cache" = NULL
     )
 
     data_each <- cb_data$data[[i]]
     X_dict <- cb_data$dict[i]
+    if (!is.null(cb_data$data[[X_dict]]$XtX)) {
+      tmp$XtX_beta_cache <- rep(0, P - length(data_each$variable_miss))
+    }
+
     # - calculate change of loglikelihood for data
     tmp$change_loglike <- estimate_change_profile(
       X = cb_data$data[[X_dict]]$X, Y = data_each[["Y"]], N = data_each$N,
@@ -184,6 +189,7 @@ colocboost_init_model <- function(cb_data,
       XtX = cb_data$data[[X_dict]]$XtX,
       beta_k = tmp$beta,
       miss_idx = data_each$variable_miss,
+      XtX_beta_cache = tmp$XtX_beta_cache,
       ref_label = cb_data$data[[X_dict]]$ref_label
     )
     # - initial z-score between X and residual based on correlation
@@ -240,7 +246,8 @@ colocboost_init_para <- function(cb_data, cb_model, tau = 0.01,
                                  jk_equiv_corr = 0.8,
                                  jk_equiv_loglik = 1,
                                  func_compare = "min_max",
-                                 coloc_thresh =  0.1) {
+                                 coloc_thresh =  0.1,
+                                 ld_mismatch = "none") {
   #################  initialization #######################################
   # - sample size
   N <- sapply(cb_data$data, function(dt) dt$N)
@@ -312,7 +319,8 @@ colocboost_init_para <- function(cb_data, cb_model, tau = 0.01,
     "func_multi_test" = func_multi_test,
     "multi_test_thresh" = multi_test_thresh,
     "multi_test_max" = multi_test_max,
-    "model_used" = "original"
+    "model_used" = "original",
+    "ld_mismatch" = ld_mismatch
   )
   class(cb_model_para) <- "colocboost"
 
@@ -391,7 +399,7 @@ get_correlation <- function(X = NULL, res = NULL, XtY = NULL, N = NULL,
     }
     if (identical(ref_label, "No_ref")) {
       var_r <- YtY - 2 * sum(beta_k * XtY) + sum(beta_k^2)
-    } else if (!is.null(XtX_beta_cache)) {
+    } else if (!is.null(XtX_beta_cache) && length(XtX_beta_cache) == length(beta_k)) {
       var_r <- YtY - 2 * sum(beta_k * XtY) + sum(XtX_beta_cache * beta_k)
     } else {
       XtX_beta_val <- compute_XtX_product(XtX, beta_k, ref_label)
@@ -591,7 +599,8 @@ process_sumstat <- function(Z, N, Var_y, SeBhat,
       "XtY" = NULL,
       "YtY" = NULL,
       "N" = N[[i]],
-      "variable_miss" = NULL
+      "variable_miss" = NULL,
+      "R_finite_B" = NULL
     )
 
     # Get current status
diff --git a/R/colocboost_update.R b/R/colocboost_update.R
index 86993d0..4037214 100644
--- a/R/colocboost_update.R
+++ b/R/colocboost_update.R
@@ -110,15 +110,27 @@ colocboost_update <- function(cb_model, cb_model_para, cb_data) {
       ref_label_i <- cb_data$data[[X_dict]]$ref_label
       cb_model[[i]]$res <- rep(0, cb_model_para$P)
       if (length(cb_data$data[[i]]$variable_miss) != 0) {
-        beta <- cb_model[[i]]$beta[-cb_data$data[[i]]$variable_miss]  / beta_scaling
-        xty <- cb_data$data[[i]]$XtY[-cb_data$data[[i]]$variable_miss]
-        XtX_beta <- compute_XtX_product(xtx, beta, ref_label_i)
-        cb_model[[i]]$res[-cb_data$data[[i]]$variable_miss] <- xty - scaling_factor * XtX_beta
-
+        obs_idx <- setdiff(seq_len(cb_model_para$P), cb_data$data[[i]]$variable_miss)
+        beta <- cb_model[[i]]$beta[obs_idx] / beta_scaling
+        xty <- cb_data$data[[i]]$XtY[obs_idx]
+        delta_beta <- step1 * beta_grad[obs_idx] / beta_scaling
+        XtX_beta_cache <- cb_model[[i]]$XtX_beta_cache
+        if (!is.null(XtX_beta_cache) && length(XtX_beta_cache) == length(beta)) {
+          XtX_beta <- XtX_beta_cache + compute_XtX_product(xtx, delta_beta, ref_label_i)
+        } else {
+          XtX_beta <- compute_XtX_product(xtx, beta, ref_label_i)
+        }
+        cb_model[[i]]$res[obs_idx] <- xty - scaling_factor * XtX_beta
       } else {
         beta <- cb_model[[i]]$beta / beta_scaling
         xty <- cb_data$data[[i]]$XtY
-        XtX_beta <- compute_XtX_product(xtx, beta, ref_label_i)
+        delta_beta <- step1 * beta_grad / beta_scaling
+        XtX_beta_cache <- cb_model[[i]]$XtX_beta_cache
+        if (!is.null(XtX_beta_cache) && length(XtX_beta_cache) == length(beta)) {
+          XtX_beta <- XtX_beta_cache + compute_XtX_product(xtx, delta_beta, ref_label_i)
+        } else {
+          XtX_beta <- compute_XtX_product(xtx, beta, ref_label_i)
+        }
         cb_model[[i]]$res <- xty - scaling_factor * XtX_beta
       }
       # - cache XtX %*% beta for reuse in get_correlation (avoids redundant O(P^2) computation)