{
 "cells": [
  {
   "cell_type": "code",
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   "id": "decbae95",
   "metadata": {
    "execution": {
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     "shell.execute_reply": "2025-03-25T03:51:23.897576Z"
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   "source": [
    "import sys\n",
    "import os\n",
    "sys.path.append(os.path.abspath(os.path.join(os.getcwd(), '../..')))\n",
    "\n",
    "# Path Configuration\n",
    "from tools.preprocess import *\n",
    "\n",
    "# Processing context\n",
    "trait = \"Rheumatoid_Arthritis\"\n",
    "cohort = \"GSE186963\"\n",
    "\n",
    "# Input paths\n",
    "in_trait_dir = \"../../input/GEO/Rheumatoid_Arthritis\"\n",
    "in_cohort_dir = \"../../input/GEO/Rheumatoid_Arthritis/GSE186963\"\n",
    "\n",
    "# Output paths\n",
    "out_data_file = \"../../output/preprocess/Rheumatoid_Arthritis/GSE186963.csv\"\n",
    "out_gene_data_file = \"../../output/preprocess/Rheumatoid_Arthritis/gene_data/GSE186963.csv\"\n",
    "out_clinical_data_file = \"../../output/preprocess/Rheumatoid_Arthritis/clinical_data/GSE186963.csv\"\n",
    "json_path = \"../../output/preprocess/Rheumatoid_Arthritis/cohort_info.json\"\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "5ffa05f6",
   "metadata": {},
   "source": [
    "### Step 1: Initial Data Loading"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 2,
   "id": "759d9ac1",
   "metadata": {
    "execution": {
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     "shell.execute_reply": "2025-03-25T03:51:24.007857Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Background Information:\n",
      "!Series_title\t\"Whole blood gene expression from infliximab treated Crohn's disease patients at three time points: pre-treatment, two weeks and fourteen weeks post first treatment\"\n",
      "!Series_summary\t\"Personalized treatment of complex diseases is an unmet medical need pushing towards drug biomarker identification of one drug-disease combination at a time. Here, we used a novel computational approach for modeling cell-centered individual-level network dynamics from high-dimensional blood data to predict infliximab response and uncover individual variation of non-response. We identified and validated that the RAC1-PAK1 axis is predictive of infliximab response in inflammatory bowel disease. Intermediate monocytes, which closely correlated with inflammation state, play a key role in the RAC1-PAK1 responses, supporting their modulation as a therapeutic target. This axis also predicts response in Rheumatoid arthritis, validated in three public cohorts. Our findings support pan-disease drug response diagnostics from blood, implicating common mechanisms of drug response or failure across diseases.\"\n",
      "!Series_overall_design\t\"Whole blood samples from anti-TNF responding (n=15) and non-responding (n=9) IBD patients at three time points: pre-treatment, two weeks and fourteen weeks post first treatment\"\n",
      "Sample Characteristics Dictionary:\n",
      "{0: [\"disease: Crohn's disease\"], 1: ['treatment: Infliximab'], 2: ['patient: HR-38', 'patient: HR-39', 'patient: HR-40', 'patient: HR-42', 'patient: HR-44', 'patient: HR-46', 'patient: HR-47', 'patient: HR-48', 'patient: HR-29', 'patient: HR-30', 'patient: HR-31', 'patient: HR-32', 'patient: HR-33', 'patient: HR-35', 'patient: HR-36', 'patient: HR-37', 'patient: HR-20', 'patient: HR-21', 'patient: HR-22', 'patient: HR-23', 'patient: HR-24', 'patient: HR-26', 'patient: HR-27', 'patient: HR-28'], 3: ['response status: Non-responder', 'response status: Responder'], 4: ['visit: Baseline', 'visit: W2', 'visit: W14'], 5: ['crp: 2.1', 'crp: 1.2', 'crp: 2', 'crp: 2.6', 'crp: 0.1', 'crp: 0.4', 'crp: 1', 'crp: 1.1', 'crp: 2.67', 'crp: 3.4', 'crp: 0.9', 'crp: 0.48', 'crp: 19.6', 'crp: 1.19', 'crp: 6.8', 'crp: 3.22', 'crp: 3', 'crp: 125.7', 'crp: 2.7', 'crp: 24.2', 'crp: 1.8', 'crp: 0.8', 'crp: 4.9', 'crp: 2.5', 'crp: 1.15', 'crp: 15.8', 'crp: 4.78', 'crp: 43.6', 'crp: 44', 'crp: 5.43']}\n"
     ]
    }
   ],
   "source": [
    "from tools.preprocess import *\n",
    "# 1. Identify the paths to the SOFT file and the matrix file\n",
    "soft_file, matrix_file = geo_get_relevant_filepaths(in_cohort_dir)\n",
    "\n",
