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{
 "cells": [
  {
   "cell_type": "code",
   "execution_count": 1,
   "id": "394504c0",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T08:18:02.168910Z",
     "iopub.status.busy": "2025-03-25T08:18:02.168677Z",
     "iopub.status.idle": "2025-03-25T08:18:02.332527Z",
     "shell.execute_reply": "2025-03-25T08:18:02.332102Z"
    }
   },
   "outputs": [],
   "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 = \"Chronic_kidney_disease\"\n",
    "cohort = \"GSE142153\"\n",
    "\n",
    "# Input paths\n",
    "in_trait_dir = \"../../input/GEO/Chronic_kidney_disease\"\n",
    "in_cohort_dir = \"../../input/GEO/Chronic_kidney_disease/GSE142153\"\n",
    "\n",
    "# Output paths\n",
    "out_data_file = \"../../output/preprocess/Chronic_kidney_disease/GSE142153.csv\"\n",
    "out_gene_data_file = \"../../output/preprocess/Chronic_kidney_disease/gene_data/GSE142153.csv\"\n",
    "out_clinical_data_file = \"../../output/preprocess/Chronic_kidney_disease/clinical_data/GSE142153.csv\"\n",
    "json_path = \"../../output/preprocess/Chronic_kidney_disease/cohort_info.json\"\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "ed80e421",
   "metadata": {},
   "source": [
    "### Step 1: Initial Data Loading"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 2,
   "id": "878c22bd",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T08:18:02.333954Z",
     "iopub.status.busy": "2025-03-25T08:18:02.333819Z",
     "iopub.status.idle": "2025-03-25T08:18:02.407552Z",
     "shell.execute_reply": "2025-03-25T08:18:02.407176Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Background Information:\n",
      "!Series_title\t\"Human PBMCs: Healthy vs Diabetic nephropathy vs ESRD\"\n",
      "!Series_summary\t\"Transcriptional profiling of human PBMCs comparing healthy controls, patients with diabetic nephropathy and patients with ESRD. PBMCs were analyzed as they mediate inflammatory injury. Goal was to determine effects of increasing severity of diabetic nephropathy on global PBMC gene expression. Microarray analysis of PBMCs taken from patients with varying degrees of diabetic nephropathy.\"\n",
      "!Series_overall_design\t\"3 condition experiment - Healthy control (10) vs diabetic nephropathy (23) vs ESRD (7)\"\n",
      "Sample Characteristics Dictionary:\n",
      "{0: ['tissue: peripheral blood'], 1: ['diagnosis: healthy control', 'diagnosis: diabetic nephropathy', 'diagnosis: ESRD']}\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": "2e77ec63",
   "metadata": {},
   "source": [
    "### Step 2: Dataset Analysis and Clinical Feature Extraction"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 3,
   "id": "d2dd4c06",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T08:18:02.408761Z",
     "iopub.status.busy": "2025-03-25T08:18:02.408657Z",
     "iopub.status.idle": "2025-03-25T08:18:02.415814Z",
     "shell.execute_reply": "2025-03-25T08:18:02.415444Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Preview of clinical features:\n",
      "{'GSM4221568': [0.0], 'GSM4221569': [0.0], 'GSM4221570': [0.0], 'GSM4221571': [0.0], 'GSM4221572': [0.0], 'GSM4221573': [0.0], 'GSM4221574': [0.0], 'GSM4221575': [0.0], 'GSM4221576': [0.0], 'GSM4221577': [0.0], 'GSM4221578': [1.0], 'GSM4221579': [1.0], 'GSM4221580': [1.0], 'GSM4221581': [1.0], 'GSM4221582': [1.0], 'GSM4221583': [1.0], 'GSM4221584': [1.0], 'GSM4221585': [1.0], 'GSM4221586': [1.0], 'GSM4221587': [1.0], 'GSM4221588': [1.0], 'GSM4221589': [1.0], 'GSM4221590': [1.0], 'GSM4221591': [1.0], 'GSM4221592': [1.0], 'GSM4221593': [1.0], 'GSM4221594': [1.0], 'GSM4221595': [1.0], 'GSM4221596': [1.0], 'GSM4221597': [1.0], 'GSM4221598': [1.0], 'GSM4221599': [1.0], 'GSM4221600': [1.0], 'GSM4221601': [1.0], 'GSM4221602': [1.0], 'GSM4221603': [1.0], 'GSM4221604': [1.0], 'GSM4221605': [1.0], 'GSM4221606': [1.0], 'GSM4221607': [1.0]}\n",
