84

Human Genome Center

Division of Health Medical Intelligence
健康医療インテリジェンス分野
Professor
Associate Professor
Assistant Professor

Seiya Imoto, Ph.D.
Yao-zhong Zhang, Ph.D.
Noriaki Sato, M.D., Ph.D.

教 授
准教授
助 教

博士（数理学）
博士（情報理工学）
博士（医学）

井
張
佐

元

清
耀
憲

藤

哉
中
明

Laboratory of Sequence Analysis
シークエンスデータ情報処理分野
Professor
Seiya Imoto, Ph.D.
Associate Professor Kotoe Katayama, Ph.D.

教 授
准教授

博士（数理学）
博士（情報学）

井
片

元
山

清
琴

哉
絵

Our mission is to realize genomic medicine based on the integrated data analysisof whole genomes of human and commensal microbiota by supercomputing.
Development of computational data analysis methods including artificial intelligencefor genomic, health, and medical big data is one of our main focuses. We promote
integrative analysis of human whole genome, RNA and other omics data,
commensal microbiota including bacteriome and virome, and health and medicalrelated big data. Furthermore, health medical intelligence aims at using the analysis
results of such big data to create personalized health-medical action plan ofindividuals.

1.  
Whole Genome Sequencing and Genomic
Medicinea.  Creating New Genomic Medicine by Integrating Human Whole Genome and Commensal
Microbiota
Katayama K, Sato N, Shimizu E, Kasajima R,
Yamaguchi K, Yokoyama K, Yadome M, Hyugaji T,
Komura M, Yamamoto M, Saito A, Zhang Y-Z, Fujimoto K, Kobayashi M, Ogawa M, Takei T, Yasui H,
Yuji K, Takane K, Ikenoue T, Robert B, Shibuya T,
Hiroshima Y, Hasegawa T, Miyagi Y, Muto K, Goyama S, Shida D, Boku N, Kawabata K, Miyano S,
Yamaguchi R, Uematsu S, Kumasaka N, Takahashi

S, Nanya Y, Furukawa Y, Imoto S
Using state-of-the-art genome analysis and artificial intelligence, our mission is to implement “newgenomic medicine” by integrating human genome information and human symbiotic microbial metagenome information.
In Japan, gene panel testing was covered by national health insurance from Jun 2019, however, it
analyzed several hundreds of genes, which were
known cancer-related genes. Since the gene panel has
trivial limitation due to its focused genes, Japanese
government considered to extend the gene panel towhole genome. However, it remains a question thatwhether the whole genome sequence information is

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enough to realize precision medicine.
Although human genome has 20 thousand genes,
intestinal microbiota has 20 million genes, and theywork together with human genes for keeping homeostasis of our lives. In recent years, with the advancement of sequencing technology, we could have awhole figure of intestinal microbiota and found its
dysbiosis leads to various diseases. We are proceeding a research for utilizing the information of intestinal microbiota (meta-genome) and human genome tocreate new genomic medicine in Society5.0. For thispurpose, we need to establish an artificial intelligenceto translate the information of human genome andmeta-genome to clinical actions of physicians.
b.  Establishment of Data Analysis Center in Action Plan for Whole Genome Analysis of Ministry of Health, Labour and Welfare
Katayama K, Shibuya T, Yamaguchi R, Kumasaka
N, Matsuda K, Miyo K1, Okamura H2, Ota K2, Shintani A2, Shiraishi Y3, Kohno T3, Kato M3, Okada Y4,
Fujimoto A4, Kasai S5, Imoto S: 1National Center for
Global Health and Medicine, 2Osaka Metropolitan
University, 3National Cancer Center, Japan, 4University of Tokyo School of Medicine, Japan, 5Information-Technology Promotion Agency, Japan
Based on the Whole Genome Analysis Action Plan
(Version 1) formulated on December 20, 2019 by the
Ministry of Health, Labour and Welfare, the AMED
project was launched in 2021 aiming at returning theresult of WGS analysis to the patients as medical actions. This national project covers a wide range of intractable cancers, including gastrointestinal, hematological, pediatric, rare, gynecological, and respiratory
cancers. A total of 9,900 patients will be subjected towhole genome sequencing analysis with depth of 30x
for normal and 120x for tumor samples, and RNA sequencing will also be conducted.
Our team (PI: Prof. Seiya Imoto of IMSUT) isbuilding the Analysis Data Center to collect and compile a database of genomic data and clinical information of these cancer patients. The mission of the Analysis Data Center is to construct a unified analysis
pipeline for primary analysis of genomic data, to collect clinical information, to build a reporting systemthat can be used in expert panels, to build a securedata sharing system, and to build an analysis environment that can perform advanced secondary analysis in a hybrid computational environment of
on-premises and cloud.
2.  Metagenome Analysis of Intestinal Microbiota
a.  Unveiling viral dark matter by whole metagenome analysis of bacteriome and virome
Fujimoto K, Kimura Y, Shimohigoshi M, Sato N,

