DCM_analysis.ipynb

{
  "nbformat": 4,
  "nbformat_minor": 5,
  "metadata": {
    "kernelspec": {
      "display_name": "Python 3 (ipykernel)",
      "language": "python",
      "name": "python3"
    },
    "language_info": {
      "codemirror_mode": {
        "name": "ipython",
        "version": 3
      },
      "file_extension": ".py",
      "mimetype": "text/x-python",
      "name": "python",
      "nbconvert_exporter": "python",
      "pygments_lexer": "ipython3",
      "version": "3.9.2"
    },
    "colab": {
      "name": "DCM_analysis.ipynb",
      "provenance": [],
      "include_colab_link": true
    }
  },
  "cells": [
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "view-in-github",
        "colab_type": "text"
      },
      "source": [
        "<a href=\"https://colab.research.google.com/github/louadi/NEASE-tutorials/blob/main/DCM_analysis.ipynb\" target=\"_parent\"><img src=\"https://colab.research.google.com/assets/colab-badge.svg\" alt=\"Open In Colab\"/></a>"
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "rf9sJ1rj0ttM"
      },
      "source": [
        "!pip install nease"
      ],
      "id": "rf9sJ1rj0ttM",
      "execution_count": null,
      "outputs": []
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "TQEthjOa1_Do"
      },
      "source": [
        " If you run this on google colab all you need to do is to upload your table containing list of events\n"
      ],
      "id": "TQEthjOa1_Do"
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "cf1NpVu81-FM"
      },
      "source": [
        ""
      ],
      "id": "cf1NpVu81-FM"
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "94b20cf3-be2b-4306-9010-9b94bea2d492"
      },
      "source": [
        "#import nease\n",
        "import nease\n",
        "\n",
        "import pandas as pd\n"
      ],
      "id": "94b20cf3-be2b-4306-9010-9b94bea2d492",
      "execution_count": 1,
      "outputs": []
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "276955e4-c2f8-4ec3-8515-84b8d324f477"
      },
      "source": [
        "### Input of NEASE"
      ],
      "id": "276955e4-c2f8-4ec3-8515-84b8d324f477"
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "c3b24f77-2272-4315-8d32-96ec137f8fa6",
        "outputId": "a0068fbc-dbac-493f-e2f2-6ab293f75e54",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 419
        }
      },
      "source": [
        "# RNA-Seq data processed fron:  https://doi.org/10.1186/S13059-017-1286-Z\n",
        "# Additional file 4 from the paper: Differential exon usage between DCM patients and controls.\n",
        "\n",
        "table_dcm=pd.read_json('dcm.json')\n",
        "table_dcm"
      ],
      "id": "c3b24f77-2272-4315-8d32-96ec137f8fa6",
      "execution_count": 2,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Gene stable ID</th>\n",
              "      <th>new_start</th>\n",
              "      <th>new_end</th>\n",
              "      <th>beta</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>ENSG00000154263</td>\n",
              "      <td>69314431</td>\n",
              "      <td>69315425</td>\n",
              "      <td>-0.105828</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>ENSG00000154265</td>\n",
              "      <td>69314431</td>\n",
              "      <td>69315425</td>\n",
              "      <td>-0.105828</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>ENSG00000005471</td>\n",
              "      <td>87411893</td>\n",
              "      <td>87412033</td>\n",
              "      <td>0.135682</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>ENSG00000197150</td>\n",
              "      <td>151031241</td>\n",
              "      <td>151031291</td>\n",
              "      <td>0.150763</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>ENSG00000124574</td>\n",
              "      <td>43431751</td>\n",
              "      <td>43432141</td>\n",
              "      <td>0.107582</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>...</th>\n",
              "      <td>...</td>\n",
              "      <td>...</td>\n",
              "      <td>...</td>\n",
              "      <td>...</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1022</th>\n",
              "      <td>ENSG00000162086</td>\n",
              "      <td>3313049</td>\n",
              "      <td>3313175</td>\n",
              "      <td>0.131544</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1023</th>\n",
              "      <td>ENSG00000198482</td>\n",
              "      <td>52547512</td>\n",
              "      <td>52547638</td>\n",
              "      <td>-0.104090</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1024</th>\n",
              "      <td>ENSG00000176371</td>\n",
              "      <td>84616309</td>\n",
              "      <td>84616614</td>\n",
              "      <td>-0.246228</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1025</th>\n",
              "      <td>ENSG00000140987</td>\n",
              "      <td>3397745</td>\n",
              "      <td>3397787</td>\n",
              "      <td>-0.161007</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1026</th>\n",
              "      <td>ENSG00000070476</td>\n",
              "      <td>126461083</td>\n",
              "      <td>126461534</td>\n",
              "      <td>0.219728</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "<p>1027 rows × 4 columns</p>\n",
              "</div>"
            ],
            "text/plain": [
              "       Gene stable ID  new_start    new_end      beta\n",
              "0     ENSG00000154263   69314431   69315425 -0.105828\n",
              "1     ENSG00000154265   69314431   69315425 -0.105828\n",
              "2     ENSG00000005471   87411893   87412033  0.135682\n",
              "3     ENSG00000197150  151031241  151031291  0.150763\n",
              "4     ENSG00000124574   43431751   43432141  0.107582\n",
              "...               ...        ...        ...       ...\n",
              "1022  ENSG00000162086    3313049    3313175  0.131544\n",
              "1023  ENSG00000198482   52547512   52547638 -0.104090\n",
              "1024  ENSG00000176371   84616309   84616614 -0.246228\n",
              "1025  ENSG00000140987    3397745    3397787 -0.161007\n",
              "1026  ENSG00000070476  126461083  126461534  0.219728\n",
              "\n",
              "[1027 rows x 4 columns]"
            ]
          },
          "metadata": {},
          "execution_count": 2
        }
      ]
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "610b125e-d990-40a4-b87c-c6b7bba045d0"
      },
      "source": [
        "## Run NEASE\n"
      ],
      "id": "610b125e-d990-40a4-b87c-c6b7bba045d0"
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "18a5aafb-e074-48ed-bfd7-766ce2c428df",
        "outputId": "c075e72c-7ade-486c-aae3-df858a3d870b",
        "colab": {
          "base_uri": "https://localhost:8080/"
        }
      },
      "source": [
        "# Run nease with standard input.\n",
        "events=nease.run(table_dcm, organism='Human')\n"
      ],
      "id": "18a5aafb-e074-48ed-bfd7-766ce2c428df",
      "execution_count": 3,
      "outputs": [
        {
          "output_type": "stream",
          "name": "stdout",
          "text": [
            "\n",
            "You selected to remove all exons that are predicted to disturb the ORF or known to result in a non-coding gene.\n",
            "If you would like to change this option and include all exons, please change the parameter remove_non_in_frame to False. \n",
            "\n",
            "47 Exons out of 1027 were removed.\n",
            "\n",
            "\t\tData Summary\n",
            "**************************************************\n",
            "221 protein domains are affected by AS.\n",
            "\n",
            "14 linear motifs are affected by AS.\n",
            "29 interacting resiude are affected by AS.\n",
            "\n",
            "111 of the affected domains/motifs have known interactions.\n",
            "1028 protein interactions/binding affected.\n",
            "\n",
            "**************************************************\n",
            "Running enrichment analysis...\n",
            "NEASE enrichment done.\n"
          ]
        }
      ]
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "98081550-8868-43de-91f3-5ace63685cf5"
      },
      "source": [
        "### Classic gene enrichment"
      ],
      "id": "98081550-8868-43de-91f3-5ace63685cf5"
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "60561056-5400-428d-ad75-762deddd2425",
        "outputId": "01520d8e-3a05-4673-8ad9-46275808c595",
        "colab": {
          "base_uri": "https://localhost:8080/"
        }
      },
      "source": [
        "# This is an enrichement at gene level: all (diff) spliced genes.\n",
        "# The function use the library gseapy and need gseapy_databases parameter \n",
        "# let first check what libraries are available on gseapy for Human\n",
        "\n",
        "import gseapy as gp\n",
        "Human = gp.get_library_name(organism='Human')\n",
        "Human[:10]"
      ],
      "id": "60561056-5400-428d-ad75-762deddd2425",
      "execution_count": 4,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/plain": [
              "['ARCHS4_Cell-lines',\n",
              " 'ARCHS4_IDG_Coexp',\n",
              " 'ARCHS4_Kinases_Coexp',\n",
              " 'ARCHS4_TFs_Coexp',\n",
              " 'ARCHS4_Tissues',\n",
              " 'Achilles_fitness_decrease',\n",
              " 'Achilles_fitness_increase',\n",
              " 'Aging_Perturbations_from_GEO_down',\n",
              " 'Aging_Perturbations_from_GEO_up',\n",
              " 'Allen_Brain_Atlas_10x_scRNA_2021']"
            ]
          },
          "metadata": {},
          "execution_count": 4
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "6c133125-aaf1-4597-aef8-905083fd73cc",
        "outputId": "c66610aa-0070-49e8-8b4c-e995ba1cc2f7",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 512
        }
      },
      "source": [
        "# Run on KEGG gene set\n",
        "enr=events.classic_enrich(gseapy_databases=['KEGG_2019_Human'])\n",
        "enr.head(10)"
      ],
      "id": "6c133125-aaf1-4597-aef8-905083fd73cc",
      "execution_count": 5,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Gene_set</th>\n",
              "      <th>Term</th>\n",
              "      <th>Overlap</th>\n",
              "      <th>P-value</th>\n",
              "      <th>Adjusted P-value</th>\n",
              "      <th>Old P-value</th>\n",
              "      <th>Old Adjusted P-value</th>\n",
              "      <th>Odds Ratio</th>\n",
              "      <th>Combined Score</th>\n",
              "      <th>Genes</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>KEGG_2019_Human</td>\n",
              "      <td>Oxytocin signaling pathway</td>\n",
              "      <td>20/153</td>\n",
              "      <td>0.000001</td>\n",
              "      <td>0.000253</td>\n",
              "      <td>0</td>\n",
              "      <td>0</td>\n",
              "      <td>3.960521</td>\n",
              "      <td>54.327432</td>\n",
              "      <td>CAMK2B;CAMK2D;CAMK1D;PLA2G4B;CACNA2D3;PRKAG2;NFATC1;CACNA1C;ADCY1;ADCY6;CAMKK2;GNAO1;CACNB2;RCAN1;MYL6;PLCB4;MAPK1;PPP1R12B;PLCB1;PRKACB</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>KEGG_2019_Human</td>\n",