      "Clinical features saved to ../../output/preprocess/Chronic_kidney_disease/clinical_data/GSE142153.csv\n"
     ]
    }
   ],
   "source": [
    "# 1. Gene Expression Data Availability\n",
    "# Based on the background information, this dataset contains transcriptional profiling data\n",
    "# which indicates gene expression data is available\n",
    "is_gene_available = True\n",
    "\n",
    "# 2. Variable Availability and Data Type Conversion\n",
    "# 2.1 Data Availability\n",
    "\n",
    "# For trait (diabetic nephropathy/chronic kidney disease):\n",
    "# Row 1 contains diagnosis information with multiple values\n",
    "trait_row = 1\n",
    "\n",
    "# Age data is not available in the sample characteristics\n",
    "age_row = None\n",
    "\n",
    "# Gender data is not available in the sample characteristics\n",
    "gender_row = None\n",
    "\n",
    "# 2.2 Data Type Conversion\n",
    "\n",
    "# Convert trait values to binary (0 for control, 1 for disease)\n",
    "def convert_trait(value):\n",
    "    if isinstance(value, str):\n",
    "        # Extract the value after colon if exists\n",
    "        if ':' in value:\n",
    "            value = value.split(':', 1)[1].strip()\n",
    "        \n",
    "        # Convert based on diagnosis\n",
    "        if 'healthy control' in value.lower():\n",
    "            return 0  # Control\n",
    "        elif 'diabetic nephropathy' in value.lower() or 'esrd' in value.lower():\n",
    "            return 1  # Disease (Diabetic nephropathy or ESRD both indicate kidney disease)\n",
    "    return None\n",
    "\n",
    "# Since age data is not available, we define a placeholder function\n",
    "def convert_age(value):\n",
    "    return None\n",
    "\n",
    "# Since gender data is not available, we define a placeholder function\n",
    "def convert_gender(value):\n",
    "    return None\n",
    "\n",
    "# 3. Save Metadata\n",
    "# Determine if trait data is available\n",
    "is_trait_available = trait_row is not None\n",
    "\n",
    "# Validate and save cohort info\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",
    "if trait_row is not None:\n",
    "    # Extract clinical features\n",
    "    clinical_features_df = geo_select_clinical_features(\n",
    "        clinical_df=clinical_data,\n",
    "        trait=trait,\n",
    "        trait_row=trait_row,\n",
    "        convert_trait=convert_trait,\n",
    "        age_row=age_row,\n",
    "        convert_age=convert_age,\n",
    "        gender_row=gender_row,\n",
    "        convert_gender=convert_gender\n",
    "    )\n",
    "    \n",
    "    # Preview the clinical features dataframe\n",
    "    print(\"Preview of clinical features:\")\n",
    "    print(preview_df(clinical_features_df))\n",
    "    \n",
    "    # Create output directory if it doesn't exist\n",
    "    os.makedirs(os.path.dirname(out_clinical_data_file), exist_ok=True)\n",
    "    \n",
    "    # Save the clinical features to a CSV file\n",
    "    clinical_features_df.to_csv(out_clinical_data_file)\n",
    "    print(f\"Clinical features saved to {out_clinical_data_file}\")\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "358db33d",
   "metadata": {},
   "source": [
    "### Step 3: Gene Data Extraction"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 4,
   "id": "378d24ff",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T08:18:02.416966Z",
     "iopub.status.busy": "2025-03-25T08:18:02.416864Z",