Zhang Y-Z, Katayama K, Satoh M, Sato S, Tremmel
G, Uematsu M, Kawaguchi Y, Usui Y, Nakano Y,
Hayashi T, Kashima K, Yuki Y, Yamaguchi K, Furukawa Y, Kakuta M, Akiyama Y4, Yamaguchi R,
Crowe SE5, Ernst PB6, Miyano S, Kiyono H, Imoto
S, Uematsu S: 4Department of Computer Science,
Tokyo Institute of Technology, Japan, 5Departmentof Medicine, University of California, San Diego,
USA, 6CU-UCSD Center for Mucosal Immunology,
Allergy and Vaccines, University of California San
Diego, USA.
The application of bacteriophages (phages) is proposed as a highly specific therapy for intestinal pathobiont elimination. However, the infectious associations between phages and bacteria in the humanintestine, which is essential information for the development of phage therapies, have yet to be fully elucidated. Here, we report the intestinal viral microbiomes (viromes), together with bacterial microbiomes(bacteriomes), in 101 healthy Japanese individuals.
Based on the genomic sequences of bacteriomes andviromes from the same fecal samples, the host bacteria-phage associations are illustrated for both temperate and virulent phages. To verify the usefulness ofthe comprehensive host bacteria-phage information,
we screened Clostridioides difficile-specific phages
and identified antibacterial enzymes whose activity is
confirmed both in vitro and in vivo. These comprehensive metagenome analyses reveal not only hostbacteria-phage associations in the human intestine
but also provide vital information for the development of phage therapies against intestinal pathobionts.
b.  Functional restoration of bacteriomes and viromes by fecal microbiota transplantation
Fujimoto K, Kimura Y, Allegretti JR7, Yamamoto
M, Zhang Y-Z, Katayama K, Tremmel G, Kawaguchi Y8, Shimohigoshi M8, Hayashi T8, Uematsu M8,
Yamaguchi K, Furukawa Y, Akiyama Y9, Yamaguchi R, Crowe SE10, Ernst PB10, Miyano S, Kiyono H,
Imoto S, Uematsu S: 7Brigham and Women’s Hospital, Boston, Massachusetts, USA. 8Osaka City University, 9Department of Computer Science, Tokyo
Institute of Technology, 10University of California,
San Diego.
Fecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI). However, the overall mechanisms
underlying FMT success await comprehensive elucidation, and the safety of FMT has recently become aserious concern because of the occurrence of drug-resistant bacteremia transmitted by FMT. We investigated whether functional restoration of the bacteriomes and viromes by FMT could be an indicator of
successful FMT. The human intestinal bacteriomes

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and viromes from 9 patients with rCDI who had undergone successful FMT and their donors were analyzed. Prophage-based and CRISPR spacer-based
host bacteria–phage associations in samples from recipients before and after FMT and in donor samples
were examined. The gene functions of intestinal microorganisms affected by FMT were evaluated.
Metagenomic sequencing of both the viromes andbacteriomes revealed that FMT does change the characteristics of intestinal bacteriomes and viromes inrecipients after FMT compared with those before
FMT. In particular, many Proteobacteria, the fecal
abundance of which was high before FMT, were eliminated, and the proportion of Microviridae increased
in recipients. Most temperate phages also behaved inparallel with the host bacteria that were altered by
FMT. Furthermore, the identification of bacterial andviral gene functions before and after FMT revealed
that some distinctive pathways, including fluorobenzoate degradation and secondary bile acid biosynthesis, were significantly represented.
3.  Health Medical Data Sciencea.  Halcyon: an accurate basecaller exploiting an
encoder-decoder model with monotonic attention
Konishi H, Yamaguchi R, Yamaguchi K, Furukawa
Y, Imoto S
In recent years, nanopore sequencing technology
has enabled inexpensive long-read sequencing, which
promises reads longer than a few thousand bases.
Such long-read sequences contribute to the precise
detection of structural variations and accurate haplotype phasing. However, deciphering precise DNA sequences from noisy and complicated nanopore raw
signals remains a crucial demand for downstream
analyses based on higher-quality nanopore sequencing, although various basecallers have been introduced to date.
To address this need, we developed a novel basecaller, Halcyon, that incorporates neural-network
techniques frequently used in the field of machinetranslation. Our model employs monotonic-attention
mechanisms to learn semantic correspondences between nucleotides and signal levels without any
pre-segmentation against input signals. We evaluatedperformance with a human whole-genome sequencing dataset and demonstrated that Halcyon outperformed existing third-party basecallers and achieved
competitive performance against the latest Oxford
Nanopore Technologies’ basecallers.
b.  
Immunogenomic pan-cancer landscape reveals immune escape mechanisms and immunoediting histories

Mizuno S11, Yamaguchi R, Hasegawa T, Hayashi S,
Fujita M12, Zhang F13, Koh Y14, Lee S-Y15, Yoon
S-S14, Shimizu E, Komura M, Fujimoto A12, Nagai
M16, Kato M16, Liang H17, Miyano S, Zhang Z13, Nakagawa H12, Imoto S: 11Kyushu University, 12Riken,
13
Peking University, 14Seoul National University
Hospital, 15Samsung SDS, 16National Cancer Center,
Japan, 17The University of Texas MD Anderson
Cancer Center, USA.
Immune reactions in the tumor microenvironment
are an important hallmark of cancer, and emerging
immune therapies have been proven effective against
several types of cancers. To investigate cancer genome-immune interactions and the role of immunoediting or immune escape mechanisms in cancer
development, we analyzed 2834 whole genome andRNA sequencing datasets across 31 distinct tumor
types with respect to key immunogenomic aspects
and provided comprehensive immunogenomic profiles of pan-cancers. We found that selective copy
number changes in immune-related genes may contribute to immune escape. Furthermore, we developed an index of the immunoediting history of eachtumor sample based on the information of mutations
in exonic regions and pseudogenes and evaluated theimmunoediting history of each tumor. Our immuno-genomic analyses of pan-cancers have the potential to identify a subset of tumors with immunogenicity and diverse backgrounds or intrinsic pathways
associated with their immune status and immunoediting history.
c.  Enhancing breakpoint resolution with deep
segmentation model: a general refinement
method for read-depth based structural variant
callers
Zhang Y-Z, Imoto S, Miyano S, Yamaguchi R:
Read-depths (RDs) are frequently used in identifying structural variants (SVs) from sequencing data.
For existing RD-based SV callers, it is difficult forthem to determine breakpoints in single-nucleotide
resolution due to the noisiness of RD data and thebin-based calculation. In this paper, we propose to
use the deep segmentation model UNet to learn basewise RD patterns surrounding breakpoints of known
SVs. We integrate model predictions with an RDbased SV caller to enhance breakpoints in single-nucleotide resolution. We show that UNet can be trainedwith a small amount of data and can be applied bothin-sample and cross-sample. An enhancement pipeline named RDBKE significantly increases the number of SVs with more precise breakpoints on simulated and real data.
4.  COVID-19