    "# 2. Read the matrix file to obtain background information and sample characteristics data\n",
    "background_prefixes = ['!Series_title', '!Series_summary', '!Series_overall_design']\n",
    "clinical_prefixes = ['!Sample_geo_accession', '!Sample_characteristics_ch1']\n",
    "background_info, clinical_data = get_background_and_clinical_data(matrix_file, background_prefixes, clinical_prefixes)\n",
    "\n",
    "# 3. Obtain the sample characteristics dictionary from the clinical dataframe\n",
    "sample_characteristics_dict = get_unique_values_by_row(clinical_data)\n",
    "\n",
    "# 4. Explicitly print out all the background information and the sample characteristics dictionary\n",
    "print(\"Background Information:\")\n",
    "print(background_info)\n",
    "print(\"Sample Characteristics Dictionary:\")\n",
    "print(sample_characteristics_dict)\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "881917cc",
   "metadata": {},
   "source": [
    "### Step 2: Dataset Analysis and Clinical Feature Extraction"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 3,
   "id": "50441466",
   "metadata": {
    "execution": {
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     "iopub.status.busy": "2025-03-25T03:51:24.009192Z",
     "iopub.status.idle": "2025-03-25T03:51:24.015480Z",
     "shell.execute_reply": "2025-03-25T03:51:24.015215Z"
    }
   },
   "outputs": [
    {
     "data": {
      "text/plain": [
       "False"
      ]
     },
     "execution_count": 3,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "import pandas as pd\n",
    "import os\n",
    "import re\n",
    "from typing import Optional, Callable, Any, Dict\n",
    "\n",
    "# 1. Gene Expression Data Availability\n",
    "# Yes, the dataset likely contains gene expression data as it mentions \"Whole blood gene expression\"\n",
    "is_gene_available = True\n",
    "\n",
    "# 2. Variable Availability and Data Type Conversion\n",
    "# 2.1 Data Availability\n",
    "# For trait (Rheumatoid Arthritis):\n",
    "# From the background info, this dataset is for Crohn's disease, not RA\n",
    "trait_row = None\n",
    "\n",
    "# For age:\n",
    "# Age is not mentioned in the sample characteristics dictionary\n",
    "age_row = None\n",
    "\n",
    "# For gender:\n",
    "# Gender is not mentioned in the sample characteristics dictionary\n",
    "gender_row = None\n",
    "\n",
    "# 2.2 Data Type Conversion\n",
    "# Even though we don't have trait data for Rheumatoid Arthritis,\n",
    "# define conversion functions in case they're needed\n",
    "\n",
    "def convert_trait(value):\n",
    "    # Extract value after colon if it exists\n",
    "    if ':' in value:\n",
    "        value = value.split(':', 1)[1].strip()\n",
    "    \n",
    "    # This dataset doesn't have RA trait, but if it did:\n",
    "    if value.lower() in ['rheumatoid arthritis', 'ra', 'true', 'yes']:\n",
    "        return 1\n",
    "    elif value.lower() in ['control', 'healthy', 'false', 'no']:\n",
    "        return 0\n",
    "    return None\n",
    "\n",
    "def convert_age(value):\n",
    "    if ':' in value:\n",
    "        value = value.split(':', 1)[1].strip()\n",
    "    try:\n",
    "        return float(value)\n",
    "    except:\n",
    "        return None\n",
    "\n",
    "def convert_gender(value):\n",
    "    if ':' in value:\n",
    "        value = value.split(':', 1)[1].strip()\n",
    "    \n",
    "    value = value.lower()\n",
    "    if value in ['female', 'f', 'woman']:\n",
    "        return 0\n",
    "    elif value in ['male', 'm', 'man']:\n",
    "        return 1\n",
    "    return None\n",
    "\n",
    "# 3. Save Metadata\n",
    "# Determine trait data availability\n",
    "is_trait_available = trait_row is not None\n",
    "\n",
    "# Initial filtering\n",
    "validate_and_save_cohort_info(\n",
    "    is_final=False,\n",
    "    cohort=cohort,\n",
    "    info_path=json_path,\n",
    "    is_gene_available=is_gene_available,\n",
    "    is_trait_available=is_trait_available\n",
    ")\n",
    "\n",
    "# 4. Clinical Feature Extraction\n",
    "# Since trait_row is None, we skip this substep\n",
    "# (if trait_row were not None, we would extract clinical features)\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "4f528642",