     "iopub.status.idle": "2025-03-25T08:18:02.541979Z",
     "shell.execute_reply": "2025-03-25T08:18:02.541457Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "SOFT file: ../../input/GEO/Chronic_kidney_disease/GSE142153/GSE142153_family.soft.gz\n",
      "Matrix file: ../../input/GEO/Chronic_kidney_disease/GSE142153/GSE142153_series_matrix.txt.gz\n",
      "Gene data shape: (30811, 40)\n",
      "First 20 gene/probe identifiers:\n",
      "['A_23_P100001', 'A_23_P100022', 'A_23_P100056', 'A_23_P100074', 'A_23_P100111', 'A_23_P100127', 'A_23_P100133', 'A_23_P100141', 'A_23_P100156', 'A_23_P100189', 'A_23_P100203', 'A_23_P100220', 'A_23_P100240', 'A_23_P10025', 'A_23_P100278', 'A_23_P100292', 'A_23_P100315', 'A_23_P100344', 'A_23_P100355', 'A_23_P100386']\n"
     ]
    }
   ],
   "source": [
    "# 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",
    "print(f\"SOFT file: {soft_file}\")\n",
    "print(f\"Matrix file: {matrix_file}\")\n",
    "\n",
    "# Set gene availability flag\n",
    "is_gene_available = True  # Assume gene data is available\n",
    "\n",
    "# Extract gene data\n",
    "try:\n",
    "    # Extract gene data from the matrix file\n",
    "    gene_data = get_genetic_data(matrix_file)\n",
    "    print(f\"Gene data shape: {gene_data.shape}\")\n",
    "    \n",
    "    # Print the first 20 gene/probe identifiers\n",
    "    print(\"First 20 gene/probe identifiers:\")\n",
    "    print(gene_data.index[:20].tolist())\n",
    "except Exception as e:\n",
    "    print(f\"Error extracting gene data: {e}\")\n",
    "    print(f\"File path: {matrix_file}\")\n",
    "    print(\"Please check if the file exists and contains the expected markers.\")\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "550aa3ea",
   "metadata": {},
   "source": [
    "### Step 4: Gene Identifier Review"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 5,
   "id": "182fdc77",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T08:18:02.543412Z",
     "iopub.status.busy": "2025-03-25T08:18:02.543298Z",
     "iopub.status.idle": "2025-03-25T08:18:02.545385Z",
     "shell.execute_reply": "2025-03-25T08:18:02.545014Z"
    }
   },
   "outputs": [],
   "source": [
    "# Looking at the gene identifiers, these are Agilent microarray probe IDs (starting with 'A_23_P'),\n",
    "# not standard human gene symbols. These probe IDs will need to be mapped to gene symbols.\n",
    "\n",
    "requires_gene_mapping = True\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "dbad4b86",
   "metadata": {},
   "source": [
    "### Step 5: Gene Annotation"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 6,
   "id": "5dd772d3",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T08:18:02.546720Z",
     "iopub.status.busy": "2025-03-25T08:18:02.546619Z",
     "iopub.status.idle": "2025-03-25T08:18:04.675136Z",
     "shell.execute_reply": "2025-03-25T08:18:04.674493Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "\n",
      "Gene annotation preview:\n",
      "Columns in gene annotation: ['ID', 'SPOT_ID', 'CONTROL_TYPE', 'REFSEQ', 'GB_ACC', 'GENE', 'GENE_SYMBOL', 'GENE_NAME', 'UNIGENE_ID', 'ENSEMBL_ID', 'TIGR_ID', 'ACCESSION_STRING', 'CHROMOSOMAL_LOCATION', 'CYTOBAND', 'DESCRIPTION', 'GO_ID', 'SEQUENCE']\n",