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a.  A nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan
Japan COVID-19 Task Force
Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we
conducted a genome-wide association study (GWAS)
involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves ofthe pandemic, with 3,289 unaffected controls. We
identified a variant on chromosome 5 at 5q35
(rs60200309-A), close to the dedicator of cytokinesis 2gene (DOCK2), which was associated with severe
COVID-19 in patients less than 65 years of age. Thisrisk allele was prevalent in East Asian individuals butrare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased
expression of DOCK2 associated with the risk allele
in these younger patients. DOCK2 expression was
suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61
individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing
effect of the risk allele on DOCK2 expression in
non-classical monocytes. Immunohistochemistry oflung specimens from patients with severe COVID-19
pneumonia showed suppressed DOCK2 expression.
Moreover, inhibition of DOCK2 function with CPYPP
increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized byweight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated
type I interferon responses. We conclude that DOCK2
has an important role in the host immune response to
SARS-CoV-2 infection and the development of severe
COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
b.  COVID-19 risk assessment at the Tokyo 2020
Olympic Games
Murakami M18, Miura F19, Kitajima M20, Fujii K21,
Yasutaka T22, Iwasaki Y22, Ono K22, Shimazu Y23,
Sorano S24, Okuda T25, Ozaki A26, Katayama K, Nishikawa Y27, Kobashi Y28, Sawano T29, Abe T23, Saito
MM30, Tsubokura M18, Naito W22, Imoto S: 18Fukushima Medical University, 19Ehime University, 20Hokkaido University, 21Kao, 22National Institute of Advanced Industrial Science and Technology (AIST),
23
Southern TOHOKU General Hospital, 24Nagasaki
University, 25Keio University, 26Jyoban Hospital of
Tokiwa Foundation, 27Kyoto University, 28SeireikaiGroup Hirata Central Hospital, 29Sendai Open Hospital, 30University of Nagasaki
The 2020 Olympic/Paralympic Games have been

postponed to 2021, due to the COVID-19 pandemic.
We developed a model that integrated source–environment–receptor pathways to evaluate how preventive efforts can reduce the infection risk among spectators at the opening ceremony of Tokyo Olympic
Games. We simulated viral loads of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emitted from infectors through talking/coughing/sneezing and modeled temporal environmental behaviors,
including virus inactivation and transfer. We performed Monte Carlo simulations to estimate the expected number of newly infected individuals withand without preventive measures, yielding the crude
probability of a spectator being an infector among the
60,000 people expected to attend the opening ceremony. Two indicators, i.e., the expected number of newly
infected individuals and the newly infected individuals per infector entry, were proposed to demonstrate
the extent of achievable infection risk reduction levels
by implementing possible preventive measures. A
no-prevention scenario produced 1.5–1.7 newly infected individuals per infector entry, whereas a combination of cooperative preventive measures by organizers and the spectators achieved a 99% risk
reduction, corresponding to 0.009–0.012 newly infected individuals per infector entry. The expected number of newly infected individuals was calculated as
0.005 for the combination of cooperative preventive
scenarios with the crude probability of a spectator being an infector of 1 × 10−5. Based on our estimates, acombination of cooperative preventions between organizers and spectators is required to prevent a viralspread at the Tokyo Olympic/Paralympic Games.
Further, under the assumption that society accepts <10 newly infected persons traced to events held during the entire Olympic/Paralympic Games, we propose a crude probability of infectors of < 5 × 10−5 as abenchmark for the suppression of the infection. Thisis the first study to develop a model that can assess
the infection risk among spectators due to exposure
pathways at a mass gathering event.
c.  COVID-19 wastewater surveillance implemented in the Tokyo 2020 Olympic and Paralympic
Village
Kitajima M31, Murakami M32, Iwamoto R33, Katayama H34, Imoto S: 31Hokkaido University, 32Center
for Infectious Disease Education and Research, Osaka University, 33Shionogi & Co. Ltd., 34Graduate
School of Engineering, The University of Tokyo
Wastewater-based epidemiology (WBE), which
has attracted attention as a COVID-19 surveillance
tool,1 was implemented in the Tokyo 2020 Olympic
and Paralympic Village in order to better understand
COVID-19 incidence in the village.2 Between July 14
and September 8, 2021, 690 wastewater samples—361
and 329 samples collected via passive and grab sam-88pling, respectively—were collected from manholes inthe village. We collected wastewater samples, in addition to clinical data (i.e., confirmed positive cases),from seven distinct areas comprising the entire residential buildings. The wastewater samples were examined for the presence and concentration of SARSCoV-2 RNA using a highly sensitive reverse transcri-ption (RT)-qPCR-based detection method. We tested
for SARS-CoV-2 RNA in wastewater and reported
data daily to the Tokyo Organising Committee of the
Olympic and Paralympic Games. The reported data
were used as one of the indicators reflecting COVID-19 incidence to support judgement of the need forenhanced infection prevention measures.

