AASLD2018[212]HBsAg的发病率和预测因子 10,614名未治疗患者的血清

StephenW

212
Incidence and Predictors of HBsAg
Seroclearance in 10,614 Untreated Patients
on Long-Term Follow-up: A Collaborative Study
from North America and Asia Pacific
Yee Hui Yeo1, Hsiu J. Ho2, Hwai-I Yang3, Tai-Chung Tseng4,
Huy N. Trinh5, Young Min Park6, Tetsuya Hosaka7, Min-Sun
Kwak8, James Fung9, Teerapat Ungtrakul10, Ming-Lung Yu11,
Jiayi Li12, Jian Zhang13, An K. Le1, Tassanee Sriprayoon14,
Tawesak Tanwandee15, Man-Fung Yuen16, Hyo-Suk Lee8,
Fumitaka Suzuki7, Mariko Kobayashi17, Jia-Horng Kao4,
Chun-Ying Wu18 and Mindie H. Nguyen1, (1)Division of
Gastroenterology and Hepatology, Stanford University Medical
Center, (2)Division of Translational Research, Taipei Veterans
General Hospital, (3)Genomics Research Center, Academia
Sinica, (4)Department of Internal Medicine, Division of
Gastroenterology and Hepatology, National Taiwan University
Hospital, Taipei, Taiwan, (5)San Jose Gastroenterology, (6)
Department of Internal Medicine, and Biomedical Research
Center, Bundang Jesaeng General Hospital, (7)Hepatology,
Toranomon Hospital, (8)Department of Internal Medicine and
Liver Research Institute, Seoul National University Hospital, (9)
Medicine, Queen Mary Hospital, (10)Faculty of Medicine and
Public Health, HRH Princess Chulabhorn College of Medical
Science, (11)Internal Medicine, Kaohsiung Medical University
Hospital, Kaohsiung Medical University, (12)Palo Alto Medical
Foundation, Mountain View Division, (13)Chinese Hospital,
(14)Department of Medicine, Siriraj Hospital, (15)Internal
Medicine, Mahidol University, (16)Medicine, Queen Mary
Hospital, Hong Kong, (17)Research Institute for Hepatology,
Toranomon Hospital, (18)Taipei Veterans General Hospital
Background: Spontaneous HBsAg seroclearance is the
functional cure of hepatitis B virus and is associated with a
better prognosis. However, the reported rates of seroclearance
have been limited by small sample size. In this study, we
combined data from nine cohorts to investigate the incidence
and determinants of HBsAg seroclearance. Methods: Data
were obtained from nine cohorts in North America (one
cohort, n= 1,635) and Asia (eight cohorts, n=8979) totalling
10,614 CHB patients who never received treatment for
hepatitis B infection. Serial laboratory data were collected
to determine HBsAg seroclearance, defined as having
two undetectable HBsAg results six months apart. Annual,
and cumulative incidence rates of HBsAg seroclearance
were estimated. Subgroup analyses and multivariable Cox
proportional hazard regression were performed to assess the
determinants of HBsAg seroclearance. Results: A total of
1,273 spontaneous incident HBsAg seroclearance occurred
during 95,886 person years of follow-up. The pooled annual
seroclearance rate was 1.33% (95% CI: 1.26-1.40), while 5-,
