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Pattern Extraction and Patient-Level Prediction of Adverse Events Using Meta-Analysis and Matrix Decomposition








Pattern Extraction and Patient-Level Prediction of Adverse Events Using Meta-Analysis and Matrix Decomposition


Kentaro Matsuura


Tokyo University of Science






7 Aug 2019


In clinical studies, adverse events (AEs) occurring in each patient from the beginning to the end of the study are recorded. The primary purpose of assessing AEs is to determine which AE sets (patterns) are most likely to occur. A secondary purpose is to predict AEs at the patient level. The aim of our research was to develop a method which simultaneously serves both of these purposes. We constructed a statistical model including nonnegative matrix factorization by incorporating prior knowledge of AE-specific structures such as severity and drug mechanism of action. We also constructed a statistical model using a meta-analysis framework in order to be able to process data from multiple clinical studies because insufficient information is derived from a single trial. We used real data from three Phase III studies to evaluate the operating characteristics of the proposed method. The data included two mechanisms of action, five treatments, 3,317 patients, and 848 AE types. As a result, we extracted a limited number of treatment-specific AE patterns such as “nausea and vomiting pattern”, “constipation pattern”, and “neuropathy pattern”, which coincided with background knowledge. Based on patient AE occurring within the treatment cycles, we quantitatively predicted the AEs most likely to occur in the future (submitted for publication).Next, using big data in ClinicalStudyDataRequest.com, we would like to incorporate temporal order of AEs, dose response curves, patient information including age, weight and blood test values, pharmacodynamics data such as exposure etc. into our statistical model. We believe that our research will enable time-dependent AE pattern extraction, improving prediction performance, and then the proposal of drugs that are likely to reduce AEs for each patient.