              "      <td>Adrenergic signaling in cardiomyocytes</td>\n",
              "      <td>19/145</td>\n",
              "      <td>0.000002</td>\n",
              "      <td>0.000253</td>\n",
              "      <td>0</td>\n",
              "      <td>0</td>\n",
              "      <td>3.967512</td>\n",
              "      <td>52.134866</td>\n",
              "      <td>CAMK2B;CAMK2D;CACNA2D3;CREM;ATP2B4;CACNA1C;PPP2R5C;ADCY1;ADRA1A;ADCY6;CACNB2;PLCB4;CREB3L2;AKT1;MAPK1;PLCB1;PRKACB;CREB5;RAPGEF4</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>KEGG_2019_Human</td>\n",
              "      <td>cAMP signaling pathway</td>\n",
              "      <td>21/212</td>\n",
              "      <td>0.000047</td>\n",
              "      <td>0.003472</td>\n",
              "      <td>0</td>\n",
              "      <td>0</td>\n",
              "      <td>2.890941</td>\n",
              "      <td>28.788422</td>\n",
              "      <td>CHRM2;CAMK2B;GABBR1;CAMK2D;BDNF;PTCH1;PDE4D;PTGER3;PDE4C;ATP2B4;NFATC1;ADCY1;CACNA1C;ADCY6;CREB3L2;AKT1;PLCE1;MAPK1;PRKACB;RAPGEF4;CREB5</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>KEGG_2019_Human</td>\n",
              "      <td>Aldosterone synthesis and secretion</td>\n",
              "      <td>13/98</td>\n",
              "      <td>0.000070</td>\n",
              "      <td>0.003472</td>\n",
              "      <td>0</td>\n",
              "      <td>0</td>\n",
              "      <td>3.999631</td>\n",
              "      <td>38.236501</td>\n",
              "      <td>CAMK2B;SCARB1;CAMK2D;CAMK1D;ATP2B4;CACNA1C;ADCY1;ADCY6;PLCB4;CREB3L2;PLCB1;PRKACB;CREB5</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>KEGG_2019_Human</td>\n",
              "      <td>Cholinergic synapse</td>\n",
              "      <td>14/112</td>\n",
              "      <td>0.000073</td>\n",
              "      <td>0.003472</td>\n",
              "      <td>0</td>\n",
              "      <td>0</td>\n",
              "      <td>3.738486</td>\n",
              "      <td>35.614117</td>\n",
              "      <td>CHRM2;CAMK2B;CAMK2D;CACNA1C;ADCY1;ADCY6;GNAO1;PLCB4;CREB3L2;AKT1;MAPK1;PLCB1;PRKACB;CREB5</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>5</th>\n",
              "      <td>KEGG_2019_Human</td>\n",
              "      <td>Insulin secretion</td>\n",
              "      <td>12/86</td>\n",
              "      <td>0.000081</td>\n",
              "      <td>0.003472</td>\n",
              "      <td>0</td>\n",
              "      <td>0</td>\n",
              "      <td>4.237425</td>\n",
              "      <td>39.934022</td>\n",
              "      <td>CAMK2B;CAMK2D;PLCB4;CREB3L2;KCNMA1;ADCY1;CACNA1C;PLCB1;PRKACB;ADCY6;RAPGEF4;CREB5</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>6</th>\n",
              "      <td>KEGG_2019_Human</td>\n",
              "      <td>Morphine addiction</td>\n",
              "      <td>12/91</td>\n",
              "      <td>0.000141</td>\n",
              "      <td>0.005183</td>\n",
              "      <td>0</td>\n",
              "      <td>0</td>\n",
              "      <td>3.968199</td>\n",
              "      <td>35.195814</td>\n",
              "      <td>GNAO1;GABBR1;PDE1C;GRK4;PDE4D;PDE1A;PDE4C;ARRB1;ADCY1;GABRE;PRKACB;ADCY6</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>7</th>\n",
              "      <td>KEGG_2019_Human</td>\n",
              "      <td>Dilated cardiomyopathy (DCM)</td>\n",
              "      <td>11/91</td>\n",
              "      <td>0.000566</td>\n",
              "      <td>0.015902</td>\n",
              "      <td>0</td>\n",
              "      <td>0</td>\n",
              "      <td>3.586973</td>\n",
              "      <td>26.820198</td>\n",
              "      <td>CACNB2;ITGB4;ITGA1;CACNA2D3;DMD;ADCY1;CACNA1C;IGF1;PRKACB;ADCY6;TTN</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>8</th>\n",
              "      <td>KEGG_2019_Human</td>\n",
              "      <td>Parathyroid hormone synthesis, secretion and action</td>\n",
              "      <td>12/106</td>\n",
              "      <td>0.000590</td>\n",
              "      <td>0.015902</td>\n",
              "      <td>0</td>\n",
              "      <td>0</td>\n",
              "      <td>3.332367</td>\n",
              "      <td>24.775598</td>\n",
              "      <td>PLCB4;PDE4D;CREB3L2;PDE4C;MAPK1;ARRB1;ADCY1;PLCB1;PRKACB;ADCY6;FGFR1;CREB5</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>9</th>\n",
              "      <td>KEGG_2019_Human</td>\n",
              "      <td>Cortisol synthesis and secretion</td>\n",
              "      <td>9/65</td>\n",
              "      <td>0.000656</td>\n",
              "      <td>0.015902</td>\n",
              "      <td>0</td>\n",
              "      <td>0</td>\n",
              "      <td>4.186422</td>\n",
              "      <td>30.683743</td>\n",
              "      <td>SCARB1;PLCB4;CREB3L2;ADCY1;CACNA1C;PLCB1;PRKACB;ADCY6;CREB5</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "          Gene_set  ...                                                                                                                                     Genes\n",
              "0  KEGG_2019_Human  ...  CAMK2B;CAMK2D;CAMK1D;PLA2G4B;CACNA2D3;PRKAG2;NFATC1;CACNA1C;ADCY1;ADCY6;CAMKK2;GNAO1;CACNB2;RCAN1;MYL6;PLCB4;MAPK1;PPP1R12B;PLCB1;PRKACB\n",
              "1  KEGG_2019_Human  ...          CAMK2B;CAMK2D;CACNA2D3;CREM;ATP2B4;CACNA1C;PPP2R5C;ADCY1;ADRA1A;ADCY6;CACNB2;PLCB4;CREB3L2;AKT1;MAPK1;PLCB1;PRKACB;CREB5;RAPGEF4\n",
              "2  KEGG_2019_Human  ...  CHRM2;CAMK2B;GABBR1;CAMK2D;BDNF;PTCH1;PDE4D;PTGER3;PDE4C;ATP2B4;NFATC1;ADCY1;CACNA1C;ADCY6;CREB3L2;AKT1;PLCE1;MAPK1;PRKACB;RAPGEF4;CREB5\n",
              "3  KEGG_2019_Human  ...                                                   CAMK2B;SCARB1;CAMK2D;CAMK1D;ATP2B4;CACNA1C;ADCY1;ADCY6;PLCB4;CREB3L2;PLCB1;PRKACB;CREB5\n",
              "4  KEGG_2019_Human  ...                                                 CHRM2;CAMK2B;CAMK2D;CACNA1C;ADCY1;ADCY6;GNAO1;PLCB4;CREB3L2;AKT1;MAPK1;PLCB1;PRKACB;CREB5\n",
              "5  KEGG_2019_Human  ...                                                         CAMK2B;CAMK2D;PLCB4;CREB3L2;KCNMA1;ADCY1;CACNA1C;PLCB1;PRKACB;ADCY6;RAPGEF4;CREB5\n",
              "6  KEGG_2019_Human  ...                                                                  GNAO1;GABBR1;PDE1C;GRK4;PDE4D;PDE1A;PDE4C;ARRB1;ADCY1;GABRE;PRKACB;ADCY6\n",
              "7  KEGG_2019_Human  ...                                                                       CACNB2;ITGB4;ITGA1;CACNA2D3;DMD;ADCY1;CACNA1C;IGF1;PRKACB;ADCY6;TTN\n",
              "8  KEGG_2019_Human  ...                                                                PLCB4;PDE4D;CREB3L2;PDE4C;MAPK1;ARRB1;ADCY1;PLCB1;PRKACB;ADCY6;FGFR1;CREB5\n",
              "9  KEGG_2019_Human  ...                                                                               SCARB1;PLCB4;CREB3L2;ADCY1;CACNA1C;PLCB1;PRKACB;ADCY6;CREB5\n",
              "\n",
              "[10 rows x 10 columns]"
            ]
          },
          "metadata": {},
          "execution_count": 5
        }
      ]
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "0b37b486-db0c-46a5-936d-3e33c421ffb0"
      },
      "source": [
        "### NEASE analysis\n"
      ],
      "id": "0b37b486-db0c-46a5-936d-3e33c421ffb0"
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "4b38c73c-801e-45ba-8eff-4938940bd1db",
        "outputId": "7b26b0ea-f095-4158-ae5c-654b479909c9",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 427
        }
      },
      "source": [
        "# get stats of the data\n",
        "events.get_stats()\n"
      ],
      "id": "4b38c73c-801e-45ba-8eff-4938940bd1db",
      "execution_count": 6,
      "outputs": [
        {
          "output_type": "display_data",
          "data": {
            "image/png": "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\n",
            "text/plain": [
              "<Figure size 864x504 with 2 Axes>"
            ]
          },
          "metadata": {
            "needs_background": "light"
          }
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "d32f512c-c17f-4ee2-a550-ab4a3aab0cf6",
        "outputId": "76a6b66a-64c4-40a2-c5c8-cddde94a1fa3",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 359
        }
      },
      "source": [
        "# Get list of all protein domais affected by AS.\n",
        "# A link to DIGGER database for lost/gained domain and their binding.\n",
        "\n",
        "domains=events.get_domains()\n",
        "domains.head(10)"
      ],
      "id": "d32f512c-c17f-4ee2-a550-ab4a3aab0cf6",
      "execution_count": 7,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Gene name</th>\n",
              "      <th>NCBI gene ID</th>\n",
              "      <th>Gene stable ID</th>\n",
              "      <th>Exon stable ID</th>\n",
              "      <th>Pfam ID</th>\n",
              "      <th>dPSI</th>\n",
              "      <th>Interacting domain</th>\n",
              "      <th>Interaction type</th>\n",
              "      <th>Visualization link</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>ZC3HAV1</td>\n",
              "      <td>56829</td>\n",
              "      <td>ENSG00000105939</td>\n",
              "      <td>ENSE00001939369</td>\n",
              "      <td>PF02825</td>\n",
              "      <td>-0.675285</td>\n",
              "      <td>True</td>\n",
              "      <td>DDI</td>\n",
              "      <td>https://exbio.wzw.tum.de/digger/ID/exon/ENSE00001939369</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>PLXNA4</td>\n",
              "      <td>91584</td>\n",
              "      <td>ENSG00000221866</td>\n",
              "      <td>ENSE00001477854</td>\n",
              "      <td>PF01403</td>\n",
              "      <td>-0.579010</td>\n",
              "      <td>False</td>\n",
              "      <td>None</td>\n",
              "      <td></td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>ALS2</td>\n",
              "      <td>57679</td>\n",
              "      <td>ENSG00000003393</td>\n",
              "      <td>ENSE00001844466</td>\n",
              "      <td>PF00415</td>\n",
              "      <td>-0.510964</td>\n",
              "      <td>True</td>\n",
              "      <td>DDI</td>\n",
              "      <td>https://exbio.wzw.tum.de/digger/ID/exon/ENSE00001844466</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>XRN1</td>\n",
              "      <td>54464</td>\n",
              "      <td>ENSG00000114127</td>\n",
              "      <td>ENSE00001810566</td>\n",
              "      <td>PF17846</td>\n",
              "      <td>-0.479034</td>\n",
              "      <td>False</td>\n",
              "      <td>None</td>\n",
              "      <td></td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>ZNF655</td>\n",
              "      <td>79027</td>\n",
              "      <td>ENSG00000197343</td>\n",
              "      <td>ENSE00003602592</td>\n",
              "      <td>PF01352</td>\n",
              "      <td>-0.458799</td>\n",
              "      <td>False</td>\n",
              "      <td>None</td>\n",
              "      <td></td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>5</th>\n",
              "      <td>NFASC</td>\n",