10-, 15-, and 20-year cumulative incidence rate were 5.01%,
11.36%, 19.44%, and 25.49%, respectively. After adjusting for
sex, age, baseline HBeAg status, cirrhosis at baseline, ALT
level, clinical setting, and ethnicity, the hazard of spontaneous
HBsAg seroclearance during follow-up was significantly
higher in males (HR=1.17, 95%CI: 1.04-1.33 vs. female), older
age group (age≥55: HR=1.79, 95%CI: 1.49-2.15; age 45-54:
HR=1.52, 95%CI: 1.28-1.80; age 35-44: HR=1.25, 95%CI:
1.06-1.48 vs. age≤35), higher baseline ALT level (HR=1.01,
95%CI: 1.00-1.01 for every 10 unit increase) and lower in
those with baseline HBeAg (+) (HR=0.25, 95%CI: 0.19-
0.32 vs. HBeAg[-]), higher HBV DNA level (>20,000IU/mL:
HR=0.35, 95%CI: 0.28-0.43; 2,000-20,000IU/mL: HR=0.43,
95%CI: 0.36-0.52 vs. HBV DNA<2,000IU/mL),and higher
quantitative HBsAg (qHBsAg) level (>1,000IU/mL: HR=0.21,
95%CI: 0.18-0.25 vs qHBsAg≤1000IU/mL). Subgroup analysis
showed that patients with genotype C had higher likelihood of
achieving HBsAg seroclearance than those with genotype B.
Conclusion: The spontaneous annual HBsAg seroclearance
rate in hepatitis B patients is 1.33%, with approximately 25%
of patients achieving seroclearance after 20 years of followup.
Being male, older, and HBeAg-negative and having
higher ALT, lower HBV DNA level, and lower qHBsAg level
were associated with a higher likelihood of attaining HBsAg
seroclearance.
Disclosures:
Tai-Chung Tseng – Abbott: Grant/Research Support
Huy N. Trinh – gilead: Advisory Committee or Review Panel; gilead: Consulting;
Gilead, Intercept: Grant/Research Support
James Fung – Novartis: Grant/Research Support
Ming-Lung Yu – Abbvie, Abbott, Ascletis, BMS, Gilead, J&J, Merck,
Pharmaessential.: Advisory Committee or Review Panel; Abbvie, Abbott,
Ascletis, BMS, Gilead, J&J, Merck, Novartis, Pharmaessential and Roche.:
Speaking and Teaching; BMS, Gilead, and Merck: Grant/Research Support
Man-Fung Yuen – Abbvie: Advisory Committee or Review Panel; Arrowhead:
Grant/Research Support; Bristol Myers Squibb: Grant/Research Support;
Gilead: Advisory Committee or Review Panel; Fujerubio: Speaking and
Teaching; Roche: Advisory Committee or Review Panel; MSD: Advisory
Committee or Review Panel
Mindie H. Nguyen – Norvatis: Advisory Committee or Review Panel; Spring
Bank: Advisory Committee or Review Panel; Gilead: Advisory Committee or
Review Panel; B K Kee Foundation: Grant/Research Support; Gilead: Grant/
Research Support; Janssen: Advisory Committee or Review Panel; Eisai:
Advisory Committee or Review Panel; Exact Science: Grant/Research Support;
The following people have nothing to disclose: Yee Hui Yeo, Hsiu J. Ho, Hwai-I
Yang, Young Min Park, Tetsuya Hosaka, Min-Sun Kwak, Teerapat Ungtrakul,
Jiayi Li, Jian Zhang, An K. Le, Tassanee Sriprayoon, Tawesak Tanwandee, Hyo-
Suk Lee, Fumitaka Suzuki, Mariko Kobayashi, Jia-Horng Kao, Chun-Ying Wu