      "{'ID': ['A_23_P100001', 'A_23_P100011', 'A_23_P100022', 'A_23_P100056', 'A_23_P100074'], 'SPOT_ID': ['A_23_P100001', 'A_23_P100011', 'A_23_P100022', 'A_23_P100056', 'A_23_P100074'], 'CONTROL_TYPE': ['FALSE', 'FALSE', 'FALSE', 'FALSE', 'FALSE'], 'REFSEQ': ['NM_207446', 'NM_005829', 'NM_014848', 'NM_194272', 'NM_020371'], 'GB_ACC': ['NM_207446', 'NM_005829', 'NM_014848', 'NM_194272', 'NM_020371'], 'GENE': [400451.0, 10239.0, 9899.0, 348093.0, 57099.0], 'GENE_SYMBOL': ['FAM174B', 'AP3S2', 'SV2B', 'RBPMS2', 'AVEN'], 'GENE_NAME': ['family with sequence similarity 174, member B', 'adaptor-related protein complex 3, sigma 2 subunit', 'synaptic vesicle glycoprotein 2B', 'RNA binding protein with multiple splicing 2', 'apoptosis, caspase activation inhibitor'], 'UNIGENE_ID': ['Hs.27373', 'Hs.632161', 'Hs.21754', 'Hs.436518', 'Hs.555966'], 'ENSEMBL_ID': ['ENST00000557398', nan, 'ENST00000557410', 'ENST00000300069', 'ENST00000306730'], 'TIGR_ID': [nan, nan, nan, nan, nan], 'ACCESSION_STRING': ['ref|NM_207446|ens|ENST00000557398|ens|ENST00000553393|ens|ENST00000327355', 'ref|NM_005829|ref|NM_001199058|ref|NR_023361|ref|NR_037582', 'ref|NM_014848|ref|NM_001167580|ens|ENST00000557410|ens|ENST00000330276', 'ref|NM_194272|ens|ENST00000300069|gb|AK127873|gb|AK124123', 'ref|NM_020371|ens|ENST00000306730|gb|AF283508|gb|BC010488'], 'CHROMOSOMAL_LOCATION': ['chr15:93160848-93160789', 'chr15:90378743-90378684', 'chr15:91838329-91838388', 'chr15:65032375-65032316', 'chr15:34158739-34158680'], 'CYTOBAND': ['hs|15q26.1', 'hs|15q26.1', 'hs|15q26.1', 'hs|15q22.31', 'hs|15q14'], 'DESCRIPTION': ['Homo sapiens family with sequence similarity 174, member B (FAM174B), mRNA [NM_207446]', 'Homo sapiens adaptor-related protein complex 3, sigma 2 subunit (AP3S2), transcript variant 1, mRNA [NM_005829]', 'Homo sapiens synaptic vesicle glycoprotein 2B (SV2B), transcript variant 1, mRNA [NM_014848]', 'Homo sapiens RNA binding protein with multiple splicing 2 (RBPMS2), mRNA [NM_194272]', 'Homo sapiens apoptosis, caspase activation inhibitor (AVEN), mRNA [NM_020371]'], 'GO_ID': ['GO:0016020(membrane)|GO:0016021(integral to membrane)', 'GO:0005794(Golgi apparatus)|GO:0006886(intracellular protein transport)|GO:0008565(protein transporter activity)|GO:0016020(membrane)|GO:0016192(vesicle-mediated transport)|GO:0030117(membrane coat)|GO:0030659(cytoplasmic vesicle membrane)|GO:0031410(cytoplasmic vesicle)', 'GO:0001669(acrosomal vesicle)|GO:0006836(neurotransmitter transport)|GO:0016020(membrane)|GO:0016021(integral to membrane)|GO:0022857(transmembrane transporter activity)|GO:0030054(cell junction)|GO:0030672(synaptic vesicle membrane)|GO:0031410(cytoplasmic vesicle)|GO:0045202(synapse)', 'GO:0000166(nucleotide binding)|GO:0003676(nucleic acid binding)', 'GO:0005515(protein binding)|GO:0005622(intracellular)|GO:0005624(membrane fraction)|GO:0006915(apoptosis)|GO:0006916(anti-apoptosis)|GO:0012505(endomembrane system)|GO:0016020(membrane)'], 'SEQUENCE': ['ATCTCATGGAAAAGCTGGATTCCTCTGCCTTACGCAGAAACACCCGGGCTCCATCTGCCA', 'TCAAGTATTGGCCTGACATAGAGTCCTTAAGACAAGCAAAGACAAGCAAGGCAAGCACGT', 'ATGTCGGCTGTGGAGGGTTAAAGGGATGAGGCTTTCCTTTGTTTAGCAAATCTGTTCACA', 'CCCTGTCAGATAAGTTTAATGTTTAGTTTGAGGCATGAAGAAGAAAAGGGTTTCCATTCT', 'GACCAGCCAGTTTACAAGCATGTCTCAAGCTAGTGTGTTCCATTATGCTCACAGCAGTAA']}\n",
      "\n",
      "Complete sample of a few rows:\n",
      "             ID       SPOT_ID CONTROL_TYPE     REFSEQ     GB_ACC      GENE GENE_SYMBOL                                           GENE_NAME UNIGENE_ID       ENSEMBL_ID  TIGR_ID                                                           ACCESSION_STRING     CHROMOSOMAL_LOCATION    CYTOBAND                                                                                                      DESCRIPTION                                                                                                                                                                                                                                                                                          GO_ID                                                      SEQUENCE\n",
