Study on statistical methods to integrate high-dimensional and heterogenous biomedical data for predicting and controlling disease progression

• Project/Area Number: 18H03329
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 62010:Life, health and medical informatics-related
• Research Institution: Aichi Cancer Center Research Institute (2019-2020); The University of Tokyo (2018)
• Principal Investigator: Yamaguchi Rui 愛知県がんセンター(研究所), システム解析学分野, 分野長 (90380675)
• Co-Investigator(Kenkyū-buntansha): 横山 和明 東京大学, 医科学研究所, 助教 (00647498)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
• Keywords: 病態予測 / 情報統合 / 異種多次元データ / 異種情報統合 / 有用情報抽出 / 微小残存病変 / 変異検出 / 病態遷移モデル / 個別変異データ / スパースモデリング / 病態予測モデル

Outline of Final Research Achievements

In this research project, we studied computational methodologies to extract useful information from heterogeneous and multi-dimensional biomedical data from each patient in order to predict and control disease progression. We proposed a new method to integrate Bayes Factors from multiple models. Using that, we can build an accurate somatic mutation caller for multiple samples within a single patient. We also devised an explainable AI to extract useful information from the complex biomedical data such as networks. In addition, we monitored circulating tumor DNAs (ctDNAs) to identify minimal residual diseases (MRDs) for blood cancer patients. We showed ctDNA is useful for predicting disease progression of blood cancers. We are continuing to make a method combining ctDNA and other biomedical data for more accurate prediction of disease progression.

Academic Significance and Societal Importance of the Research Achievements

技術の進展により、患者一人ひとりから多種多様な生体データの情報が得られるようになりつつある。本研究では、それらの異種かつ多要素の膨大なデータを統合的に活用し、個人ごとに異なる病態の経過を、予測しかつ制御するための情報を抽出する数理的方法論を構築することを目標とした。その結果、新たな情報統合および情報抽出のための手法を複数開発した。また実際の臨床データの計測と解析から腫瘍由来循環DNAが血液がんの病態の進展の予測に有用である知見も得た。これらの知見は、今後の更なる精緻な病態遷移予測モデルの開発につながることが期待される。