StephenW

212
HBsAg的发病率和预测因子
10,614名未治疗患者的血清清除率
长期随访：协作研究
来自北美和亚太地区
Yee Hui Yeo，Hsiu J. Ho2，Hwai-I Yang3，Tai-Chung Tseng4，
Huy N. Trinh5，Young Min Park6，Tetsuya Hosaka7，Min-Sun
Kwak8，James Fung9，Teerapat Ungtrakul10，Ming-Lung Yu11，
Jiayi Li12，Jian Zhang13，An K. Le1，Tassanee Sriprayoon14，
Tawesak Tanwandee15，Man-Fung Yuen16，Hyo-Suk Lee8，
Fumitaka Suzuki7，Mariko Kobayashi17，Jia-Horng Kao4，
吴春英18和Mindie H. Nguyen，（1）分部
斯坦福大学医学院消化内科和肝脏病学
中心，（2）台北退伍军人转化研究部
综合医院，（3）中国科学院基因组学研究中心
中国科学院（4）内科
台湾大学消化内科和肝病学
医院，台北，台湾，（5）San Jose Gastroenterology，（6）
内科和生物医学研究系
盆唐市Jesaeng综合医院中心，（7）肝病学，
虎之门医院，（8）内科和
首尔国立大学医院肝脏研究所，（9）
医学，玛丽医院，（10）医学院和医学院
公共卫生，Chulabhorn公主医学院
科学，（11）内科，高雄医科大学
高雄医科大学附属医院，（12）Palo Alto Medical
基础，山景部，（13）中国医院，
（14）Siriraj医院医学系，（15）内科
医学，玛希隆大学，（16）医学，玛丽女王
香港医院，（17）肝病研究所，
Toranomon医院，（18）台北退伍军人总医院
背景：自发性HBsAg血清清除是
乙型肝炎病毒的功能性治愈与a有关
预后较好。但是，报告的血清清除率
受到小样本量的限制。在这项研究中，我们
综合来自9个队列的数据来调查发病率
和HBsAg血清清除的决定因素。方法：数据
来自北美的九个队列（一个
队列，n = 1,635）和亚洲（8个队列，n = 8979）总计
从未接受过治疗的10,614名CHB患者
乙型肝炎感染。收集系列实验室数据
确定HBsAg血清清除率，定义为具有
两个不可检测的HBsAg结果相隔六个月。每年，
和HBsAg血清清除的累积发病率
估计。亚组分析和多变量Cox
进行比例风险回归评估
HBsAg血清清除的决定因素。结果：共计
发生1,273例自发性HBsAg血清清除事件
在95,886人年的随访期间。汇总的年度报告
血清清除率为1.33％（95％CI：1.26-1.40），而5-，
10年，15年和20年累积发病率分别为5.01％，
分别为11.36％，19.44％和25.49％。调整后
性别，年龄，基线HBeAg状态，基线肝硬化，ALT
水平，临床环境和种族，自发性的危害
随访期间HBsAg血清清除率显着
男性较高（HR = 1.17,95％CI：1.04-1.33 vs.女性），年龄较大
年龄组（年龄≥55岁：HR = 1.79,95％CI：1.49-2.15;年龄45-54岁：
HR = 1.52,95％CI：1.28-1.80;年龄35-44岁：HR = 1.25,95％CI：
1.06-1.48 vs.年龄≤35），基线ALT水平较高（HR = 1.01，
95％CI：每10个单位增加1.00-1.01）并且降低
那些有基线HBeAg（+）的人（HR = 0.25,95％CI：0.19-
0.32 vs. HBeAg [ - ]），HBV DNA水平较高（> 20,000IU / mL：
HR = 0.35,95％CI：0.28-0.43; 2,000-20,000IU / mL：HR = 0.43，
95％CI：0.36-0.52对比HBV DNA <2,000IU / mL），并且更高
定量HBsAg（qHBsAg）水平（> 1,000IU / mL：HR = 0.21，
95％CI：0.18-0.25对qHBsAg≤1000IU/ mL）。亚组分析
表明具有基因型C的患者具有更高的可能性
与基因型B相比，实现HBsAg血清清除率。
结论：自发性年度HBsAg血清清除率
乙型肝炎患者的发病率为1.33％，约为25％
在随访20年后达到血清清除率的患者
男性，年龄较大，HBeAg阴性且有
ALT升高，HBV DNA水平降低，qHBsAg水平降低
与获得HBsAg的可能性较高有关
血清清除。
披露：
Tai-Chung Tseng - Abbott：资助/研究支持
Huy N. Trinh - 吉利德：咨询委员会或审查小组;吉利德：咨询;
吉利德，拦截：补助金/研究支持
James Fung - 诺华：资助/研究支持
Ming-Lung Yu - Abbvie，Abbott，Ascletis，BMS，Gilead，J＆J，Merck，
药剂师：咨询委员会或审查小组; Abbvie，Abbott，
Ascletis，BMS，Gilead，J＆J，Merck，Novartis，Pharmae​​ssential和Roche。：
口语与教学; BMS，Gilead和Merck：拨款/研究支持
Man-Fung Yuen - Abbvie：咨询委员会或审查小组;箭头：
拨款/研究支持; Bristol Myers Squibb：拨款/研究支持;
吉利德：咨询委员会或审查小组; Fujerubio：说话和
教学;罗氏：咨询委员会或审查小组; MSD：咨询
委员会或审查小组
Mindie H. Nguyen - Norvatis：咨询委员会或审查小组;弹簧
银行：咨询委员会或审查小组;吉利德：咨询委员会或
审查小组; B K Kee基金会：拨款/研究支持;基列：格兰特/
研究支持; Janssen：咨询委员会或审查小组;卫材：
咨询委员会或审查小组;精确科学：资助/研究支持;
以下人士无需透露：Yee Hui Yeo，Hsiu J. Ho，Hwai-I
Yang，Young Min Park，Tetsuya Hosaka，Min-Sun Kwak，Teerapat Ungtrakul，
李嘉义，张健，安凯乐，Tassanee Sriprayoon，Tawesak Tanwandee，Hyo-
Suk Lee，Fumitaka Suzuki，Mariko Kobayashi，Jia-Horng Kao，Chun-Ying Wu