              "      <td>23114</td>\n",
              "      <td>ENSG00000163531</td>\n",
              "      <td>ENSE00001556394</td>\n",
              "      <td>PF07679</td>\n",
              "      <td>-0.433055</td>\n",
              "      <td>False</td>\n",
              "      <td>None</td>\n",
              "      <td></td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>6</th>\n",
              "      <td>MCM9</td>\n",
              "      <td>254394</td>\n",
              "      <td>ENSG00000111877</td>\n",
              "      <td>ENSE00001356493</td>\n",
              "      <td>PF00493</td>\n",
              "      <td>-0.428684</td>\n",
              "      <td>True</td>\n",
              "      <td>DDI</td>\n",
              "      <td>https://exbio.wzw.tum.de/digger/ID/exon/ENSE00001356493</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>7</th>\n",
              "      <td>DENND1B</td>\n",
              "      <td>163486</td>\n",
              "      <td>ENSG00000213047</td>\n",
              "      <td>ENSE00001196169</td>\n",
              "      <td>PF03455</td>\n",
              "      <td>-0.425418</td>\n",
              "      <td>False</td>\n",
              "      <td>None</td>\n",
              "      <td></td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>8</th>\n",
              "      <td>ALG13</td>\n",
              "      <td>79868</td>\n",
              "      <td>ENSG00000101901</td>\n",
              "      <td>ENSE00003760070</td>\n",
              "      <td>PF04101</td>\n",
              "      <td>-0.411372</td>\n",
              "      <td>False</td>\n",
              "      <td>None</td>\n",
              "      <td></td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>9</th>\n",
              "      <td>NUP98</td>\n",
              "      <td>4928</td>\n",
              "      <td>ENSG00000110713</td>\n",
              "      <td>ENSE00002163402</td>\n",
              "      <td>PF04096</td>\n",
              "      <td>-0.410950</td>\n",
              "      <td>True</td>\n",
              "      <td>DDI</td>\n",
              "      <td>https://exbio.wzw.tum.de/digger/ID/exon/ENSE00002163402</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "  Gene name  ...                                       Visualization link\n",
              "0   ZC3HAV1  ...  https://exbio.wzw.tum.de/digger/ID/exon/ENSE00001939369\n",
              "1    PLXNA4  ...                                                         \n",
              "2      ALS2  ...  https://exbio.wzw.tum.de/digger/ID/exon/ENSE00001844466\n",
              "3      XRN1  ...                                                         \n",
              "4    ZNF655  ...                                                         \n",
              "5     NFASC  ...                                                         \n",
              "6      MCM9  ...  https://exbio.wzw.tum.de/digger/ID/exon/ENSE00001356493\n",
              "7   DENND1B  ...                                                         \n",
              "8     ALG13  ...                                                         \n",
              "9     NUP98  ...  https://exbio.wzw.tum.de/digger/ID/exon/ENSE00002163402\n",
              "\n",
              "[10 rows x 9 columns]"
            ]
          },
          "metadata": {},
          "execution_count": 7
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "75cd058b-29f1-441a-add1-c94ca1cd6592",
        "outputId": "a1fbab28-cc20-45e1-d708-1137d26e959e",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 700
        }
      },
      "source": [
        "# get the affected linear motifs\n",
        "events.get_elm()"
      ],
      "id": "75cd058b-29f1-441a-add1-c94ca1cd6592",
      "execution_count": 8,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Gene name</th>\n",
              "      <th>entrezgene</th>\n",
              "      <th>Gene stable ID</th>\n",
              "      <th>ELMIdentifier</th>\n",
              "      <th>dPSI</th>\n",
              "      <th>ELM link</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>BCL2L11</td>\n",
              "      <td>10018</td>\n",
              "      <td>ENSG00000153094</td>\n",
              "      <td>LIG_Dynein_DLC8_1</td>\n",
              "      <td>-0.106673</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_Dynein_DLC8_1</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>BRCA1</td>\n",
              "      <td>672</td>\n",
              "      <td>ENSG00000012048</td>\n",
              "      <td>MOD_PKB_1</td>\n",
              "      <td>0.106918</td>\n",
              "      <td>http://elm.eu.org/elms/MOD_PKB_1</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>BRCA1</td>\n",
              "      <td>672</td>\n",
              "      <td>ENSG00000012048</td>\n",
              "      <td>TRG_NLS_MonoExtN_4</td>\n",
              "      <td>0.106918</td>\n",
              "      <td>http://elm.eu.org/elms/TRG_NLS_MonoExtN_4</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>BRCA1</td>\n",
              "      <td>672</td>\n",
              "      <td>ENSG00000012048</td>\n",
              "      <td>TRG_NLS_MonoExtC_3</td>\n",
              "      <td>0.106918</td>\n",
              "      <td>http://elm.eu.org/elms/TRG_NLS_MonoExtC_3</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>BRCA1</td>\n",
              "      <td>672</td>\n",
              "      <td>ENSG00000012048</td>\n",
              "      <td>TRG_NLS_MonoCore_2</td>\n",
              "      <td>0.106918</td>\n",
              "      <td>http://elm.eu.org/elms/TRG_NLS_MonoCore_2</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>5</th>\n",
              "      <td>BRCA1</td>\n",
              "      <td>672</td>\n",
              "      <td>ENSG00000012048</td>\n",
              "      <td>DOC_PP1_RVXF_1</td>\n",
              "      <td>0.106918</td>\n",
              "      <td>http://elm.eu.org/elms/DOC_PP1_RVXF_1</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>6</th>\n",
              "      <td>ZHX1</td>\n",
              "      <td>11244</td>\n",
              "      <td>ENSG00000165156</td>\n",
              "      <td>LIG_SUMO_SIM_par_1</td>\n",
              "      <td>0.159270</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_SUMO_SIM_par_1</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>7</th>\n",
              "      <td>ELK4</td>\n",
              "      <td>2005</td>\n",
              "      <td>ENSG00000158711</td>\n",
              "      <td>DOC_MAPK_FxFP_2</td>\n",
              "      <td>-0.141280</td>\n",
              "      <td>http://elm.eu.org/elms/DOC_MAPK_FxFP_2</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>8</th>\n",
              "      <td>ELK4</td>\n",
              "      <td>2005</td>\n",
              "      <td>ENSG00000158711</td>\n",
              "      <td>MOD_ProDKin_1</td>\n",
              "      <td>-0.141280</td>\n",
              "      <td>http://elm.eu.org/elms/MOD_ProDKin_1</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>9</th>\n",
              "      <td>ELK4</td>\n",
              "      <td>2005</td>\n",
              "      <td>ENSG00000158711</td>\n",
              "      <td>DOC_MAPK_gen_1</td>\n",
              "      <td>-0.141280</td>\n",
              "      <td>http://elm.eu.org/elms/DOC_MAPK_gen_1</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>10</th>\n",
              "      <td>MAF</td>\n",
              "      <td>4094</td>\n",
              "      <td>ENSG00000178573</td>\n",
              "      <td>LIG_KEPE_2</td>\n",
              "      <td>0.107880</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_KEPE_2</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>11</th>\n",
              "      <td>NFATC1</td>\n",
              "      <td>4772</td>\n",
              "      <td>ENSG00000131196</td>\n",
              "      <td>LIG_KEPE_2</td>\n",
              "      <td>-0.201043</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_KEPE_2</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>12</th>\n",
              "      <td>PML</td>\n",
              "      <td>5371</td>\n",
              "      <td>ENSG00000140464</td>\n",
              "      <td>LIG_SUMO_SIM_par_1</td>\n",
              "      <td>-0.127493</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_SUMO_SIM_par_1</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>13</th>\n",
              "      <td>PML</td>\n",
              "      <td>5371</td>\n",
              "      <td>ENSG00000140464</td>\n",
              "      <td>LIG_SUMO_SIM_anti_2</td>\n",
              "      <td>-0.127493</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_SUMO_SIM_anti_2</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>14</th>\n",
              "      <td>PML</td>\n",
              "      <td>5371</td>\n",
              "      <td>ENSG00000140464</td>\n",
              "      <td>LIG_SUMO_SIM_par_1</td>\n",
              "      <td>-0.189905</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_SUMO_SIM_par_1</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>15</th>\n",
              "      <td>PML</td>\n",
              "      <td>5371</td>\n",
              "      <td>ENSG00000140464</td>\n",
              "      <td>LIG_SUMO_SIM_anti_2</td>\n",
              "      <td>-0.189905</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_SUMO_SIM_anti_2</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>16</th>\n",
              "      <td>PML</td>\n",
              "      <td>5371</td>\n",
              "      <td>ENSG00000140464</td>\n",
              "      <td>DOC_WW_Pin1_4</td>\n",
              "      <td>-0.189905</td>\n",
              "      <td>http://elm.eu.org/elms/DOC_WW_Pin1_4</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>17</th>\n",
              "      <td>PML</td>\n",
              "      <td>5371</td>\n",
              "      <td>ENSG00000140464</td>\n",
              "      <td>LIG_SUMO_SIM_par_1</td>\n",
              "      <td>-0.142303</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_SUMO_SIM_par_1</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>18</th>\n",
              "      <td>PML</td>\n",
              "      <td>5371</td>\n",
              "      <td>ENSG00000140464</td>\n",
              "      <td>LIG_SUMO_SIM_anti_2</td>\n",
              "      <td>-0.142303</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_SUMO_SIM_anti_2</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>19</th>\n",
              "      <td>PML</td>\n",
              "      <td>5371</td>\n",
              "      <td>ENSG00000140464</td>\n",
              "      <td>DOC_WW_Pin1_4</td>\n",
              "      <td>-0.142303</td>\n",
              "      <td>http://elm.eu.org/elms/DOC_WW_Pin1_4</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>20</th>\n",
              "      <td>PRDM2</td>\n",
              "      <td>7799</td>\n",
              "      <td>ENSG00000116731</td>\n",
              "      <td>LIG_Rb_LxCxE_1</td>\n",
              "      <td>0.254461</td>\n",
              "      <td>http://elm.eu.org/elms/LIG_Rb_LxCxE_1</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "   Gene name entrezgene  ...      dPSI                                    ELM link\n",