      "0  A_23_P100001  A_23_P100001        FALSE  NM_207446  NM_207446  400451.0     FAM174B       family with sequence similarity 174, member B   Hs.27373  ENST00000557398      NaN  ref|NM_207446|ens|ENST00000557398|ens|ENST00000553393|ens|ENST00000327355  chr15:93160848-93160789  hs|15q26.1                           Homo sapiens family with sequence similarity 174, member B (FAM174B), mRNA [NM_207446]                                                                                                                                                                                                                                          GO:0016020(membrane)|GO:0016021(integral to membrane)  ATCTCATGGAAAAGCTGGATTCCTCTGCCTTACGCAGAAACACCCGGGCTCCATCTGCCA\n",
      "1  A_23_P100011  A_23_P100011        FALSE  NM_005829  NM_005829   10239.0       AP3S2  adaptor-related protein complex 3, sigma 2 subunit  Hs.632161              NaN      NaN                 ref|NM_005829|ref|NM_001199058|ref|NR_023361|ref|NR_037582  chr15:90378743-90378684  hs|15q26.1  Homo sapiens adaptor-related protein complex 3, sigma 2 subunit (AP3S2), transcript variant 1, mRNA [NM_005829]                GO:0005794(Golgi apparatus)|GO:0006886(intracellular protein transport)|GO:0008565(protein transporter activity)|GO:0016020(membrane)|GO:0016192(vesicle-mediated transport)|GO:0030117(membrane coat)|GO:0030659(cytoplasmic vesicle membrane)|GO:0031410(cytoplasmic vesicle)  TCAAGTATTGGCCTGACATAGAGTCCTTAAGACAAGCAAAGACAAGCAAGGCAAGCACGT\n",
      "2  A_23_P100022  A_23_P100022        FALSE  NM_014848  NM_014848    9899.0        SV2B                    synaptic vesicle glycoprotein 2B   Hs.21754  ENST00000557410      NaN     ref|NM_014848|ref|NM_001167580|ens|ENST00000557410|ens|ENST00000330276  chr15:91838329-91838388  hs|15q26.1                     Homo sapiens synaptic vesicle glycoprotein 2B (SV2B), transcript variant 1, mRNA [NM_014848]  GO:0001669(acrosomal vesicle)|GO:0006836(neurotransmitter transport)|GO:0016020(membrane)|GO:0016021(integral to membrane)|GO:0022857(transmembrane transporter activity)|GO:0030054(cell junction)|GO:0030672(synaptic vesicle membrane)|GO:0031410(cytoplasmic vesicle)|GO:0045202(synapse)  ATGTCGGCTGTGGAGGGTTAAAGGGATGAGGCTTTCCTTTGTTTAGCAAATCTGTTCACA\n",
      "\n",
      "Potential gene-related columns: ['ID', 'SPOT_ID', 'GENE', 'GENE_SYMBOL', 'GENE_NAME', 'UNIGENE_ID', 'ENSEMBL_ID', 'TIGR_ID', 'GO_ID']\n",
      "\n",
      "Sample mappings from 'ID' to 'GENE_SYMBOL':\n",
      "             ID GENE_SYMBOL\n",
      "0  A_23_P100001     FAM174B\n",
      "1  A_23_P100011       AP3S2\n",
      "2  A_23_P100022        SV2B\n",
      "3  A_23_P100056      RBPMS2\n",
      "4  A_23_P100074        AVEN\n",
      "5  A_23_P100092     ZSCAN29\n",
      "6  A_23_P100103       VPS39\n",
      "7  A_23_P100111         CHP\n",
      "8  A_23_P100127       CASC5\n",
      "9  A_23_P100133       ATMIN\n",
      "\n",
      "Number of probes with gene ID mappings: 30936\n",
      "Sample of valid mappings:\n",
      "             ID GENE_SYMBOL\n",
      "0  A_23_P100001     FAM174B\n",
      "1  A_23_P100011       AP3S2\n",
      "2  A_23_P100022        SV2B\n",
      "3  A_23_P100056      RBPMS2\n",
      "4  A_23_P100074        AVEN\n"
     ]
    }
   ],
   "source": [
    "# 1. Use the 'get_gene_annotation' function from the library to get gene annotation data from the SOFT file.\n",
    "soft_file, matrix_file = geo_get_relevant_filepaths(in_cohort_dir)\n",
    "gene_annotation = get_gene_annotation(soft_file)\n",
    "\n",
    "# 2. Analyze the gene annotation dataframe to identify which columns contain the gene identifiers and gene symbols\n",
    "print(\"\\nGene annotation preview:\")\n",