Publications
1.		Nakagawara K, Shiraishi Y, Chubachi S, Tanabe N,
Maetani T, Asakura T, Namkoong H, Tanaka H,
Shimada T, Azekawa S, Otake S, Fukushima T,
Watase M, Terai H, Sasaki M, Ueda S, Kato Y, Harada N, Suzuki S, Yoshida S, Tateno H, Yamada Y,
Jinzaki M, Hirai T, Okada Y, Koike R, Ishii M, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T,
Fukunaga K. Integrated assessment of computed
tomography density in pectoralis and erector spinae muscles as a prognostic biomarker for coronavirus disease 2019. Clin Nutr. 2024 Feb 5;43(3):815824. doi: 10.1016/j.clnu.2024.02.004. Online aheadof print.
2.		Momose H, Kurita N, Nishikii H, Yusa N,
Yokoyama K, Shimizu E, Imoto S, Nanmoku T,
Maruyama Y, Sakamoto T, Yokoyama Y, Kato T,
Matsuoka R, Obara N, Sakata-Yanagimoto M, Chiba S. Durable remission of T-cell prolymphocytic
leukemia with CLEC16A::IL2 after allogeneic hematopoietic stem cell transplantation. Rinsho
Ketsueki. 2024;65(1):35-40. doi: 10.11406/rinketsu.
65.35
3.		Kuwatsuka Y, Kasajima R, Yamaguchi R, Uchida
N, Konuma T, Tanaka M, Shingai N, Miyakoshi S,
Kozai Y, Uehara Y, Eto T, Toyosaki M, Nishida T,
Ishimaru F, Kato K, Fukuda T, Imoto S, Atsuta Y,
Takahashi S. Machine learning prediction modelfor neutrophil recovery after unrelated cord bloodtransplantation. Transplant Cell Ther. 2024 Feb
7:S2666-6367(24)00182-9. doi: 10.1016/j.jtct.2024.
02.001. Online ahead of print.
4.		Matsubara Y, Kiyohara H, Mikami Y, Nanki K,
Namkoong H, Chubachi S, Tanaka H, Azekawa S,
Sugimoto S, Yoshimatsu Y, Sujino T, Takabayashi
K, Hosoe N, Sato T, Ishii M, Hasegawa N, Okada
Y, Koike R, Kitagawa Y, Kimura A, Imoto S, Miyano S, Ogawa S, Fukunaga K, Kanai T; Japan
COVID-19 Task Force. Gastrointestinal symptoms
in COVID-19 and disease severity: a Japanese registry-based retrospective cohort study. J Gastroenterol. 2024 Jan 25. doi: 10.1007/s00535-02302071-x. Online ahead of print.
5.		Heryanto YD, Zhang YZ, Imoto S. Predicting cell
types with supervised contrastive learning on
cells and their types. Sci Rep. 2024 Jan 3;14(1):430.
doi: 10.1038/s41598-023-50185-2.
6.		Kusumoto T, Chubachi S, Namkoong H, Tanaka
H, Lee H, Otake S, Nakagawara K, Fukushima T,

Morita A, Watase M, Asakura T, Masaki K, Kamata H, Ishii M, Hasegawa N, Harada N, Ueda T,
Ueda S, Ishiguro T, Arimura K, Saito F, Yoshiyama
T, Nakano Y, Mutoh Y, Suzuki Y, Edahiro R, Murakami K, Sato Y, Okada Y, Koike R, Kitagawa Y,
Tokunaga K, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K. Characteristics of patients with COVID-19 who have deteriorating
chest X-ray findings within 48 h: a retrospective
cohort study. Sci Rep. 2023 Dec 12;13(1):22054.
doi: 10.1038/s41598-023-49340-6.
7.		Khor AHP, Koguchi T, Liu H, Kakuta M, Matsubara D, Wen R, Sagiya Y, Imoto S, Nakagawa H,
Matsuda K, Tanikawa C. Regulation of the innate
immune response and gut microbiome by p53.
Cancer Sci. 2023 Dec 4. doi: 10.1111/cas.15991. Online ahead of print.
8.		Saito H, Yoshimura H, Yoshida M, Tani Y, Kawashima M, Uchiyama T, Zhao T, Yamamoto C,
Kobashi Y, Sawano T, Imoto S, Park H, Nakamura
N, Iwami S, Kaneko Y, Nakayama A, Kodama T,
Wakui M, Kawamura T, Tsubokura M. Antibody
profiling of microbial antigens in the blood of
COVID-19 mRNA vaccine recipients using microbial protein microarrays. Vaccines (Basel). 2023
Nov 7;11(11):1694. doi: 10.3390/vaccines11111694.
9.		Sato N, Shiraki A, Mori KP, Sakai K, Takemura Y,
Yanagita M, Imoto S, Tanabe K, Shiraki K. Preemptive intravenous human immunoglobulin G suppresses BK polyomavirus replication and spreadof infection in vitro. Am J Transplant. 2023 Nov
15:S1600-6135(23)00862-6.
doi:
10.1016/j.
ajt.2023.11.007. Online ahead of print.
10.	Sakurai K, Chubachi S, Asakura T, Namkoong H,
Tanaka H, Azekawa S, Shimada T, Otake S, Nakagawara K, Fukushima T, Lee H, Watase M, Kusumoto T, Masaki K, Kamata H, Ishii M, Hasegawa
N, Okada Y, Koike R, Kitagawa Y, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K.
Prognostic significance of hypertension history
and blood pressure on admission in Japanese patients with coronavirus disease 2019: integrative
analysis from the Japan COVID-19 Task Force.
Hypertens Res. 2023 Nov 2. doi: 10.1038/s41440023-01490-w.
11.	Fukushima T, Maetani T, Chubachi S, Tanabe N,
Asakura T, Namkoong H, Tanaka H, Shimada T,
Azekawa S, Otake S, Nakagawara K, Watase M,