              "0    BCL2L11      10018  ... -0.106673    http://elm.eu.org/elms/LIG_Dynein_DLC8_1\n",
              "1      BRCA1        672  ...  0.106918            http://elm.eu.org/elms/MOD_PKB_1\n",
              "2      BRCA1        672  ...  0.106918   http://elm.eu.org/elms/TRG_NLS_MonoExtN_4\n",
              "3      BRCA1        672  ...  0.106918   http://elm.eu.org/elms/TRG_NLS_MonoExtC_3\n",
              "4      BRCA1        672  ...  0.106918   http://elm.eu.org/elms/TRG_NLS_MonoCore_2\n",
              "5      BRCA1        672  ...  0.106918       http://elm.eu.org/elms/DOC_PP1_RVXF_1\n",
              "6       ZHX1      11244  ...  0.159270   http://elm.eu.org/elms/LIG_SUMO_SIM_par_1\n",
              "7       ELK4       2005  ... -0.141280      http://elm.eu.org/elms/DOC_MAPK_FxFP_2\n",
              "8       ELK4       2005  ... -0.141280        http://elm.eu.org/elms/MOD_ProDKin_1\n",
              "9       ELK4       2005  ... -0.141280       http://elm.eu.org/elms/DOC_MAPK_gen_1\n",
              "10       MAF       4094  ...  0.107880           http://elm.eu.org/elms/LIG_KEPE_2\n",
              "11    NFATC1       4772  ... -0.201043           http://elm.eu.org/elms/LIG_KEPE_2\n",
              "12       PML       5371  ... -0.127493   http://elm.eu.org/elms/LIG_SUMO_SIM_par_1\n",
              "13       PML       5371  ... -0.127493  http://elm.eu.org/elms/LIG_SUMO_SIM_anti_2\n",
              "14       PML       5371  ... -0.189905   http://elm.eu.org/elms/LIG_SUMO_SIM_par_1\n",
              "15       PML       5371  ... -0.189905  http://elm.eu.org/elms/LIG_SUMO_SIM_anti_2\n",
              "16       PML       5371  ... -0.189905        http://elm.eu.org/elms/DOC_WW_Pin1_4\n",
              "17       PML       5371  ... -0.142303   http://elm.eu.org/elms/LIG_SUMO_SIM_par_1\n",
              "18       PML       5371  ... -0.142303  http://elm.eu.org/elms/LIG_SUMO_SIM_anti_2\n",
              "19       PML       5371  ... -0.142303        http://elm.eu.org/elms/DOC_WW_Pin1_4\n",
              "20     PRDM2       7799  ...  0.254461       http://elm.eu.org/elms/LIG_Rb_LxCxE_1\n",
              "\n",
              "[21 rows x 6 columns]"
            ]
          },
          "metadata": {},
          "execution_count": 8
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "c843f40c-7442-4fc9-b632-85d57dfdbfa4",
        "outputId": "2582ff6b-e41a-4476-cf39-81f79d08a16c",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 948
        }
      },
      "source": [
        "# get interacting residues affected by AS\n",
        "events.get_pdb()"
      ],
      "id": "c843f40c-7442-4fc9-b632-85d57dfdbfa4",
      "execution_count": 9,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Gene name</th>\n",
              "      <th>NCBI gene ID</th>\n",
              "      <th>Gene stable ID</th>\n",
              "      <th>Co-resolved interactions symbol</th>\n",
              "      <th>Co-resolved interactions</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>RRAGB</td>\n",
              "      <td>10325</td>\n",
              "      <td>ENSG00000083750</td>\n",
              "      <td>DEPDC5</td>\n",
              "      <td>9681</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>RALGPS1</td>\n",
              "      <td>9649</td>\n",
              "      <td>ENSG00000136828</td>\n",
              "      <td>RALGPS1</td>\n",
              "      <td>9649</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>BRCC3</td>\n",
              "      <td>79184</td>\n",
              "      <td>ENSG00000185515</td>\n",
              "      <td>BABAM2</td>\n",
              "      <td>9577</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>CNOT1</td>\n",
              "      <td>23019</td>\n",
              "      <td>ENSG00000125107</td>\n",
              "      <td>CNOT9</td>\n",
              "      <td>9125</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>LATS1</td>\n",
              "      <td>9113</td>\n",
              "      <td>ENSG00000131023</td>\n",
              "      <td>MOB1B,LATS1,MOB1A</td>\n",
              "      <td>92597,9113,55233</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>5</th>\n",
              "      <td>XIAP</td>\n",
              "      <td>331</td>\n",
              "      <td>ENSG00000101966</td>\n",
              "      <td>DIABLO,CASP9,CASP3,XIAP,TAB1</td>\n",
              "      <td>56616,842,836,331,10454</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>6</th>\n",
              "      <td>CNNM2</td>\n",
              "      <td>54805</td>\n",
              "      <td>ENSG00000148842</td>\n",
              "      <td>PTP4A1</td>\n",
              "      <td>7803</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>7</th>\n",
              "      <td>RWDD3</td>\n",
              "      <td>25950</td>\n",
              "      <td>ENSG00000122481</td>\n",
              "      <td>UBE2I</td>\n",
              "      <td>7329</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>8</th>\n",
              "      <td>ELK4</td>\n",
              "      <td>2005</td>\n",
              "      <td>ENSG00000158711</td>\n",
              "      <td>SRF</td>\n",
              "      <td>6722</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>9</th>\n",
              "      <td>SKP2</td>\n",
              "      <td>6502</td>\n",
              "      <td>ENSG00000145604</td>\n",
              "      <td>SKP1,CKS1B</td>\n",
              "      <td>6500,1163</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>10</th>\n",
              "      <td>FBXO44</td>\n",
              "      <td>93611</td>\n",
              "      <td>ENSG00000132879</td>\n",
              "      <td>SKP1</td>\n",
              "      <td>6500</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>11</th>\n",
              "      <td>CXCL12</td>\n",
              "      <td>6387</td>\n",
              "      <td>ENSG00000107562</td>\n",
              "      <td>CXCL12,CXCR4</td>\n",
              "      <td>6387,7852</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>12</th>\n",
              "      <td>PTGER3</td>\n",
              "      <td>5733</td>\n",
              "      <td>ENSG00000050628</td>\n",
              "      <td>PTGER3</td>\n",
              "      <td>5733</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>13</th>\n",
              "      <td>PPP2R5C</td>\n",
              "      <td>5527</td>\n",
              "      <td>ENSG00000078304</td>\n",
              "      <td>PPP2R1A</td>\n",
              "      <td>5518</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>14</th>\n",
              "      <td>CSAD</td>\n",
              "      <td>51380</td>\n",
              "      <td>ENSG00000139631</td>\n",
              "      <td>CSAD</td>\n",
              "      <td>51380</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>15</th>\n",
              "      <td>NUP98</td>\n",
              "      <td>4928</td>\n",
              "      <td>ENSG00000110713</td>\n",
              "      <td>NUP98</td>\n",
              "      <td>4928</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>16</th>\n",
              "      <td>NPR3</td>\n",
              "      <td>4883</td>\n",
              "      <td>ENSG00000113389</td>\n",
              "      <td>NPPA,NPPC,NPR3,NPPB</td>\n",
              "      <td>4878,4880,4883,4879</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>17</th>\n",
              "      <td>NCF4</td>\n",
              "      <td>4689</td>\n",
              "      <td>ENSG00000100365</td>\n",
              "      <td>NCF2</td>\n",
              "      <td>4688</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>18</th>\n",
              "      <td>RAP1GDS1</td>\n",
              "      <td>5910</td>\n",
              "      <td>ENSG00000138698</td>\n",
              "      <td>RHOA,RHOC</td>\n",
              "      <td>387,389</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>19</th>\n",
              "      <td>IL1RAP</td>\n",
              "      <td>3556</td>\n",
              "      <td>ENSG00000196083</td>\n",
              "      <td>IL1R1,IL1B</td>\n",
              "      <td>3554,3553</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>20</th>\n",
              "      <td>HGF</td>\n",
              "      <td>3082</td>\n",
              "      <td>ENSG00000019991</td>\n",
              "      <td>HGF</td>\n",
              "      <td>3082</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>21</th>\n",
              "      <td>DPF3</td>\n",
              "      <td>8110</td>\n",
              "      <td>ENSG00000205683</td>\n",
              "      <td>H4C12,H4C15,H4C4,H4C3,H4C14,H4C5,H4C11,H4C13,DPF3,H4C8,H3,H4C6,H4,H4C2,H4C9,H4C1</td>\n",
              "      <td>8362,554313,8360,8364,8370,8367,8363,8368,8110,8365,3021,8361,121504,8366,8294,8359</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>22</th>\n",
              "      <td>GRK4</td>\n",
              "      <td>2868</td>\n",
              "      <td>ENSG00000125388</td>\n",
              "      <td>GRK4</td>\n",
              "      <td>2868</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>23</th>\n",
              "      <td>RCOR3</td>\n",
              "      <td>55758</td>\n",
              "      <td>ENSG00000117625</td>\n",
              "      <td>KDM1A</td>\n",
              "      <td>23028</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>24</th>\n",
              "      <td>ESR2</td>\n",
              "      <td>2100</td>\n",
              "      <td>ENSG00000140009</td>\n",
              "      <td>ESR2</td>\n",
              "      <td>2100</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>25</th>\n",
              "      <td>CSNK2A3</td>\n",
              "      <td>283106</td>\n",
              "      <td>ENSG00000254598</td>\n",
              "      <td>CSNK2A1,CSNK2A3,CSNK2B</td>\n",
              "      <td>283106,1460,1457</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>26</th>\n",
              "      <td>GNAO1</td>\n",
              "      <td>2775</td>\n",
              "      <td>ENSG00000087258</td>\n",
              "      <td>HTR1B,CHRM2</td>\n",
              "      <td>3351,1129</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>27</th>\n",
              "      <td>DENND1B</td>\n",
              "      <td>163486</td>\n",
              "      <td>ENSG00000213047</td>\n",
              "      <td>RAB35</td>\n",
              "      <td>11021</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>28</th>\n",
              "      <td>RBM12</td>\n",
              "      <td>10137</td>\n",
              "      <td>ENSG00000244462</td>\n",
              "      <td>RBM12</td>\n",
              "      <td>10137</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "   Gene name  ...                                                             Co-resolved interactions\n",
              "0      RRAGB  ...                                                                                 9681\n",
              "1    RALGPS1  ...                                                                                 9649\n",
              "2      BRCC3  ...                                                                                 9577\n",
              "3      CNOT1  ...                                                                                 9125\n",
