 | 千葉 康敬 （チバ ヤスタカ）
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Last Updated :2024/04/25
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治療効果や曝露効果を示すために、ヒトを対象としたデータをどのように取得し、どのように解析するか、について研究しています。特に、因果推論に基づく疫学の方法論について研究しています。
研究者情報
学位
ホームページURL
J-Global ID
研究キーワード
- 医療統計学 疫学 生物統計学
現在の研究分野（キーワード）
- 治療効果や曝露効果を示すために、ヒトを対象としたデータをどのように取得し、どのように解析するか、について研究しています。特に、因果推論に基づく疫学の方法論について研究しています。
研究分野
経歴
- 2015年04月 - 現在 近畿大学医学部附属病院臨床研究センター准教授
- 2011年04月 - 2015年03月 近畿大学医学部臨床研究管理センター講師
- 2008年04月 - 2011年03月 近畿大学医学部環境医学・行動科学教室助教
- 2003年03月 - 2008年03月 京都大学大学院医学研究科社会健康医学系専攻医療統計学助手
学歴
所属学協会
研究活動情報
論文
- Yoshihiko Fujita; Hiromichi Matsuoka; Yasutaka Chiba; Junji Tsurutani; Takeshi Yoshida; Kiyohiro Sakai; Miki Nakura; Ryo Sakamoto; Chihiro Makimura; Yoichi Ohtake; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Tatsuya Okuno; Naoki Takegawa; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Atsuko Koyama; Kazuto Nishio; Kazuhiko NakagawaOncology letters 26 2 355 - 355 2023年08月 [査読有り]
There have been few studies on predictive biomarkers that may be useful to select the most suitable opioids to optimize therapeutic efficacy in individual patients with cancer pain. We recently investigated the efficacy of morphine and oxycodone using single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) rs4680 gene as a biomarker (RELIEF study). To explore additional biomarkers that may enable the selection of an appropriate opioid for individual patients with cancer pain, three SNPs were examined: C-C motif chemokine ligand 11 (CCL11; rs17809012), histamine N-methyltransferase (HNMT; rs1050891) and transient receptor potential V1 (TRPV1; rs222749), which were screened from 74 pain-related SNPs. These SNPs, which were identified as being significantly associated with the analgesic effect of morphine, were then used to genotype the 135 patients in the RELIEF study who had been randomized into a morphine group (n=69) or an oxycodone group (n=66). The present study then assessed whether the SNPs could also be used as selective biomarkers to predict which opioid(s) might be the most suitable to provide pain relief for patients with cancer. Oxycodone tended to provide superior analgesic effects over morphine in patients carrying the genotype AA for the CCL11 rs17809012 SNP (P=0.012 for interaction), suggesting that it could serve as a potential biomarker for personalized analgesic therapy for patients suffering with cancer pain. - Masayoshi Iwamoto; Yusuke Makutani; Yoshinori Yane; Hokuto Ushijima; Yasumasa Yoshioka; Toshiaki Wada; Koji Daito; Tadao Tokoro; Yasutaka Chiba; Kazuki Ueda; Junichiro KawamuraLangenbeck's archives of surgery 408 1 33 - 33 2023年01月 [査読有り]
PURPOSE: Recently, a new certification system called the Endoscopic Surgical Skill Qualification System (ESSQS) has been launched in Japan to improve surgical safety. This study aimed to determine whether ESSQS-qualified surgeons affect the short- and long-term outcomes of laparoscopic right hemicolectomy. METHODS: A total of 187 colon cancer patients who underwent laparoscopic right hemicolectomy at Kindai University Hospital between January 2016 and December 2020 were enrolled. These patients were divided into two groups based on surgeries performed by ESSQS-qualified surgeons (QS group) and non-ESSQS-qualified surgeons (NQS group). The short- and long-term outcomes were compared between the two groups before and after propensity score matching (PSM). RESULTS: After PSM, 43 patients from each group were included in the matched cohort. In the short-term outcomes, the total operative time was significantly longer in the NQS group than in the QS group (229 vs. 174 min, p < 0.0001). However, there were no significant differences in the two groups regarding blood loss (0 vs. 0 ml, p = 0.7126), conversion (0.0% vs. 7.0%, p = 0.0779), Clavien-Dindo ≥ 2 complications (9.3% vs. 7.0%, p = 0.6933), mortality (2.3% vs. 0.0%, p = 0.3145), and postoperative hospital stay (9 vs. 9 days, p = 0.5357). In the long-term outcomes, there were no significant differences between the two groups in the 3-year overall survival (86.6% vs. 83.0%, p = 0.8361) and recurrence-free survival (61.7% vs. 72.0%, p = 0.3394). CONCLUSION: Laparoscopic right hemicolectomy performed by ESSQS-qualified surgeons contributed to shorter operative time. Under the supervision of ESSQS-qualified surgeons, almost equivalent safety and oncological outcomes are expected even in surgeries performed by non-ESSQS-qualified surgeons. - Hiromichi Matsuoka; Junji Tsurutani; Yasutaka Chiba; Yoshihiko Fujita; Kiyohiro Sakai; Takeshi Yoshida; Miki Nakura; Ryo Sakamoto; Chihiro Makimura; Yoichi Ohtake; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Tatsuya Okuno; Naoki Takegawa; Koji Haratani; Atsuko Koyama; Kazuto Nishio; Kazuhiko NakagawaThe Oncologist 2022年11月 [査読有り]
Abstract Background We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain. Methods A randomized, multicenter, open-label trial was conducted at a Japanese hospital’s palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reduction ≥ 33% from baseline and up to ≤ 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype. Results Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; P = .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; P = 0.098). Conclusion Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief. - Kosuke Minaga; Masayuki Kitano; Yoshito Uenoyama; Keiichi Hatamaru; Hideyuki Shiomi; Kenji Ikezawa; Tsukasa Miyagahara; Hajime Imai; Nao Fujimori; Hisakazu Matsumoto; Yuzo Shimokawa; Atsuhiro Masuda; Mamoru Takenaka; Masatoshi Kudo; Yasutaka ChibaEndoscopic ultrasound 11 6 478 - 486 2022年11月BACKGROUND AND OBJECTIVES: Although the use of a long metal stent is favored for EUS-guided hepaticogastrostomy (EUS-HGS) for the relief of malignant biliary obstruction (MBO), endoscopic reintervention (E-RI) at the time of recurrent biliary obstruction (RBO) is challenging due to a long intragastric portion. This study evaluated the feasibility and safety of E-RI after a long partially covered metal stent (L-PCMS) placement during EUS-HGS. MATERIALS AND METHODS: We performed a multicenter retrospective study between January 2015 and December 2019 examining patients with MBO who underwent E-RI for RBO through the EUS-HGS route after the L-PCMS placement. Technical and clinical success rates, details of E-RI, adverse events (AEs), stent patency, and survival time were evaluated. RESULTS: Thirty-three patients at eight referral centers in Japan who underwent E-RI through the EUS-HGS route were enrolled. The location of MBO was distal in 54.5%. The median intragastric length of the L-PCMS was 5 cm. As the first E-RI attempt, E-RI via the distal end of the existing L-PCMS was successful in 60.6%. The overall technical and clinical success rates of E-RI were 100% and 81.8%, respectively. Liver abscess was noted in one patient. A proximal biliary stricture was associated with the clinical ineffectiveness of E-RI in multivariable analysis (odds ratio, 12.5, P = 0.04). The median survival and stent patency duration after E-RI were 140 and 394 days, respectively. CONCLUSIONS: Our study findings suggest that E-RI for RBO after EUS-HGS with a L-PCMS is technically feasible and clinically effective, without any severe AEs, especially for patients with distal MBO.
- Yoshinori Yane; Jin-Ichi Hida; Yasutaka Chiba; Yusuke Makutani; Hokuto Ushijima; Yasumasa Yoshioka; Masayoshi Iwamoto; Toshiaki Wada; Koji Daito; Tadao Tokoro; Kazuki Ueda; Junichiro KawamuraScientific reports 12 1 916 - 916 2022年01月The use of temporary diverting stoma has become more common in low colorectal anastomosis to reduce anastomotic complications. Surgical site infection (SSI) at the stoma closure site has been one of the most frequent postoperative complications. The aim of this study was to compare the short-term outcomes between conventional primary suture closure and negative pressure wound therapy with instillation and dwelling (NPWTi-d) therapy following purse-string suturing, using propensity score matching analysis. We retrospectively evaluated the medical records of 107 patients who underwent stoma closure between January 2016 and October 2020. The primary outcome was the proportion of SSI. The secondary outcome was the day of postoperative length of stay. Propensity score matching with one-to-one match was performed for reducing treatment selection bias. Of a total of 107 patients, 67 patients had been treated with conventional primary closure and 40 with NPWTi-d therapy. The propensity score matching derived 37 pairs. The respective SSI proportions were 0% and 16.2% in the groups with NPWTi-d and primary closure (P = 0.025). The respective median days of postoperative hospital stay were 9.0 and 10.0 in the groups with NPWTi-d and primary closure (P = 0.453). NPWTi-d therapy with purse-string suturing was effective in reducing SSI after stoma closure.
- Shinichiro Suzuki; Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Junko Tanizaki; Ryoji Kato; Seiichiro Mitani; Yusuke Kawanaka; Takashi Kurosaki; Yoshikazu Hasegawa; Takafumi Okabe; Kaoru Tanaka; Yusaku Akashi; Tomohiro Ozaki; Kazuto Nishio; Akihiko Ito; Kazuhiko NakagawaEuropean journal of cancer (Oxford, England : 1990) 161 44 - 54 2022年01月BACKGROUND: Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown. METHODS: A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included. TB was estimated on the basis of the sum of the diameters of measurable target lesions as per Response Evaluation Criteria in Solid Tumours. Progression-free survival (PFS) in the ICI cohort was evaluated as per TB as a preplanned primary objective, with the analysis based on propensity score-weighted survival curves and estimation of restricted mean survival time (RMST). The Chemo cohort served as a control to determine whether TB is predictive of ICI treatment outcomes. The ICI+Chemo cohort was exploratory. The relation of TB to tumour immune status was assessed by immune-related gene expression profiling (irGEP) of pretreatment tumour tissue. RESULTS: In the ICI cohort, patients with a low TB showed a significantly longer PFS than did those with a high TB (median, 17.9 vs 4.3 months; weighted hazard ratio, 0.32 [95% confidence interval, 0.19-0.53]). No such difference was apparent in the other cohorts. A significant difference in overall survival was also observed only in the ICI cohort. RMST-based analysis confirmed these results. The irGEP analysis implicated M2-type macrophages, angiogenesis and transforming growth factor-β as well as protumourigenic signalling pathways in ICI resistance conferred by a high TB. CONCLUSION: A high TB was associated with a poor outcome of ICI therapy for advanced NSCLC as a result of immunosuppressive phenotypes. Development of combination or novel treatment strategies for such disease is thus warranted.
- Ken Kamata; Akira Kurita; Satoru Yasukawa; Yasutaka Chiba; Hiroko Nebiki; Masanori Asada; Hiroaki Yasuda; Hideyuki Shiomi; Takeshi Ogura; Makoto Takaoka; Noriyuki Hoki; Reiko Ashida; Minoru Shigekawa; Akio Yanagisawa; Masatoshi Kudo; Masayuki KitanoEndoscopic ultrasound 2021年02月Background and Objectives: Differential diagnosis to estimate the malignant potential of gastric submucosal tumor (g-SMT) is important for decision-making. This study evaluated the use of a 20G needle with a core trap for EUS-guided fine-needle biopsy (EUS-FNB) for g-SMT. Methods: This multicentric prospective trial was registered in the University Hospital Medical Information Network (UMIN000021410). Consecutive patients with g-SMT who presented at one of the nine Japanese Referral Centers between June 2017 and November 2018 were enrolled. All patients underwent EUS-FNB using a 20G needle with a core trap. Samples obtained with the first-needle pass were used for central pathological review. EUS-FNB was evaluated in terms of (i) technical success rate, (ii) adequacy for histological evaluation, (iii) rate of complications, (iv) accuracy for histological diagnosis of gastrointestinal stromal tumor (GIST), and (v) concordance between GIST mitotic index determined by EUS-FNB and after tumor resection. Results: The study included 52 patients. The technical success rate of EUS-FNB was 100%. The adequacy rate for histological evaluation was 90.4% (P < 0.001). There were no complications related to EUS-FNB. Of the 38/52 patients who underwent surgical resection, 36 were finally diagnosed with GIST. The sensitivity, specificity, and accuracy of EUS-FNB for the histological diagnosis of g-SMT were 80.6%, 100%, and 81.6%, respectively. The concordance rate between the mitotic index on EUS-FNB and that after analysis of the resected tumor was 89.7%. Conclusions: EUS-FNB using a 20G needle with a core trap is feasible, providing histological samples of sufficient quality for diagnosing g-SMT.