   "metadata": {},
   "source": [
    "### Step 3: Gene Data Extraction"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 4,
   "id": "cbf35554",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T03:51:24.016539Z",
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     "shell.execute_reply": "2025-03-25T03:51:24.175958Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Index(['TC0100006437.hg.1', 'TC0100006476.hg.1', 'TC0100006479.hg.1',\n",
      "       'TC0100006480.hg.1', 'TC0100006483.hg.1', 'TC0100006486.hg.1',\n",
      "       'TC0100006490.hg.1', 'TC0100006492.hg.1', 'TC0100006494.hg.1',\n",
      "       'TC0100006497.hg.1', 'TC0100006499.hg.1', 'TC0100006501.hg.1',\n",
      "       'TC0100006502.hg.1', 'TC0100006514.hg.1', 'TC0100006516.hg.1',\n",
      "       'TC0100006517.hg.1', 'TC0100006524.hg.1', 'TC0100006540.hg.1',\n",
      "       'TC0100006548.hg.1', 'TC0100006550.hg.1'],\n",
      "      dtype='object', name='ID')\n"
     ]
    }
   ],
   "source": [
    "# 1. Use the get_genetic_data function from the library to get the gene_data from the matrix_file previously defined.\n",
    "gene_data = get_genetic_data(matrix_file)\n",
    "\n",
    "# 2. Print the first 20 row IDs (gene or probe identifiers) for future observation.\n",
    "print(gene_data.index[:20])\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "44da5abe",
   "metadata": {},
   "source": [
    "### Step 4: Gene Identifier Review"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 5,
   "id": "6b644500",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T03:51:24.177624Z",
     "iopub.status.busy": "2025-03-25T03:51:24.177502Z",
     "iopub.status.idle": "2025-03-25T03:51:24.179375Z",
     "shell.execute_reply": "2025-03-25T03:51:24.179099Z"
    }
   },
   "outputs": [],
   "source": [
    "# These gene identifiers appear to be probe IDs from a microarray platform, likely Affymetrix \n",
    "# or similar custom array. They follow a format like \"TC0100006437.hg.1\" which indicates \n",
    "# they are transcript cluster IDs with a human genome reference (.hg).\n",
    "# These are definitely not standard human gene symbols (like BRCA1, TP53, etc.).\n",
    "# They will need to be mapped to standard gene symbols for meaningful biological interpretation.\n",
    "\n",
    "requires_gene_mapping = True\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "7c83f175",
   "metadata": {},
   "source": [
    "### Step 5: Gene Annotation"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 6,
   "id": "db86868a",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T03:51:24.180453Z",
     "iopub.status.busy": "2025-03-25T03:51:24.180348Z",
     "iopub.status.idle": "2025-03-25T03:51:27.180738Z",
     "shell.execute_reply": "2025-03-25T03:51:27.180414Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Gene annotation preview:\n",
      "{'ID': ['TC0100006437.hg.1', 'TC0100006476.hg.1', 'TC0100006479.hg.1', 'TC0100006480.hg.1', 'TC0100006483.hg.1'], 'probeset_id': ['TC0100006437.hg.1', 'TC0100006476.hg.1', 'TC0100006479.hg.1', 'TC0100006480.hg.1', 'TC0100006483.hg.1'], 'seqname': ['chr1', 'chr1', 'chr1', 'chr1', 'chr1'], 'strand': ['+', '+', '+', '+', '+'], 'start': ['69091', '924880', '960587', '966497', '1001138'], 'stop': ['70008', '944581', '965719', '975865', '1014541'], 'total_probes': [10.0, 10.0, 10.0, 10.0, 10.0], 'category': ['main', 'main', 'main', 'main', 'main'], 'SPOT_ID': ['Coding', 'Multiple_Complex', 'Multiple_Complex', 'Multiple_Complex', 'Multiple_Complex'], 'SPOT_ID.1': ['NM_001005484 // RefSeq // Homo sapiens olfactory receptor, family 4, subfamily F, member 5 (OR4F5), mRNA. // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000335137 // ENSEMBL // olfactory receptor, family 4, subfamily F, member 5 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000003223 // Havana transcript // olfactory receptor, family 4, subfamily F, member 5[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// uc001aal.1 // UCSC Genes // Homo sapiens olfactory receptor, family 4, subfamily F, member 5 (OR4F5), mRNA. // chr1 // 100 // 100 // 0 // --- // 0 /// CCDS30547.1 // ccdsGene // olfactory receptor, family 4, subfamily F, member 5 [Source:HGNC Symbol;Acc:HGNC:14825] // chr1 // 100 // 100 // 0 // --- // 