antiHBVren

Incidence and Predictors of HBsAg Seroclearance in 10,614

Untreated Patients on Long-Term Follow-up:
A Collaborative Study from North America and Asia Pacific Yee Hui Yeo1, Hsiu J. Ho2, Hwai-I Yang3, Tai-Chung Tseng4, Huy N. Trinh5, Young Min Park6, Tetsuya Hosaka7, Min-Sun Kwak8, James Fung9, Teerapat Ungtrakul10, Ming-Lung Yu11, Jiayi Li12, Jian Zhang13, An K. Le1, Tassanee Sriprayoon14, Tawesak Tanwandee15, Man-Fung Yuen16, Hyo-Suk Lee8, Fumitaka Suzuki7, Mariko Kobayashi17, Jia-Horng Kao4, Chun-Ying Wu18 and Mindie H. Nguyen1, (1)Division of Gastroenterology and Hepatology, Stanford University Medical Center, (2)Division of Translational Research, Taipei Veterans General Hospital, (3)Genomics Research Center, Academia Sinica, (4)Department of Internal Medicine, Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan, (5)San Jose Gastroenterology, (6) Department of Internal Medicine, and Biomedical Research Center, Bundang Jesaeng General Hospital, (7)Hepatology, Toranomon Hospital, (8)Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, (9) Medicine, Queen Mary Hospital, (10)Faculty of Medicine and Public Health, HRH Princess Chulabhorn College of Medical Science, (11)Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, (12)Palo Alto Medical Foundation, Mountain View Division, (13)Chinese Hospital, (14)Department of Medicine, Siriraj Hospital, (15)Internal Medicine, Mahidol University, (16)Medicine, Queen Mary Hospital, Hong Kong, (17)Research Institute for Hepatology, Toranomon Hospital, (18)Taipei Veterans General Hospital

Background:
Spontaneous HBsAg seroclearance is the functional cure of hepatitis B virus and is associated with a better prognosis. However, the reported rates of seroclearance have been limited by small sample size. In this study, we combined data from nine cohorts to investigate the incidence and determinants of HBsAg seroclearance.

Methods:
Data were obtained from nine cohorts in North America (one cohort, n= 1,635) and Asia (eight cohorts, n=8979) totalling 10,614 CHB patients who never received treatment for hepatitis B infection. Serial laboratory data were collected to determine HBsAg seroclearance, defined as having two undetectable HBsAg results six months apart. Annual, and cumulative incidence rates of HBsAg seroclearance were estimated. Subgroup analyses and multivariable Cox proportional hazard regression were performed to assess the determinants of HBsAg seroclearance.

Results:
A total of 1,273 spontaneous incident HBsAg seroclearance occurred during 95,886 person years of follow-up. The pooled annual seroclearance rate was 1.33% (95% CI: 1.26-1.40), while 5-, 10-, 15-, and 20-year cumulative incidence rate were 5.01%, 11.36%, 19.44%, and 25.49%, respectively. After adjusting for sex, age, baseline HBeAg status, cirrhosis at baseline, ALT level, clinical setting, and ethnicity, the hazard of spontaneous HBsAg seroclearance during follow-up was significantly higher in males (HR=1.17, 95%CI: 1.04-1.33 vs. female), older age group (age≥55: HR=1.79, 95%CI: 1.49-2.15; age 45-54: HR=1.52, 95%CI: 1.28-1.80; age 35-44: HR=1.25, 95%CI: 1.06-1.48 vs. age≤35), higher baseline ALT level (HR=1.01, 95%CI: 1.00-1.01 for every 10 unit increase) and lower in those with baseline HBeAg (+) (HR=0.25, 95%CI: 0.19- 0.32 vs. HBeAg[-]), higher HBV DNA level (>20,000IU/mL: HR=0.35, 95%CI: 0.28-0.43; 2,000-20,000IU/mL: HR=0.43, 95%CI: 0.36-0.52 vs. HBV DNA<2,000IU/mL),and higher quantitative HBsAg (qHBsAg) level (>1,000IU/mL: HR=0.21, 95%CI: 0.18-0.25 vs qHBsAg≤1000IU/mL). Subgroup analysis showed that patients with genotype C had higher likelihood of achieving HBsAg seroclearance than those with genotype B.