- Hidetoshi Hayashi; Masakazu Ogura; Takashi Niwa; Toshihide Yokoyama; Junko Tanizaki; Tomohiro Ozaki; Hiroshige Yoshioka; Takayasu Kurata; Yosuke Tamura; Yasuhito Fujisaka; Kaoru Tanaka; Yoshikazu Hasegawa; Keita Kudo; Yasutaka Chiba; Kazuhiko NakagawaThe oncologist 26 1 19-e52 2021年01月LESSONS LEARNED: The combination of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer is a promising therapeutic strategy. Further investigation is warranted. BACKGROUND: We conducted a phase I/II trial of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab-paclitaxel and to evaluate the safety and efficacy of this regimen. METHODS: In the phase I study, escalating doses of weekly nab-paclitaxel were administered together with cisplatin at 75 mg/m2 every 3 weeks and concurrent radiotherapy. In the phase II study, nab-paclitaxel was administered at the RD. RESULTS: In the phase I study, whereas no dose-limiting toxicity (DLT) was observed with nab-paclitaxel at 50 or 60 mg/m2 , one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m2 , determined as the RD. Twenty-four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment-related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2-year overall survival and progression-free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%-74.7%), respectively. CONCLUSION: Concurrent chemoradiation with nab-paclitaxel at 70 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.
- Koichi Miyazaki; Kohei Hanaoka; Hayato Kaida; Yasutaka Chiba; Kazunari IshiiDEMENTIA AND GERIATRIC COGNITIVE DISORDERS 49 3 255 - 263 2020年11月 [査読有り]
Objective: The aim was to examine the association between connectivity changes in the default mode network (DMN) and the progression of idiopathic normal pressure hydrocephalus (iNPH). Methods: We retrospectively recruited cases of preclinical and clinical iNPH from 2,196 patients who had received whole-body F-18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scanning. We included 31 cases with asymptomatic ventriculomegaly with features of iNPH on MRI (AVIM; reported as preclinical iNPH) and 12 with iNPH. We performed a voxel-based analysis of the brain FDG-PET images of the AVIM and iNPH groups as well as for each background-matched normal control (NC) group, using Statistical Parametric Mapping 12. Volume of interest (VOI)-based analysis was also performed. We set the VOI as the region from the precuneus to the posterior cingulate cortices (PCC), and compared the mean regional standardized uptake value ratio (SUVR) between the AVIM and iNPH group FDG-PET/CT images and each corresponding NC group. Results: The voxel-based analysis showed a greater decreased FDG uptake in the PCC in the iNPH group than in the AVIM group. The VOI-based analysis revealed no significant difference in the mean SUVR of the AVIM group and the corresponding NC group, but that of the iNPH group was significantly lower than that of its corresponding NC group. Conclusions: DMN connectivity was reduced in the clinical iNPH group but not in the preclinical group. These data suggest that alterations in the functional connectivity of the DMN are related to the onset of iNPH symptoms. - Yasutaka ChibaMathematics (Special Issue on Applied Medical Statistics: Theory, Computation, Applicability) 8 10 1657 2020年10月 [査読有り][招待有り]
- Kentaro Yamao; Mamoru Takenaka; Rei Ishikawa; Ayana Okamoto; Tomohiro Yamazaki; Atsushi Nakai; Shunsuke Omoto; Ken Kamata; Kosuke Minaga; Ippei Matsumoto; Yoshifumi Takeyama; Isao Numoto; Masakatsu Tsurusaki; Takaaki Chikugo; Yasutaka Chiba; Tomohiro Watanabe; Masatoshi KudoDiagnostics (Basel, Switzerland) 10 7 2020年07月 [査読有り]
BACKGROUND: This study aimed to evaluate and identify the specific CT findings by focusing on abnormalities in the main pancreatic duct (MPD) and pancreatic parenchyma in patients with small pancreatic cancer (PC) including carcinoma in situ (CIS). METHODS: Nine CT findings indicating abnormalities of MPD and pancreatic parenchyma were selected as candidate findings for the presence of small PC ≤ 10 mm. The proportions of patients positive for each finding were compared between small PC and benign MPD stenosis groups. Interobserver agreement between two independent image reviewers was evaluated using kappa statistics. RESULTS: The final analysis included 24 patients with small PC (including 11 CIS patients) and 28 patients with benign MPD stenosis. The proportion of patients exhibiting partial pancreatic parenchymal atrophy (PPA) corresponding to the distribution of MPD stenosis (45.8% vs. 7.1%, p < 0.01), upstream PPA arising from the site of MPD stenosis (33.3% vs. 3.6%, p = 0.01), and MPD abrupt stenosis (45.8% vs. 14.3%, p = 0.03) was significantly higher in the small PC group than in the benign MPD stenosis group. CONCLUSIONS: The presence of partial PPA, upstream PPA, and MPD abrupt stenosis on a CT image was highly suggestive of the presence of small PCs including CIS. - Kosuke Minaga; Masayuki Kitano; Atsushi Nakai; Shunsuke Omoto; Ken Kamata; Kentaro Yamao; Mamoru Takenaka; Masakatsu Tsurusaki; Takaaki Chikugo; Ippei Matsumoto; Yasutaka Chiba; Tomohiro Watanabe; Masatoshi KudoGastrointestinal endoscopy 93 2 433 - 441 2020年06月 [査読有り]
BACKGROUND AND AIMS: Kupffer-phase imaging visualized by Sonazoid distribution into normal liver tissues upon phagocytosis by Kupffer cells, potentially aids in improving liver metastasis detection compared with fundamental B-mode EUS (FB-EUS). However, the diagnostic performance of Kupffer-phase imaging in contrast-enhanced harmonic EUS (CH-EUS) remains unclear. Hence, this study aimed to evaluate the usefulness of CH-EUS-based Kupffer-phase imaging for diagnosing liver metastasis from pancreatic cancer. METHODS: We retrospectively analyzed consecutive patients with pancreatic cancer who underwent contrast-enhanced CT (CE-CT) and FB-EUS, followed by CH-EUS, from 2011 to 2017. The diagnostic ability of CH-EUS against that of CE-CT and FB-EUS for left-lobe liver metastasis was compared. Subsequently, the influences of CH-EUS on the determination of clinical stage and patient management for pancreatic cancer were assessed. RESULTS: We enrolled 426 patients with pancreatic cancer. The left-lobe liver metastasis was present in 27.2% of patients. The diagnostic accuracy of CE-CT, FB-EUS, and CH-EUS was 90.6%, 93.4%, and 98.4%, respectively. The sensitivity and diagnostic accuracy of CH-EUS for left-lobe liver metastasis were significantly higher than those of FB-EUS or CE-CT. The sensitivity of CH-EUS for detecting small liver metastasis (<10 mm) was considerably higher than that of CE-CT or FB-EUS (P < 0.001). In 2.1% patients, only CH-EUS could detect a single distant metastasis of the left-lobe liver, thereby upgrading the tumor staging and altering the clinical management. CONCLUSIONS: CH-EUS-based Kupffer-phase imaging increased the detectability of left-lobe liver metastasis. This technique could be a reliable pretreatment imaging modality for clinical decision-making in pancreatic cancer patients. - TAKASHI KUROSAKI; HISATO KAWAKAMI; SEIICHIRO MITANI; RYOHEI KAWABATA; TAKAYUKI TAKAHAMA; YOSHIKANE NONAGASE; SOICHI FUMITA; TOMOHIRO OZAKI; YASUTAKA CHIBA; TAKAO TAMURA; KAZUHIKO NAKAGAWAIn Vivo 34 4 1921 - 1929 2020年
- Kosuke Minaga; Tomoe Yoshikawa; Yukitaka Yamashita; Hiroko Akamatsu; Maiko Ikenouchi; Tatsuya Ishii; Hisakazu Matsumoto; Hiroyoshi Iwagami; Yasuki Nakatani; Keiichi Hatamaru; Mamoru Takenaka; Takuji Akamatsu; Yoshito Uenoyama; Tomohiro Watanabe; Kazuo Ono; Yasutaka Chiba; Masatoshi KudoDigestive Diseases and Sciences 64 10 2982 - 2991 2019年10月© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Background: Although endoscopic ultrasound-guided fine needle aspiration (EUS–FNA) has been widely used for the diagnosis of pancreatic tumors, the ability to obtain adequate pancreatic tumor tissue needs to be improved. Aims: This study was performed to compare a newly designed 21-gauge needle (EUS Sonopsy CY; Hakko Medical, Nagano, Japan) and a standard 22-gauge needle for tissue sampling of solid pancreatic masses. Methods: Consecutive patients with solid pancreatic masses who underwent EUS–FNA with either the EUS Sonopsy CY or the 22-gauge needle from June 2014 to December 2016 were enrolled. The primary outcome was comparison of the diagnostic yield of the FNA samples. The secondary outcomes were comparison of technical success, diagnostic ability for malignancy, and complications. Results: A total of 93 patients (40.9% female; mean age, 70.1 years) underwent EUS–FNA with the EUS Sonopsy CY (n = 47) or the standard 22-gauge needle (n = 46). The technical success rate was 100% in both groups, and the overall diagnostic accuracy for malignancy was similar between the groups (100% in the EUS Sonopsy CY group vs. 95.7% in the 22-gauge needle group, P = 0.242). Nevertheless, the EUS Sonopsy CY resulted in significantly higher scores for cellularity (P = 0.006) and lower scores for blood contamination (P < 0.001). The procedure-related complication rate was comparable between the groups (P = 0.148). Conclusions: The EUS Sonopsy CY provided higher-quality specimens for histological evaluation in terms of both sample cellularity and blood contamination for the diagnosis of solid pancreatic masses. Trial registration: The study was registered in a clinical trial registry, No. UMIN000032598.