    "print(f\"Columns in gene annotation: {gene_annotation.columns.tolist()}\")\n",
    "print(preview_df(gene_annotation, n=5))\n",
    "\n",
    "# Get a more complete view to understand the annotation structure\n",
    "print(\"\\nComplete sample of a few rows:\")\n",
    "print(gene_annotation.iloc[:3].to_string())\n",
    "\n",
    "# Check if there are any columns that might contain gene information beyond what we've seen\n",
    "potential_gene_columns = [col for col in gene_annotation.columns if \n",
    "                          any(term in col.upper() for term in [\"GENE\", \"SYMBOL\", \"NAME\", \"ID\"])]\n",
    "print(f\"\\nPotential gene-related columns: {potential_gene_columns}\")\n",
    "\n",
    "# Look for additional columns that might contain gene symbols\n",
    "# Since we only have 'ID' and 'ENTREZ_GENE_ID', check if we need to use Entrez IDs for mapping\n",
    "gene_id_col = 'ID'\n",
    "gene_symbol_col = None\n",
    "\n",
    "# Check various potential column names for gene symbols\n",
    "for col_name in ['GENE_SYMBOL', 'SYMBOL', 'GENE', 'GENE_NAME', 'GB_ACC']:\n",
    "    if col_name in gene_annotation.columns:\n",
    "        gene_symbol_col = col_name\n",
    "        break\n",
    "\n",
    "# If no dedicated symbol column is found, we'll need to use ENTREZ_GENE_ID\n",
    "if gene_symbol_col is None and 'ENTREZ_GENE_ID' in gene_annotation.columns:\n",
    "    gene_symbol_col = 'ENTREZ_GENE_ID'\n",
    "    print(\"\\nNo direct gene symbol column found. Will use Entrez Gene IDs for mapping.\")\n",
    "\n",
    "if gene_id_col in gene_annotation.columns and gene_symbol_col is not None:\n",
    "    print(f\"\\nSample mappings from '{gene_id_col}' to '{gene_symbol_col}':\")\n",
    "    sample_mappings = gene_annotation[[gene_id_col, gene_symbol_col]].head(10)\n",
    "    print(sample_mappings)\n",
    "    \n",
    "    # Check for non-null mappings to confirm data quality\n",
    "    non_null_mappings = gene_annotation[[gene_id_col, gene_symbol_col]].dropna(subset=[gene_symbol_col])\n",
    "    print(f\"\\nNumber of probes with gene ID mappings: {len(non_null_mappings)}\")\n",
    "    print(f\"Sample of valid mappings:\")\n",
    "    print(non_null_mappings.head(5))\n",
    "else:\n",
    "    print(\"Required mapping columns not found in the annotation data. Will need to explore alternative mapping approaches.\")\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "413446a6",
   "metadata": {},
   "source": [
    "### Step 6: Gene Identifier Mapping"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 7,
   "id": "18cd37cd",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T08:18:04.677016Z",
     "iopub.status.busy": "2025-03-25T08:18:04.676897Z",
     "iopub.status.idle": "2025-03-25T08:18:05.134533Z",
     "shell.execute_reply": "2025-03-25T08:18:05.133902Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Using 'ID' as probe identifier column and 'GENE_SYMBOL' as gene symbol column\n",
      "Gene mapping dataframe shape: (30936, 2)\n",
      "Sample of gene mapping:\n",
      "             ID     Gene\n",
      "0  A_23_P100001  FAM174B\n",
      "1  A_23_P100011    AP3S2\n",
      "2  A_23_P100022     SV2B\n",
      "3  A_23_P100056   RBPMS2\n",
      "4  A_23_P100074     AVEN\n",
      "Gene expression data shape after mapping: (18440, 40)\n",
      "First few rows and columns of gene expression data:\n",
      "          GSM4221568  GSM4221569  GSM4221570  GSM4221571  GSM4221572\n",
      "Gene                                                                \n",
      "A1BG        1.689609    0.116657    0.729824    1.233267   -0.753530\n",
      "A1BG-AS1    1.735950    1.614540    1.115200    0.556956    0.662771\n",