Conclusion:
The spontaneous annual HBsAg seroclearance rate in hepatitis B patients is 1.33%, with approximately 25% of patients achieving seroclearance after 20 years of followup. Being male, older, and HBeAg-negative and having higher ALT, lower HBV DNA level, and lower qHBsAg level were associated with a higher likelihood of attaining HBsAg seroclearance.

Disclosures:
Tai-Chung Tseng – Abbott: Grant/Research Support Huy N. Trinh – gilead: Advisory Committee or Review Panel; gilead: Consulting; Gilead, Intercept: Grant/Research Support James Fung – Novartis: Grant/Research Support Ming-Lung Yu – Abbvie, Abbott, Ascletis, BMS, Gilead, J&J, Merck, Pharmaessential.: Advisory Committee or Review Panel; Abbvie, Abbott, Ascletis, BMS, Gilead, J&J, Merck, Novartis, Pharmaessential and Roche.: Speaking and Teaching; BMS, Gilead, and Merck: Grant/Research Support Man-Fung Yuen – Abbvie: Advisory Committee or Review Panel; Arrowhead: Grant/Research Support; Bristol Myers Squibb: Grant/Research Support; Gilead: Advisory Committee or Review Panel; Fujerubio: Speaking and Teaching; Roche: Advisory Committee or Review Panel; MSD: Advisory Committee or Review Panel Mindie H. Nguyen – Norvatis: Advisory Committee or Review Panel; Spring Bank: Advisory Committee or Review Panel; Gilead: Advisory Committee or Review Panel; B K Kee Foundation: Grant/Research Support; Gilead: Grant/ Research Support; Janssen: Advisory Committee or Review Panel; Eisai: Advisory Committee or Review Panel; Exact Science: Grant/Research Support; The following people have nothing to disclose: Yee Hui Yeo, Hsiu J. Ho, Hwai-I Yang, Young Min Park, Tetsuya Hosaka, Min-Sun Kwak, Teerapat Ungtrakul, Jiayi Li, Jian Zhang, An K. Le, Tassanee Sriprayoon, Tawesak Tanwandee, Hyo- Suk Lee, Fumitaka Suzuki, Mariko Kobayashi, Jia-Horng Kao, Chun-Ying Wu

antiHBVren

10,614例HBsAg血清清除的发生率和预测因子

未经治疗的患者进行长期随访：
来自北美和亚太地区的合作研究Yee Hui Yeo，Hsiu J. Ho2，Hwai-I Yang3，Tai-Chung Tseng4，Huy N. Trinh5，Young Min Park6，Tetsuya Hosaka7，Min-Sun Kwak8，James Fung9，Teerapat Ungtrakul10 ，Ming-Lung Yu11，Jiayi Li12，Jian Zhang13，An K. Le1，Tassanee Sriprayoon14，Tawesak Tanwandee15，Man-Fung Yuen16，Hyo-Suk Lee8，Fumitaka Suzuki7，Mariko Kobayashi17，Jia-Horng Kao4，Chun-Ying Wu18和Mindie H. Nguyen，（1）斯坦福大学医学中心消化内科和肝病学系，（2）台北退伍军人总医院转化研究部，（3）中国科学院基因组学研究中心，（4）内科，科室台湾台北国立台湾大学医院消化内科，（5）圣何塞消化内科，（6）盆唐耶赛总医院内科，生物医学研究中心，（7）虎之门医院肝病学，（8）内科和肝脏研究所tute，首尔国立大学医院，（9）医学，玛丽医院，（10）医学和公共卫生学院，Chulabhorn公主医学院，（11）高雄医科大学附属高雄医科大学内科，（11） 12）帕洛阿尔托医学基金会，山景科，（13）中国医院，（14）医学系，Siriraj医院，（15）Mahidol大学内科，（16）医学，香港玛丽医院，（17） ）虎之门医院肝病研究所，（18）台北退伍军人总医院