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(AVOREN)", "Description": "A randomised, double-blind phase III study to evaluate the efficacy and safety of bevacizumab in combination with interferon alfa-2a (roferon) versus interferon alfa-2a and placebo as first line treatment administered to nephrectomized patients with metastatic clear cell renal cell carcinoma" },{ "PostingID": 1316, "Title": "ROCHE-NO16966", "Description": "2 x 2 Factorial randomized phase III study of intermittent oral capecitabine in combination with intravenous oxaliplatin (q3w) (\"XELOX\") with/without intravenous bevacizumab (q3w) versus bolus and continuous infusion fluorouracil/intravenous leucovorin with intravenous oxaliplatin (q2w) (\"FOLFOX-4\") with/without intravenous bevacizumab (q2w) as first-line treatment for patients with metastatic colorectal cancer." },{ "PostingID": 2545, "Title": "ROCHE-BO17706", "Description": "A Randomized, Double-blind Study of the Effect of Avastin Plus Gemcitabine and Erlotinib Compared With Placebo Plus Gemcitabine 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With Chemotherapy Regimens in Subjects With Previously Treated Metastatic Breast Cancer" },{ "PostingID": 2550, "Title": "ROCHE-AVF4095G", "Description": "A Phase III, Multicenter, Randomized, Blinded, Placebo-controlled Trial of Carboplatin and Gemcitabine Plus Bevacizumab in Patients With Platinum-sensitive Recurrent Ovary, Primary Peritoneal, or Fallopian Tube Carcinoma" },{ "PostingID": 2560, "Title": "ROCHE-MO22224", "Description": "AURELIA: A Multi-center, Open-label, Randomised, Two-arm Phase III Trial of the Effect on Progression Free Survival of Bevacizumab Plus Chemotherapy Versus Chemotherapy Alone in Patients With Platinum-resistant, Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer" },{ "PostingID": 2561, "Title": "ROCHE-NO16967", "Description": "A Randomized, Open-label Study of the Effect of Intermittent Xeloda Versus iv Fluorouracil/Leucovorin, Both in Combination With Eloxatin, on Tumor Progression in Patients With Metastatic Colorectal Cancer Who Received Prior CPT-11 and 5-fluorouracil/Leucovorin" },{ "PostingID": 2562, "Title": "ROCHE-NO16968", "Description": "A randomized, open-label study of the effect of intermittent Xeloda in combination with Eloxatin, versus fluorouracil/leucovorin, on disease-free survival in patients who have undergone surgery for colon cancer" },{ "PostingID": 2563, "Title": "ROCHE-NO17629", "Description": "A Randomized, Open-label Study of the Effect of Adjuvant Therapy With Adriamycin Plus Cytoxan Followed by Taxotere or Taxotere Plus Xeloda on Overall Survival in Female Patients With High-risk Breast Cancer." },{ "PostingID": 2574, "Title": "ROCHE-BO21977", "Description": "A randomized, Multicenter, Phase III Open-Label study of the efficacy and safety of Trastuzumab-MCC-DM1 vs. Capecitabine + Lapatinib in patients with HER2-Positive locally advanced or metastic breast cancer who have received prior Trastuzumab-based therapy." },{ "PostingID": 2650, "Title": "LILLY-H3E-MC-JMHD", "Description": "PointBreak: a Randomized Phase III Study of Pemetrexed plus Carboplatin and Bevacizumab Followed by Maintenance Pemetrexed and Bevacizumab versus Paclitaxel plus Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in Patients with Stage IIIB or IV Nonsquamous Non-small Cell Lung Cancer" },{ "PostingID": 3183, "Title": "LILLY-H3E-EW-S124", "Description": "A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed Plus Best Supportive Care Versus Best Supportive Care Immediately Following Induction Treatment With Pemetrexed + Cisplatin for Advanced Non-squamous Non-Small Cell Lung Cancer." },{ "PostingID": 3204, "Title": "LILLY-H3E-MC-JMEN", "Description": "A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care versus Best Supportive Care Immediately Following Induction Treatment for Advanced Non-Small Cell Lung Cancer" },{ "PostingID": 3358, "Title": "ROCHE-BO16216", "Description": "A randomized, open-label study of the effect of Herceptin plus Arimidex compared with Arimidex alone on progression-free survival in patients with HER2-positive and hormone-receptor positive metastatic breast cancer" },{ "PostingID": 3744, "Title": "LILLY-I4T-IE-JVBD", "Description": "A Phase 3, Randomized, Double-Blinded Study of IMC-1121B and Best Supportive Care (BSC) Versus Placebo and BSC in the Treatment of Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Following Disease Progression on First-Line Platinum- or Fluoropyrimidine-Containing Combination Therapy" },{ "PostingID": 3745, "Title": "LILLY-I4T-IE-JVBE", "Description": "A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 3 Study of Weekly Paclitaxel With or Without Ramucirumab (IMC-1121B) Drug Product in Patients With Metastatic Gastric Adenocarcinoma, Refractory to or Progressive After First-Line Therapy With Platinum and Fluoropyrimidine" },{ "PostingID": 3846, "Title": "ROCHE-BO18192", "Description": "A randomized, double-blind study to evaluate the effect of Tarceva or placebo following platinum-based CT on overall