Research Products

• [Journal Article] 急性骨髄性白血病や骨髄異形成症候群において同種移植後の循環腫瘍DNA残存は再発を予測するバイオマーカーである (2021)
  • Author(s): 横山和明
  • Journal Title: 臨床血液 Volume: -
  • NAID: 130008063721
  • Peer Reviewed
• [Journal Article] Global gene network exploration based on explainable artificial intelligence approach (2020)
  • Author(s): Park Heewon、Maruhashi Koji、Yamaguchi Rui、Imoto Seiya、Miyano Satoru
  • Journal Title: PLOS ONE Volume: 15 Issue: 11 Pages: e0241508-e0241508
  • DOI: 10.1371/journal.pone.0241508
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Automatic sparse principal component analysis (2020)
  • Author(s): Park Heewon、Yamaguchi Rui、Imoto Seiya、Miyano Satoru
  • Journal Title: Canadian Journal of Statistics Volume: Online first Issue: 3 Pages: 1-24
  • DOI: 10.1002/cjs.11579
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Theoretical Foundation of the Performance of Phylogeny-Based Somatic Variant Detection (2020)
  • Author(s): Moriyama Takuya、Imoto Seiya、Miyano Satoru、Yamaguchi Rui
  • Journal Title: Lecture Notes in Computer Science Volume: 12508 Pages: 87-101
  • DOI: 10.1007/978-3-030-64511-3_9
  • ISBN: 9783030645106, 9783030645113
  • Peer Reviewed / Open Access
• [Journal Article] Artificial intelligence-guided precision medicine in hematological disorders (2020)
  • Author(s): 横山 和明
  • Journal Title: Rinsho Ketsueki Volume: 61 Issue: 5 Pages: 554-563
  • DOI: 10.11406/rinketsu.61.554
  • NAID: 130007852311
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Successful clinical sequencing by molecular tumor board in an elderly patient with refractory Sezary syndrome (2020)
  • Author(s): Hijikata K, Yokoyama K (co-1st and co-corresponding author), Yokoyama N, Matsubara Y, Shimizu E, Nakashima M, Yamagishi M, Ota Y, Lim L, Yamaguchi R, Ito M, Tanaka Y, Denda T, Tani K, Yotsuyanagi H, Imoto S, Miyano S, Uchimaru K, Tojo A.
  • Journal Title: JCO Precis Oncol Volume: 4 Issue: 4 Pages: 534-560
  • DOI: 10.1200/po.19.00254
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An Unusually Short Latent Period of Therapy-Related Myeloid Neoplasm Harboring a Rare MLL-EP300 Rearrangement: Case Report and Literature Review (2019)
  • Author(s): Takeda R, Yokoyama K (corresponding author), Kobayashi S, Kawamata T, S Nakamura, Tomofusa F, Ito M, Yusa N, Shimizu E, Ohno N, Yamaguchi R, Imoto S, Miyano S, Uchimaru K, and Tojo A.
  • Journal Title: Case Rep Hematol Volume: epub Pages: 4532434-4532434
  • DOI: 10.1155/2019/4532434
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS. (2019)
  • Author(s): Nakamura S, Yokoyama K (co-1st and co-corresponding author), Shimizu E, Yusa N, Kondoh K, Ogawa M, Takei T, Kobayashi A, Ito M, Isobe M, Konuma T, Kato S, Kasajima R, Wada Y, Inoue-Nagamura T, Yamaguchi R, Takahashi S, Imoto S, Miyano S, and Tojo A.
  • Journal Title: Blood Volume: 133 Issue: 25 Pages: 2682-2695
  • DOI: 10.1182/blood-2018-10-880690
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The first case of elderly TCF3-HLF-positive B-cell acute lymphoblastic leukemia. (2019)
  • Author(s): Takeda R, Yokoyama K (corresponding author), Ogawa M, Kawamata T, Tomofusa F, Kondoh K, Tomomi T, Nakamura S, Ito M, Yusa N, Shimizu E, Ohno N, Uchimaru K, Yamaguchi R, Imoto S, Miyano S, and Tojo A.
  • Journal Title: Leuk lymphoma. Volume: 60 Issue: 11 Pages: 2821-2824