0', 'NM_152486 // RefSeq // Homo sapiens sterile alpha motif domain containing 11 (SAMD11), mRNA. // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000341065 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000342066 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000420190 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000437963 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000455979 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000464948 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000466827 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000474461 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000478729 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:processed_transcript] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000616016 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000616125 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000617307 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000618181 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000618323 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000618779 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000620200 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000622503 // ENSEMBL // sterile alpha motif domain containing 11 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// BC024295 // GenBank // Homo sapiens sterile alpha motif domain containing 11, mRNA (cDNA clone MGC:39333 IMAGE:3354502), complete cds. // chr1 // 100 // 100 // 0 // --- // 0 /// BC033213 // GenBank // Homo sapiens sterile alpha motif domain containing 11, mRNA (cDNA clone MGC:45873 IMAGE:5014368), complete cds. // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097860 // Havana transcript // sterile alpha motif domain containing 11[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097862 // Havana transcript // sterile alpha motif domain containing 11[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097863 // Havana transcript // sterile alpha motif domain containing 11[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097865 // Havana transcript // sterile alpha motif domain containing 11[gene_biotype:protein_coding transcript_biotype:processed_transcript] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097866 // Havana transcript // sterile alpha motif domain containing 11[gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097867 // Havana transcript // sterile alpha motif domain containing 11[gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097868 // Havana transcript // sterile alpha motif domain containing 11[gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000276866 // Havana transcript // sterile alpha motif domain containing 11[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000316521 // Havana transcript // sterile alpha motif domain containing 11[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// CCDS2.2 // ccdsGene // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009185 // circbase // Salzman2013 ANNOTATED, CDS, coding, INTERNAL, OVCODE, OVERLAPTX, OVEXON best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009186 // circbase // Salzman2013 ANNOTATED, CDS, coding, INTERNAL, OVCODE, OVERLAPTX, OVEXON best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009187 // circbase // Salzman2013 ANNOTATED, CDS, coding, INTERNAL, OVCODE, OVEXON best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009188 // circbase // Salzman2013 ANNOTATED, CDS, coding, INTERNAL, OVCODE, OVEXON best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009189 // circbase // Salzman2013 ALT_DONOR, CDS, coding, INTERNAL, OVCODE, OVEXON best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009190 // circbase // Salzman2013 ANNOTATED, CDS, coding, INTERNAL, OVCODE, OVEXON best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009191 // circbase // Salzman2013 ANNOTATED, CDS, coding, INTERNAL, OVCODE, OVEXON best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009192 // circbase // Salzman2013 ANNOTATED, CDS, coding, INTERNAL, OVCODE, OVERLAPTX, OVEXON best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009193 // circbase // Salzman2013 ANNOTATED, CDS, coding, INTERNAL, OVCODE, OVERLAPTX, OVEXON best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009194 // circbase // Salzman2013 ANNOTATED, CDS, coding, OVCODE, OVERLAPTX, OVEXON, UTR3 best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009195 // circbase // Salzman2013 ANNOTATED, CDS, coding, INTERNAL, OVCODE, OVERLAPTX, OVEXON best transcript NM_152486 // chr1 // 100 // 100 // 0 // --- // 0 /// uc001abw.2 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc031pjt.2 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc031pju.2 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc031pkg.2 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc031pkh.2 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc031pkk.2 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc031pkm.2 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc031pko.2 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057axs.1 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057axt.1 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057axu.1 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057axv.1 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057axw.1 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057axx.1 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057axy.1 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057axz.1 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057aya.1 // UCSC Genes // sterile alpha motif domain containing 11 [Source:HGNC Symbol;Acc:HGNC:28706] // chr1 // 100 // 100 // 0 // --- // 0 /// NONHSAT000212 // lncRNAWiki // Non-coding transcript identified by NONCODE // chr1 // 100 // 100 // 0 // --- // 0 /// NONHSAT000212 // NONCODE // Non-coding transcript identified by NONCODE: Exonic // chr1 // 100 // 100 // 0 // --- // 0 /// NONHSAT000213 // lncRNAWiki // Non-coding transcript identified by NONCODE // chr1 // 100 // 100 // 0 // --- // 0 /// NONHSAT000213 // NONCODE // Non-coding transcript identified by NONCODE: Exonic // chr1 // 100 // 100 // 0 // --- // 0', 'NM_198317 // RefSeq // Homo sapiens kelch-like family member 17 (KLHL17), mRNA. // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000338591 // ENSEMBL // kelch-like family member 17 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000463212 // ENSEMBL // kelch-like family member 17 [gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000466300 // ENSEMBL // kelch-like family member 17 [gene_biotype:protein_coding transcript_biotype:nonsense_mediated_decay] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000481067 // ENSEMBL // kelch-like family member 17 [gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000622660 // ENSEMBL // kelch-like family member 17 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097875 // Havana transcript // kelch-like 17 (Drosophila)[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097877 // Havana transcript // kelch-like 17 (Drosophila)[gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097878 // Havana transcript // kelch-like 17 (Drosophila)[gene_biotype:protein_coding transcript_biotype:nonsense_mediated_decay] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097931 // Havana transcript // kelch-like 17 (Drosophila)[gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// BC166618 // GenBank // Synthetic construct Homo sapiens clone IMAGE:100066344, MGC:195481 kelch-like 17 (Drosophila) (KLHL17) mRNA, encodes complete protein. // chr1 // 100 // 100 // 0 // --- // 0 /// CCDS30550.1 // ccdsGene // kelch-like family member 17 [Source:HGNC Symbol;Acc:HGNC:24023] // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009209 // circbase // Salzman2013 ANNOTATED, CDS, coding, INTERNAL, OVCODE, OVEXON best transcript NM_198317 // chr1 // 100 // 100 // 0 // --- // 0 /// uc001aca.3 // UCSC Genes // kelch-like family member 17 [Source:HGNC Symbol;Acc:HGNC:24023] // chr1 // 100 // 100 // 0 // --- // 0 /// uc001acb.2 // UCSC Genes // kelch-like family member 17 [Source:HGNC Symbol;Acc:HGNC:24023] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057ayg.1 // UCSC Genes // kelch-like family member 17 [Source:HGNC Symbol;Acc:HGNC:24023] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057ayh.1 // UCSC Genes // kelch-like family member 17 [Source:HGNC Symbol;Acc:HGNC:24023] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057ayi.1 // UCSC Genes // kelch-like family member 17 [Source:HGNC Symbol;Acc:HGNC:24023] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057ayj.1 // UCSC Genes // N/A // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000617073 // ENSEMBL // ncrna:novel chromosome:GRCh38:1:965110:965166:1 gene:ENSG00000277294 gene_biotype:miRNA transcript_biotype:miRNA // chr1 // 100 // 100 // 0 // --- // 0 /// NONHSAT000216 // lncRNAWiki // Non-coding transcript identified by NONCODE // chr1 // 100 // 100 // 0 // --- // 0 /// NONHSAT000216 // NONCODE // Non-coding transcript identified by NONCODE: Exonic // chr1 // 100 // 100 // 0 // --- // 0', 'NM_001160184 // RefSeq // Homo sapiens pleckstrin homology domain containing, family N member 1 (PLEKHN1), transcript variant 2, mRNA. // chr1 // 100 // 100 // 0 // --- // 0 /// NM_032129 // RefSeq // Homo sapiens pleckstrin homology domain containing, family N member 1 (PLEKHN1), transcript variant 1, mRNA. // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000379407 // ENSEMBL // pleckstrin homology domain containing, family N member 1 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000379409 // ENSEMBL // pleckstrin homology domain containing, family N member 1 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000379410 // ENSEMBL // pleckstrin homology domain containing, family N member 1 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000480267 // ENSEMBL // pleckstrin homology domain containing, family N member 1 [gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000491024 // ENSEMBL // pleckstrin homology domain containing, family N member 1 [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// BC101386 // GenBank // Homo sapiens pleckstrin homology domain containing, family N member 1, mRNA (cDNA clone MGC:120613 IMAGE:40026400), complete cds. // chr1 // 100 // 100 // 0 // --- // 0 /// BC101387 // GenBank // Homo sapiens pleckstrin homology domain containing, family N member 1, mRNA (cDNA clone MGC:120616 IMAGE:40026404), complete cds. // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097940 // Havana transcript // pleckstrin homology domain containing, family N member 1[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097941 // Havana transcript // pleckstrin homology domain containing, family N member 1[gene_biotype:protein_coding transcript_biotype:retained_intron] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097942 // Havana transcript // pleckstrin homology domain containing, family N member 1[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000473255 // Havana transcript // pleckstrin homology domain containing, family N member 1[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000473256 // Havana transcript // pleckstrin homology domain containing, family N member 1[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// CCDS4.1 // ccdsGene // pleckstrin homology domain containing, family N member 1 [Source:HGNC Symbol;Acc:HGNC:25284] // chr1 // 100 // 100 // 0 // --- // 0 /// CCDS53256.1 // ccdsGene // pleckstrin homology domain containing, family N member 1 [Source:HGNC Symbol;Acc:HGNC:25284] // chr1 // 100 // 100 // 0 // --- // 0 /// PLEKHN1.aAug10 // Ace View // Transcript Identified by AceView, Entrez Gene ID(s) 84069 // chr1 // 100 // 100 // 0 // --- // 0 /// PLEKHN1.bAug10 // Ace View // Transcript Identified by AceView, Entrez Gene ID(s) 84069, RefSeq ID(s) NM_032129 // chr1 // 100 // 100 // 0 // --- // 0 /// uc001acd.4 // UCSC Genes // pleckstrin homology domain containing, family N member 1 [Source:HGNC Symbol;Acc:HGNC:25284] // chr1 // 100 // 100 // 0 // --- // 0 /// uc001ace.4 // UCSC Genes // pleckstrin homology domain containing, family N member 1 [Source:HGNC Symbol;Acc:HGNC:25284] // chr1 // 100 // 100 // 0 // --- // 0 /// uc001acf.4 // UCSC Genes // pleckstrin homology domain containing, family N member 1 [Source:HGNC Symbol;Acc:HGNC:25284] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057ayk.1 // UCSC Genes // pleckstrin homology domain containing, family N member 1 [Source:HGNC Symbol;Acc:HGNC:25284] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057ayl.1 // UCSC Genes // pleckstrin homology domain containing, family N member 1 [Source:HGNC Symbol;Acc:HGNC:25284] // chr1 // 100 // 100 // 0 // --- // 0 /// NONHSAT000217 // lncRNAWiki // Non-coding transcript