89
Shiraishi Y, Terai H, Sasaki M, Ueda S, Kato Y, Harada N, Suzuki S, Yoshida S, Tateno H, Yamada Y,
Jinzaki M, Hirai T, Okada Y, Koike R, Ishii M, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T,
Fukunaga K. Epicardial adipose tissue measured
from analysis of adipose tissue area using chest
CT imaging is the best potential predictor of COVID-19 severity. Metabolism. 2023 Oct 31:155715.
doi: 10.1016/j.metabol.2023.155715.
12.	Wang QS, Edahiro R, Namkoong H, Hasegawa T,
Shirai Y, Sonehara K; Japan COVID-19 Task Force;
Kumanogoh A, Ishii M, Koike R, Kimura A, Imoto
S, Miyano S, Ogawa S, Kanai T, Fukunaga K, Okada Y. Estimating gene-level false discovery probability improves eQTL statistical fine-mapping precision. NAR Genom Bioinform. 2023 Oct 30;5(4):lqad090. doi: 10.1093/nargab/lqad090.
13.	Heryanto YD, Imoto S. The transcriptome signature analysis of the epithelial-mesenchymal transition and immune cell infiltration in colon adenocarcinoma. Sci Rep. 2023 Oct 26;13(1):18383. doi:
10.1038/s41598-023-45792-y.
14.	Sato N, Uematsu M, Fujimoto K, Uematsu S, Imoto S. ggkegg: analysis and visualization of KEGG
data utilizing grammar of graphics. Bioinformatics. 2023 Oct 16:btad622. doi: 10.1093/bioinformatics/btad622. Online ahead of print.
15.	Zhang YZ, Bai Z, Imoto S. Investigation of the
BERT model on nucleotide sequences with
non-standard pre-training and evaluation of different k-mer embeddings. Bioinformatics. 2023
Oct 10:btad617. doi: 10.1093/bioinformatics/
btad617. Online ahead of print.
16.	Tanaka H, Maetani T, Chubachi S, Tanabe N, Shiraishi Y, Asakura T, Namkoong H, Shimada T,
Azekawa S, Otake S, Nakagawara K, Fukushima
T, Watase M, Terai H, Sasaki M, Ueda S, Kato Y,
Harada N, Suzuki S, Yoshida S, Tateno H, Yamada
Y, Jinzaki M, Hirai T, Okada Y, Koike R, Ishii M,
Hasegawa N, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K. Clinical utilization of
artificial intelligence-based COVID-19 pneumonia
quantification using chest computed tomography- a multicenter retrospective cohort study in Japan. Respir Res. 2023 Oct 5;24(1):241. doi: 10.1186/
s12931-023-02530-2.
17.	Suzuki M, Kasajima R, Yokose T, Shimizu E, Hatakeyama S, Yamaguchi K, Yokoyama K, Katayama K, Yamaguchi R, Furukawa Y, Miyano S, Imoto S, Shinozaki-Ushiku A, Ushiku T, Miyagi Y.
KMT2C expression and DNA homologous recombination repair factors in lung cancers with a highgrade fetal adenocarcinoma component. Transl
Lung Cancer Res. 2023 Aug 30;12(8):1738-1751.
doi: 10.21037/tlcr-23-137. Epub 2023 Aug 16.
18.	COVID-19 Host Genetics Initiative. A second update on mapping the human genetic architectureof COVID-19. Nature. 2023 Sep;621(7977):E7-E26.
doi: 10.1038/s41586-023-06355-3. Epub 2023 Sep 6.

19.	Kawachi K, Tang X, Kasajima R, Yamanaka T,
Shimizu E, Katayama K, Yamaguchi R, Yokoyama
K, Yamaguchi K, Furukawa Y, Miyano S, Imoto S,
Yoshioka E, Washimi K, Okubo Y, Sato S, Yokose
T, Miyagi Y. Genetic analysis of low-grade adenosquamous carcinoma of the breast progressing tohigh-grade metaplastic carcinoma. Breast Cancer
Res Treat. 2023 Aug 31. doi: 10.1007/s10549-02307078-9.
20.	Park H, Imoto S, Miyano S. Comprehensive information-based differential gene regulatory networks analysis (CIdrgn): Application to gastriccancer and chemotherapy-responsive gene network identification. PLoS One, 2023 Aug 23;18(8):e0286044. doi: 10.1371/journal.pone.0286044.
21.	Liu Y, Zhang YZ, Imoto S. Microbial Gene Ontology informed deep neural network for microbe
functionality discovery in human diseases. PLoS
One, 2023 Aug 21;18(8):e0290307. doi: 10.1371/
journal.pone.0290307.
22.	Kusumoto T, Chubachi S, Namkoong H, Tanaka
H, Lee H, Azekawa S, Otake S, Nakagawara K,
Fukushima T, Morita A, Watase M, Sakurai K,
Asakura T, Masaki K, Kamata H, Ishii M, Hasegawa N, Harada N, Ueda T, Ueda S, Ishiguro T, Arimura K, Saito F, Yoshiyama T, Nakano Y, Mutoh
Y, Suzuki Y, Edahiro R, Sano H, Sato Y, Okada Y,
Koike R, Kitagawa Y, Tokunaga K, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K.
Association between ABO blood group/genotype
and COVID-19 in a Japanese population. Ann Hematol, 2023 Aug 15. doi: 10.1007/s00277-02305407-y. Online ahead of print.
23.	Wang Z, Gao Q, Yi X, Zhang X, Zhang Y, Zhang D,
Liò P, Bain C, Bassed R, Li S, Guo Y, Imoto S, Yao
J, Daly RJ, Song J. Surformer: an interpretable pattern-perceptive survival transformer for cancer
survival prediction from histopathology wholeslide images. Comput Methods Programs Biomed,
2023
Jul
28;241:107733.
doi:
10.1016/j.
cmpb.2023.107733. Online ahead of print.
24.	Tanaka H, Namkoong H, Chubachi S, Irie S, Uwamino Y, Lee H, Azekawa S, Otake S, Nakagawara
K, Fukushima T, Watase M, Kusumoto T, Masaki
K, Kamata H, Ishii M, Okada Y, Takano T, Imoto S,
Koike R, Kimura A, Miyano S, Ogawa S, Kanai T,
Sato TA, Fukunaga K; Japan COVID-19 Task
Force. Clinical characteristics of patients with
COVID-19 harboring detectable intracellular
SARS-CoV-2 RNA in peripheral blood cells. Int J
Infect Dis, 2023 Aug 2:S1201-9712(23)00680-X. doi:
10.1016/j.ijid.2023.07.030. Online ahead of print.
25.	Zhang YZ, Liu Y, Bai Z, Fujimoto K, Uematsu S,
Imoto S. Zero-shot-capable identification ofphage-host relationships with whole-genome sequence representation by contrastive learning.
Brief Bioinform, 2023 Jul 18:bbad239. doi: 10.1093/
bib/bbad239. Online ahead of print.
26.	Tanaka H, Chubachi S, Namkoong H, Sato Y,