  • DOI: 10.1080/10428194.2019.1602267
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Accurate and Flexible Bayesian Mutation Call from Multi-regional Tumor Samples (2019)
  • Author(s): Moriyama Takuya、Imoto Seiya、Miyano Satoru、Yamaguchi Rui
  • Journal Title: Lecture Notes in Computer Science Volume: 11826 Pages: 47-61
  • DOI: 10.1007/978-3-030-35210-3_4
  • ISBN: 9783030352097, 9783030352103
  • Peer Reviewed
• [Journal Article] Myeloablative single-unit cord blood transplantation overcomes the negative prognostic impact of FLT3-ITD in adult acute myeloid leukemia (2019)
  • Author(s): Konuma Takaaki、Kato Seiko、Oiwa-Monna Maki、Mizusawa Mai、Isobe Masamichi、Yokoyama Kazuaki、Takahashi Satoshi、Tojo Arinobu
  • Journal Title: Leukemia & Lymphoma Volume: - Issue: 9 Pages: 2320-2323
  • DOI: 10.1080/10428194.2019.1579325
  • Peer Reviewed
• [Journal Article] Circulating tumor DNA dynamically predicts response and/or relapse in patients with hematological malignancies (2018)
  • Author(s): Nakamura S, Yokoyama K, Yusa N, Ogawa M, Takei T, Kobayashi A, Ito M, Shimizu E, Kasajima R, Wada Y, Yamaguchi R, Imoto S, Nagamura-Inoue T, Miyano S, Tojo A
  • Journal Title: Int J Hematol Volume: 108(4) Issue: 4 Pages: 402-410
  • DOI: 10.1007/s12185-018-2487-2
  • Peer Reviewed
• [Presentation] Theoretical Foundation of the Performance of Phylogeny-Based Somatic Variant Detection (2020)
  • Author(s): Moriyama Takuya、Imoto Seiya、Miyano Satoru、Yamaguchi Rui
  • Organizer: International Symposium on Mathematical and Computational Oncology
  • Int'l Joint Research
• [Presentation] 急性骨髄性白血病や骨髄異形成症候群において同種移植後の循環腫瘍DNA残存は再発を予測するバイオマーカーである (2020)
  • Author(s): 横山和明
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] The impact of circulating tumor DNA status on acute myeloid leukemia and myelodysplastic syndromes with alloSCT: Interim results of a prospective study (2020)
  • Author(s): Ogawa M, Yokoyama K, et al.
  • Organizer: 46th EBMT2020
  • Int'l Joint Research
• [Presentation] Cell free-DNA based detection of minimal residual disease post allogenic-stem cell transplantation in acute myeloid leukemia and myelodysplastic syndromes (2020)
  • Author(s): Kazuaki Yokoyama, Nozomi Yusa, Mika Ito, Miho Ogawa, Kanya Kondoh, Eigo Shimizu, Seiya Imoto, Arinobu Tojo, Satoshi Takahashi
  • Organizer: 7th US-Japan Workshop on Biomarkers for Cancer Early Detection
  • Int'l Joint Research
• [Presentation] がんのプレシジョン・メディスンにおけるAI活用の試み (2019)
  • Author(s): 横山和明
  • Organizer: 日本血液学会学術集会
  • Invited
• [Presentation] 腫瘍由来循環DNAを用いたAMLおよびMDSの移植後微小残存病変検出に関する後方視的解析 (2019)
  • Author(s): 横山和明
  • Organizer: 神奈川移植Forum
  • Invited
• [Presentation] 治療関連骨髄系腫瘍15例のゲノム解析と液体生検によるファウンダークローンの後方視的追跡 (2019)
  • Author(s): 近藤 幹也, 横山 和明, 遊佐 希, 伊藤 美香, 清水 英悟, 中村 聡介, 小川 弥穂, 武井 智美, 小林 麻子, 笠島 理加, 和田 結花, 山口 類, 井元 清哉, 長村 登紀子, 内丸 薫, 宮野 悟, 東條 有伸
  • Organizer: 日本血液学会学術集会
• [Presentation] 臨床シークエンスにて確定診断に至った慢性好中球性白血病の２例 (2019)
  • Author(s): 小川 弥穂, 横山 和明, 塚田 信弘, 余語 孝夫3, 近藤 幹也, 武井 智美, 中村 聡介, 伊藤 美香, 小林 麻子, 遊佐 希, 山本 茉子, 笠島 理加, 清水 英悟, 山口 類, 井元 清哉, 宮野 悟, 東條 有伸
  • Organizer: 日本血液学会学術集会
• [Presentation] Accurate and Flexible Bayesian Mutation Call from Multi-regional Tumor Samples (2019)
  • Author(s): Moriyama Takuya、Imoto Seiya、Miyano Satoru、Yamaguchi Rui
  • Organizer: International Symposium on Mathematical and Computational Oncology