identified by NONCODE // chr1 // 100 // 100 // 0 // --- // 0 /// NONHSAT000217 // NONCODE // Non-coding transcript identified by NONCODE: Exonic // chr1 // 100 // 100 // 0 // --- // 0', 'NM_005101 // RefSeq // Homo sapiens ISG15 ubiquitin-like modifier (ISG15), mRNA. // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000379389 // ENSEMBL // ISG15 ubiquitin-like modifier [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000624652 // ENSEMBL // ISG15 ubiquitin-like modifier [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// ENST00000624697 // ENSEMBL // ISG15 ubiquitin-like modifier [gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// BC009507 // GenBank // Homo sapiens ISG15 ubiquitin-like modifier, mRNA (cDNA clone MGC:3945 IMAGE:3545944), complete cds. // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000097989 // Havana transcript // ISG15 ubiquitin-like modifier[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000479384 // Havana transcript // ISG15 ubiquitin-like modifier[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// OTTHUMT00000479385 // Havana transcript // ISG15 ubiquitin-like modifier[gene_biotype:protein_coding transcript_biotype:protein_coding] // chr1 // 100 // 100 // 0 // --- // 0 /// CCDS6.1 // ccdsGene // ISG15 ubiquitin-like modifier [Source:HGNC Symbol;Acc:HGNC:4053] // chr1 // 100 // 100 // 0 // --- // 0 /// hsa_circ_0009211 // circbase // Salzman2013 ANNOTATED, CDS, coding, OVCODE, OVEXON, UTR3 best transcript NM_005101 // chr1 // 100 // 100 // 0 // --- // 0 /// ISG15.bAug10 // Ace View // Transcript Identified by AceView, Entrez Gene ID(s) 9636 // chr1 // 100 // 100 // 0 // --- // 0 /// ISG15.cAug10 // Ace View // Transcript Identified by AceView, Entrez Gene ID(s) 9636 // chr1 // 100 // 100 // 0 // --- // 0 /// uc001acj.5 // UCSC Genes // ISG15 ubiquitin-like modifier [Source:HGNC Symbol;Acc:HGNC:4053] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057ayq.1 // UCSC Genes // ISG15 ubiquitin-like modifier [Source:HGNC Symbol;Acc:HGNC:4053] // chr1 // 100 // 100 // 0 // --- // 0 /// uc057ayr.1 // UCSC Genes // ISG15 ubiquitin-like modifier [Source:HGNC Symbol;Acc:HGNC:4053] // chr1 // 100 // 100 // 0 // --- // 0']}\n"
     ]
    }
   ],
   "source": [
    "# 1. Use the 'get_gene_annotation' function from the library to get gene annotation data from the SOFT file.\n",
    "gene_annotation = get_gene_annotation(soft_file)\n",
    "\n",
    "# 2. Use the 'preview_df' function from the library to preview the data and print out the results.\n",
    "print(\"Gene annotation preview:\")\n",
    "print(preview_df(gene_annotation))\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "c4c94928",
   "metadata": {},
   "source": [
    "### Step 6: Gene Identifier Mapping"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 7,
   "id": "568ab3de",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T03:51:27.181972Z",
     "iopub.status.busy": "2025-03-25T03:51:27.181859Z",
     "iopub.status.idle": "2025-03-25T03:51:30.049782Z",
     "shell.execute_reply": "2025-03-25T03:51:30.049212Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Number of mappings before filtering: 27189\n",
      "Sample of mapping dataframe (first 3 rows):\n",
      "                  ID                                               Gene\n",
      "0  TC0100006437.hg.1  NM_001005484 // RefSeq // Homo sapiens olfacto...\n",
      "1  TC0100006476.hg.1  NM_152486 // RefSeq // Homo sapiens sterile al...\n",
      "2  TC0100006479.hg.1  NM_198317 // RefSeq // Homo sapiens kelch-like...\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Before normalization - number of genes: 85192\n",
      "Before normalization - first 5 genes: Index(['A-', 'A-1', 'A-2', 'A-52', 'A-E'], dtype='object', name='Gene')\n",
      "After normalization - number of genes: 19964\n",
      "After normalization - first 5 genes: Index(['A1BG', 'A1CF', 'A2M', 'A2ML1', 'A3GALT2'], dtype='object', name='Gene')\n"
     ]
    }
   ],
   "source": [
    "# 1. Determine which columns contain gene identifiers and gene symbols\n",
    "# 'ID' in gene_annotation matches the probe IDs in gene_data.index\n",
    "# 'SPOT_ID.1' contains the gene information with gene symbols\n",
    "\n",
    "# 2. Create a gene mapping dataframe\n",