背景：
自发性HBsAg血清清除是乙型肝炎病毒的功能性治愈，并且与更好的预后相关。然而，报告的血清清除率受到小样本量的限制。在这项研究中，我们将来自9个队列的数据结合起来，以研究HBsAg血清清除的发生率和决定因素。

方法：
数据来自北美的9个队列（一个队列，n = 1,635）和亚洲（8个队列，n = 8979），共计10,614名从未接受乙型肝炎感染治疗的CHB患者。收集连续的实验室数据以确定HBsAg血清清除率，定义为间隔六个月具有两个不可检测的HBsAg结果。估计HBsAg血清清除的年度和累积发病率。进行亚组分析和多变量Cox比例风险回归以评估HBsAg血清清除的决定因素。

结果：
在95,886人的随访期间共发生1,273例自发性HBsAg血清清除率。汇总年血清清除率为1.33％（95％CI：1.26-1.40），而5,10,15和20年累积发病率分别为5.01％，11.36％，19.44％和25.49％。 。在调整性别，年龄，基线HBeAg状态，基线肝硬化，ALT水平，临床环境和种族后，随访期间自发性HBsAg血清清除率的风险在男性中显着较高（HR = 1.17,95％CI：1.04- 1.33对女性），年龄较大（年龄≥55：HR = 1.79,95％CI：1.49-2.15;年龄45-54：HR = 1.52,95％CI：1.28-1.80;年龄35-44：HR = 1.25,95％CI：1.06-1.48对年龄≤35），基线ALT水平较高（HR = 1.01,95％CI：每10个单位增加1.00-1.01），基线HBeAg（+）水平较低（HR） = 0.25,95％CI：相对于HBeAg [ - ]为0.19-0.32），HBV DNA水平较高（> 20,000IU / mL：HR = 0.35,95％CI：0.28-0.43; 2,000-20,000IU / mL：HR = 0.43,95％CI：0.36-0.52对比HBV DNA <2,000IU / mL）和更高定量HBsAg（qHBsAg）水平（> 1,000IU / mL：HR = 0.21,95％CI：0.18-0.25对qHBsAg≤1000IU /毫升）。亚组分析显示，基因型C患者获得HBsAg血清清除的可能性高于基因型B患者。

结论：
乙型肝炎患者的自发年HBsAg血清清除率为1.33％，大约25％的患者在随访20年后达到血清清除率。男性，年龄较大，HBeAg阴性且ALT较高，HBV DNA水平较低，qHBsAg水平较低，这与获得HBsAg血清清除率的可能性较高有关。

披露：
Tai-Chung Tseng - Abbott：拨款/研究支持Huy N. Trinh - 吉利德：咨询委员会或审查小组;吉利德：咨询; Gilead，Intercept：拨款/研究支持James Fung - 诺华：拨款/研究支持Ming-Lung Yu - Abbvie，Abbott，Ascletis，BMS，Gilead，J＆J，Merck，Pharmae​​ssential：咨询委员会或审核小组; Abbvie，Abbott，Ascletis，BMS，Gilead，J＆J，Merck，Novartis，Pharmae​​ssential和Roche：Speaking and Teaching; BMS，Gilead和Merck：拨款/研究支持Man-Fung Yuen - Abbvie：咨询委员会或审核小组; Arrowhead：拨款/研究支持; Bristol Myers Squibb：拨款/研究支持;吉利德：咨询委员会或审查小组; Fujerubio：口语和教学;罗氏：咨询委员会或审查小组; MSD：咨询委员会或审查小组Mindie H. Nguyen - Norvatis：咨询委员会或审查小组;春季银行：咨询委员会或审查小组;吉利德：咨询委员会或审查小组; B K Kee基金会：拨款/研究支持;吉利德：资助/研究支持; Janssen：咨询委员会或审查小组; Eisai：咨询委员会或审查小组;精确科学：资助/研究支持;以下人士无需透露：Yee Hui Yeo，Hsiu J. Ho，Hwai-I Yang，Young Min Park，Tetsuya Hosaka，Min-Sun Kwak，Teerapat Ungtrakul，Jiayi Li，Jian Zhang，An K. Le，Tassanee Sriprayoon ，Tawesak Tanwandee，Hyo-Suk Lee，Fumitaka Suzuki，Mariko Kobayashi，Jia-Horng Kao，Chun-Ying Wu