              "4      LATS1  ...                                                                     92597,9113,55233\n",
              "5       XIAP  ...                                                              56616,842,836,331,10454\n",
              "6      CNNM2  ...                                                                                 7803\n",
              "7      RWDD3  ...                                                                                 7329\n",
              "8       ELK4  ...                                                                                 6722\n",
              "9       SKP2  ...                                                                            6500,1163\n",
              "10    FBXO44  ...                                                                                 6500\n",
              "11    CXCL12  ...                                                                            6387,7852\n",
              "12    PTGER3  ...                                                                                 5733\n",
              "13   PPP2R5C  ...                                                                                 5518\n",
              "14      CSAD  ...                                                                                51380\n",
              "15     NUP98  ...                                                                                 4928\n",
              "16      NPR3  ...                                                                  4878,4880,4883,4879\n",
              "17      NCF4  ...                                                                                 4688\n",
              "18  RAP1GDS1  ...                                                                              387,389\n",
              "19    IL1RAP  ...                                                                            3554,3553\n",
              "20       HGF  ...                                                                                 3082\n",
              "21      DPF3  ...  8362,554313,8360,8364,8370,8367,8363,8368,8110,8365,3021,8361,121504,8366,8294,8359\n",
              "22      GRK4  ...                                                                                 2868\n",
              "23     RCOR3  ...                                                                                23028\n",
              "24      ESR2  ...                                                                                 2100\n",
              "25   CSNK2A3  ...                                                                     283106,1460,1457\n",
              "26     GNAO1  ...                                                                            3351,1129\n",
              "27   DENND1B  ...                                                                                11021\n",
              "28     RBM12  ...                                                                                10137\n",
              "\n",
              "[29 rows x 5 columns]"
            ]
          },
          "metadata": {},
          "execution_count": 9
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "007510e7-b3f5-4d7e-921b-7c71ffc3ec45",
        "outputId": "2b0863c0-18fc-4945-8cc8-93a6df758cc6",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 413
        }
      },
      "source": [
        "# List of affected interactions (domain and motifs binding)\n",
        "edges=events.get_edges()\n",
        "edges.head(10)"
      ],
      "id": "007510e7-b3f5-4d7e-921b-7c71ffc3ec45",
      "execution_count": 10,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Gene name</th>\n",
              "      <th>NCBI gene ID</th>\n",
              "      <th>Identifier</th>\n",
              "      <th>dPSI</th>\n",
              "      <th>Number of affected interactions</th>\n",
              "      <th>Affected binding</th>\n",
              "      <th>Affected binding (NCBI)</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>WWP2</td>\n",
              "      <td>11060</td>\n",
              "      <td>PF00397</td>\n",
              "      <td>-0.185343</td>\n",
              "      <td>98</td>\n",
              "      <td>SRSF1,NCBP2,HNRNPA0,DAZAP1,TXNIP,POLR2C,NCL,WWP2,CPSF6,SNRNP70,U2AF2,ELAVL1,SRPK2,LIN7C,ITCH,DVL1,ZNF638,ARRDC3,HNRNPC,EIF3G,CSNK2A1,PTBP1,PATJ,RBM10,HNRNPF,HNRNPH1,RBM14,SRPK1,MYC,HNRNPD,KHSRP,ARRDC4,SHC1,IQGAP1,LARP7,HNRNPH3,PDLIM7,RBM28,IGF2BP1,SRSF10,SF3B4,TAGLN2,U2SURP,SMAD3,SRSF2,TP73,RBM39,HNRNPR,SFPQ,CTNNB1,SRSF3,IGF2BP2,OGT,HNRNPA1,HNRNPM,SNRPB2,DVL2,SAFB,NIFK,HNRNPL,AMOT,PABPC1,HNRNPA2B1,NELFE,RALY,HNRNPA3,WWP1,EIF3B,SYNCRIP,SCNN1B,G3BP1,RPAP3,EWSR1,FLNA,NONO,SRSF7,SCNN1G,SCNN1A,CDK9,POLR2A,PABPC4,SART3,SRSF5,G3BP2,STAT3,MKNK2,ARRDC1,U2AF1,ALYREF,CPSF7,RBM34,TJP1,TAF15,RBM17,RBMX,MPP5,TRA2A,SRSF6</td>\n",
              "      <td>6426,22916,10949,26528,10628,5432,4691,11060,11052,6625,11338,1994,6733,55327,83737,1855,27332,57561,3183,8666,1457,5725,10207,8241,3185,3187,10432,6732,4609,3184,8570,91947,6464,8826,51574,3189,9260,55131,10642,10772,10262,8407,23350,4088,6427,7161,9584,10236,6421,1499,6428,10644,8473,3178,4670,6629,1856,6294,84365,3191,154796,26986,3181,7936,22913,220988,11059,8662,10492,6338,10146,79657,2130,2316,4841,6432,6340,6337,1025,5430,8761,9733,6430,9908,6774,2872,92714,7307,10189,79869,23029,7082,8148,84991,27316,64398,29896,6431</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>ESR2</td>\n",
              "      <td>2100</td>\n",
              "      <td>PF00104</td>\n",
              "      <td>-0.302430</td>\n",
              "      <td>80</td>\n",
              "      <td>TLK2,PIK3R4,NCAM2,ADNP,CIT,ARNT,RPS6KB2,FNDC3B,ZHX2,CLK3,CAMK2D,SRPK2,PEAK1,PRKCI,RPS6KB1,CSNK1A1,WNK1,TBK1,TAOK2,DAPK3,CSNK2A1,MINK1,GAK,NR2F6,CDK13,SRPK1,ZFHX3,ZHX3,MAPK3,LMX1B,ESR1,MARK2,EIF2AK2,CDK11B,SCYL1,TRIO,MARK3,KPNA1,PKP4,NCOA3,CTNNB1,CUX1,PRPF4B,CERS2,CDK8,VRK2,CDC42BPG,MAPKAPK2,SCYL2,TTK,PBX1,MID1,MAPK1,MYLK2,PTPRK,MEOX2,NRIP1,NR2F2,ESR2,OXSR1,DYRK1A,CDK12,NKX2,SIX4,ESRRB,CDK9,STK26,PTPRF,MKNK2,BMP2K,NCOA2,CDK19,RPS6KA4,CSNK1G3,CDC42BPB,NCOA1,PRAG1,EPHA4,PA2G4,ARVCF</td>\n",
              "      <td>11011,30849,4685,23394,11113,405,6199,64778,22882,1198,817,6733,79834,5584,6198,1452,65125,29110,9344,1613,1457,50488,2580,2063,8621,6732,463,23051,5595,4010,2099,2011,5610,984,57410,7204,4140,3836,8502,8202,1499,1523,8899,29956,1024,7444,55561,9261,55681,7272,5087,4281,5594,85366,5796,4223,8204,7026,2100,9943,1859,51755,159296,51804,2103,1025,51765,5792,2872,55589,10499,23097,8986,1456,9578,8648,157285,2043,5036,421</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>CLK1</td>\n",
              "      <td>1195</td>\n",
              "      <td>PF00069</td>\n",
              "      <td>0.140012</td>\n",
              "      <td>71</td>\n",
              "      <td>H2BC12,SRSF3,MAP3K21,CDK12,SRSF1,PRPF4B,SRSF7,TRA2B,HNRNPA1,ISG15,CUL3,HNRNPA0,ANKFY1,SRPK1,MFHAS1,FAT1,PATZ1,SAFB,CENPE,RLF,MYOM1,SFMBT2,THY1,CLK1,SRSF5,STIP1,NCL,BAG3,YWHAG,PPFIBP2,ARHGEF12,SPEN,PPIG,SVOP,RASL12,KIF14,NPM1,STK31,WDR66,GRM6,HTATSF1,CTNND2,DNAJC13,CWC27,RBM15,KIF23,HNRNPA3,AC020929.1,GEMIN5,ZNF148,SRPK2,IMPDH2,ABCA13,PPP1CB,DNAJC24,MKRN2,UBL5,DBR1,CLK2,UNC13B,KRT8,TJP2,RBMX,PTPN22,RAPH1,HIVEP1,TRA2A,RBM39,SRSF6,PHLDB2,CELSR3</td>\n",
              "      <td>85236,6428,6426,84451,51755,8899,6432,6434,3178,9636,8452,10949,51479,6732,9258,2195,23598,90102,6294,1062,6018,8736,57713,7070,1195,6430,10963,4691,9531,7532,8495,23365,23013,9360,55530,51285,9928,4869,56164,2916,27336,1501,23317,10283,64783,9493,220988,57731,25929,7707,6733,3615,154664,5500,120526,23609,59286,51163,1196,10497,3856,9414,27316,26191,65059,3096,29896,9584,6431,144406,1951</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>FGFR1</td>\n",
              "      <td>2260</td>\n",
              "      <td>PF00047</td>\n",
              "      <td>0.119626</td>\n",
              "      <td>53</td>\n",
              "      <td>PLCG1,HEPACAM2,YES1,GRB14,CD79B,NCAM1,AKT1,PTPN11,NCK1,AGER,MFHAS1,CEACAM21,CDK9,RPS6KA3,SLA,OPCML,VAV1,PLCG2,SHC1,PIK3R1,JAK2,FGFR2,SRC,IL27RA,PDGFRB,STAT3,SCN3B,RASA1,PTK6,ITK,ANOS1,FGFR1,LTBR,SH3BP2,DLK1,PIK3R2,PTPN1,TNS2,L1CAM,NECTIN1,LRRN2,SHB,RPS6KA1,NCK2,CRK,SHE,CRKL,RAET1E,TNFRSF10B,AP006333.1,FCGRT,EPHA4,CTNNB1</td>\n",
              "      <td>5335,253012,7525,2888,974,4684,207,5781,4690,177,9258,90273,6197,1025,4978,6503,7409,5336,6464,5295,3717,2217,6714,9466,5159,6774,55800,5921,5753,3702,3730,2260,4055,6452,8788,5296,5770,23371,3897,5818,10446,6461,6195,8440,1398,126669,1399,135250,8795,23769,2263,2043,1499</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>MYO19</td>\n",
              "      <td>80179</td>\n",
              "      <td>PF00063</td>\n",
              "      <td>-0.154152</td>\n",
              "      <td>51</td>\n",
              "      <td>MYO1C,MYLK,ACTR2,CORO2A,INF2,CORO1C,TPM1,MYL6,ACTN1,TPM4,MYO5C,PHKG2,IQGAP1,ACTN4,MAPK14,MYO18A,AHNAK,MYO1E,ERBIN,ARPC1B,SPTAN1,MYL2,BMP2K,CORO1B,SPTBN2,MYL10,MYL12A,LMO7,CTTN,TJP1,SPTBN1,MYO10,TPM2,MYO5A,MYH9,MYO6,ACTG1,TPM3,SIPA1,ACTR3,MYO1B,TJP2,COBL,WDR1,PPP1R9A,MYO5B,PPP1R9B,GNB2,DAPK3,MYH10,ACTR10</td>\n",
              "      <td>4641,4638,7464,64423,10097,23603,7168,4637,87,7171,55930,5261,8826,81,1432,399687,79026,4643,55914,10095,6709,4633,55589,57175,6712,93408,10627,4008,2017,7082,6711,4651,7169,4644,4627,4646,71,7170,6494,10096,4430,9414,23242,9948,55607,4645,84687,2783,1613,4628,55860</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>5</th>\n",
              "      <td>XIAP</td>\n",
              "      <td>331</td>\n",
              "      <td>PF00653</td>\n",
              "      <td>-0.112442</td>\n",
              "      <td>41</td>\n",
              "      <td>IKBKE,AKT1,CASP2,BRCA1,CDK1,STRADB,CHEK1,BCL10,CASP9,CASP3,BMPR2,CASP6,SIAH1,XIAP,RIPK4,TRAF2,RFFL,DIABLO,APAF1,CASP10,NOD2,BIRC3,NOD1,NEK6,MDM2,RIPK3,BIRC2,BIRC7,CASP4,CASP8,TAB1,BIRC5,ACVR1B,TBK1,GSK3B,MAP3K2,CASP7,LATS1,RIPK2,CASP12,MAP3K3</td>\n",
              "      <td>9641,207,835,672,55437,1111,8915,842,836,659,839,6477,331,54101,7186,117584,56616,317,843,64127,330,10392,10783,4193,11035,329,79444,837,841,8767,10454,332,91,29110,2932,10746,840,9113,983,100506742,4215</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>6</th>\n",
              "      <td>SPTAN1</td>\n",
              "      <td>6709</td>\n",
              "      <td>PF00435</td>\n",
              "      <td>0.139279</td>\n",
              "      <td>35</td>\n",
              "      <td>SPTB,MYO1C,MAPRE1,SMURF1,ABL1,CDK9,CAPN1,MYO19,MYO5C,IQGAP1,MYO18A,PLEKHA4,SAV1,CDK2,SPTBN2,PLS1,SOS1,EHBP1L1,AC020929.1,TJP1,PLEC,SPTBN1,MYH9,KALRN,PLEKHA5,YAP1,ANLN,GRK5,MAPK6,FLNA,MYH7,DYRK1A,SPTBN5,GAK,MAPK9</td>\n",
              "      <td>6710,5601,4641,22919,57154,25,1025,823,80179,55930,8826,399687,57664,60485,6712,5357,6654,254102,57731,7082,5339,6711,4627,8997,54477,10413,54443,2869,5597,2316,4625,1859,51332,2580,1017</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>7</th>\n",
              "      <td>BRCA1</td>\n",
              "      <td>672</td>\n",
              "      <td>MOD_PKB_1</td>\n",
              "      <td>0.106918</td>\n",
              "      <td>28</td>\n",