survival and disease progression in patients with advanced, recurrent or metastatic NSCLS who have not experienced disease progression or unacceptable toxicity during chemotherapy" },{ "PostingID": 3847, "Title": "ROCHE-BO18602", "Description": "An open-label, randomized study to evaluate the effect of Tarceva, compared with Alimta (pemetrexed) or Taxotere (docetaxel),on survival in patients with advanced, recurrent or metastatic non-small cell lung cancer who have experienced disease progression during platinum-based chemotherapy" },{ "PostingID": 3851, "Title": "ROCHE-AVF3671G", "Description": "A randomized, Double-BLIND, Placebo-controlled, phase IIIb trial comparing BEVACIZUMAB therapy WITH OR WITHOUT ERLotInib AFTER COMPLETION OF CHEMOTHERAPY WITH BEVACIZUMAB for the first-line treatment of Locally Advanced, Recurrent, or metastatic nON SMALL CELL LUNG CANCER" },{ "PostingID": 4044, "Title": "NOVARTIS-CRAD001R2301", "Description": "A Randomized, Double-blind, Multi-center Phase III Study Comparing Everolimus (RAD001) Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Patients With Advanced Gastric Cancer After Progression on 1 or 2 Prior Systemic Chemotherapy" },{ "PostingID": 4137, "Title": "NOVARTIS-CRAD001A2309", "Description": "Efficacy and Safety Study Comparing Concentration-controlled Everolimus in Two Doses (1.5 and 3.0 mg/Day Starting Doses) With Reduced Cyclosporine Versus 1.44 g Mycophenolic Acid (as Sodium Salt) With Standard Dose Cyclosporine in de Novo Renal Transplant Recipients" },{ "PostingID": 4141, "Title": "NOVARTIS-CRAD001H2304", "Description": "A 24 Month, Multicenter, Open-label, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients" },{ "PostingID": 4200, "Title": "LILLY-H3E-MC-JMIG", "Description": "Phase 3 Study of Pemetrexed, Cisplatin, and Radiotherapy Followed by Consolidation Pemetrexed versus Etoposide, Cisplatin, and Radiotherapy Followed by Consolidation Cytotoxic Chemotherapy of Choice in Patients with Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer Other than Predominantly Squamous Cell Histology" },{ "PostingID": 4533, "Title": "LILLY-14X-IE-JFCC", "Description": "A Randomized, Multicenter, Open-Label Phase 3 Study of Gemcitabine-Cisplatin Chemotherapy Plus Necitumumab (IMC-11F8) Versus Gemcitabine-Cisplatin Chemotherapy Alone in the First-Line Treatment of Patients With Stage IV Squamous Non-Small Cell Lung Cancer (NSCLC) (SQUIRE)" },{ "PostingID": 4540, "Title": "LILLY-I4T-MC-JVBA", "Description": "A Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab versus Docetaxel and Placebo in the Treatment of Stage IV Non-Small Cell Lung Cancer Following Disease Progression after One Prior Platinum-Based Therapy (REVEL)" },{ "PostingID": 4541, "Title": "LILLY-I4T-MC-JVBB", "Description": "A Randomized, Double-Blind, Multicenter Phase 3 Study of Irinotecan, Folinic Acid, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab or Placebo in Patients With Metastatic Colorectal Carcinoma Progressive During or Following First-Line Combination Therapy With Bevacizumab, Oxaliplatin, and a Fluoropyrimidine (RAISE)" },{ "PostingID": 4550, "Title": "ROCHE-BO22589", "Description": "A Study of Trastuzumab-DM1 Plus Pertuzumab Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer" },{ "PostingID": 4551, "Title": "ROCHE-BO25734", "Description": "A Phase III Randomized, Multicenter, Two Arm, Open-label Trial to Evaluate the Efficacy of Trastuzumab Emtansine Compared With Treatment of Physician's Choice in Patients With HER2-positive Metastatic Breast Cancer Who Have Received at Least Two Prior Regimens of HER2 Directed Therapy" },{ "PostingID": 4801, "Title": "ROCHE-AVF4200G/BO20904", "Description": "(AVAGAST) A Double-blind, Randomised, Multicenter, Phase III Study of Bevacizumab in Combination With Capecitabine and Cisplatin Versus Placebo in Combination With Capecitabine and Cisplatin, as First-line Therapy in Patients With Advanced Gastric Cancer" },{ "PostingID": 4802, "Title": "ROCHE-ML22367", "Description": "(AVATAR) A Double-Blind, Randomized, Multicenter, Phase III Study of Bevacizumab in Combination With Capecitabine and Cisplatin Versus Placebo in Combination With Capecitabine and Cisplatin, as First-Line Therapy in Patients With Advanced Gastric Cancer." },{ "PostingID": 5013, "Title": "LILLY-B9E-US-S302", "Description": "Phase III Randomized Trial of Induction Chemotherapy With Gemcitabine and Carboplatin Followed by Elective Paclitaxel Consolidation Versus Paclitaxel and Carboplatin Followed by Elective Paclitaxel Consolidation in Patients With Primary Epithelial Ovarian, Primary Peritoneal Cancer or Fallopian Tube Carcinoma" },{ "PostingID": 5060, "Title": "LILLY-I4X-IE-JFCB", "Description": "A Randomized, Multicenter, Open-Label Phase 3 Study of Pemetrexed-Cisplatin Chemotherapy Plus Necitumumab (IMC-11F8) Versus Pemetrexed-Cisplatin Chemotherapy Alone in the First-Line Treatment of Patients With Stage IV Nonsquamous Non-Small Cell Lung Cancer (NSCLC)" },{ "PostingID": 5066, "Title": "ROCHE-BO16348", "Description": "A Randomized Three-Arm, Multicenter