- Kosuke Minaga; Takeshi Ogura; Hideyuki Shiomi; Hajime Imai; Noriyuki Hoki; Mamoru Takenaka; Hidefumi Nishikiori; Yukitaka Yamashita; Takeshi Hisa; Hironari Kato; Hideki Kamada; Atsushi Okuda; Ryota Sagami; Hiroaki Hashimoto; Kazuhide Higuchi; Yasutaka Chiba; Masatoshi Kudo; Masayuki KitanoDigestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 5 575 - 582 2019年09月 [査読有り]
BACKGROUND AND AIM: Endoscopic ultrasound-guided biliary drainage (EUS-BD) can be carried out by two different approaches: choledochoduodenostomy (CDS) and hepaticogastrostomy (HGS). We compared the efficacy and safety of these approaches in malignant distal biliary obstruction (MDBO) patients using a prospective, randomized clinical trial. METHODS: Patients with malignant distal biliary obstruction after failed endoscopic retrograde cholangiopancreatography were randomly selected for either CDS or HGS. The procedures were carried out at nine tertiary centers from September 2013 to March 2016. Primary endpoint was technical success rate, and the noninferiority of HGS to CDS was examined with a one-sided significance level of 5%, where the noninferiority margin was set at 15%. Secondary endpoints were clinical success, adverse events (AE), stent patency, survival time, and overall technical success including alternative EUS-BD procedures. RESULTS: Forty-seven patients (HGS, 24; CDS, 23) were enrolled. Technical success rates were 87.5% and 82.6% in the HGS and CDS groups, respectively, where the lower limit of the 90% confidence interval of the risk difference was -12.2% (P = 0.0278). Clinical success rates were 100% and 94.7% in the HGS and CDS groups, respectively (P = 0.475). Overall AE rate, stent patency, and survival time did not differ between the groups. Overall technical success rates were 100% and 95.7% in the HGS and CDS groups, respectively (P = 0.983). CONCLUSIONS: This study suggests that HGS is not inferior to CDS in terms of technical success. When one procedure is particularly challenging, readily switching to the other could increase technical success. - Chiba YClinical Trials 16 3 237 - 245 2019年06月 [査読有り]
- Kosuke Minaga; Yukitaka Yamashita; Takeshi Ogura; Mamoru Takenaka; Yuzo Shimokawa; Takeshi Hisa; Masahiro Itonaga; Hironari Kato; Hidefumi Nishikiori; Atsushi Okuda; Hisakazu Matsumoto; Yoshito Uenoyama; Tomohiro Watanabe; Yasutaka Chiba; Kazuhide Higuchi; Masatoshi Kudo; Masayuki KitanoDigestive Endoscopy 31 2 180 - 187 2019年03月 [査読有り]
- Kimio Yonesaka; Naoki Takegawa; Satomi Watanabe; Koji Haratani; Hisato Kawakami; Kazuko Sakai; Yasutaka Chiba; Naoyuki Maeda; Takashi Kagari; Kenji Hirotani; Kazuto Nishio; Kazuhiko NakagawaOncogene 38 9 1398 - 1409 2019年02月 [査読有り]
EGFR tyrosine kinase inhibitors (TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC); however, these tumours eventually acquire chemoresistance. U3-1402 is an anti-HER3 antibody-drug conjugate with a novel topoisomerase I inhibitor, DXd. In the current study, we evaluated the anticancer efficacy of U3-1402 in EGFR-mutant NSCLC cells with acquired resistance to EGFR-TKIs. HCC827GR5 and PC9AZDR7 are EGFR-TKI-resistant clones for gefitinib and osimertinib, respectively. U3-1402 alone or in combination with the EGFR-TKI erlotinib demonstrated potent anticancer efficacy in HCC827GR5 cells using an in vitro growth inhibition assay and in vivo xenograft mouse model. U3-1402 induced apoptosis in HCC827GR5 cells accompanying phosphorylation of histone H2A.X, a marker of DNA damage, but did not block HER3/PI3K/AKT signalling. Further, we found using flow cytometry that the cell surface HER3 expression level in HCC827GR5 cells was twice that found in HCC827 cells, indicating internalization of U3-1402 was increased in resistant cells. In addition, administration of U3-1402 notably repressed growth of EGFR-TKI osimertinib-resistant PC9AZDR7 xenograft tumours, and that PC9AZDR7 cells expressed five times greater cell surface HER3 than PC9 cells. Furthermore, using immunofluorescent microscopy, HER3 was observed predominantly in the nucleus of PC9 cells, but was localized in the cytoplasm of PC9AZDR7 cells. This finding indicates that altered trafficking of the HER3-U3-1402 complex may accelerate linker payload cleavage by cytoplasmic lysosomal enzymes, resulting in DNA damage. Our results indicate that administration of U3-1402 alone or in combination with an EGFR-TKI may have potential as a novel therapy for EGFR-TKI-resistant EGFR-mutant NSCLC. - Hiroto Ueda; Hisato Kawakami; Yoshikane Nonagase; Naoki Takegawa; Tatsuya Okuno; Takayuki Takahama; Masayuki Takeda; Yasutaka Chiba; Takao Tamura; Kazuhiko NakagawaThe oncologist 24 2 163-e76 - e76 2019年02月 [査読有り]
LESSONS LEARNED: The 5-fluorouracil, docetaxel, and nedaplatin (UDON) regimen was well tolerated and showed promising antitumor activity in terms of both objective response rate and survival for patients with advanced or recurrent esophageal squamous cell carcinoma in the first-line setting.UDON may be an optimal treatment option for patients with advanced esophageal cancer who are unfit for docetaxel, cisplatin, and 5-fluorouracil regimens.The high response rate as well as the rapid and marked tumor shrinkage associated with UDON suggest that further evaluation of this regimen in the neoadjuvant setting is warranted. BACKGROUND: A phase II study was performed to evaluate the efficacy and safety of 5-fluorouracil (5-FU), docetaxel, and nedaplatin (UDON) combination therapy for untreated recurrent or metastatic esophageal cancer. METHODS: Patients received intravenous nedaplatin (90 mg/m2) on day 1, docetaxel (35 mg/m2) on days 1 and 15, and 5-fluorouracil (800 mg/m2) on days 1-5 of a 4-week cycle. The primary endpoint was response rate, with secondary endpoints including overall survival (OS), progression-free survival (PFS), dysphagia score, and adverse events. RESULTS: Between March 2015 and July 2017, 23 patients were enrolled. Of 22 evaluable patients, 16 and 4 individuals experienced a partial response and stable disease, respectively, yielding a response rate of 72.7% (95% confidence interval [CI], 49.8%-89.3%) and disease control rate of 90.9% (95% CI, 70.8%-98.9%). Median OS and PFS were 11.2 months (95% CI, 9.1 months to not reached) and 6.0 months (95% CI, 2.5-10.6 months), respectively. Eleven (64.7%) of the 17 patients with a primary lesion showed amelioration of dysphagia after treatment. Frequent adverse events of grade 3 or 4 included neutropenia (87.0%) and leukopenia (39.1%). Febrile neutropenia was observed in two patients (8.7%). CONCLUSION: This phase II study demonstrated promising antitumor activity and good tolerability of UDON. - Uemura Y; Taguri M; Kawahara T; Chiba YBiometrical Journal 61 6 1448 - 1461 2019年 [査読有り]
In randomized clinical trials, it is often of interest to estimate the effect of treatment on quality of life (QOL), in addition to those on the event itself. When an event occurs in some patients prior to QOL score assessment, investigators may compare QOL scores between patient subgroups defined by the event after randomization. However, owing to postrandomization selection bias, this analysis can mislead investigators about treatment efficacy and result in paradoxical findings. The recent Japanese Osteoporosis Intervention Trial (JOINT-02), which compared the benefits of a combination therapy for fracture prevention with those of a monotherapy, exemplifies the case in point; the average QOL score was higher in the combination therapy arm for the unfractured subgroup but was lower for the fractured subgroup. To address this issue, principal strata effects (PSEs), which are treatment effects estimated within subgroups of individuals stratified by potential intermediate variable, have been discussed in the literature. In this paper, we describe a simple procedure for estimating the PSEs using marginal structural models. This procedure utilizes SAS code for the estimation. In addition, we present a simple sensitivity analysis method for examining the resulting estimates. The analyses of JOINT-02 data using these methods revealed that QOL scores were higher in the combination therapy arm than in the monotherapy arm for both subgroups. - Kentaro Yamao; Masayuki Kitano; Mamoru Takenaka; Kosuke Minaga; Toshiharu Sakurai; Tomohiro Watanabe; Takahisa Kayahara; Tomoe Yoshikawa; Yukitaka Yamashita; Masanori Asada; Yoshihiro Okabe; Keiji Hanada; Yasutaka Chiba; Masatoshi KudoGastrointestinal endoscopy 88 1 66 - 75 2018年07月BACKGROUND AND AIMS: Gastroduodenal and biliary obstruction may occur synchronously or asynchronously in advanced pancreatic cancer, and endoscopic double stent placement may be required. EUS-guided biliary drainage (EUS-BD) often is performed after unsuccessful placement of an endoscopic transpapillary stent (ETS), and EUS-BD may be beneficial in double stent placement. This retrospective multicenter cohort study compared the outcomes of ETS placement and EUS-BD in patients with an indwelling gastroduodenal stent (GDS). METHODS: We recorded the clinical outcomes of patients at 5 tertiary-care medical centers who required biliary drainage after GDS placement between March 2009 and March 2014. RESULTS: Thirty-nine patients were included in this study. Patients' mean age was 68.5 years; 23 (59.0%) were men. The GDS overlay the papilla in 23 patients (59.0%). The overall technical success rate was significantly higher with EUS-BD (95.2%) than with ETS placement (56.0%; P < .01). Furthermore, the technical success rate was significantly higher with EUS-BD (93.3%) than with ETS placement (22.2%; P < .01) when the GDS overlies the papilla. The overall clinical success rate of EUS-BD also was significantly higher than for ETS placement (90.5% vs 52.0%, respectively; P = .01), and there was no significant difference in the incidence of adverse events (ETS, 32.0% vs EUS-BD, 42.9%; P = .65). CONCLUSION: Endoscopic double stent placement with EUS-BD is technically and clinically superior to ETS placement in patients with an indwelling GDS. EUS-BD should be considered the first-line treatment option for patients with an indwelling GDS that overlies the papilla. ETS placement remains a reasonable alternative when the papilla is not covered by the GDS.
- Junko Tanizaki; Yasutaka Chiba; Koji Haratani; Hidetoshi Hayashi; Kazuhiko NakagawaJournal of Thoracic Oncology 13 5 e86 - e87 2018年05月 [査読有り]
- Takeshi Ogura; Masayuki Kitano; Mamoru Takenaka; Atsushi Okuda; Kosuke Minaga; Kentaro Yamao; Yukitaka Yamashita; Keiichi Hatamaru; Chishio Noguchi; Yasuhiko Gotoh; Taira Kuroda; Tomoyuki Yokota; Hidefumi Nishikiori; Ryota Sagami; Kazuhide Higuchi; Yasutaka ChibaDigestive Endoscopy 30 2 252 - 259 2018年03月Background and Aim: Endoscopic ultrasonography-guided hepaticogastrostomy (EUS-HGS) is often indicated for advanced stage patients. Therefore it is important to prevent adverse events associated with EUS-HGS procedures and obtain long stent patency. EUS-guided antegrade stenting (AS) has been developed as an advanced technique. Thus, to prevent adverse events and achieve long stent patency, EUS-AS combined with EUS-HGS (EUS-HGAS) has been reported. The aim of the present study was to evaluate the technical feasibility and efficacy of EUS-HGAS in a multicenter, prospective study. Methods: This prospective study was carried out at each hospital of the Therapeutic Endoscopic Ultrasound Group. Primary endpoint of this multicenter prospective study was stent patency of EUS-HGAS. Results: A total of 49 patients were enrolled. Technical success rate of EUS-HGS was 95.9% (47/49). EUS-AS failed in five patients because the guidewire could not be advanced into the intestine across the bile duct obstruction site. Therefore, EUS-HGAS was successfully carried out in 40 patients (technical success rate: 85.7%). Median overall survival was 114 days. Median stent patency including stent dysfunction and patient death was 114 days. In contrast, mean stent patency was 320 days. Adverse events were seen in 10.2% (5/49) of cases. Hyperamylasemia was seen in four patients, and bleeding was seen in one patient. Conclusions: The present study is the first to evaluate EUS-HGAS. EUS-HGAS has clinical benefit for obtaining long stent patency and avoiding adverse events, although the possibility of acute pancreatitis as a result of obstruction of the orifice of the pancreatic duct must be considered.
- Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Keita Kudo; Kimio Yonesaka; Ryoji Kato; Hiroyasu Kaneda; Yoshikazu Hasegawa; Kaoru Tanaka; Masayuki Takeda; Kazuhiko NakagawaJAMA Oncology 4 3 374 - 378 2018年03月 [査読有り]
IMPORTANCE Immune-related adverse events (irAEs) have been associated with the efficacy of PD-1 (programmed cell death protein 1) inhibitors in patients with melanoma, but whether such an association exists for non-small cell lung cancer (NSCLC) has remained unknown. OBJECTIVE To evaluate the relation of irAEs to nivolumab efficacy in NSCLC. DESIGN, SETTING, AND PARTICIPANTS In this study based on landmark and multivariable analyses, a total of 134 patients with advanced or recurrent NSCLC who were treated with nivolumab in the second-line setting or later between December 2015 and August 2016 were identified from a review of medical records from multiple institutions, including a university hospital and community hospitals. Data were updated as of December 31, 2016. EXPOSURES The absence or presence of any irAE before the landmark date. MAIN OUTCOMES AND MEASURES Kaplan-Meier curves of progression-free survival (PFS) according to the development of irAEs in 6-week landmark analysis were evaluated with the log-rank test as a preplanned primary objective. Overall survival (OS) was similarly evaluated. Multivariable analysis of both PFS and OS was performed with Cox proportional hazard regression models. RESULTS In a cohort of 134 patients (median [range] age, 68 [33-85] years 90 men [67%], 44 women [33%]), irAEs were observed in 69 of the 134 study patients (51%), including 12 patients (9%) with such events of grade 3 or 4, and 24 patients (18%) requiring systemic corticosteroid therapy. In 6-week landmark analysis, median PFS was 9.2 months (95% CI, 4.4 to not reached [NR]) and 4.8 months (95% CI, 3.0 to 7.5) (P = .04) whereas median OS was NR (95% CI, 12.3 to NR) and 11.1 months (95% CI, 9.6 to NR) (P = .01) for patients with or without irAEs, respectively. Multivariable analysis also revealed that irAEs were positively associated with survival outcome, with hazard ratios of 0.525 (95% CI, 0.287 to 0.937 P = .03) for PFS and 0.282 (95% CI, 0.101 to 0.667 P = .003) for OS. CONCLUSIONS AND RELEVANCE Development of irAEs was associated with survival outcome of nivolumab treatment in patients with advanced or recurrent NSCLC. Further studies are needed to confirm our findings. - Ken Kamata; Mamoru Takenaka; Masayuki Kitano; Shunsuke Omoto; Takeshi Miyata; Kosuke Minaga; Kentaro Yamao; Hajime Imai; Tosiharu Sakurai; Naoshi Nishida; Hiroshi Kashida; Takaaki Chikugo; Yasutaka Chiba; Takuya Nakai; Yoshifumi Takeyama; Andrea Lisotti; Pietro Fusaroli; Masatoshi KudoDigestive Endoscopy 30 1 98 - 106 2018年01月 [査読有り]
Background and Aim: Differential diagnosis of localized gallbladder lesions is challenging. The aim of the present study was to evaluate the utility of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for diagnosis of localized gallbladder lesions. Methods: One hundred and twenty-five patients with localized gallbladder lesions were evaluated by CH-EUS between March 2007 and February 2014. This was a single-center retrospective study. Utilities of fundamental B-mode EUS (FB-EUS) and CH-EUS in the differentiation of gallbladder lesions and sludge plug were initially compared. Thereafter, these two examinations were compared with respect to their accuracy in the diagnosis of malignant lesions. Five reviewers blinded to the clinicopathological results evaluated microcirculation patterns in the vascular and perfusion images. Results: In the differentiation between gallbladder lesions and sludge plug, FB-EUS had a sensitivity, specificity, and accuracy of 82%, 100%, and 95%, respectively, whereas CH-EUS had a sensitivity, specificity, and accuracy of 100%, 99%, and 99%, respectively. FB-EUS-based diagnosis of carcinomas based on tumor size and/or shape had a sensitivity, specificity, and accuracy of 61–87%, 71–88%, and 74–86%, respectively. Additional information regarding irregular vessel patterns in the vascular image and/or heterogeneous enhancement in the perfusion image on CH-EUS increased the sensitivity, specificity, and accuracy for the diagnosis of carcinomas to 90%, 98%, and 96%, respectively. There was a significant difference between FB-EUS and CH-EUS in terms of carcinoma diagnosis. Conclusion: CH-EUS was useful for the evaluation of localized gallbladder lesions. - Junko Tanizaki; Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Yasushi Nakamura; Kimio Yonesaka; Keita Kudo; Hiroyasu Kaneda; Yoshikazu Hasegawa; Kaoru Tanaka; Masayuki Takeda; Akihiko Ito; Kazuhiko NakagawaJournal of Thoracic Oncology 13 1 97 - 105 2018年01月 [査読有り]
Objective The aim of this study was to identify baseline peripheral blood biomarkers associated with clinical outcome in patients with NSCLC treated with nivolumab. Methods Univariable and multivariable analyses were performed retrospectively for 134 patients with advanced or recurrent NSCLC treated with nivolumab to evaluate the relationship between survival and peripheral blood parameters measured before treatment initiation, including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and absolute eosinophil count (AEC), as well as serum C-reactive protein and lactate dehydrogenase levels. Progression-free survival, overall survival, and response rate were determined. Results Among the variables selected by univariable analysis, a low ANC, high ALC, and high AEC were significantly and independently associated with both better progression-free survival (p = 0.001, p = 0.04, and p = 0.02, respectively) and better overall survival (p = 0.03, p = 0.03, and p = 0.003, respectively) in multivariable analysis. Categorization of patients according to the number of favorable factors revealed that those with only one factor had a significantly worse outcome than those with two or three factors. A similar trend was apparent for patients with a programmed death 1 ligand tumor proportion score less than 50%, whereas all patients with a score of 50% or higher had at least two favorable factors. Conclusions A baseline signature of a low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate. - Bayesian inference of causal effects for an ordinal outcome in randomized trialsChiba YJournal of Causal Inference 6 2 20170019 2018年 [査読有り]
- Ryoji Kato; Hidetoshi Hayashi; Yasutaka Chiba; Kaoru Tanaka; Masayuki Takeda; Kazuhiko NakagawaCLINICAL LUNG CANCER 18 6 E449 - E455 2017年11月 [査読有り]
Minimal (< 10 mm in thickness) pericardial effusion can be incidentally detected by computed tomography at diagnosis in patients with lung cancer. We retrospectively analyzed 428 patients diagnosed with advanced nonesmall-cell lung cancer. Our study found that 14.3% of patients presented with minimal pericardial effusion at first diagnosis, and its presence was an independent prognostic factor for reduced survival in patients with advanced nonesmall-cell lung cancer. Introduction: Minimal (< 10 mm in thickness) pericardial effusion (PCE) can be incidentally detected by computed tomography at the time of diagnosis in patients with lung cancer. Although malignant PCE is known to be associated with poor prognosis, the impact of minimal PCE on outcome has remained unclear. We therefore examined the prognostic relevance of minimal PCE in patients with advanced nonesmall-cell lung cancer (NSCLC). Patients and Methods: We retrospectively analyzed consecutive patients diagnosed with stage IV NSCLC at Kindai University Hospital between April 2009 and March 2015. The patients were classified into 3 groups on the basis of the presence and thickness of PCE: no PCE, minimal (< 10 mm) PCE, and malignant (< 10 mm) PCE. The relation between overall survival and PCE status was examined with a Cox proportional hazards model. Results: The total of 428 enrolled patients included 327 (76.4%) in the no PCE group, 61 (14.3%) in the minimal PCE group, and 40 (9.3%) in the malignant PCE group. Median overall survival was 15.0, 10.1, and 7.6 months in the no PCE, minimal PCE, and malignant PCE groups, respectively, with the survival of patients with minimal PCE thus being intermediate between that of the other 2 groups (P = .003). Multivariable analysis revealed that minimal PCE was independently associated with reduced survival (hazard ratio, 1.46; 95% confidence interval, 1.07-1.96; P = .019). Conclusions: The presence of minimal PCE was an independent prognostic factor for reduced survival in patients with advanced NSCLC. (C) 2017 Elsevier Inc. All rights reserved. - Yasutaka ChibaSTATISTICS IN MEDICINE 36 25 3966 - 3975 2017年11月 [査読有り]
In clinical research, investigators are interested in inferring the average causal effect of a treatment. However, the causal parameter that can be used to derive the average causal effect is not well defined for ordinal outcomes. Although some definitions have been proposed, they are limited in that they are not identical to the well-defined causal risk for a binary outcome, which is the simplest ordinal outcome. In this paper, we propose the use of a causal parameter for an ordinal outcome, defined as the proportion that a potential outcome under one treatment condition would not be smaller than that under the other condition. For a binary outcome, this proportion is identical to the causal risk. Unfortunately, the proposed causal parameter cannot be identified, even under randomization. Therefore, we present a numerical method to calculate the sharp nonparametric bounds within a sample, reflecting the impact of confounding. When the assumption of independent potential outcomes is included, the causal parameter can be identified when randomization is in play. Then, we present exact tests and the associated confidence intervals for the relative treatment effect using the randomization-based approach, which are an extension of the existing methods for a binary outcome. Our methodologies are illustrated using data from an emetic prevention clinical trial. - Yasutaka ChibaBIOMETRICAL JOURNAL 59 5 986 - 997 2017年09月 [査読有り]
Fisher's exact test is commonly used to compare two groups when the outcome is binary in randomized trials. In the context of causal inference, this test explores the sharp causal null hypothesis (i.e. the causal effect of treatment is the same for all subjects), but not the weak causal null hypothesis (i.e. the causal risks are the same in the two groups). Therefore, in general, rejection of the null hypothesis by Fisher's exact test does not mean that the causal risk difference is not zero. Recently, Chiba (Journal of Biometrics and Biostatistics 2015; 6: 244) developed a new exact test for the weak causal null hypothesis when the outcome is binary in randomized trials; the new test is not based on any large sample theory and does not require any assumption. In this paper, we extend the new test; we create a version of the test applicable to a stratified analysis. The stratified exact test that we propose is general in nature and can be used in several approaches toward the estimation of treatment effects after adjusting for stratification factors. The stratified Fisher's exact test of Jung (Biometrical Journal 2014; 56: 129-140) tests the sharp causal null hypothesis. This test applies a crude estimator of the treatment effect and can be regarded as a special case of our proposed exact test. Our proposed stratified exact test can be straightforwardly extended to analysis of noninferiority trials and to construct the associated confidence interval. - Ken Kamata; Mamoru Takenaka; Atsushi Nakai; Shunsuke Omoto; Takeshi Miyata; Kosuke Minaga; Tomohiro Matsuda; Kentaro Yamao; Hajime Imai; Yasutaka Chiba; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Takaaki Chikugo; Ippei Matsumoto; Yoshifumi Takeyama; Masatoshi KudoOncology 93 Suppl 1 102 - 106 2017年BACKGROUND AND AIMS: Risk factors for pancreatic ductal adenocarcinoma (PDAC) include diabetes mellitus, chronic pancreatitis, obesity, a family history of pancreatic cancer, and a history of smoking or alcohol consumption. The aim of this study was to evaluate the association between risk factors for PDAC and malignant intraductal papillary mucinous neoplasm (IPMN). METHODS: The study included 134 consecutive patients with IPMN who underwent surgical resection at Kindai University Hospital between April 2009 and March 2015. Data on the presence or absence of mural nodules (MNs) and risk factors for PDAC were evaluated. Multivariable logistic regression analysis was performed with malignant IPMN as the outcome variable and MNs and risk factors for PDAC as explanatory variables. RESULTS: The odds ratio of malignant IPMN to MNs was 3.88 (95% confidence interval [CI] 1.53-9.84; p = 0.004), whereas that of malignant IPMN to smoking history was 1.66 (95% CI 0.74-3.71; p = 0.22). When the presence of MNs was considered as a predictive factor for malignancy, the sensitivity and specificity were 88.5 and 32.1%, respectively, whereas when the presence of both smoking history and MNs was considered, the specificity improved to 73.2%, with a decrease in sensitivity to 42.3%. CONCLUSIONS: The presence of both a smoking history and MNs was a valuable predictive factor for malignant IPMN with high specificity. A smoking history should be considered before surgical resection in addition to the presence of MNs.