              "      <td>LRRK1,AKT1,CDK8,CDK9,PLK1,CDK16,CDK4,CHEK1,CDK7,TTN,AURKA,AURKC,MAP3K1,MAPK3,OBSCN,MAPK1,CAMK2D,CHEK2,CLK2,MAP4K4,PRKAA2,BRSK1,MAP3K14,CSNK2A1,CDK1,CSNK1D,MAP3K3,CDK2</td>\n",
              "      <td>9448,5595,5594,1196,5563,817,84446,6795,1453,9020,5127,5347,1017,1457,983,1025,1022,1111,11200,7273,4214,79705,1019,207,4215,1024,6790,84033</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>8</th>\n",
              "      <td>ZNF397</td>\n",
              "      <td>84307</td>\n",
              "      <td>PF00096</td>\n",
              "      <td>0.146217</td>\n",
              "      <td>26</td>\n",
              "      <td>ZSCAN20,ZSCAN21,ZKSCAN8,ZNF174,ZSCAN30,ZKSCAN1,ZNF496,ZNF500,ZNF444,ZKSCAN3,ZNF394,LMO4,ZSCAN32,ZNF197,STK40,ZNF446,ZNF410,ZNF24,PRKAA2,ZNF483,COP1,ZSCAN29,ZKSCAN4,ZNF213,ZNF232,ZNF263</td>\n",
              "      <td>7579,7589,7745,7727,100101467,7586,84838,26048,55311,80317,84124,8543,54925,7775,10168,83931,55663,57862,7572,5563,64326,146050,387032,7760,158399,10127</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>9</th>\n",
              "      <td>HERC2</td>\n",
              "      <td>8924</td>\n",
              "      <td>PF00415</td>\n",
              "      <td>0.362158</td>\n",
              "      <td>22</td>\n",
              "      <td>LRRK2,CDK12,RAB5A,HERC2,SRPK1,CDK8,STK33,HERC1,CDC42,RAB34,PHKG2,NEK11,AGAP3,STK11,RAB5B,HERC3,MARK2,CLK2,AURKB,TBK1,MAPK6,CTNNB1</td>\n",
              "      <td>120892,51755,5868,8924,6732,1024,65975,8925,998,83871,5261,79858,116988,6794,5869,8916,2011,1196,9212,29110,5597,1499</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "  Gene name  ...                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Affected binding (NCBI)\n",
              "0      WWP2  ...  6426,22916,10949,26528,10628,5432,4691,11060,11052,6625,11338,1994,6733,55327,83737,1855,27332,57561,3183,8666,1457,5725,10207,8241,3185,3187,10432,6732,4609,3184,8570,91947,6464,8826,51574,3189,9260,55131,10642,10772,10262,8407,23350,4088,6427,7161,9584,10236,6421,1499,6428,10644,8473,3178,4670,6629,1856,6294,84365,3191,154796,26986,3181,7936,22913,220988,11059,8662,10492,6338,10146,79657,2130,2316,4841,6432,6340,6337,1025,5430,8761,9733,6430,9908,6774,2872,92714,7307,10189,79869,23029,7082,8148,84991,27316,64398,29896,6431\n",
              "1      ESR2  ...                                                                                                                11011,30849,4685,23394,11113,405,6199,64778,22882,1198,817,6733,79834,5584,6198,1452,65125,29110,9344,1613,1457,50488,2580,2063,8621,6732,463,23051,5595,4010,2099,2011,5610,984,57410,7204,4140,3836,8502,8202,1499,1523,8899,29956,1024,7444,55561,9261,55681,7272,5087,4281,5594,85366,5796,4223,8204,7026,2100,9943,1859,51755,159296,51804,2103,1025,51765,5792,2872,55589,10499,23097,8986,1456,9578,8648,157285,2043,5036,421\n",
              "2      CLK1  ...                                                                                                                                              85236,6428,6426,84451,51755,8899,6432,6434,3178,9636,8452,10949,51479,6732,9258,2195,23598,90102,6294,1062,6018,8736,57713,7070,1195,6430,10963,4691,9531,7532,8495,23365,23013,9360,55530,51285,9928,4869,56164,2916,27336,1501,23317,10283,64783,9493,220988,57731,25929,7707,6733,3615,154664,5500,120526,23609,59286,51163,1196,10497,3856,9414,27316,26191,65059,3096,29896,9584,6431,144406,1951\n",
              "3     FGFR1  ...                                                                                                                                                                                                                                                                    5335,253012,7525,2888,974,4684,207,5781,4690,177,9258,90273,6197,1025,4978,6503,7409,5336,6464,5295,3717,2217,6714,9466,5159,6774,55800,5921,5753,3702,3730,2260,4055,6452,8788,5296,5770,23371,3897,5818,10446,6461,6195,8440,1398,126669,1399,135250,8795,23769,2263,2043,1499\n",
              "4     MYO19  ...                                                                                                                                                                                                                                                                          4641,4638,7464,64423,10097,23603,7168,4637,87,7171,55930,5261,8826,81,1432,399687,79026,4643,55914,10095,6709,4633,55589,57175,6712,93408,10627,4008,2017,7082,6711,4651,7169,4644,4627,4646,71,7170,6494,10096,4430,9414,23242,9948,55607,4645,84687,2783,1613,4628,55860\n",
              "5      XIAP  ...                                                                                                                                                                                                                                                                                                                                         9641,207,835,672,55437,1111,8915,842,836,659,839,6477,331,54101,7186,117584,56616,317,843,64127,330,10392,10783,4193,11035,329,79444,837,841,8767,10454,332,91,29110,2932,10746,840,9113,983,100506742,4215\n",
              "6    SPTAN1  ...                                                                                                                                                                                                                                                                                                                                                          6710,5601,4641,22919,57154,25,1025,823,80179,55930,8826,399687,57664,60485,6712,5357,6654,254102,57731,7082,5339,6711,4627,8997,54477,10413,54443,2869,5597,2316,4625,1859,51332,2580,1017\n",
              "7     BRCA1  ...                                                                                                                                                                                                                                                                                                                                                                                                        9448,5595,5594,1196,5563,817,84446,6795,1453,9020,5127,5347,1017,1457,983,1025,1022,1111,11200,7273,4214,79705,1019,207,4215,1024,6790,84033\n",
              "8    ZNF397  ...                                                                                                                                                                                                                                                                                                                                                                                            7579,7589,7745,7727,100101467,7586,84838,26048,55311,80317,84124,8543,54925,7775,10168,83931,55663,57862,7572,5563,64326,146050,387032,7760,158399,10127\n",
              "9     HERC2  ...                                                                                                                                                                                                                                                                                                                                                                                                                               120892,51755,5868,8924,6732,1024,65975,8925,998,83871,5261,79858,116988,6794,5869,8916,2011,1196,9212,29110,5597,1499\n",
              "\n",
              "[10 rows x 7 columns]"
            ]
          },
          "metadata": {},
          "execution_count": 10
        }
      ]
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "fe0f49c4-4bad-4aed-b822-8e8401613741"
      },
      "source": [
        "### NEASE edge enrichment "
      ],
      "id": "fe0f49c4-4bad-4aed-b822-8e8401613741"
    },
    {
      "cell_type": "code",
      "metadata": {
        "tags": [],
        "id": "9a2b3182-3d9a-4b7d-957b-5b963978c787",
        "outputId": "2b8ec3b7-c8f6-44cc-ae7d-18a7ff198ec8",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 1000
        }
      },
      "source": [
        "# Run nease enrichment on affected edges\n",
        "nease_enr=events.enrich(database=['KEGG']).sort_values('p_value')\n",
        "nease_enr.head(25)"
      ],
      "id": "9a2b3182-3d9a-4b7d-957b-5b963978c787",
      "execution_count": 11,
      "outputs": [
        {
          "output_type": "stream",
          "name": "stdout",
          "text": [
            "NEASE enrichment for the pathway databases:\n",
            " ['KEGG']\n",
            "Found 3 enriched pathways after multiple testing correction.\n",
            "\n"
          ]
        },
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Pathway ID</th>\n",
              "      <th>Pathway name</th>\n",
              "      <th>Source</th>\n",
              "      <th>Spliced genes (number of interactions affecting the pathway)</th>\n",
              "      <th>p_value</th>\n",
              "      <th>adj p_value</th>\n",
              "      <th>Nease score</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>path:hsa04080</td>\n",
              "      <td>Neuroactive ligand-receptor interaction - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>PTGER3 (1), GABBR1 (1), CLK1 (1), ARRB1 (11), ADRA1A (2), GNAO1 (7)</td>\n",
              "      <td>0.000002</td>\n",
              "      <td>0.000551</td>\n",
              "      <td>12.888861</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>path:hsa04261</td>\n",
              "      <td>Adrenergic signaling in cardiomyocytes - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>PPP2R5C (9), ESR2 (3), ERBB3 (2), TTN (1), USP49 (1), ZHX1 (1), GRK4 (1), MYO19 (6), ELK4 (2), CLK1 (1), SPTAN1 (1), ARRB1 (2), FGFR1 (1), XIAP (1), MAF (1), ADRA1A (2), CACNA1C (2), GNAO1 (4), BRCA1 (8)</td>\n",
              "      <td>0.000008</td>\n",
              "      <td>0.001254</td>\n",
              "      <td>13.508347</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>path:hsa04022</td>\n",
              "      <td>cGMP-PKG signaling pathway - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>PPP2R5C (3), ESR2 (3), ERBB3 (1), TTN (2), NFATC1 (1), NPR3 (1), ZHX1 (1), GRK4 (1), MYO19 (1), ELK4 (3), CLK1 (1), SPTAN1 (1), ARRB1 (4), FGFR1 (1), XIAP (1), PPP1R12B (1), MAF (1), ADRA1A (2), CACNA1C (1), GNAO1 (5), BRCA1 (6), RAP1GDS1 (1)</td>\n",
              "      <td>0.000157</td>\n",
              "      <td>0.016794</td>\n",
              "      <td>10.756143</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>5</th>\n",
              "      <td>path:hsa04520</td>\n",
              "      <td>Adherens junction - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>IL1RAP (1), HERC2 (2), ESR2 (5), ERBB3 (2), PRDM2 (2), RCOR3 (1), MAGIX (1), TTN (3), PCDH1 (1), CSNK2A3 (3), WWP2 (5), NCAM1 (1), TNC (1), ZHX1 (1), MYO19 (6), APBB3 (1), ELK4 (2), PTPN18 (1), SPTAN1 (2), FGFR1 (6), BRCA1 (4), RAP1GDS1 (1)</td>\n",
              "      <td>0.000673</td>\n",
              "      <td>0.053855</td>\n",
              "      <td>8.971383</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>path:hsa04810</td>\n",
              "      <td>Regulation of actin cytoskeleton - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>HERC2 (1), PPP2R5C (3), CXCL12 (2), ESR2 (3), ERBB3 (2), PRDM2 (1), GIT2 (1), TTN (6), PTGER3 (2), WWP2 (1), NCAM1 (1), TNC (2), MYO19 (11), APBB3 (1), TSSK1B (1), ELK4 (2), PTPN18 (1), CLK1 (2), SPTAN1 (3), FGFR1 (9), USP53 (1), PPP1R12B (1), ABI2 (4), GNAO1 (1), BRCA1 (5), RAP1GDS1 (1)</td>\n",