90
Asakura T, Lee H, Azekawa S, Otake S, Nakagawara K, Fukushima T, Watase M, Sakurai K, Kusumoto T, Kondo Y, Masaki K, Kamata H, Ishii M,
Kaneko Y, Hasegawa N, Ueda S, Sasaki M, Izumo
T, Inomata M, Miyazawa N, Kimura Y, Suzuki Y,
Harada N, Ichikawa M, Takata T, Ishikura H,
Yoshiyama T, Kokuto H, Murakami K, Sano H,
Ueda T, Kuwahara N, Fujiwara A, Ogura T, Inoue
T, Asami T, Mutoh Y, Nakachi I, Baba R, Nishi K,
Tani M, Kagyo J, Hashiguchi M, Oguma T, Asano
K, Nishikawa M, Watanabe H, Okada Y, Koike R,
Kitagawa Y, Kimura A, Imoto S, Miyano S, Ogawa
S, Kanai T, Fukunaga K. Propensity-score matchedanalysis of the effectiveness of baricitinib in patients with coronavirus disease 2019 (COVID-19)
using nationwide real-world data: an observational matched cohort study from the Japan COVID-19
Task Force. Open Forum Infect Dis. 2023 Jun
8;10(7):ofad311. doi: 10.1093/ofid/ofad311.
27.	Takeshita JI, Murakami M, Kamo M, Naito W, Yasutaka T, Imoto S. Quantifying the effect of isolation and negative certification on COVID-19 transmission. Sci Rep. 2023 Jul 12;13(1):11264. doi:
10.1038/s41598-023-37872-w.
28.	Yamauchi T, Koyama N, Hirai A, Suganuma H,
Suzuki S, Murashita K, Mikami T, Tamada Y, Sato
N, Imoto S, Itoh K, Nakaji S. Definition of a dietary
pattern expressing the intake of vegetables andfruits and its association with intestinal microbiota. Nutrients, 2023 Apr 27;15(9):2104. doi: 10.3390/
nu15092104.
29.	Xu J, Li F, Li C, Guo X, Landersdorfer C, Shen HH,
Peleg AY, Li J, Imoto S, Yao J, Akutsu T, Song J.
iAMPCN: a deep-learning approach for identifying antimicrobial peptides and their functional activities. Brief Bioinform, 2023 Jun 27:bbad240. doi:
10.1093/bib/bbad240.
30.	Sato A, Kobayashi M, Yusa N, Ogawa M, Shimizu
E, Kawamata T, Yokoyama K, Ota Y, Ichinohe T,
Ohno H, Mori Y, Sakaida E, Kondo T, Imoto S,
Nannya Y, Mitani K, Tojo A. Clinical and prognostic features of Langerhans cell histiocytosis in
adults. Cancer Sci, 2023 Jun 26. doi: 10.1111/cas.
15879.
31.	Azekawa S, Chubachi S, Asakura T, Namkoong H,
Sato Y, Edahiro R, Lee H, Tanaka H, Otake S, Nakagawara K, Fukushima T, Watase M, Sakurai K,
Kusumoto T, Masaki K, Kamata H, Ishii M, Hasegawa N, Okada Y, Koike R, Kitagawa Y, Kimura A,
Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga
K; Japan COVID-19 Task Force. Serum KL-6 levels
predict clinical outcomes and are associated with
MUC1 polymorphism in Japanese patients with
COVID-19. BMJ Open Respir Res, 2023 May;10(1):e001625. doi: 10.1136/bmjresp-2023-001625.
32.	Washimi K, Kasajima R, Shimizu E, Sato S, Okubo
Y, Yoshioka E, Narimatsu H, Hiruma T, Katayama
K, Yamaguchi R, Yamaguchi K, Furukawa Y, Miyano S, Imoto S, Yokose T, Miyagi Y. Histologicalmarkers, sickle-shaped blood vessels, myxoidarea, and infiltrating growth pattern help stratify
the prognosis of patients with myxofibrosarcoma/
undifferentiated sarcoma. Sci Rep, 2023 Apr
25;13(1):6744. doi: 10.1038/s41598-023-34026-w.
33.	Jikuya R, Johnson TA, Maejima K, An J, Ju YS, Lee
H, Ha K, Song W, Kim Y, Okawa Y, Sasagawa S,
Kanazashi Y, Fujita M, Imoto S, Mitome T, Ohtake
S, Noguchi G, Kawaura S, Iribe Y, Aomori K, Tatenuma T, Komeya M, Ito H, Ito Y, Muraoka K,
Furuya M, Kato I, Fujii S, Hamanoue H, Tamura T,
Baba M, Suda T, Kodama T, Makiyama K, Yao M,
Shuch BM, Ricketts CJ, Schmidt LS, Linehan WM,
Nakagawa H, Hasumi H. Comparative analyses
define differences between BHD-associated renal
tumour and sporadic chromophobe renal cell carcinoma. EBioMedicine, 2023 May 12;92:104596.
doi: 10.1016/j.ebiom.2023.104596. Online ahead ofprint.
34.	Yamaguchi K, Nakagawa S, Saku A, Isobe Y,
Yamaguchi R, Sheridan P, Takane K, Ikenoue T,
Zhu C, Miura M, Okawara Y, Nagatoishi S, Kozuka-Hata H, Oyama M, Aikou S, Ahiko Y, Shida D,
Tsumoto K, Miyano S, Imoto S, Furukawa Y. Bromodomain protein BRD8 regulates cell cycle progression in colorectal cancer cells through a
TIP60-independent regulation of the pre-RC complex. iScience, 2023 Apr 1;26(4):106563. doi: 10.
1016/j.isci.2023.106563. eCollection 2023 Apr 21.
35.	Ozawa T, Asakura T, Chubachi S, Namkoong H,
Tanaka H, Lee K, Fukushima T, Otake S, Nakagawara K, Watase M, Masaki K, Kamata H, Ishii M,
Hasegawa N, Harada N, Ueda T, Ueda S, Ishiguro
T, Arimura K, Saito F, Yoshiyama T, Nakano Y,
Mutoh Y, Suzuki Y, Edahiro R, Murakami K, Okada Y, Koike R, Kitagawa Y, Tokunaga K, Kimura
A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K; Japan COVID-19 Task Force. Use of the neutrophil-to-lymphocyte ratio and an oxygen requirement to predict disease severity in patientswith COVID-19. Respir Investig, 2023 Apr 19;
61(4):454-459. doi: 10.1016/j.resinv.2023.03.007.
36.	Iwamoto R, Yamaguchi K, Katayama K, Ando H,
Setsukinai KI, Kobayashi H, Okabe S, Imoto S,
Kitajima M. Identification of SARS-CoV-2 variants
in wastewater using targeted amplicon sequencing during a low COVID-19 prevalence period inJapan. Science of the Total Environment, 2023
Apr 25:163706. doi: 10.1016/j.scitotenv.2023.163706.
Online ahead of print.
37.	Nakagawara K, Kamata H, Chubachi S, Namkoong H, Tanaka H, Lee H, Otake S, Fukushima T,
Kusumoto T, Morita A, Azekawa S, Watase M,
Asakura T, Masaki K, Ishii M, Endo A, Koike R,
Ishikura H, Takata T, Matsushita Y, Harada N, Kokutou H, Yoshiyama T, Kataoka K, Mutoh Y, Miyawaki M, Ueda S, Ono H, Ono T, Shoko T, Muranaka H, Kawamura K, Mori N, Mochimaru T,
Fukui M, Chihara Y, Nagasaki Y, Okamoto M,