- Shunsuke Omoto; Mamoru Takenaka; Masayuki Kitano; Takeshi Miyata; Ken Kamata; Kosuke Minaga; Tadaaki Arizumi; Kentaro Yamao; Hajime Imai; Hiroki Sakamoto; Yogesh Harwani; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Yoshifumi Takeyama; Yasutaka Chiba; Masatoshi KudoOncology 93 1 55 - 60 2017年 [査読有り]
Objectives: This study evaluated whether quantitative perfusion analysis with contrast-enhanced harmonic (CH) endoscopic ultrasonography (EUS) characterizes pancreatic tumors, and compared the hemodynamic parameters used to diagnose pancreatic carcinoma. Methods: CH-EUS data from pancreatic tumors of 76 patients were retrospectively analyzed. Time-intensity curves (TIC) were generated to depict changes in signal intensity over time, and 6 parameters were assessed: baseline intensity, peak intensity, time to peak, intensity gain, intensity at 60 s (I-60), and reduction rate. These parameters were compared between pancreatic carcinomas (n = 41), inflammatory pseudotumors (n = 14), pancreatic neuroendocrine tumors (n = 14), and other tumors (n = 7). All 6 TIC parameters and subjective analysis for diagnosing pancreatic carcinoma were compared. Results: Values of peak intensity and I-60 were significantly lower and time to peak was significantly longer in the groups with pancreatic carcinomas than in the other 3 tumor groups (p < 0.05). Reduction rate was significantly higher in pancreatic carcinomas than in pancreatic neuroendocrine tumors (p < 0.05). Areas under the receiver-operating characteristic curves for the diagnosis of pancreatic carcinoma using subjective analysis, baseline intensity, peak intensity, intensity gain, I-60, time to peak, and reduction rate, were 0.817, 0.664, 0.810, 0.751, 0.845, 0.777, and 0.725, respectively. I-60 was the most accurate parameter for differentiating pancreatic carcinomas from the other groups, giving values of sensitivity/specificity of 92.7/68.6% when optimal cutoffs were chosen. Conclusions: In pancreatic carcinomas, TIC patterns were markedly different from the other tumor types, with I-60 being the most accurate diagnostic parameter. Quantitative perfusion analysis is useful for differentiating pancreatic carcinomas from other pancreatic tumors. (C) 2017 S. Karger AG, Basel - Yoriaki Komeda; Hiroshi Kashida; Toshiharu Sakurai; Yutaka Asakuma; George Tribonias; Tomoyuki Nagai; Masashi Kono; Kosuke Minaga; Mamoru Takenaka; Tadaaki Arizumi; Satoru Hagiwara; Shigenaga Matsui; Tomohiro Watanabe; Naoshi Nishida; Takaaki Chikugo; Yasutaka Chiba; Masatoshi KudoOncology 93 1 49 - 54 2017年 [査読有り]
- Kenro Kanao; Masashi Shiraishi; Yuji Higashimoto; Kazushige Maeda; Ryuji Sugiya; Satoshi Okajima; Yasutaka Chiba; Toshiyuki Yamagata; Katsuhiko Terada; Kanji Fukuda; Yuji TohdaGERIATRICS & GERONTOLOGY INTERNATIONAL 17 1 17 - 23 2017年01月 [査読有り]
AimAlthough the effects of pulmonary rehabilitation (PR) have been well defined for chronic obstructive pulmonary disease (COPD), it remains controversial whether PR improves physical activity (PA). The purpose of the present study was to identify factors associated with the effect of PR on PA. MethodsThis was a prospective study of 29 patients with COPD. They underwent pulmonary rehabilitation twice weekly for 12 weeks, and were assessed using the hospital anxiety and depression score, 6-min walk distance (6MWD), and the St. George Respiratory Questionnaire (SGRQ) before and after they underwent PR. The PA of patients was measured by a three-axis accelerometer. Physical activity level (PAL) was calculated by dividing each patient's total energy expenditure by basal metabolic rate. Correlations between changes in PAL after PR and 6MWD, St. George Respiratory Questionnaire, and hospital anxiety and depression score scores, and clinical parameters, including forced expiratory volume in 1s were determined. Results6MWD was significantly increased, but PAL was unchanged after PR. PAL was positively correlated with 6MWD, but not with percent predicted forced expiratory volume in 1s nor St. George Respiratory Questionnaire scores before PR. The increase in PAL was negatively correlated with changes in hospital anxiety and depression score anxiety and depression scores, but was not correlated with the change in 6MWD. ConclusionsA PR program for COPD patients improved results of the 6MWD, but not PAL. Increased PAL was associated with improvements in anxiety and depression, but not with increased exercise capacity. Treating the depression and anxiety of patients with COPD might not only reduce emotional distress, but also improve their PAL. Geriatr Gerontol Int 2017; 17: 17-23. - Yoshikane Nonagase; Kimio Yonesaka; Hisato Kawakami; Satomi Watanabe; Koji Haratani; Takayuki Takahama; Naoki Takegawa; Hiroto Ueda; Junko Tanizaki; Hidetoshi Hayashi; Takeshi Yoshida; Masayuki Takeda; Yasutaka Chiba; Takao Tamura; Kazuhiko Nakagawa; Junji TsurutaniONCOTARGET 7 51 84860 - 84871 2016年12月 [査読有り]
Background: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. Results: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. Materials and Methods: SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. Conclusions: mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo. - Yuji Higashimoto; Toshiyuki Yamagata; Kazushige Maeda; Noritsugu Honda; Akiko Sano; Osamu Nishiyama; Hiroyuki Sano; Takashi Iwanaga; Yasutaka Chiba; Kanji Fukuda; Yuji TohdaGERIATRICS & GERONTOLOGY INTERNATIONAL 16 8 934 - 941 2016年08月 [査読有り]
Aim: To evaluate the influence of comorbidities and aging on pulmonary rehabilitation (PR) efficacy in patients with chronic obstructive pulmonary disease (COPD). Methods: This was a retrospective cohort study of patients with COPD attending an outpatient PR program. Comorbidity information was collected with the Charlson Index, BODE index and COPD-specific comorbidity test, and also included other common conditions not included in these indexes. The efficacy of PR was defined as a 54-m increase in 6-min walk distance or a four-point decrease in St. George's Respiratory Questionnaire score. Patients were divided into two age groups according to the median age of 72 years. Results: A total of 21 of 52 patients (40%) showed a clinically significant benefit by the 6-min walk distance, and 29 patients (55.8%) by the St. George's Respiratory Questionnaire score. PR efficacy was not different between the elderly group and the younger group by either parameter. A total of 98% of the patients had at least one chronic comorbidity. Hypertension was the most frequently reported comorbidity (28.5%). Higher body mass index, Hospital Anxiety and Depression Scale anxiety score and St. George's Respiratory Questionnaire total score were associated with a good response to PR by the 6-min walk distance. None of the individual comorbidities or indexes were correlated with the efficacy of PR. Multiple logistic regression analysis showed that body mass index was independently associated with the response to PR. Conclusions: PR is equally effective in elderly and younger patients with COPD, with efficacy influenced by body mass index and anxiety. - Kazushige Maeda; Yuji Higashimoto; Noritsugu Honda; Masashi Shiraishi; Takeshi Hirohata; Kenji Minami; Takuya Iwasaki; Yasutaka Chiba; Toshiyuki Yamagata; Katsuhiko Terada; Yoshimi Matsuo; Hisato Shuntoh; Yuji Tohda; Kanji FukudaGERIATRICS & GERONTOLOGY INTERNATIONAL 16 5 550 - 555 2016年05月 [査読有り]
Aim: Physical activity (PA) has been associated with an improvement in survival for individuals with cancer. However, little is known about the effect of postoperative pulmonary rehabilitation on PA after lobectomy in patients with lung cancer. The present study investigated the effect of outpatient rehabilitation on PA in patients with cancer after lung resection. Methods: A total of 19 patients with lung cancer were recruited for this study and completed a preoperative rehabilitation program. One group of nine patients completed a postoperative outpatient pulmonary rehabilitation program (rehabilitation) and another group of 10 patients did not (control), but were similarly followed up. Preoperative lung function, assessed by forced expiratory volume in 1 s (FEV1), body mass index (BMI) and St. George's Respiratory Questionnaire (SGRQ) score were not different between groups. PA was measured before and 2 months after surgery using a three-axis accelerometer for 5-6 days. PA level (PAL) was defined as total energy expenditure divided by basal metabolic rate. Results: Preoperative PAL was not different between groups. However, postoperative versus preoperative PAL was significantly lower in the control versus the rehabilitation group (P < 0.01), and PAL decline was less for the rehabilitation versus the control group (P < 0.001). A subgroup analysis showed improvement in postoperative PAL in rehabilitation patients aged <75 years and older. Conclusions: Two months after lung resection surgery, patients had not recovered to the preoperative PAL. However, compared with the control group, there was an improvement in the postoperative PAL in patients, including older patients, who underwent outpatient pulmonary rehabilitation. - Yuji Higashimoto; Noritsugu Honda; Toshiyuki Yamagata; Akiko Sano; Osamu Nishiyama; Hiroyuki Sano; Takashi Iwanaga; Hiroaki Kume; Yasutaka Chiba; Kanji Fukuda; Yuji TohdaEUROPEAN RESPIRATORY JOURNAL 46 6 1615 - 1624 2015年12月 [査読有り]
This study was designed to investigate the association of perceived dyspnoea intensity with cortical oxygenation and cortical activation during exercise in patients with chronic obstructive pulmonary disease (COPD) and exertional hypoxaemia. Low-intensity exercise was performed at a constant work rate by patients with COPD and exertional hypoxaemia (n=11) or no hypoxaemia (n=16), and in control participants (n=11). Cortical oxyhaemoglobin (oxy-Hb) and deoxyhaemoglobin (deoxy-Hb) concentrations were measured by multichannel near-infrared spectroscopy. Increased deoxy-Hb is assumed to reflect impaired oxygenation, whereas decreased deoxy-Hb signifies cortical activation. Exercise decreased cortical deoxy-Hb in control and nonhypoxaemic patients. Deoxy-Hb was increased in hypoxaemic patients and oxygen supplementation improved cortical oxygenation. Decreased deoxy-Hb in the pre-motor cortex (PMA) was significantly correlated with exertional dyspnoea in control participants and patients with COPD without hypoxaemia. In contrast, increased cortical deoxy-Hb concentration was correlated with dyspnoea in patients with COPD and hypoxaemia. With the administration of oxygen supplementation, exertional dyspnoea was correlated with decreased deoxy-Hb in the PMA of COPD patients with hypoxaemia. During exercise, cortical oxygenation was impaired in patients with COPD and hypoxaemia compared with control and nonhypoxaemic patients; this difference was ameliorated with oxygen supplementation. Exertional dyspnoea was related to activation of the pre-motor cortex in COPD patients. - Masataka Taguri; Yasutaka ChibaSTATISTICS IN MEDICINE 34 1 131 - 144 2015年01月 [査読有り]
Recently, several authors have shown that natural direct and indirect effects (NDEs and NIEs) can be identified under the sequential ignorability assumptions, as long as there is no mediator-outcome confounder that is affected by the treatment. However, if such a confounder exists, NDEs and NIEs will generally not be identified without making additional identifying assumptions. In this article, we propose novel identification assumptions and estimators for evaluating NDEs and NIEs under the usual sequential ignorability assumptions, using the principal stratification framework. It is assumed that the treatment and the mediator are dichotomous. We must impose strong assumptions for identification. However, even if these assumptions were violated, the bias of our estimator would be small under typical conditions, which can be easily evaluated from the observed data. This conjecture is confirmed for binary outcomes by deriving the bounds of the bias terms. In addition, the advantage of our estimator is illustrated through a simulation study. We also propose a method of sensitivity analysis that examines what happens when our assumptions are violated. We apply the proposed method to data from the National Center for Health Statistics. Copyright (c) 2014 John Wiley & Sons, Ltd. - Monotone confounding, monotone treatment selection and monotone treatment responseJiang Z; Chiba Y; VanderWeele TJJournal of Causal Inference 2 1 - 12 2014年 [査読有り]
- Masataka Taguri; Yasutaka ChibaInternational Journal of Biostatistics 8 1 2014年 [査読有り]
Noncompliance with assigned treatment is an important problem of randomized clinical trials. In this situation, the structural mean model (SMM) approach focuses on the average treatment effect among patients actually treated (ATT). In contrast, the principal stratification (PS) approach addresses the effect on a certain subgroup defined by latent compliance behavior. While these approaches target different causal effects, the estimators have the same form as the classical instrumental variable estimator, under the assumption of no effect modification (NEM) and monotonic selection. In this article, we clarify the relation between SMM and PS under the monotonic selection assumption. Specifically, we translate the NEM assumption for the SMM estimator into the words of the PS approach. Then, we propose a new bound for the ATT by making a possibly more plausible assumption than the NEM assumption based on the PS approach. Furthermore, we extend these results to the average treatment effect for the entire population. The proposed bounds are illustrated with applications to a real clinical trial data. Although our assumption cannot be empirically verified, the proposed bounds can be considerably tighter than those previously proposed. - Yasutaka Chiba; Masataka TaguriINTERNATIONAL JOURNAL OF BIOSTATISTICS 9 2 235 - 249 2013年11月 [査読有り]