              "      <td>0.001124</td>\n",
              "      <td>0.071965</td>\n",
              "      <td>9.780929</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>path:hsa04510</td>\n",
              "      <td>Focal adhesion - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>ZC3HAV1 (1), HERC2 (2), PPP2R5C (3), ESR2 (4), ERBB3 (4), PRDM2 (1), TTN (5), PTGER3 (2), FLT1 (2), WWP2 (3), HGF (1), TNC (2), ZHX1 (2), MYO19 (7), APBB3 (1), ELK4 (3), PTPN18 (2), CLK1 (1), SPTAN1 (3), FGFR1 (10), USP53 (2), XIAP (5), PPP1R12B (1), BRCA1 (7), RAP1GDS1 (1)</td>\n",
              "      <td>0.001886</td>\n",
              "      <td>0.093997</td>\n",
              "      <td>9.437541</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>9</th>\n",
              "      <td>path:hsa04020</td>\n",
              "      <td>Calcium signaling pathway - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>HERC2 (1), CXCL12 (1), ESR2 (2), ERBB3 (5), TTN (1), USP49 (1), PTGER3 (1), TNC (1), GRK4 (1), MYO19 (2), APBB3 (1), PTPN18 (1), ARRB1 (4), FGFR1 (3), ADRA1A (2), CACNA1C (2), GNAO1 (2), BRCA1 (1)</td>\n",
              "      <td>0.002056</td>\n",
              "      <td>0.093997</td>\n",
              "      <td>6.008179</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>6</th>\n",
              "      <td>path:hsa05168</td>\n",
              "      <td>Herpes simplex infection - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>NUP98 (1), IL1RAP (1), HERC2 (2), PPP2R5C (3), ESR2 (4), ERBB3 (3), PRDM2 (1), TTN (1), TRIM9 (1), RBM12 (1), CSNK2A3 (3), FLT1 (1), WWP2 (10), SP100 (1), ZHX1 (1), MBP (1), ELK4 (1), CLK1 (7), SPTAN1 (2), RBM41 (2), FBXO44 (1), FGFR1 (3), XIAP (7), MAF (1), BRCA1 (6), SKP2 (1)</td>\n",
              "      <td>0.003316</td>\n",
              "      <td>0.132638</td>\n",
              "      <td>7.840522</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>7</th>\n",
              "      <td>path:hsa04066</td>\n",
              "      <td>HIF-1 signaling pathway - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>ESR2 (7), ERBB3 (4), PRDM2 (1), TTN (3), PTGER3 (2), FLT1 (1), WWP2 (2), NPR3 (1), EIF4EBP3 (2), TNC (1), ZHX1 (1), APBB3 (1), ELK4 (2), PTPN18 (1), FGFR1 (7), XIAP (1), GNAO1 (1), BRCA1 (4)</td>\n",
              "      <td>0.005648</td>\n",
              "      <td>0.200805</td>\n",
              "      <td>6.358679</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>15</th>\n",
              "      <td>path:hsa04742</td>\n",
              "      <td>Taste transduction - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>ERBB3 (1), USP49 (1), WWP2 (3), GABBR1 (1), GNAO1 (1)</td>\n",
              "      <td>0.006309</td>\n",
              "      <td>0.201876</td>\n",
              "      <td>4.919493</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>18</th>\n",
              "      <td>path:hsa03015</td>\n",
              "      <td>mRNA surveillance pathway - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>NUP98 (1), PPP2R5C (9), PELO (1), RBM12 (2), WWP2 (7), MKRN1 (1), ZHX1 (1), CLK1 (1), BRCA1 (4)</td>\n",
              "      <td>0.008155</td>\n",
              "      <td>0.234236</td>\n",
              "      <td>4.670209</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>11</th>\n",
              "      <td>path:hsa04670</td>\n",
              "      <td>Leukocyte transendothelial migration - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>HERC2 (2), CXCL12 (2), ESR2 (1), TTN (2), PTGER3 (2), WWP2 (1), MYO19 (8), CLK1 (1), NCF4 (2), FGFR1 (8), GNAO1 (3), BRCA1 (1), RAP1GDS1 (1)</td>\n",
              "      <td>0.008784</td>\n",
              "      <td>0.234236</td>\n",
              "      <td>5.440497</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>10</th>\n",
              "      <td>path:hsa04611</td>\n",
              "      <td>Platelet activation - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>PPP2R5C (3), ESR2 (4), ERBB3 (2), PRDM2 (1), TTN (1), USP49 (1), PTGER3 (2), ZHX1 (1), MYO19 (4), ELK4 (2), CLK1 (2), FGFR1 (5), XIAP (1), PPP1R12B (1), GNAO1 (3), BRCA1 (6), RAP1GDS1 (1)</td>\n",
              "      <td>0.009526</td>\n",
              "      <td>0.234481</td>\n",
              "      <td>5.716530</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>33</th>\n",
              "      <td>path:hsa04215</td>\n",
              "      <td>Apoptosis - multiple species - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>ZC3HAV1 (1), ELK4 (1), SPTAN1 (1), XIAP (11)</td>\n",
              "      <td>0.010898</td>\n",
              "      <td>0.234965</td>\n",
              "      <td>3.399413</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>17</th>\n",
              "      <td>path:hsa04270</td>\n",
              "      <td>Vascular smooth muscle contraction - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>PPP2R5C (3), ESR2 (3), ERBB3 (1), TTN (2), USP49 (1), GRK4 (1), MYO19 (2), ELK4 (2), CLK1 (2), ARRB1 (2), PPP1R12B (1), ADRA1A (2), CACNA1C (1), BRCA1 (5), RAP1GDS1 (1)</td>\n",
              "      <td>0.011784</td>\n",
              "      <td>0.234965</td>\n",
              "      <td>4.724304</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>14</th>\n",
              "      <td>path:hsa04540</td>\n",
              "      <td>Gap junction - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>ESR2 (2), ERBB3 (3), PRDM2 (1), MAGIX (1), ASB4 (4), TTN (4), TRIM9 (1), USP49 (1), WWP2 (1), TNC (1), MYO19 (1), APBB3 (1), TSSK1B (1), ELK4 (2), PTPN18 (2), SPTAN1 (2), ARRB1 (1), FGFR1 (2), USP53 (1), XIAP (2), GNAO1 (3), BRCA1 (4)</td>\n",
              "      <td>0.011822</td>\n",
              "      <td>0.234965</td>\n",
              "      <td>5.099200</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>26</th>\n",
              "      <td>path:hsa05110</td>\n",
              "      <td>Vibrio cholerae infection - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>SEC24A (1), SLC22A23 (1), ERBB3 (1), MAGIX (2), USP49 (1), WWP2 (1), MYO19 (3), CLK1 (1), SPTAN1 (1), FGFR1 (2)</td>\n",
              "      <td>0.012483</td>\n",
              "      <td>0.234965</td>\n",
              "      <td>3.807396</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>22</th>\n",
              "      <td>path:hsa05020</td>\n",
              "      <td>Prion diseases - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>IL1RAP (1), ESR2 (3), ERBB3 (1), TTN (2), USP49 (1), ELK4 (2), CLK1 (1), FGFR1 (1), XIAP (1), BRCA1 (2)</td>\n",
              "      <td>0.016089</td>\n",
              "      <td>0.253511</td>\n",
              "      <td>4.010323</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>12</th>\n",
              "      <td>path:hsa05205</td>\n",
              "      <td>Proteoglycans in cancer - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>HERC2 (2), PPP2R5C (3), ESR2 (7), ERBB3 (6), PRDM2 (2), TTN (6), USP49 (1), PTGER3 (2), FLT1 (1), OBSCN (1), WWP2 (5), HGF (1), NCAM1 (1), TNC (2), ZHX1 (1), MYO19 (4), APBB3 (1), TSSK1B (1), ELK4 (2), PTPN18 (2), CLK1 (2), SPTAN1 (3), FGFR1 (10), USP53 (1), XIAP (3), PPP1R12B (1), GNAO1 (1), BRCA1 (8), RAP1GDS1 (1)</td>\n",
              "      <td>0.016894</td>\n",
              "      <td>0.253511</td>\n",
              "      <td>5.316806</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>13</th>\n",
              "      <td>path:hsa04024</td>\n",
              "      <td>cAMP signaling pathway - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>PPP2R5C (3), ESR2 (3), ERBB3 (2), PRDM2 (1), TTN (3), USP49 (1), PTGER3 (3), ZHX1 (1), GRK4 (1), ELK4 (3), GABBR1 (1), CLK1 (1), SPTAN1 (1), ARRB1 (2), FGFR1 (4), XIAP (1), PPP1R12B (1), MAF (1), CACNA1C (2), GNAO1 (6), BRCA1 (7), RAP1GDS1 (1)</td>\n",
              "      <td>0.017592</td>\n",
              "      <td>0.253511</td>\n",
              "      <td>5.264038</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>36</th>\n",
              "      <td>path:hsa04672</td>\n",
              "      <td>Intestinal immune network for IgA production - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>CXCL12 (2), ERBB3 (1), MBP (1), FGFR1 (1), BRCA1 (1)</td>\n",
              "      <td>0.017759</td>\n",
              "      <td>0.253511</td>\n",
              "      <td>3.032110</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>20</th>\n",
              "      <td>path:hsa04514</td>\n",
              "      <td>Cell adhesion molecules (CAMs) - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>IL1RAP (1), CXCL12 (1), ESR2 (2), ERBB3 (4), PCDH1 (1), MBP (1), FGFR1 (3)</td>\n",
              "      <td>0.018361</td>\n",
              "      <td>0.253511</td>\n",
              "      <td>4.252578</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>25</th>\n",
              "      <td>path:hsa04934</td>\n",
              "      <td>Cushing syndrome - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>HERC2 (1), ESR2 (6), ERBB3 (2), TTN (4), USP49 (1), WWP2 (3), TNC (1), ZHX1 (1), BCL11A (2), APBB3 (1), ELK4 (2), PTPN18 (1), SPTAN1 (1), ARRB1 (1), FGFR1 (1), XIAP (1), MAF (1), KCNRG (1), GNAO1 (5), BRCA1 (6)</td>\n",
              "      <td>0.018549</td>\n",
              "      <td>0.253511</td>\n",
              "      <td>3.872166</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>8</th>\n",
              "      <td>path:hsa04915</td>\n",
              "      <td>Estrogen signaling pathway - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>ESR2 (7), ERBB3 (3), PRDM2 (3), TTN (4), USP49 (1), PTGER3 (2), WWP2 (1), TNC (1), ZHX1 (1), GRK4 (2), APBB3 (1), TSSK1B (5), ELK4 (2), PTPN18 (2), GABBR1 (1), SPTAN1 (1), RARG (3), FGFR1 (5), USP53 (1), XIAP (1), MAF (2), CACNA1C (1), GNAO1 (4), BRCA1 (3)</td>\n",
              "      <td>0.019300</td>\n",
              "      <td>0.253511</td>\n",
              "      <td>6.181481</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>32</th>\n",
              "      <td>path:hsa05414</td>\n",
              "      <td>Dilated cardiomyopathy (DCM) - Homo sapiens (human)</td>\n",
              "      <td>KEGG</td>\n",
              "      <td>ERBB3 (1), TTN (1), USP49 (1), OBSCN (1), MYO19 (6), SPTAN1 (1), ARRB1 (1), CACNA1C (1), BRCA1 (1)</td>\n",
              "      <td>0.019806</td>\n",
              "      <td>0.253511</td>\n",
              "      <td>3.406427</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "       Pathway ID  ... Nease score\n",
              "1   path:hsa04080  ...   12.888861\n",
              "0   path:hsa04261  ...   13.508347\n",
              "2   path:hsa04022  ...   10.756143\n",
              "5   path:hsa04520  ...    8.971383\n",
              "3   path:hsa04810  ...    9.780929\n",
              "4   path:hsa04510  ...    9.437541\n",
              "9   path:hsa04020  ...    6.008179\n",
              "6   path:hsa05168  ...    7.840522\n",
              "7   path:hsa04066  ...    6.358679\n",
              "15  path:hsa04742  ...    4.919493\n",
              "18  path:hsa03015  ...    4.670209\n",
              "11  path:hsa04670  ...    5.440497\n",
              "10  path:hsa04611  ...    5.716530\n",
              "33  path:hsa04215  ...    3.399413\n",