    "mapping_df = get_gene_mapping(gene_annotation, 'ID', 'SPOT_ID.1')\n",
    "\n",
    "# Check the mapping dataframe content\n",
    "print(f\"Number of mappings before filtering: {len(mapping_df)}\")\n",
    "print(f\"Sample of mapping dataframe (first 3 rows):\")\n",
    "print(mapping_df.head(3))\n",
    "\n",
    "# 3. Convert probe-level measurements to gene expression data\n",
    "gene_data = apply_gene_mapping(gene_data, mapping_df)\n",
    "\n",
    "# Print info before normalization\n",
    "print(f\"Before normalization - number of genes: {len(gene_data)}\")\n",
    "if len(gene_data) > 0:\n",
    "    print(f\"Before normalization - first 5 genes: {gene_data.index[:5]}\")\n",
    "else:\n",
    "    print(\"No genes were mapped successfully before normalization.\")\n",
    "\n",
    "# Normalize gene symbols to ensure consistency\n",
    "gene_data = normalize_gene_symbols_in_index(gene_data)\n",
    "\n",
    "# Print info after normalization\n",
    "print(f\"After normalization - number of genes: {len(gene_data)}\")\n",
    "if len(gene_data) > 0:\n",
    "    print(f\"After normalization - first 5 genes: {gene_data.index[:5]}\")\n",
    "else:\n",
    "    print(\"No genes were mapped successfully after normalization.\")\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "912f7c75",
   "metadata": {},
   "source": [
    "### Step 7: Data Normalization and Linking"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 8,
   "id": "94856f76",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T03:51:30.051808Z",
     "iopub.status.busy": "2025-03-25T03:51:30.051642Z",
     "iopub.status.idle": "2025-03-25T03:51:31.262032Z",
     "shell.execute_reply": "2025-03-25T03:51:31.261650Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Normalized gene data saved to ../../output/preprocess/Rheumatoid_Arthritis/gene_data/GSE186963.csv\n",
      "No trait data available for linking with gene expression data.\n",
      "Abnormality detected in the cohort: GSE186963. Preprocessing failed.\n",
      "No valid linked data to save - dataset doesn't contain Rheumatoid Arthritis data\n"
     ]
    }
   ],
   "source": [
    "# 1. We cannot process clinical features since trait_row is None (no RA data in this dataset)\n",
    "# This means we're skipping the clinical feature extraction step as specified in the instructions\n",
    "\n",
    "# Save the gene data that we've already normalized\n",
    "os.makedirs(os.path.dirname(out_gene_data_file), exist_ok=True)\n",
    "gene_data.to_csv(out_gene_data_file)\n",
    "print(f\"Normalized gene data saved to {out_gene_data_file}\")\n",
    "\n",
    "# Since there's no trait data in this dataset, we cannot link clinical and genetic data\n",
    "# We'll create empty placeholder data to properly finish the process\n",
    "print(\"No trait data available for linking with gene expression data.\")\n",
    "\n",
    "# Create a small placeholder dataframe with proper structure\n",
    "empty_clinical_df = pd.DataFrame(columns=[trait])\n",
    "# Use first few samples from gene_data for consistent structure\n",
    "sample_ids = gene_data.columns[:5] if len(gene_data.columns) >= 5 else gene_data.columns\n",
    "empty_clinical_df = pd.DataFrame(index=sample_ids, columns=[trait])\n",
    "empty_clinical_df[trait] = None  # All None values for trait\n",
    "\n",
    "# Skip handling missing values since we don't have valid linked data\n",
    "\n",
    "# 5. We'll mark this dataset as not usable due to missing trait data\n",
    "is_trait_biased = True  # Not actually assessed, but marked as biased since trait data is missing\n",
    "is_usable = validate_and_save_cohort_info(\n",
    "    is_final=True, \n",
    "    cohort=cohort, \n",
    "    info_path=json_path, \n",
    "    is_gene_available=True, \n",
    "    is_trait_available=False,  # No trait data\n",
    "    is_biased=is_trait_biased, \n",
    "    df=empty_clinical_df,\n",
    "    note=\"This dataset contains gene expression data for Crohn's disease, not Rheumatoid Arthritis\"\n",
    ")\n",
    "\n",
    "# 6. Not saving linked data as it's not usable for our purposes\n",
    "print(\"No valid linked data to save - dataset doesn't contain Rheumatoid Arthritis data\")"
   ]
  }
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