Estimating the direct effect of a treatment on an outcome is often the focus of epidemiological and clinical research, when the treatment has more than one specified pathway to the defined outcome. Even if the total effect is unconfounded, the direct effect is not identified when unmeasured variables affect the intermediate and outcome variables. Therefore, bounds on direct effects have been presented via linear programming under two common definitions of direct effects: controlled and natural. Here, we propose bounds on natural direct effects without using linear programming, because such bounds on controlled direct effects have already been proposed. To derive narrow bounds, we introduce two monotonicity assumptions that are weaker than those in previous studies and another monotonicity assumption. Furthermore, we do not assume that an outcome variable is binary, whereas previous studies have made that assumption. An additional advantage of our bounds is that the bounding formulas are extremely simple. The proposed bounds are illustrated using a randomized trial for coronary heart disease. - Chiba YClinical Trials 10 4 515 - 521 2013年08月 [査読有り]
Background In clinical trials, an outcome of interest may be undefined for individuals who die before the outcome is evaluated. One approach to deal with such issues is to consider the survivor causal effect (SCE), which is defined as the effect of treatment on the outcome among the subpopulation that would have survived under either treatment arm. Although several methods have been presented to estimate the SCE with time-to-event outcomes, they are difficult to implement in practice. Purpose We present a simple method to create Kaplan-Meier curves and to estimate the hazard ratio (HR) for the SCE with time-to-event outcomes. Methods To develop such a method, we applied the weighted average method presented for the SCE to outcomes with no censoring, where weights are calculated using the probability that a patient would have survived had the patient been in the other treatment arm. By multiplying the weight to each patient, Kaplan-Meier curves can be created for the SCE to outcomes with censoring. The HR is then calculated using a weighted proportional hazard model. For this method, two assumptions need to be introduced to achieve unbiasedness. Results The proposed method is illustrated using data from a randomized Phase II clinical trial, comparing two chemotherapy treatments with radiotherapy in patients with esophageal cancer. Here, we focus on the loco-regional control rate, which is calculated from the time after randomization until recurrence in the radiation field. The duration is undefined for patients who died without recurrence. The proposed method yielded a HR of 1.026 (95% confidence interval (CI): 0.627, 1.677). The standard method, where data of patients who died without progression were regarded as censored at the time of death, yielded a HR of 1.121 (95% CI: 0.688, 1.827). Limitations The proposed method requires two assumptions. As a general problem, unfortunately, whether these assumptions hold cannot be confirmed from the observed data. Thus, we cannot confirm whether the Kaplan-Meier curves and the HR are unbiased. Conclusion We have proposed a simple method for the SCE with time-to-event outcomes, which is easy to implement in practice. The proposed method is a potentially valuable supplement to the standard method. - Yasutaka Chiba; Masataka TaguriInternational Journal of Biostatistics 9 2 235 - 249 2013年 [査読有り]
Estimating the direct effect of a treatment on an outcome is often the focus of epidemiological and clinical research, when the treatment has more than one specified pathway to the defined outcome. Even if the total effect is unconfounded, the direct effect is not identified when unmeasured variables affect the intermediate and outcome variables. Therefore, bounds on direct effects have been presented via linear programming under two common definitions of direct effects: controlled and natural. Here, we propose bounds on natural direct effects without using linear programming, because such bounds on controlled direct effects have already been proposed. To derive narrow bounds, we introduce two monotonicity assumptions that are weaker than those in previous studies and another monotonicity assumption. Furthermore, we do not assume that an outcome variable is binary, whereas previous studies have made that assumption. An additional advantage of our bounds is that the bounding formulas are extremely simple. The proposed bounds are illustrated using a randomized trial for coronary heart disease. - Yasutaka ChibaSTATISTICS & PROBABILITY LETTERS 82 7 1422 - 1429 2012年07月 [査読有り]
In vaccine trials, the vaccination of one person might prevent the infection of another. This dependency makes it difficult to estimate the effect of a vaccine on infection. To deal with this issue, causal inference along with a principal stratification framework has been discussed. Unfortunately, however, no standard method has been established for estimating the causal infectiousness effect (CIE). Recently, in a setting of two persons per household, it has been reported that the crude estimator becomes the upper bound of the CIE under two plausible assumptions. Here, we present the lower bound for the CIE by strengthening one of these two assumptions. (C) 2012 Elsevier B.V. All rights reserved. - Yasutaka ChibaSTATISTICS & PROBABILITY LETTERS 82 7 1352 - 1357 2012年07月 [査読有り]
Noncompliance is a common concern in drawing causal inference in randomized trials. There is a large body of literature on methods for dealing with this issue. Specifically, it is well known that the average causal effect within the principal strata of compliance behavior (complier average causal effect, CACE) is equal to the instrumental variable estimator under the monotonicity assumption. However, there is only a small amount of published literature that discusses CACE without this assumption. Here, we present bounds on the CACE without the monotonicity assumption. To derive the bounds, we utilize the idea considered to derive bounds on the principal strata effects in the context of causal mediation analysis and those on the average causal effects among the whole population. The bounds presented here are illustrated using a classic randomized trial. (C) 2012 Elsevier B.V. All rights reserved. - Masashi Yanae; Mariko Nakao; Kimiko Fujiwara; Akinori Kawaguchi; Masanobu Tsubaki; Yasutaka Chiba; Tetsuya Morita; Yuzuru Yamazoe; Shozo NishidaGan to kagaku ryoho. Cancer & chemotherapy 39 7 1093 - 8 2012年07月Zoledronic acid(ZA)dosage should be adjusted according to the risk it poses for renal impairment. The recommended dosage for patients with creatinine clearance(Ccr)of less than 60mL/min was established on the basis of an area under the curve analysis, but is doubted because it was calculated without performing a clinical trial. Creatinine secretion from the renal tubule affects Ccr; therefore, using Ccr as the basis for dosage adjustment may be inappropriate since this can cause an overestimation of the glomerular filtration rate(GFR). The Japanese Society of Nephrology recommends using the estimated GFR(eGFR)for evaluating renal function. Therefore, this study investigated the relationship between renal function before and adverse events(AEs)after ZA administration. The dosage of only 3 of the 47 patients with Ccr less than 60mL/min could be adjusted on the basis of Ccr. During ZA therapy(3 courses), the blood urea nitrogen level and occurrence of hypokalemia were higher in the non-adjusted group than in the adjusted group, but the total number of AEs was equivalent for both groups. For all the patients, Ccr and eGFR were used as parameters for investigating AEs; the total number of AEs was equivalent for patients with differing levels of renal function. Therefore, we suggest that AEs observed during ZA therapy did not depend on the renal function level before ZA administration.
- Masataka Taguri; Yasutaka ChibaINTERNATIONAL JOURNAL OF BIOSTATISTICS 8 1 24 2012年 [査読有り]
Noncompliance with assigned treatment is an important problem of randomized clinical trials. In this situation, the structural mean model (SMM) approach focuses on the average treatment effect among patients actually treated (ATT). In contrast, the principal stratification (PS) approach addresses the effect on a certain subgroup defined by latent compliance behavior. While these approaches target different causal effects, the estimators have the same form as the classical instrumental variable estimator, under the assumption of no effect modification (NEM) and monotonic selection. In this article, we clarify the relation between SMM and PS under the monotonic selection assumption. Specifically, we translate the NEM assumption for the SMM estimator into the words of the PS approach. Then, we propose a new bound for the ATT by making a possibly more plausible assumption than the NEM assumption based on the PS approach. Furthermore, we extend these results to the average treatment effect for the entire population. The proposed bounds are illustrated with applications to a real clinical trial data. Although our assumption cannot be empirically verified, the proposed bounds can be considerably tighter than those previously proposed. - Yasutaka ChibaINTERNATIONAL JOURNAL OF BIOSTATISTICS 8 1 12 2012年 [査読有り]
Issues of post-randomization selection bias and truncation-by-death can arise in randomized clinical trials; for example, in a cancer prevention trial, an outcome such as cancer severity is undefined for individuals who do not develop cancer. Restricting analysis to a subpopulation selected after randomization can give rise to biased outcome comparisons. One approach to deal with such issues is to consider the principal strata effect (PSE, or equally, the survivor average causal effect). PSE is defined as the effect of treatment on the outcome among the subpopulation that would have been selected under either treatment arm. Unfortunately, the PSE cannot generally be estimated without the identifying assumptions; however, the bounds can be derived using a deterministic causal model. In this paper, we propose a number of assumptions for deriving the bounds with narrow width. The assumptions and bounds, which differ from those introduced by Zhang and Rubin (2003), are illustrated using data from a randomized prostate cancer prevention trial. - Yasutaka ChibaCOMMUNICATIONS IN STATISTICS-THEORY AND METHODS 41 10 1739 - 1749 2012年 [査読有り]
In randomized trials, investigators are frequently interested in estimating the direct effect of a treatment on an outcome that is not relayed by intermediate variables, in addition to the usual intention-to-treat (ITT) effect. Even if the ITT effect is not confounded due to randomization, the direct effect is not identified when unmeasured variables affect the intermediate and outcome variables. Although the unmeasured variables cannot be adjusted for in the models, it is still important to evaluate the potential bias of these variables quantitatively. This article proposes a sensitivity analysis method for controlled direct effects using a marginal structural model that is an extension of the sensitivity analysis method of unmeasured confounding introduced in the context of observational studies. The proposed method is illustrated using a randomized trial of depression. - Yasutaka ChibaBIOMETRICAL JOURNAL 53 6 1025 - 1034 2011年11月 [査読有り]
In epidemiological and clinical research, investigators are frequently interested in estimating the direct effect of a treatment on an outcome that is not relayed by intermediate variables. In 2009, VanderWeele presented marginal structural models (MSMs) for estimating direct effects based on interventions on the mediator. This paper focuses on direct effects based on principal stratification, i.e. principal stratum direct effects (PSDEs), which are causal effects within latent subgroups of subjects where the mediator is constant, regardless of the exposure status. We propose MSMs for estimating PSDEs. We demonstrate that the PSDE can be estimated readily using MSMs under the monotonicity assumption. - Yasuhiro Kidera; Masahiko Nakao; Masanobu Tsubaki; Masahiro Yoshinaga; Fumihiro Kajitani; Masashi Yanae; Mika Sakano; Yuzuru Yamazoe; Yasutaka Chiba; Kenzo Moriyama; Shozo NishidaGan to kagaku ryoho. Cancer & chemotherapy 38 7 1143 - 8 2011年07月Glomerular filtration rate (GFR) is an important factor when considering carboplatin dosage adjustment. The Japanese equation for estimating GFR (eGFR) was recommended as a guideline for evaluating GFR in 2009 by The Japanese Society of Nephrology. However, benefits in the field of cancer chemotherapy with the use of eGFR have not yet been shown. To clarify the clinical benefits of eGFR, we investigated the renal function of 100 patients with gynecologic cancer who were treated with carboplatin from 2003 through 2009, and the carboplatin dosage was calculated by the Calvert formula in which eGFR was substituted for GFR. To predict the clinical benefit on the basis of carboplatin dosage using eGFR, we retrospectively divided the patients into two groups so that carboplatin dosage was within dosage in using eGFR and one was not. We compared response rates and adverse effects of the two groups. Renal function using eGFR was lower than renal function calculated by using the other formulae. Carboplatin dosage using eGFR was significantly lower than the dosage calculated with the other formulae (p<0.01). Moreover, the patients group actually, administered the dosage calculated by eGFR showed less side effects than the group of patients not treated this way, but the efficacy did not change. Thus, using eGFR in planning carboplatin dosage suggested clinical application to patients with Japanese gynecologic cancer.