      "A1CF       -5.546720   -6.946890   -9.237430   -7.895080   -6.992950\n",
      "A2LD1       1.611080    1.368170    0.811205    1.717300    1.131080\n",
      "A2M        -7.113060   -6.750490   -6.552580   -6.926450   -6.712910\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Gene expression data saved to ../../output/preprocess/Chronic_kidney_disease/gene_data/GSE142153.csv\n"
     ]
    }
   ],
   "source": [
    "# 1. Determine which columns in gene_annotation contain probe IDs and gene symbols\n",
    "# Based on the preview, 'ID' contains probe identifiers and 'GENE_SYMBOL' contains gene symbols\n",
    "probe_id_col = 'ID'\n",
    "gene_symbol_col = 'GENE_SYMBOL'\n",
    "\n",
    "print(f\"Using '{probe_id_col}' as probe identifier column and '{gene_symbol_col}' as gene symbol column\")\n",
    "\n",
    "# 2. Create a gene mapping dataframe using the two columns\n",
    "gene_mapping = get_gene_mapping(gene_annotation, probe_id_col, gene_symbol_col)\n",
    "print(f\"Gene mapping dataframe shape: {gene_mapping.shape}\")\n",
    "print(\"Sample of gene mapping:\")\n",
    "print(gene_mapping.head())\n",
    "\n",
    "# 3. Apply the gene mapping to convert probe-level measurements to gene-level expression data\n",
    "gene_data = apply_gene_mapping(gene_data, gene_mapping)\n",
    "print(f\"Gene expression data shape after mapping: {gene_data.shape}\")\n",
    "print(\"First few rows and columns of gene expression data:\")\n",
    "print(gene_data.iloc[:5, :5])\n",
    "\n",
    "# Save gene data to CSV file\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\"Gene expression data saved to {out_gene_data_file}\")\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "07ddffb8",
   "metadata": {},
   "source": [
    "### Step 7: Data Normalization and Linking"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 8,
   "id": "20477b22",
   "metadata": {
    "execution": {
     "iopub.execute_input": "2025-03-25T08:18:05.136736Z",
     "iopub.status.busy": "2025-03-25T08:18:05.136581Z",
     "iopub.status.idle": "2025-03-25T08:18:12.923696Z",
     "shell.execute_reply": "2025-03-25T08:18:12.923210Z"
    }
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Loaded gene data shape: (18440, 40)\n",
      "Normalized gene data shape: (18202, 40)\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Normalized gene data saved to ../../output/preprocess/Chronic_kidney_disease/gene_data/GSE142153.csv\n",
      "Loaded clinical data shape: (1, 40)\n",
      "Linked data shape: (40, 18203)\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Linked data shape after handling missing values: (40, 18203)\n",
      "For the feature 'Chronic_kidney_disease', the least common label is '0.0' with 10 occurrences. This represents 25.00% of the dataset.\n",
      "The distribution of the feature 'Chronic_kidney_disease' in this dataset is fine.\n",
      "\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Linked data saved to ../../output/preprocess/Chronic_kidney_disease/GSE142153.csv\n"
     ]
    }
   ],
   "source": [
    "# 1. Normalize gene symbols in the gene expression data\n",
    "try:\n",
    "    gene_data = pd.read_csv(out_gene_data_file, index_col=0)\n",
    "    print(f\"Loaded gene data shape: {gene_data.shape}\")\n",
    "    \n",
    "    # Apply normalization\n",
    "    gene_data = normalize_gene_symbols_in_index(gene_data)\n",
    "    print(f\"Normalized gene data shape: {gene_data.shape}\")\n",
    "    \n",
    "    # Save the normalized gene data\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",
    "    is_gene_available = True\n",
    "except Exception as e:\n",
    "    print(f\"Error normalizing gene data: {e}\")\n",