91
Amishima M, Odani T, Tani M, Nishi K, Shirai Y,
Edahiro R, Ando A, Hashimoto N, Ogura S, Kitagawa Y, Kita T, Kagaya T, Kimura Y, Miyazawa
N, Tsuchida T, Fujitani S, Murakami K, Sano H,
Sato Y, Tanino Y, Otsuki R, Mashimo S, Kuramochi M, Hosoda Y, Hasegawa Y, Ueda T, Takaku Y,
Ishiguro T, Fujiwara A, Kuwahara N, Kitamura H,
Hagiwara E, Nakamori Y, Saito F, Kono Y, Abe S,
Ishii T, Ohba T, Kusaka Y, Watanabe H, Masuda
M, Watanabe H, Kimizuka Y, Kawana A, Kasamatsu Y, Hashimoto S, Okada Y, Takano T, Katayama K, Ai M, Kumanogoh A, Sato T, Tokunaga K,
Imoto S, Kitagawa Y, Kimura A, Miyano S, Hasegawa N, Ogawa S, Kanai T, Fukunaga K; Japan
COVID-19 Task Force. Impact of respiratory bacterial infections on mortality in Japanese patientswith COVID-19: a retrospective cohort study.
BMC Pulm Med. 2023 Apr 26;23(1):146. doi: 10.
1186/s12890-023-02418-3.
38.	Takaori A, Hashimoto D, Ikeura T, Ito T, Nakamaru K, Masuda M, Nakayama S, Yamaki S, Yamamoto T, Fujimoto K, Matsuo Y, Akagawa S, Ishida M,
Yamaguchi K, Imoto S, Hirota K, Uematsu S, Satoi
S, Sekimoto M, Naganuma M. Impact of neoadjuvant therapy on gut microbiome in patients withresectable/borderline resectable pancreatic ductal
adenocarcinoma. Pancreatology, 2023 Apr 5:
S1424-3903(23)00074-1. doi: 10.1016/j.pan.2023.04.
001. Online ahead of print.
39.	Tanaka H, Chubachi S, Asakura T, Namkoong H,
Azekawa S, Otake S, Nakagawara K, Fukushima
T, Lee H, Watase M, Sakurai K, Kusumoto T,
Masaki K, Kamata H, Ishii M, Hasegawa N, Okada Y, Koike R, Kitagawa Y, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K. Characteristics and Clinical Effectiveness of COVID-19
Vaccination in Hospitalized Patients in Omicrondominated Epidemic Wave - A Nationwide Studyin Japan. Int J Infect Dis, 2023 Apr 20:S12019712(23)00529-5. doi: 10.1016/j.ijid.2023.04.399.
Online ahead of print.
40.	Murakami M, Fujii K, Naito W, Kamo M, Kitajima
M, Yasutaka T, Imoto S. COVID-19 infection risk
assessment and management at the Tokyo 2020
Olympic and Paralympic Games: A scoping review. Journal of Infection and Public Health, 2023
Mar 28:S1876-0341(23)00107-7. doi: 10.1016/j.jiph.
2023.03.025.
41.	Heryanto YD, Imoto S. Identifying key regulatorsof keratinization in lung squamous cell cancer using integrated TCGA analysis. Cancers, 2023,
15(7), 2066. doi: 10.3390/cancers15072066.
42.	Wang Z, Bi Y, Pan T, Wang X, Bain C, Bassed R,
Imoto S, Yao J, Daly RJ, Song J. Targeting tumor
heterogeneity: multiplex-detection-based multiple instance learning for whole slide image classification. Bioinformatics, 2023 Mar 2:btad114. doi:
10.1093/bioinformatics/btad114.
43.	Abe S, Tago S, Yokoyama K, Ogawa M, Takei T,