              "17  path:hsa04270  ...    4.724304\n",
              "14  path:hsa04540  ...    5.099200\n",
              "26  path:hsa05110  ...    3.807396\n",
              "22  path:hsa05020  ...    4.010323\n",
              "12  path:hsa05205  ...    5.316806\n",
              "13  path:hsa04024  ...    5.264038\n",
              "36  path:hsa04672  ...    3.032110\n",
              "20  path:hsa04514  ...    4.252578\n",
              "25  path:hsa04934  ...    3.872166\n",
              "8   path:hsa04915  ...    6.181481\n",
              "32  path:hsa05414  ...    3.406427\n",
              "\n",
              "[25 rows x 7 columns]"
            ]
          },
          "metadata": {},
          "execution_count": 11
        }
      ]
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "96c083c5-d0ab-4ba2-adf2-e96efdb4798a"
      },
      "source": [
        "### Pathway specific analysis"
      ],
      "id": "96c083c5-d0ab-4ba2-adf2-e96efdb4798a"
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "21351558-08c6-4b43-8bd0-2b5acfe23402",
        "outputId": "846d12fa-c33b-478b-e6a1-d77b6dc61688",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 413
        }
      },
      "source": [
        "# Dilated cardiomyopathy (DCM) - Homo sapiens (human) is 7 on the list\n",
        "# run path_analysis() with DCM pathway id for more details about diff. spliced genes are their affected interactions\n",
        "events.path_analysis('path:hsa05414')"
      ],
      "id": "21351558-08c6-4b43-8bd0-2b5acfe23402",
      "execution_count": 12,
      "outputs": [
        {
          "output_type": "stream",
          "name": "stdout",
          "text": [
            "Enrichment of the pathway: Dilated cardiomyopathy (DCM) - Homo sapiens (human).\n",
            "\n",
            "Overall p_value:  0.0198055308545215\n",
            "\n",
            "\n"
          ]
        },
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Spliced genes</th>\n",
              "      <th>NCBI gene ID</th>\n",
              "      <th>Gene is known to be in the pathway</th>\n",
              "      <th>Percentage of edges associated to the pathway</th>\n",
              "      <th>p_value</th>\n",
              "      <th>Affected binding (edges)</th>\n",
              "      <th>Affected binding (NCBI)</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>MYO19</td>\n",
              "      <td>80179</td>\n",
              "      <td>False</td>\n",
              "      <td>6/51</td>\n",
              "      <td>0.000002</td>\n",
              "      <td>TPM1,TPM4,MYL2,TPM2,ACTG1,TPM3</td>\n",
              "      <td>7168,7171,4633,7169,71,7170</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>OBSCN</td>\n",
              "      <td>84033</td>\n",
              "      <td>False</td>\n",
              "      <td>1/2</td>\n",
              "      <td>0.014457</td>\n",
              "      <td>TTN</td>\n",
              "      <td>7273</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>USP49</td>\n",
              "      <td>25862</td>\n",
              "      <td>False</td>\n",
              "      <td>1/4</td>\n",
              "      <td>0.028706</td>\n",
              "      <td>PRKACA</td>\n",
              "      <td>5566</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>CACNA1C</td>\n",
              "      <td>775</td>\n",
              "      <td>True</td>\n",
              "      <td>1/4</td>\n",
              "      <td>0.028706</td>\n",
              "      <td>RYR2</td>\n",
              "      <td>6262</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>ERBB3</td>\n",
              "      <td>2065</td>\n",
              "      <td>False</td>\n",
              "      <td>1/18</td>\n",
              "      <td>0.122847</td>\n",
              "      <td>PRKACA</td>\n",
              "      <td>5566</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>5</th>\n",
              "      <td>ARRB1</td>\n",
              "      <td>408</td>\n",
              "      <td>False</td>\n",
              "      <td>1/21</td>\n",
              "      <td>0.141803</td>\n",
              "      <td>ADRB1</td>\n",
              "      <td>153</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>6</th>\n",
              "      <td>TTN</td>\n",
              "      <td>7273</td>\n",
              "      <td>True</td>\n",
              "      <td>1/24</td>\n",
              "      <td>0.160349</td>\n",
              "      <td>MYBPC3</td>\n",
              "      <td>4607</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>7</th>\n",
              "      <td>SPTAN1</td>\n",
              "      <td>6709</td>\n",
              "      <td>False</td>\n",
              "      <td>1/35</td>\n",
              "      <td>0.224993</td>\n",
              "      <td>MYH7</td>\n",
              "      <td>4625</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>8</th>\n",
              "      <td>BRCA1</td>\n",
              "      <td>672</td>\n",
              "      <td>False</td>\n",
              "      <td>1/38</td>\n",
              "      <td>0.241744</td>\n",
              "      <td>TTN</td>\n",
              "      <td>7273</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "  Spliced genes  ...      Affected binding (NCBI)\n",
              "0         MYO19  ...  7168,7171,4633,7169,71,7170\n",
              "1         OBSCN  ...                         7273\n",
              "2         USP49  ...                         5566\n",
              "3       CACNA1C  ...                         6262\n",
              "4         ERBB3  ...                         5566\n",
              "5         ARRB1  ...                          153\n",
              "6           TTN  ...                         4607\n",
              "7        SPTAN1  ...                         4625\n",
              "8         BRCA1  ...                         7273\n",
              "\n",
              "[9 rows x 7 columns]"
            ]
          },
          "metadata": {},
          "execution_count": 12
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "d1609e9a-0aab-4f04-a05a-4933aeceddea",
        "outputId": "b67b7163-8fec-4e9a-ff54-a212a4fb073c",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 80
        }
      },
      "source": [
        "# the gene MYO10 and OBSCN looks interesting, let us see what domain got affected and if the psi is positive or negative\n",
        "events.get_edges()[ events.get_edges() ['Gene name']=='OBSCN' ]"
      ],
      "id": "d1609e9a-0aab-4f04-a05a-4933aeceddea",
      "execution_count": 13,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Gene name</th>\n",
              "      <th>NCBI gene ID</th>\n",
              "      <th>Identifier</th>\n",
              "      <th>dPSI</th>\n",
              "      <th>Number of affected interactions</th>\n",
              "      <th>Affected binding</th>\n",
              "      <th>Affected binding (NCBI)</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>95</th>\n",
              "      <td>OBSCN</td>\n",
              "      <td>84033</td>\n",
              "      <td>PF07679</td>\n",
              "      <td>-0.191164</td>\n",
              "      <td>2</td>\n",
              "      <td>TTN,ANK1</td>\n",
              "      <td>7273,286</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "   Gene name NCBI gene ID  ... Affected binding  Affected binding (NCBI)\n",
              "95     OBSCN        84033  ...         TTN,ANK1                 7273,286\n",
              "\n",
              "[1 rows x 7 columns]"
            ]
          },
          "metadata": {},
          "execution_count": 13
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "0a7d845e-ffca-421d-bea7-d59d81e2c353",
        "outputId": "4036ec56-41ff-46ad-8cb8-37829d1dd4a2",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 80
        }
      },
      "source": [
        "events.get_edges()[ events.get_edges() ['Gene name']=='CACNA1C' ]"
      ],
      "id": "0a7d845e-ffca-421d-bea7-d59d81e2c353",
      "execution_count": 14,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Gene name</th>\n",
              "      <th>NCBI gene ID</th>\n",
              "      <th>Identifier</th>\n",
              "      <th>dPSI</th>\n",
              "      <th>Number of affected interactions</th>\n",
              "      <th>Affected binding</th>\n",
              "      <th>Affected binding (NCBI)</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>49</th>\n",
              "      <td>CACNA1C</td>\n",
              "      <td>775</td>\n",
              "      <td>PF00520</td>\n",
              "      <td>0.100241</td>\n",
              "      <td>4</td>\n",
              "      <td>RYR2,CALM1,CABP1,SRI</td>\n",
              "      <td>801,9478,6717,6262</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "   Gene name NCBI gene ID  ...      Affected binding  Affected binding (NCBI)\n",
              "49   CACNA1C          775  ...  RYR2,CALM1,CABP1,SRI       801,9478,6717,6262\n",
              "\n",
              "[1 rows x 7 columns]"
            ]
          },
          "metadata": {},
          "execution_count": 14
        }
      ]
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "a4b9b680-c8ed-444f-ad0d-1b1313c15951"
      },
      "source": [
        "### Visualization"
      ],
      "id": "a4b9b680-c8ed-444f-ad0d-1b1313c15951"
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "3a684fb9-d904-45f8-8e7e-ada448764d51",
        "outputId": "0f722566-f6f2-44fc-82e7-e23b22e6f18b",
        "colab": {
          "base_uri": "https://localhost:8080/"
        }
      },
      "source": [
        "# Finally we can visualize affected pathways with nease\n",
        "# Again we run it on DCM pathway\n",
        "# you can run this function several times to get a  better visualization\n",
        "\n",
        "events.Vis_path('path:hsa05414',k=0.8)"
      ],
      "id": "3a684fb9-d904-45f8-8e7e-ada448764d51",
      "execution_count": 15,
      "outputs": [
        {
          "output_type": "stream",
          "name": "stdout",
          "text": [
            "Enrichment of the pathway: Dilated cardiomyopathy (DCM) - Homo sapiens (human).\n",
            "\n",
            "Overall p_value:  0.0198055308545215\n",
            "\n",
            "\n",
            "Visualization of the pathway generated in: Dilated cardiomyopathy (DCM) - Homo sapiens (human).html\n"
          ]
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "e7e9b7ca-68de-45a8-bcd8-941f9afd021f"
      },
      "source": [
        ""
      ],
      "id": "e7e9b7ca-68de-45a8-bcd8-941f9afd021f",
      "execution_count": 15,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "2fe49177-9806-464e-8c4a-470b6560a093"
      },
      "source": [
        ""
      ],
      "id": "2fe49177-9806-464e-8c4a-470b6560a093",
      "execution_count": 15,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "c999e6ed-1bd0-4c7c-94e7-ea41f39a7c6d"
      },
      "source": [
        ""
      ],
      "id": "c999e6ed-1bd0-4c7c-94e7-ea41f39a7c6d",
      "execution_count": 15,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "0e57963d-55cd-4bdb-afb5-07a30477607a"
      },
      "source": [
        ""
      ],
      "id": "0e57963d-55cd-4bdb-afb5-07a30477607a",
      "execution_count": 15,
      "outputs": []
    }
  ]
}