    "    is_gene_available = False\n",
    "\n",
    "# 2. Load clinical data that was already processed and saved\n",
    "try:\n",
    "    clinical_data = pd.read_csv(out_clinical_data_file, index_col=0)\n",
    "    print(f\"Loaded clinical data shape: {clinical_data.shape}\")\n",
    "    is_trait_available = True\n",
    "except Exception as e:\n",
    "    print(f\"Error loading clinical data: {e}\")\n",
    "    is_trait_available = False\n",
    "\n",
    "# 3. Link clinical and genetic data if both are available\n",
    "if is_trait_available and is_gene_available:\n",
    "    try:\n",
    "        # Link the clinical and genetic data\n",
    "        linked_data = geo_link_clinical_genetic_data(clinical_data, gene_data)\n",
    "        print(f\"Linked data shape: {linked_data.shape}\")\n",
    "        \n",
    "        # Handle missing values\n",
    "        linked_data = handle_missing_values(linked_data, trait)\n",
    "        print(f\"Linked data shape after handling missing values: {linked_data.shape}\")\n",
    "        \n",
    "        # Check for bias in trait and demographic features\n",
    "        is_biased, linked_data = judge_and_remove_biased_features(linked_data, trait)\n",
    "        \n",
    "        # Validate the data quality and save cohort info\n",
    "        note = \"Dataset contains gene expression data from peripheral blood of healthy controls and patients with diabetic nephropathy and ESRD.\"\n",
    "        is_usable = validate_and_save_cohort_info(\n",
    "            is_final=True,\n",
    "            cohort=cohort,\n",
    "            info_path=json_path,\n",
    "            is_gene_available=is_gene_available,\n",
    "            is_trait_available=is_trait_available,\n",
    "            is_biased=is_biased,\n",
    "            df=linked_data,\n",
    "            note=note\n",
    "        )\n",
    "        \n",
    "        # Save the linked data if it's usable\n",
    "        if is_usable:\n",
    "            os.makedirs(os.path.dirname(out_data_file), exist_ok=True)\n",
    "            linked_data.to_csv(out_data_file)\n",
    "            print(f\"Linked data saved to {out_data_file}\")\n",
    "        else:\n",
    "            print(\"Data not usable for the trait study - not saving final linked data.\")\n",
    "    except Exception as e:\n",
    "        print(f\"Error linking or processing data: {e}\")\n",
    "        validate_and_save_cohort_info(\n",
    "            is_final=True,\n",
    "            cohort=cohort,\n",
    "            info_path=json_path,\n",
    "            is_gene_available=is_gene_available,\n",
    "            is_trait_available=is_trait_available,\n",
    "            is_biased=True,  # Assume biased if there's an error\n",
    "            df=pd.DataFrame(),  # Empty dataframe for metadata\n",
    "            note=f\"Error in data processing: {str(e)}\"\n",
    "        )\n",
    "else:\n",
    "    # We can't proceed with linking if either trait or gene data is missing\n",
    "    print(\"Cannot proceed with data linking due to missing trait or gene data.\")\n",
    "    validate_and_save_cohort_info(\n",
    "        is_final=True,\n",
    "        cohort=cohort,\n",
    "        info_path=json_path,\n",
    "        is_gene_available=is_gene_available,\n",
    "        is_trait_available=is_trait_available,\n",
    "        is_biased=True,  # Data is unusable if we're missing components\n",
    "        df=pd.DataFrame(),  # Empty dataframe for metadata\n",
    "        note=\"Missing essential data components for linking (trait data or gene expression data).\"\n",
    "    )"
   ]
  }
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