Imoto S, Fuji M. Explainable AI for estimating
pathogenicity of genetic variants using large-scale
knowledge graphs. Cancers (Basel). 2023 Feb
9;15(4):1118. doi: 10.3390/cancers15041118.
44.	Pan T, Li C, Bi Y, Wang Z, Gasser RB, Purcell AW,
Akutsu T, *Webb GI, *Imoto S, *Song J. PFresGO:
an attention mechanism-based deep-learning approach for protein annotation by integrating gene
ontology inter-relationships. Bioinformatics, 2023
Feb 16:btad094. doi: 10.1093/bioinformatics/btad094. Online ahead of print.
45.	Murakami M, Sato H, Irie T, Kamo M, Naito W,
Yasutaka T, Imoto S. Sensitivity of rapid antigen
tests for COVID-19 during the Omicron variant
outbreak among players and staff members of theJapan Professional Football League and clubs: a
retrospective observational study. BMJ Open.
2023 Jan 30;13(1):e067591. doi: 10.1136/bmjopen2022-067591.Press Release:https://www.ims.u-tokyo.ac.jp/imsut/jp/about/press/page_00215.html
46.	Nakagawara K, Kamata H, Chubachi S, Namkoong H, Tanaka H, Lee H, Otake S, Fukushima T,
Kusumoto T, Morita A, Azekawa S, Watase M,
Asakura T, Masaki K, Ishii M, Endo A, Koike R,
Ishikura H, Takata T, Matsushita Y, Harada N, Kokutou H, Yoshiyama T, Kataoka K, Mutoh Y, Miyawaki M, Ueda S, Ono H, Ono T, Shoko T, Muranaka H, Kawamura K, Mori N, Mochimaru T,
Fukui M, Chihara Y, Nagasaki Y, Okamoto M,
Amishima M, Odani T, Tani M, Nishi K, Shirai Y,
Edahiro R, Ando A, Hashimoto N, Ogura S, Kitagawa Y, Kita T, Kagaya T, Kimura Y, Miyazawa
N, Tsuchida T, Fujitani S, Murakami K, Sano H,
Sato Y, Tanino Y, Otsuki R, Mashimo S, Kuramochi M, Hosoda Y, Hasegawa Y, Ueda T, Takaku Y,
Ishiguro T, Fujiwara A, Kuwahara N, Kitamura H,
Hagiwara E, Nakamori Y, Saito F, Kono Y, Abe S,
Ishii T, Ohba T, Kusaka Y, Watanabe H, Masuda
M, Watanabe H, Kimizuka Y, Kawana A, Kasamatsu Y, Hashimoto S, Okada Y, Takano T, Katayama K, Ai M, Kumanogoh A, Sato T, Tokunaga K,
Imoto S, Kitagawa Y, Kimura A, Miyano S, Hasegawa N, Ogawa S, Kanai T, Fukunaga K; Japan
COVID-19 Task Force. Diagnostic significance of
secondary bacteremia in patients with COVID-19.
J Infect Chemother, 2023 Jan 19:S1341-321X(23)00014-4. doi: 10.1016/j.jiac.2023.01.006. Online aheadof print.
47.	Watase M, Masaki K, Chubachi S, Namkoong H,
Tanaka H, Lee H, Fukushima T, Otake S, Nakagawara K, Kusumoto T, Asakura T, Kamata H, Ishii
M, Hasegawa N, Oyamada Y, Harada N, Ueda T,
Ueda S, Ishiguro T, Arimura K, Saito F, Yoshiyama
T, Nakano Y, Mutoh Y, Suzuki Y, Edahiro R, Sano
H, Sato Y, Okada Y, Koike R, Kitagawa Y, Tokunaga K, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K; Japan COVID-19 Task Force.
Impact of accumulative smoking exposure andchronic obstructive pulmonary disease on COV-

92
ID-19 outcomes: Report based on findings fromthe Japan COVID-19 Task Force. Int J Infect Dis.
2023 Mar:128:121-127. doi: 10.1016/j.ijid.2022.12.
019.
48.	Shingaki S, Koya J, Yuasa M, Saito Y, Tabata M,
McClure MB, Ogawa S, Katayama K, Togashi Y,
Imoto S, Kogure Y, Kataoka K. Tumor-promoting
function and regulatory landscape of PD-L2 in
B-cell lymphoma. Leukemia, 2023 Feb;37(2):492496. doi: 10.1038/s41375-022-01772-1.
49.	Fukushima T, Chubachi S, Namkoong H, Asakura
T, Tanaka H, Lee H, Azekawa S, Okada Y, Koike R,
Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T,

Fukunaga K; Japan COVID-19 Task Force. Clinicalsignificance of prediabetes, undiagnosed diabetes,and diagnosed diabetes on clinical outcomes in
COVID-19: Integrative analysis from the Japan
COVID-19 Task Force. Diabetes Obes Metab. 2023
Jan;25(1):144-155. doi: 10.1111/dom.14857.
50.	Park H, Imoto S, Miyano S. Gene regulatory network-classifier: gene regulatory network-basedclassifier and its applications to gastric cancer
drug (5-fluorouracil) marker identification. J Comput Biol. 2023 Feb;30(2):223-243. doi: 10.1089/cmb.
2022.0181.