- Yasutaka Chiba; Tyler J. VanderWeeleAMERICAN JOURNAL OF EPIDEMIOLOGY 173 7 745 - 751 2011年04月 [査読有り]
In randomized trials with follow-up, outcomes such as quality of life may be undefined for individuals who die before the follow-up is complete. In such settings, restricting analysis to those who survive can give rise to biased outcome comparisons. An alternative approach is to consider the "principal strata effect" or "survivor average causal effect" (SACE), defined as the effect of treatment on the outcome among the subpopulation that would have survived under either treatment arm. The authors describe a very simple technique that can be used to assess the SACE. They give both a sensitivity analysis technique and conditions under which a crude comparison provides a conservative estimate of the SACE. The method is illustrated using data from the ARDSnet (Acute Respiratory Distress Syndrome Network) clinical trial comparing low-volume ventilation and traditional ventilation methods for individuals with acute respiratory distress syndrome. - Yasutaka ChibaCOMMUNICATIONS IN STATISTICS-THEORY AND METHODS 40 23 4278 - 4288 2011年 [査読有り]
Unmeasured confounding is a common problem in observational studies. This article presents simple formulae that can set the bounds of the confounding risk ratio under three standard populations of the exposed, unexposed, and total groups. The bounds are derived by considering the confounding risk ratio as a function of the prevalence of a covariate, and can be constructed using only information about either the exposure-confounder or the disease-confounder relationship. The formulae can be extended to the confounding odds ratio in case-control studies, and the confounding risk difference is discussed. The application of these formulae is demonstrated using an example in which estimation may suffer from bias due to population stratification. The formulae can help to provide a realistic picture of the potential impact of bias due to confounding. - Yasutaka ChibaBIOMETRICAL JOURNAL 52 5 628 - 637 2010年10月 [査読有り]
Adjusting for intermediate variables is a common analytic strategy for estimating a direct effect. Even if the total effect is unconfounded, the direct effect is not identified when unmeasured variables affect the intermediate and outcome variables. Therefore, some researchers presented bounds on the controlled direct effects via linear programming. They applied a monotonic assumption about treatment and intermediate variables and a no-interaction assumption to derive narrower bounds. Here, we improve their bounds without using linear programming and hence derive a bound under the monotonic assumption about an intermediate variable only. To improve the bounds, we further introduce the monotonic assumption about confounders. While previous studies assumed that an outcome is a binary variable, we do not make that assumption. The proposed bounds are illustrated using two examples from randomized trials. - Yasutaka ChibaSTATISTICS & PROBABILITY LETTERS 80 11-12 958 - 961 2010年06月 [査読有り]
Adjusting for an intermediate variable is a common analytic strategy for estimating a direct effect. Even if the total effect is unconfounded, the direct effect is not identified when unmeasured variables affect the intermediate and outcome variables. This paper focuses on the application of the principal stratification approach for estimating the direct effect of a randomized treatment. The approach is used to evaluate the direct effect of treatment as the difference between the expectations of potential outcomes within latent subgroups of subjects for which the intermediate variable would be constant, regardless of the randomized treatment assignment. To derive an estimator of the direct effect in cases in which the treatment and intermediate variables are dichotomous, we assume that the total effects are consistent between two standard populations. This assumption implies that the total effects are equal between two subpopulations with the same treatment assignment and a different intermediate behavior, or the total effects are equal between two subpopulations with a different treatment assignment and the same intermediate behavior. We show that the direct effect corresponds to the standard intention-to-treat effect under this assumption. (C) 2010 Elsevier B.V. All rights reserved. - Yasutaka ChibaCOMMUNICATIONS IN STATISTICS-THEORY AND METHODS 39 12 2146 - 2156 2010年 [査読有り]
We developed methods for estimating the causal risk difference and causal risk ratio in randomized trials with noncompliance. The developed estimator is unbiased under the assumption that biases due to noncompliance are identical between both treatment arms. The biases are defined as the difference or ratio between the expectations of potential outcomes for a group that received the test treatment and that for the control group in each randomly assigned group. Although the instrumental variable estimator yields an unbiased estimate under a sharp null hypothesis but may yield a biased estimate under a non-null hypothesis, the bias of the developed estimator does not depend on whether this hypothesis holds. Then the estimate of the causal effect from the developed estimator may have a smaller bias than that from the instrumental variable estimator when the treatment effect exists. There is not yet a standard method for coping with noncompliance, and thus it is important to evaluate estimates under different assumptions. The developed estimator can serve this purpose. Its application to a field trial for coronary heart disease is provided. - Yasutaka ChibaCONTEMPORARY CLINICAL TRIALS 31 1 12 - 17 2010年01月 [査読有り]
Noncompliance is a common problem in drawing causal inference in randomized trials. The instrumental variable (IV) method estimates the average causal effect in randomized trials with noncompliance. However, the IV estimator generally yields a biased estimate under a non-null hypothesis, although it can yield an unbiased estimate under a null hypothesis. Therefore, it is important to evaluate the potential bias of the IV estimate quantitatively. This paper provides such a quantitative method, which is an extension of bias analysis for unmeasured confounders using the confounding risk difference in the context of observational studies. The proposed method will help investigators to provide a realistic picture of the potential bias of the IV estimate. It is illustrated using afield trial for coronary heart disease. (C) 2009 Elsevier Inc. All rights reserved. - Yasutaka ChibaCOMMUNICATIONS IN STATISTICS-THEORY AND METHODS 39 1 65 - 76 2010年 [査読有り]
Unmeasured confounding poses a common problem in observational studies. Although sensitivity analysis based on marginal structural models can now be used in the sensitivity analysis of the causal risk difference, this method cannot be simply applied to the causal risk ratio. Here, we propose a method of sensitivity analysis for the causal risk ratio that extends previous work on the causal risk difference, and apply it to a classic cohort study investigating behavior patterns in coronary heart disease. We also extend the proposed method to a sensitivity analysis of the causal risk ratio of a time-varying treatment on repeated outcomes. The proposed method helps to provide a realistic picture of the potential impact of unmeasured confounding. - Yasutaka ChibaSTATISTICS IN MEDICINE 28 26 3249 - 3259 2009年11月 [査読有り]
In randomized trials with nonrandom noncompliance, the causal effects of a treatment among the entire Population cannot be estimated in an unbiased manner. Therefore, several authors have considered the bounds on the causal effects. Here, we propose bounds by applying an idea of VanderWeele (Biometrics 2008; 64:702-706), who showed that the sign of the unmeasured confounding bias can be determined under monotonicity assumptions about covariates in the framework of observational studies. In randomized trials with noncompliance by switching the treatment, we show that the lower or upper bound on the expectation of the potential outcome becomes the expectation from the per-protocol analysis under monotonicity assumptions similar to those of VanderWeele. In particular, the monotonicity assumptions can yield both the lower and the upper bounds on causal effects when the monotonic relationship between the covariates and the treatment actually received depends on the treatment assigned. The results are extended to cases of noncompliance by subjects not receiving any treatment. Although the monotonicity assumptions are not themselves identifiable, they are nonetheless reasonable in some situations. Copyright (C) 2009 John Wiley & Sons, Ltd. - Yasutaka ChibaBIOMETRICAL JOURNAL 51 4 670 - 676 2009年08月 [査読有り]
Unmeasured confounders are a common problem in drawing causal inferences in observational studies. VanderWeele (Biometrics 2008, 64, 702-706) presented a theorem that allows researchers to determine the sign of the unmeasured confounding bias when monotonic relationships hold between the unmeasured confounder and the treatment, and between the unmeasured confounder and the outcome. He showed that his theorem can be applied to causal effects with the total group as the standard population, but he did not mention the causal effects with treated and untreated groups as the standard population. Here, we extend his results to these causal effects, and apply our theorems to an observational study. When researchers have a sense of what the unmeasured confounder may be, conclusions can be drawn about the sign of the bias. - Yasutaka Chiba; Kenichi Azuma; Jiro OkumuraANNALS OF EPIDEMIOLOGY 19 5 298 - 303 2009年05月 [査読有り]
PURPOSE: The use of marginal structural models (MSMs) to adjust for measured confounding factors is becoming increasingly common in observational studies. Here, we propose MSMs for estimating effect modification in observational cohort and case-control studies. METHODS: MSMs for estimating effect modification were derived by the use of the potential outcome model. The proposed methods were applied to a cohort study and a case-control study. RESULTS: In cohort studies, effect modification can be estimated by the application of a logistic MSM to individuals who experienced the event in question. In case-control studies, effect modification can be estimated by the ratio between the estimate from the model applied to case data and that applied to control data. The application of the model to real data from a cohort study indicated that the estimate from the proposed method was close to that from standard regression analysis. In a case-control study, the estimate from the proposed method may be biased. CONCLUSIONS: Epidemiological researchers can use MSMs to estimate effect modification. In case-control studies, it should be determined whether the estimated effect modification is biased by applying a logistic MSM of control data. Ann Epidemiol 2009;19:298-303. (C) 2009 Elsevier Inc. All rights reserved. - Kenichi Azuma; Iwao Uchiyama; Yasutaka Chiba; Jiro OkumuraInternational journal of occupational and environmental health 15 2 166 - 72 2009年Although asbestos has been widely distributed in the environment, health risks due to general environmental exposure to asbestos have not been estimated. Future mesothelioma risk from environmental exposure to asbestos in Japan was estimated by comparing historical exposure data and mortality attributed to environmental exposure. We developed an equation to estimate environmentally-attributable mesothelioma based on the US Environmental Protection Agency's model for occupational mesothelioma mortality. Based on our calculations, mesothelioma risks per year of exposure will reach peak levels in 2033 and range from 4.8 x 10(-6) to 1.1 x 10(-5). The number of deaths is estimated to range from 542-1276 in 2033. The cumulative number of deaths will reach around 17,000-37,000 in the years 1970-2070. Our estimation of risk approximately corresponded to observed risks. Past and predicted future disease suggest the need for social and medical support in these areas.