  • Int'l Joint Research
• [Presentation] The utility of exome sequence of circulating tumor DNA in drug-resistant and/or advanced phase chronic myeloid leukemia (2019)
  • Author(s): Tomomi Takei, Kazuaki Yokoyama, Sousuke Nakamura, Miho Ogawa, Kanya Kondoh, Eigo Shimizu, Rika Kasajima, Rui Yamaguchi, Seiya Imoto, Satoru Miyano, Arinobu Tojo
  • Organizer: 日本癌学会学術総会
• [Presentation] Circulating tumor DNA predicts post-allogeneic hematopoietic stem cell transplantation in AML and MDS (2019)
  • Author(s): Nakamura S, Yokoyama K, Shimizu E, Yusa N, Ogawa M, Takei T, Kobayashi A, Ito M, Isobe M, Konuma T, Kato S, Kasajima R, Wada Y, Nagamura-Inoue T, Yamaguchi R, Takahashi S, Imoto S, Miyano S, Tojo A
  • Organizer: Molecular Med Tri-Con
  • Int'l Joint Research
• [Presentation] Prognostic Impact of Circulating Tumor DNA Status Post-Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome (2018)
  • Author(s): Nakamura S, Yokoyama K, Shimizu E, Yusa N, Kondoh K, Ogawa M, Takei T, Kobayashi A, Ito M, Isobe M, Konuma T, Kato S, Kasajima R, Wada Y, Inoue-Nagamura T, Yamaguchi R, Takahashi S, Imoto S, Miyano S, Tojo A
  • Organizer: 60th ASH Annual Meeting
  • Int'l Joint Research
• [Presentation] Residual circulating tumor DNA status in relapse prediction post allogeneic hematopoietic stem cell transplantation (2018)
  • Author(s): Nakamura S, Yokoyama K, Yusa N, Kondo K, Ogawa M, Takei T, Kobayashi A, Ito M, Jimbo K, Tanoue S, Isobe M, Konuma T, Kato S, Shimizu E, Kasajima R, Wada Y, Yamaguchi R, Imoto S, Nagamura-Inoue T, Takahashi S, Miyano S, Tojo A
  • Organizer: 第13回生命医科学研究所ネットワーク国際シンポジウム
  • Int'l Joint Research
• [Presentation] 腫瘍由来循環DNAを用いたAMLおよびMDSの移植後微小残存病変の検出に関する後方視的解析 (2018)
  • Author(s): Nakamura S, Yokoyama K, Yusa N, Kondo K, Ogawa M, Takei T, Kobayashi A, Ito M, Jimbo K, Tanoue S, Isobe M, Konuma T, Kato S, Shimizu E, Kasajima R, Wada Y, Yamaguchi R, Imoto S, Nagamura-Inoue T, Takahashi S, Miyano S, Tojo A
  • Organizer: 第80回日本血液学会学術総会
• [Presentation] Circulating tumor DNA predicts relapse after allogeneic hematopoietic stem cell transplantation in AML and MDS (2018)
  • Author(s): 中村聡介、横山和明、近藤幹也、武井智美、清水英悟、笠島理加、山口類、井元清哉、宮野悟、東條有伸
  • Organizer: 第77回日本癌学会学術集会
• [Presentation] Successful application of RHOA p.G17V for diagnosis and disease monitoring in a case of AITL (2018)
  • Author(s): 水澤 舞、小川弥穂、横山和明、川俣豊隆、安藤匠平、近藤幹也、武井智美、中村聡介、伊藤美香、遊佐 希、笠島理加、清水英悟、牧山純也、安井 寛、山口 類、井本清哉、宮野 悟、吉川賢忠、田中廣壽、今井陽一、東條有伸
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Residual circulating tumor DNA status in relapse prediction post allogeneic hematopoietic stem cell transplantation (2018)
  • Author(s): 中村 聡介、横山 和明、遊佐 希、近藤 幹也、小川 弥穂、武井 智美、小林 麻子、伊藤 美香、神保 光児、田上 晋、磯部 優理、小沼 貴晶、加藤 せい子、清水 英悟 、笠島 理加、和田 結花、山口 類、井元 清哉、長村 登紀子、高橋 聡、宮野 悟、東條 有伸
  • Organizer: 第１８回東京大学生命科学シンポジウム
• [Presentation] Impact of residual circulating tumor DNA status post allogeneic hematopoietic stem cell transplantation on outcome in acute myeloid leukemia and myelodysplastic syndrome (2018)
  • Author(s): Nakamura S, Yokoyama K, Yusa N, Kondo K, Ogawa M, Takei T, Kobayashi A, Ito M, Jimbo K, Tanoue S, Isobe M, Konuma T, Kato S, Shimizu E, Kasajima R, Wada Y, Yamaguchi R, Imoto S, Nagamura-Inoue T, Takahashi S, Miyano S, Tojo A
  • Organizer: 45th IMSUT Founding Commemorative Symposium