Comparison of 1 Year and 2 Years of Herceptin Versus No Herceptin in Women With HER2-Positive Primary Breast Cancer Who Have Completed Adjuvant Chemotherapy" },{ "PostingID": 5067, "Title": "*ROCHE-MO17527/L_9570", "Description": "A Phase III Study Comparing Adjuvant Chemotherapy Consisting of Capecitabine/Oxaliplatin versus Surgery Alone in Patients with Stage II (T1N2, T2N1, T3N0), IIIa (T2N2, T3N1, T4N0), and IIIb (T3N2) Gastric Adenocarcinoma" },{ "PostingID": 14472, "Title": "ROCHE-YO25121", "Description": "A multicenter, open-label, randomized Phase III study to evaluate the efficacy and safety of Erlotinib (Tarceva┬«) versus gemcitabine/cisplatin as the first-line treatment for stage IIIB/IV non-small cell lung cancer (NSCLC) patients with mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) in their tumors." },{ "PostingID": 14473, "Title": "ROCHE-BO20289 (Beatrice)", "Description": "An International Multi-centre Open-label 2-arm Phase III Trial of Adjuvant Bevacizumab in \"Triple Negative\" Breast Cancer." },{ "PostingID": 14474, "Title": "ROCHE-ML21217", "Description": "Available - Avastin in Addition to Platinum-based Chemotherapy is Indicated for First-lime Treatment of Patients With Locally Advanced, Metastatic or Recurrent Non-small Lung Cancer Other Than Predominantly Squamous Cell Histology" },{ "PostingID": 14486, "Title": "ROCHE-YO25404", "Description": "A Study of Bevacizumab Versus Placebo in Combination With Carboplatin/Paclitaxel in Participants With Advanced or Recurrent Non-Squamous Non-Small Cell Lung Cancer Who Have Not Received Previous Chemotherapy" },{ "PostingID": 14487, "Title": "ROCHE-AVF3991n", "Description": "An Observational Study of Avastin (Bevacizumab) in Combination With Chemotherapy for Treatment of Metastatic or Locally Advanced and Unresectable Colorectal Cancer and Locally Advanced or Metastatic Non-Small Cell Lung Cancer (Excluding Predominant Squamous Cell Histology)" },{ "PostingID": 14569, "Title": "NOVARTIS-CRAD001JDE49", "Description": "A Phase IIIB, Multi-Center, Open Label Study For Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Treated With Everolimus (RAD001) in Combination With Exemestane: 4EVER - Efficacy, Safety, Health Economics, Translational Research" },{ "PostingID": 14573, "Title": "ROCHE-MO18109", "Description": "An Expanded Access Program of Tarceva (Erlotinib) in Patients With Advanced Stage IIIB/IV Non-Small Cell Lung Cancer" },{ "PostingID": 14579, "Title": "ROCHE-GO28915", "Description": "A Study of Atezolizumab Compared With Docetaxel in Participants With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Failed Platinum-Containing Therapy" },{ "PostingID": 16078, "Title": "ROCHE-GO25632", "Description": "Study To Evaluate the Efficacy and Safety Of Bevacizumab, and Associated Biomarkers, In Combination With Paclitaxel Compared With Paclitaxel Plus Placebo as First-line Treatment Of Patients With Her2-Negative Metastatic Breast Cancer" },{ "PostingID": 16159, "Title": "NOVARTIS-CRAD001Y2301", "Description": "A Randomized Double-Blind, Placebo-Controlled Study of Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole" },{ "PostingID": 19614, "Title": "NOVARTIS-CRAD001J2301", "Description": "A Randomized Phase III, Double-Blind, Placebo-Controlled Multicenter Trial of Everolimus in Combination With Trastuzumab and Paclitaxel, as First Line Therapy in Women With HER2 Positive Locally Advanced or Metastatic Breast Cancer" },{ "PostingID": 19615, "Title": "NOVARTIS-CRAD001W2301", "Description": "A Randomized Phase III, Double-blind, Placebo-controlled Multicenter Trial of Daily Everolimus in Combination With Trastuzumab and Vinorelbine, in Pretreated Women With HER2/Neu Over-expressing Locally Advanced or Metastatic Breast Cancer" },{ "PostingID": 19661, "Title": "ROCHE-BO21990", "Description": "A randomized, double-blind, placebocontrolled, multicenter Phase III trial of bevacizumab (Bv), temozolomide (TMZ) and radiotherapy (RT), followed by Bv and TMZ versus placebo (Pl), TMZ and RT followed by Pl and TMZ in patients with newly diagnosed glioblastoma." },{ "PostingID": 19686, "Title": "NOVARTIS-CRAD001AUS92", "Description": "A 12 Month, Multi-center, Randomized, Open-label Non-inferiority Study Comparing Safety and Efficacy of Concentration-controlled Everolimus With Low Dose Tacrolimus to Mycophenolate Mofetil With Standard Dose Tacrolimus in de Novo Renal Transplant Recipients" },{ "PostingID": 19687, "Title": "NOVARTIS-CRAD001A2429", "Description": "A 24-month, multi-center, open-label, randomized, controlled trial to investigate efficacy, safety and evolution of cardiovascular parameters in de novo renal transplant recipients after early calcineurin inhibitor to everolimus conversion." },{ "PostingID": 19847, "Title": "NOVARTIS-CRAD001A2433", "Description": "A 24 Month, Multicenter, Randomized, Open-label Safety and Efficacy Study of Concentration-controlled Everolimus With Reduced Calcineurin Inhibitor vs Mycophenolate With Standard Calcineurin Inhibitor in de Novo Renal Transplantation" }]

Statistical Analysis Plan