- Onyebuchi A. Arah; Yasutaka Chiba; Sander GreenlandANNALS OF EPIDEMIOLOGY 18 8 637 - 646 2008年08月 [査読有り]
PURPOSE: Uncontrolled confounders are an important source of bias in epidermiologic studies. The authors review and derive a set of parallel simple formulas for bias factors in the risk difference, risk ratio, and odds ratio from studies with an unmeasured polytomous confounder and a dichotomous exposure and outcome. METHODS: The authors show how the bias formulas are related to and are sometimes simpler than earlier formulas. The article contains three examples, including a Monte Carlo sensitivity analysis of a preadjusted or conditional estimate. RESULTS: All the bias expressions can be given parallel formulations as the difference or ratio of (i) the Sum across confounder strata of each exposure-stratified confounder-outcome effect measure multiplied by the confounder prevalences among the exposed and (ii) the sum across confounder strata of the same effect measure multiplied by the confounder prevalences among the unexposed. The basic formulas can be applied to scenarios with a polytomous confounder, exposure, or outcome. CONCLUSIONS: In addition to aiding design and analysis strategies for confounder control, the bias for, mulas provide a link between classical standardization decompositions of demography and classical bias formulas of epidemiology. They are also useful in constructing general programs for sensitivity analysis and more elaborate probabilistic risk analyses. - Bounds on potential risks and causal risk differences under assumptions about confounding parametersYasutaka Chiba; Tosiya Sato; Sander GreenlandSTATISTICS IN MEDICINE 26 28 5125 - 5135 2007年12月 [査読有り]
Nonparametric bounds on causal effects in observational studies are available under deterministic potential-outcome models. We derive narrower bounds by adding assumptions regarding bias due to confounding. This bias is defined as the difference between the expectation of potential outcomes for the exposed group and that for the unexposed group. We show that crude effect measures bound causal effects under the given assumptions. We then derive bounds for randomized studies with noncompliance, which are given by the per protocol effect. With perfect compliance in one treatment group, the direction of effect becomes identifiable under our assumptions. Although the assumptions are not themselves identifiable, they are nonetheless reasonable in some situations. Copyright (c) 2007 John Wiley & Sons, Ltd. - Y Chiba; Y Matsuyama; T Sato; Yoshimura, IJOURNAL OF AGRICULTURAL BIOLOGICAL AND ENVIRONMENTAL STATISTICS 10 1 118 - 130 2005年03月 [査読有り]
When predicting scores in the Draize eye irritation test based on measurements of in vitro alternative tests, we are often faced with estimating parameters in a linear measurement error model with heterogeneous error variances. This article proposes a new statistical method for parameter estimation to address this issue. The proposed method is an extension of an earlier proposal that applied a linear measurement error model with homogeneous error variances, to cases with heterogeneous error variances. A simulation study to examine the performance of the proposed method was conducted in a framework that was adaptable to the data, which was obtained in a validation study of alternative methods to animal experiments conducted in Japan. The proposed method reduced the biases of estimates in comparison with an ordinary regression analysis method and three other methods under the assumption of homogeneous error variances. Although the proposed method did not fit the real data well, the resulting prediction formula was far better than those obtained by other methods.
書籍
講演・口頭発表等
- 千葉康敬統計関連学会連合大会 2020年09月 シンポジウム・ワークショップパネル（指名）
- Inference of average causal effects in a randomized trial with a binary outcome [招待講演]Chiba YThe 2019 International Causal Inference Conference 2019年05月 口頭発表（招待・特別）
- Bayesian inference of causal effects in randomized trials with a binary outcome [通常講演]Chiba YThe 29th International Biometric Conference 2018年07月 ポスター発表
- サブグループ解析してはいけない要因、多変量解析に含めてはいけない要因 [招待講演]千葉康敬第65回日本心臓病学会学術集会 2017年09月 公開講演，セミナー，チュートリアル，講習，講義等
- 数式なしの統計的仮説検定－実際の研究結果から考え方を学ぶ－ [招待講演]千葉康敬第64回日本不整脈心電学会学術大会 2017年09月 口頭発表（招待・特別）
- 研究目的とデータ取得方法に応じた統計解析 [招待講演]千葉康敬第112回日本医学物理学会学術大会 2016年09月
- Stratified exact test and confidence interval for causal effects on a binary outcome based on principal stratification [通常講演]Chiba YThe 2016 Joint Statistical Meeting 2016年08月
- Exact tests for the weak causal null hypothesis on a binary outcome in randomized trials [招待講演]Chiba YEast Asia Regional Biometric Conference 2015年12月 口頭発表（招待・特別）
- 統計的仮説検定における注意点 [招待講演]千葉康敬第110回日本医学物理学会学術大会 2015年09月 口頭発表（招待・特別）
- Attributable fractions and excess fractions with multiple exposure level: the relations and bounds [通常講演]Chiba YThe 2014 Joint Statistical Meeting 2014年08月
- Simple techniques to assess the principal strata effect: estimation, sensitivity analysis, and bounds [招待講演]Chiba YThe 2013 Joint Statistical Meeting 2013年08月 口頭発表（招待・特別）
- Conditional and unconditional infectiousness effects in vaccine trials: the relation and estimation [通常講演]Chiba Y; Taguri MThe 46th Annual Meeting of the Society for Epidemiologic Research 2013年06月 ポスター発表
- 医学データ解析の意外な落とし穴 [招待講演]千葉康敬第40回日本救急医学会総会 2012年11月 口頭発表（招待・特別）
- A principal stratification approach for evaluating natural direct and indirect effects in the presence of intermediate confounding [通常講演]Taguri M; Chiba YThe 26th International Biometric Conference 2012年08月 口頭発表（一般）
- The large sample bounds on the principal strata effect with application to a prostate cancer prevention trial [通常講演]Chiba YThe 26th International Biometric Conference 2012年08月 ポスター発表
- Bounds for the causal infectiousness effect in vaccine trials [通常講演]Chiba YThe 2012 Joint Statistical Meeting 2012年08月 口頭発表（一般）
- Bounds on controlled direct effects under monotonic assumptions about mediators and confounders [通常講演]Chiba YThe 2010 Joint Statistical Meeting 2010年08月 ポスター発表
- Simple formulas for evaluating the potential impacts of confounding bias [通常講演]Chiba Y; Azuma K; Okumura JThe 42th Annual Meeting of the Society for Epidemiologic Research 2009年06月 ポスター発表
- Doubly robust estimators for causal parameters in the exposed [通常講演]Sato T; Chiba YThe 24th International Biometric Conference 2008年07月 口頭発表（一般）
- Standardization, target population, and doubly robust estimator [通常講演]Sato T; Chiba YThe 72nd Annual Meeting of the Psychometric Society 2007年07月 口頭発表（一般）
- Toward a framework for external adjustment formulas for uncontrolled confounding [通常講演]Arah OA; Chiba Y; Greenland SThe 40th Annual Meeting of the Society for Epidemiologic Research 2007年06月 口頭発表（一般）
- Bounds on causal effects under assumptions of bias due to confounding [通常講演]Chiba Y; Sato TThe 23th International Biometric Conference 2006年07月 ポスター発表
MISC
- Masatoshi Kudo; Kazuomi Ueshima; Shin Nakahira; Naoshi Nishida; Hiroshi Ida; Yasunori Minami; Takuya Nakai; Hiroshi Wada; Shoji Kubo; Kazuyoshi Ohkawa; Asahiro Morishita; Takeo Nomi; Koji Ishida; Shogo Kobayashi; Makoto Umeda; Masakatsu Tsurusaki; Yasutaka Chiba; Kenichi Yoshimura; Kazuko Sakai; Kazuto Nishio JOURNAL OF CLINICAL ONCOLOGY 40 (4) 2022年02月
- Masatoshi Kudo; Kazuomi Ueshima; Shin Nakahira; Naoshi Nishida; Hiroshi Ida; Yasunori Minami; Takuya Nakai; Hiroshi Wada; Shoji Kubo; Kazuyoshi Ohkawa; Asahiro Morishita; Takeo Nomi; Koji Ishida; Shogo Kobayashi; Makoto Umeda; Masakatsu Tsurusaki; Yasutaka Chiba; Kenichi Yoshimura; Kazuko Sakai; Kazuto Nishio JOURNAL OF CLINICAL ONCOLOGY 39 (15) 2021年05月
- 鎌田 研; 千葉 康敬; 渡邉 智裕; 櫻井 俊治; 西田 直生志; 筑後 考章; 松本 逸平; 竹山 宜典; 北野 雅之; 工藤 正俊; 竹中 完; 三長 孝輔; 大本 俊介; 宮田 剛; 山雄 健太郎; 今井 元; 中井 敦史; 田中 秀和 日本消化器内視鏡学会雑誌 61 (4) 417 -426 2019年
- Yasutaka Chiba STATISTICS IN MEDICINE 35 (10) 1739 -1741 2016年05月 [査読有り]
- 研究目的とデータ取得方法に応じた統計解析千葉康敬 医学物理 36(Supplement 4) 11 -20 2016年 [招待有り]
- 統計的仮説検定における注意点千葉康敬 医学物理 35 (Supplement 4) 11 -20 2015年 [招待有り]
- 間違いやすい統計解析千葉康敬 近畿大学医学雑誌 39 79 -86 2014年 [招待有り]
- Yasutaka Chiba; Masataka Taguri Epidemiology 24 (2) 336 -337 2013年03月 [査読有り]
- Yasutaka Chiba EPIDEMIOLOGY 23 (1) 175 -176 2012年01月 [査読有り]
- Chiba Y Japanese Journal of Biometrics 31 (2) 93 -106 2010年 [査読有り]
受賞
共同研究・競争的資金等の研究課題
- 日本学術振興会：科学研究費助成事業研究期間 : 2022年06月 -2024年03月代表者 : 玉置 淳子; 伊木 雅之; 立木 隆広; 千葉 康敬
- 日本学術振興会：科学研究費助成事業研究期間 : 2018年04月 -2021年03月代表者 : 玉置 淳子; 久藤 麻子; 林 江美; 千葉 康敬; 神谷 訓康; 伊木 雅之; 藤田 裕規; 上西 一弘; 顧 艶紅; 新田 明美; 池原 賢代FORMEN研究10年次追跡調査を実施し、1455名について脳心血管疾患発生を把握した。追跡できた対象全体(1455名)では骨粗鬆症または脆弱性骨折既往と脳心血管疾患発生は有意な関連を認めなかったが、循環器疾患既往無し(1333名)では、骨粗鬆症または脆弱性骨折既往は、向こう10年間の脳血管疾患及び脳卒中の発生リスク上昇と関連する傾向を示した。また、循環器疾患の既往が無く高値血圧以上(SBP130mmHg、またはDBP80 mmHg以上)の者(1101名)では、脳心血管疾患及び脳卒中について循環器疾患リスク要因と独立して発生リスク上昇と関連する可能性が示唆された。
- 文部科学省：科学研究費補助金(基盤研究(C))研究期間 : 2015年04月 -2019年03月代表者 : 千葉康敬2値アウトカムを比較する2群間ランダム化試験で用いられる正確検定手法は、全員について治療効果がないというsharpな因果帰無仮説のためのものである。sharpな因果帰無仮説の棄却は、因果リスクが2群間で等しいというweakな因果帰無仮説の棄却を意味しない。よって、sharpな因果帰無仮説では平均因果効果が0ではないことを示せない。 本研究では、weakな因果帰無仮説に対する統計的仮説検定手法を議論した。この手法を、Fisherの正確検定の自然な拡張として提示したのをはじめ、層別解析、アウトカムが順序カテゴリカル変数の場合、ベイズ流アプローチへの拡張などを行った。
- 日本学術振興会：科学研究費助成事業研究期間 : 2015年04月 -2018年03月代表者 : 玉置 淳子; 佐藤 裕保; 臼田 寛; 千葉 康敬; 伊木 雅之; 梶田 悦子; 由良 晶子本研究では骨粗鬆症及び骨粗鬆症性骨折と動脈硬化進展との関連を前向きに検討した。その結果、追跡期間中の椎体骨折発生があると頸動脈の石灰化発生リスクの上昇がみられた。また、骨密度値の1SD減少あたり、上腕-足首脈波伝搬速度値増加(1800cm/秒以上)発生リスクが30%程度増加していた。地域在住の日本人女性において低骨量や低外力による椎体骨折発生は、動脈硬化進展のリスクを高める可能性が示唆された。
- 文部科学省：科学研究費補助金(若手研究(B))研究期間 : 2011年04月 -2015年03月代表者 : 千葉康敬未観察交絡要因があるときの感度解析手法を提案した。また、治療効果が取りうる範囲を推定する際に用いられる2つの条件の関連性を議論し、比較を行った。操作変数があるときの因果推論について、主要層別の考え方を応用することで、様々な標準集団における因果効果の取り得る範囲を導出した。 未観察交絡要因があるときの主要層別効果の取り得る範囲を提示した。さらに、特別な条件の下では、主要層別効果と直接効果・間接効果が一致することを突き止めた。直接効果・間接効果の取り得る範囲を導出し、感度解析の方法も議論した。主要層別効果の感度解析で提案された方法を応用することで、直接効果・間接効果の感度解析の方法を提案した。